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| | Vinorelbine Basic information |
| Product Name: | Vinorelbine | | Synonyms: | 3’,4’-didehydro-4’-deoxy-c’-norvincaleukoblastin;vinorelbine D-tartrate;CL069;Vinorelbine, 98%, from Catharanthus roseus (L.) G. Don;AspidosperMidine-3-carboxylic acid, 4-(acetyloxy)-6,7-didehydro-15-[(2R,6R,8S)-4-ethyl-1,3,6,7,8;ANX-530, KW-2307, 5'-Noranhydrovinblastine;CS-404;nor-5’-anhydrovinblastine | | CAS: | 71486-22-1 | | MF: | C45H54N4O8 | | MW: | 778.93 | | EINECS: | | | Product Categories: | ZOMIG;reference standards from Chinese medicinal herbs (TCM).;chemical reagent;pharmaceutical intermediate;phytochemical;standardized herbal extract;Active Pharmaceutical Ingredients;Antineoplastic | | Mol File: | 71486-22-1.mol |  |
| | Vinorelbine Chemical Properties |
| alpha | D20 +52.4° (c = 0.3 in CHCl3) | | density | 1.36±0.1 g/cm3(Predicted) | | storage temp. | Store at 4°C, protect from light | | solubility | >25.9mg/mL in DMSO | | form | Powder | | pka | 11.36±0.60(Predicted) |
| | Vinorelbine Usage And Synthesis |
| Description | Vinorelbine is a semisynthetic vinca alkaloid differing from vinblastine in the catharantine
moiety of the molecule. It is claimed to have a broad spectrum of action both in vifro and
in vivo; clinically it has been found effective in the treatment of non-small cell lung
cancer, advanced breast cancer, ovarian cancer and Hodgkins disease. | | Originator | CNRS (France) | | Uses | antimigraine, 5HT[1B/1D] agonist | | Uses | Vinorelbine base is an antineoplastic agent with anti-mitotic properties. | | Definition | ChEBI: A vinca alkaloid with a norvinblastine skeleton. | | Manufacturing Process | (+/-)-5-Ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester and
(+)-tartaric acid were dissolved in hot 95% ethanol. The resulting solution
was allowed to slowly cool to room temperature and refrigerated overnight.
The crystals were filtered, washed with cold ethanol, and recrystallized from
95% ethanol, cooling as before to give the (+)-tartrate salt of (+)-5-ethyl-
1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester.
The salt of (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl
ester was dissolved in on ice, and 3 N sodium hydroxide was slowly added
until the pH reached 11-12. The solution was extracted with chloroform, dried
(Na 2 SO 4 ) and evaporated in vacuum to give (+)-5-ethyl-1,2,3,6-tetrahydro-
pyridine-3-carboxylic acid ethyl ester as a mobile oil.
Reduction of (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-carboxylic acid ethyl
ester with LiAlH 4 in THF, using the usual protocols associated with this reagent
gave the (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-ol. This material was used
directly in the next step.
To a solution of the (+)-5-ethyl-1,2,3,6-tetrahydro-pyridine-3-ol in ethanol
and triethylamine water, cooled equiv.) was added allyl bromide and the
mixture heated at reflux for 12 h. The mixture was evaporated in vacuo and
the residue dissolved in chloroform and washed with 5% aqueous K 2 CO 3 . The
chloroform layer was dried (MgSO 4 ) and evaporated in vacuo to give the (+)-
1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-ol.
The (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-ol was converted into its
methanesulfonate ester in the standard manner by treatment with
methanesulfonic acid.
To a solution of the (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-methanesulfonate in acetone was added lithium bromide (6.9 g, 0.08 mol)
and the suspension heated at reflux. The acetone was evaporated in vacuo,
and the residue partitioned between chloroform and cold aqueous 5% K 2 CO 3
solution. The chloroform layer was dried (MgSO 4 ), filtered, and evaporated in
vacuo to give a brown oil. Fractional distillation gave the (+)-1-allyl-5-ethyl-
1,2,3,6-tetrahydro-pyridin-3-bromide.
To a solution of N-phenylsulfonyl indole (5.14 g, 20 mmol) in dry THF (100
ml) under argon, and cooled to -65°C., was added t-butyl lithium (13 ml, 22
mmol, 1.7 M in pentane). The solution was allowed to warm to 0°C and
stirred for 1 h. The above solution was added via canula to a stirred solution
of dimethyloxalate (9.5 g, 80 mmol) in THF (250 ml) at 0°C. After 4 h at 0°C
the mixture was quenched with saturated aqueous NH 4 Cl and extracted with
ethyl acetate (3 times 100 ml). The dried (MgSO 4 ) extract was evaporated in
vacuum, and the residue purified by chromatography over silica gel eluting
with hexane/ethyl acetate (b 10:1) to give the N-phenylsulfonyl-2-methoxalyl
indole (2.3 g, 34%). Melting point 111°-112°C (from ethyl acetate).
To the (+)-1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-bromide in a flame
dried flask under argon was added Mg powder and dry THF. The mixture was
heated at reflux and two drops of 1,2-dibromoethane added to initiate
Grignard reagent formation. After 3 h the turbid suspension was cooled to
room temperature and added to a solution of the N-phenylsulfonyl-2-
methoxalyl indole in THF, at 0°C under argon. After 30 min the solution was
quenched with saturated aqueous NH 4 Cl solution, and diluted with ethyl
acetate. The dried (MgSO 4 ) extract was evaporated in vacuo to give the (+)-
methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl 5-ethyl-
1,2,3,6-tetrahydro-peridine)]propionate consisting of a mixture of
diastereomers at C-2 (1:1). For the purpose of characterization, one of the
diastereomers was purified by chromatography over silica gel eluting with
hexane/ethyl acetate/10% aqueous NH 4 OH/MeOH (15:3:1) to give the (+)-
methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-[3-(N-allyl-5-ethyl-
1,2,3,6-tetrahydro-pyridine)]propionate.
