Fluvoxamine
2-{[(E)-{5-Methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene}amino]oxy}ethanamine[1] | |
Clinical data | |
---|---|
Trade names | Faverin, Fevarin, Floxyfral, Luvox |
AHFS/Drugs.com | monograph |
MedlinePlus | a682275 |
Pregnancy cat. |
|
Legal status | |
Routes | Oral |
Pharmacokinetic data | |
Bioavailability | 53% (90% confidence interval: 44-62%)[2] |
Protein binding | 80%[2] |
Metabolism | Hepatic (via cytochrome P450enzymes. Mostly via oxidative demethylation)[2] |
Half-life | 12-13 hours (single dose), 22 hours (repeated dosing)[2] |
Excretion | Renal (98%; 94% as metabolites, 4% as unchanged drug)[2] |
Identifiers | |
CAS number | 54739-18-3 |
ATC code | N06AB08 |
PubChem | CID 5324346 |
DrugBank | DB00176 |
ChemSpider | 4481878 |
UNII | O4L1XPO44W |
KEGG | D07984 |
ChEBI | CHEBI:5138 |
ChEMBL | CHEMBL814 |
Chemical data | |
Formula | C15H21F3N2O2 |
Mol. mass | 318.335 |
US 6433225 B1
http://www.google.co.in/patents/US6433225
U.S. Pat. No. 4,085,225 discloses the process for the preparation of fluvoxamine maleate, a compound of formula I, by alkylation reaction of 5-methoxy-4′-trifluoromethylvalerophenone oxime, a compound of formula II, with 2-chloroethylamine hydrochloride in dimethylformamide in the presence of a base viz. potassium hydroxide for two days at 25° C.
Subsequently the solvent is removed under vacuum then the residue is acidified and extracted with ether to remove the unreacted oxime. The fluvoxamine base is then obtained by extraction into ether after basification, and the ether extract is washed with NaHCO3 solution. The fluvoxamine base is then treated with maleic acid in ethanol, and the residue obtained by concentration under vacuum is recrystallised from acetonitrile to obtain fluvoxamine maleate I. This process when attempted by us was found to be very time consuming. Moreover, the requirement of various solvents posed the problem of their recovery and re-usability.
In an alternate route described in the above mentioned patent, the oxime II is converted to I in a five step process viz., alkylation of II with ethylene oxide to give the hydroxyethyl compound III, which is converted to a mesylate derivative IV with methanesulfonyl chloride and triethylamine, and then aminated with ammonia to give fluvoxamine base.
The base is then converted to the maleate salt I, which is finally purified by recrystallization from acetonitrile.
Although in principle, the process described gives the desired product, viz. fluvoxamine maleate I, it was not found to be attractive as it involves a number of unit operations, use of several solvents, and handling of toxic and explosive ethylene oxide, a potential carcinogen. The number of operations used result in long occupancy of reactors and utilities, and high-energy consumption making it a commercially unviable process on a large scale. Also, for large-scale operations, the use of several different solvents in the process poses ecological and other usual problems such as storage, their recovery and re-usability. Furthermore, purification of the intermediate III requires cumbersome technique viz. chromatography over silica gel.
The lengthy work-up procedure in U.S. Pat. No. 4,085,225 requires complete removal of organic solvents at different stages; a simple and efficient process has been found wherein:
(a) the alkylation reaction could occur very rapidly in a water immiscible inert aprotic solvent in the presence of a facilitator;
(b) the unwanted reaction components i.e. the excess base, salts and the added facilitator could be easily removed in one step by washing the reaction mixture with water;
(c) the organic layer containing fluvoxamine base treated with maleic acid; and
(d) the fluvoxamine maleate obtained in a substantially pure form by recrystallization.
PATENT CITATIONS
Cited Patent | Filing date | Publication date | Applicant | Title |
---|---|---|---|---|
US4085225 | 19 Mar 1976 | 18 Apr 1978 | U.S. Philips Corporation | Oxime ethers having anti-depressive activity |
NON-PATENT CITATIONS
Reference | ||
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1 | * | Database CAPLUS on STN, Acc. No. 1977:72203, "Substituted 4'-trifluoromethylvalerophenone O-(2-aminoethyl)oxime derivatives with antidepressive action.' NL 7503310 (abstract).* |
2 | Database CAPLUS on STN, Acc. No. 1977:72203, ‘Substituted 4'-trifluoromethylvalerophenone O-(2-aminoethyl)oxime derivatives with antidepressive action.’ NL 7503310 (abstract).* | |
3 | * | Database CAPLUS on STN, Acc. No. 1982:562585, Welle et al., "Oxime ether compounds.' CH 629761 (abstract).* |
4 | Database CAPLUS on STN, Acc. No. 1982:562585, Welle et al., ‘Oxime ether compounds.’ CH 629761 (abstract).* | |
5 | * | Database CAPLUS on STN, Acc. No. 1997:403525, Matarrese et al., "Synthesis of [O-methyl-11-C]fluvoxamine-a potential serotonin uptake site radioligand.' Appl. Radiat. Isot. (1997), 48(6), pp. 749-754 (abstract). |
6 | Database CAPLUS on STN, Acc. No. 1997:403525, Matarrese et al., ‘Synthesis of [O-methyl-11-C]fluvoxamine—a potential serotonin uptake site radioligand.’ Appl. Radiat. Isot. (1997), 48(6), pp. 749-754 (abstract). |
REFERENCED BY
Citing Patent | Filing date | Publication date | Applicant | Title |
---|---|---|---|---|
US20110092548 * | 21 Jul 2006 | 21 Apr 2011 | Takuro Minowada | Method for treating/preventing disease using cognitive ability of cerebrum and pharmaceutical |
WO2014035107A1 * | 27 Aug 2013 | 6 Mar 2014 | Estechpharma Co., Ltd. | Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same |
MORE.............
Fluvoxamine
Fluvoxamine is an antidepressant drug consisting of an oxime ether functions which can exist in an E and Z configuration. The pharmacological effect is associated with the E-isomer; thus, the European Pharmacopoeia limits the Z-isomer to less than 0.2 percent. The 1H NMR spec-trum of a 1: 1 mixture (for spectrum and structural formula see Fig. 2) reveals the resonance signals of the hydrogen at C10 (δ = 4.2-4.5 ppm) and C2 (δ = 2.5-3.0 ppm) to be well separated and, therefore, appropriate for evaluation. In order to find out the optimal pulse repetition period the T1 relaxation time was measured first. A recovery of the z-magnetization of > 99.9% was achieved using seven times the longest T1 which results in a pulse repetition time of 8 sec. Using the optimized parameter (see below) and after checking the linearity, the limit of quantification of the Z-isomer could be determined to be 0.15 %, which meets the limit demanded by the European Pharmacopoeia. For details see ref. [6].
Figure 2: 1H NMR spectrum of a mixture of the isomers of fluvoxamine, containing 47.6% E-fluvoxamine
and 53.2% Z-fluvoxamine, in MeOH-d4
and 53.2% Z-fluvoxamine, in MeOH-d4
Parameters fluvoxamine:
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