To a solution of the (+)-methyl 2-[2-(N-phenylsulfonyl)indolyl]-2-hydroxy-3-
[3-(N-allyl-5-ethyl-1,2,3,6-tetrahydropyridine)]propionate (a mixture of
diastereomers at C-2) in dry dimethoxyethane at -50°C under argon was
added sodium naphthalenide (1 M in THF). The mixture was quenched with
trifluoroacetic acid, and extracted with ethyl acetate (3 times 10 ml). The
extract was washed with saturated aqueous NaHCO 3 solution, dried (MgSO 4 )
and evaporated in vacuo to give the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3-
(N-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridine )]propionate. The mixture of
diastereomers was not separated but chromotagraphed over silica gel eluting
with hexane/ethyl acetate/10% aqueous NH 4 OH/MeOH (5:1:1) to remove
more polar impurities.
A solution of the (+)-methyl 2-(2-indolyl)-2-hydroxy-3-[3-(N-allyl-5-ethyl-
1,2,3,6-tetrahydro-pyridine)]propionate (mixture of diastereomers), and
vindoline in 1% HCl/MeOH was heated at reflux for 2 h. The solution was
evaporated in vacuo and the residue dissolved in chloroform and washed with
saturated aqueous NaHCO 3 solution. The chloroform layer was dried over
MgSO 4 , filtered, and evaporated to give a foam consisting of a mixture of S-and R-diastereomers. The diastereomeric mixture was separated by
preparative HPLC eluting with hexane/CH 2 Cl 2 /MeOH/10% aqueous NH 4 OH to
give S-(+)-4-acethoxy-9-[2-(1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3-yl)-1-
(1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6-
methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1-
ca]fluorene-5-carboxylic acid methyl ester.
The S-(+)-4-acethoxy-9-[2-(1-allyl-5-ethyl-1,2,3,6-tetrahydro-pyridin-3yl)-1-
(1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6-
methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1-
ca]fluorene-5-carboxylic acid methyl ester in 1,2-dichloroethane, containing
proton sponge at 25°C, was treated with 1-chloroethyl chloroformate (0.056
ml, 0.512 mmol, 2.0 equiv.) and the resulting solution stirred for 3 h. The
mixture was evaporated in vacuo, and the residue dissolved in methanol and
heated at reflux for 3 h. The methanol was evaporated and the residue
dissolved in chloroform and purified by chromatography over silica gel eluting
with CHCl 3 , MeOH, 10% aqueous NH 4 OH (20:1) to give S-(+)-4-acethoxy-9-
[2-(5-ethyl-1,2,3,6-tetrahydro-pyridin-3yl)-1-(1H-indol-2-yl)-1-
methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-8-methoxy-6-methyl-
3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-indeno[7,1-ca]fluorene-5-
carboxylic acid methyl ester.
To a solution of the S-(+)-4-acethoxy-9-[2-(5-ethyl-1,2,3,6-tetrahydro-
pyridin-3yl)-1-(1H-indol-2-yl)-1-methoxycarbonyl-ethyl]-3a-ethyl-5-hydroxy-
8-methoxy-6-methyl-3a,4,5,5a,6,11,12,12b-octahydro-1H-6,12a-diaza-
indeno[7,1-ca]fluorene-5-carboxylic acid methyl ester in dioxane and glacial
acetic acid was added 37% aqueous formaldehyde and the mixture stirred at
35°C for 24 h. The solution was evaporated in vacuo and the residue
suspended in chloroform and washed with cold aqueous 5% K 2 CO 3 solution.
The chloroform layer was dried (MgSO 4 ), filtered, and evaporated. The residue
was chromatographed eluting with EtOAc/MeOH, 10% NH 4 OH to give the
product navelbine. | | Brand name | Navelbine
(Pierre). | | Therapeutic Function | Antineoplastic | | Pharmacokinetics | This semisynthetic alkaloid is unique in having oral bioavailability, but it currently is available only for IV injection. The initial phase elimination half-life is on par with that observed for vincristine and vinblastine, and the terminal phase half-life is between 28 and 44 hours. | | Clinical Use | Vinorelbine is particularly useful in the treatment of
advanced non–small cell lung cancer and can be administered
alone or in combination with cisplatin. It is
thought to interfere with mitosis in dividing cells through
a relatively specific action on mitotic microtubules. | | Side effects | Although dose-limiting granulocytopenia is the major adverse effect, potentially fatal interstitial pulmonary changes have been noted, and patients with symptoms of respiratory distress should be promptly evaluated. As with all vinca alkaloids, elimination is primarily hepatobiliary, and dosage reduction should be considered in patients with liver dysfunction. | | Drug interactions | Potentially hazardous interactions with other drugs
Antibacterials: increased risk of neutropenia with
clarithromycin; possible increased risk of ventricular
arrhythmias with delamanid.
Antifungals: metabolism possibly inhibited by
itraconazole, increased risk of neurotoxicity.
Antimalarials: avoid with piperaquine with
artenimol.
Antipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis). | | Metabolism | Metabolism of vinorelbine appears to be hepatic.
All metabolites of vinorelbine are formed by the
CYP3A4 isoform of cytochromes P450, except
4-O-deacetylvinorelbine which is likely to be formed by
carboxylesterases.
4-O-deacetylvinorelbine is the only active metabolite and
the main one observed in blood. Excretion is mainly by
the biliary route (18.5
% appears in the urine). |
| | Vinorelbine Preparation Products And Raw materials |
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