Process for the preparation of fluvoxazmine maleate US 6433225 B1

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.	C
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: POM US: ℞-only
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

Process for the preparation of fluvoxazmine maleate
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.

EXAMPLE 1To a stirred mixture of toluene (1.20 lit.), PEG-400 (0.4 lit) and powdered potassium hydroxide (86.0 g on 100% basis, 1.53 mol.) at ambient temperature is added 5-methoxy-4′-trifluoromethylvalerophenone oxime (100 g, 0.363 mol.), followed by 2-chloroethyl amine hydrochloride (50.56 g, 0.435 mol.). The mixture is stirred at 30-35° C. for 2 hours. Water (1.2 lit.) is then added, stirred for 30 mins. and the aqueous layer is separated out. The organic layer is washed with water (˜3×500 ml) until the washings are neutral. To the washed organic layer is added a solution of maleic acid (14.14 g, 0.363 mol.) in water (65 ml) and the mixture is stirred at 25-30° C. temperature for 2 hours, then cooled to 5-10° C. when the maleate salt crystallizes out. The crystallized fluvoxamine maleate is filtered, washed with toluene (200 ml) and sucked to dryness. The crude fluvoxamine maleate thus obtained is dissolved in water (300 ml) at 50-55° C. to get a clear solution, then gradually cooled to 5-8° C. and then further stirred at this temperature for 2 hours. The recrystallised fluvoxamine maleate is filtered, washed with chilled water (5° C., 100 ml) and sucked dry. The product is finally dried at 50-55° C. to constant weight. The fluvoxamine maleate obtained complies with the specifications of British Pharmacopoeia, 1999.
EXAMPLE 2This process when scaled up in pilot plant on 4.0 kg scale input of 5-methoxy-4′-trifluoromethylvalerophenone oxime gave 4.5 kg (71.2%) of fluvoxamine maleate, complying to the specifications of British Pharmacopoeia, 1999.

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
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).

* Cited by examiner

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

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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

Parameters fluvoxamine:
 

Bruker Avance 400 MHz operating at 400.13 MHz equipped with BBO-head for ( 1H-channel, X-channel). The data processing was performed using BRUKER X-WIN NMR 3.0 software under Microsoft Windows. Pulse repetition period: 8 sec Number of scans: 128 Spectral width: 4595 Hz Transmitter offset: 2.76 ppm Digital resolution: 0.14 Hz/pt Solution: 15 mg fluvoxamine in 650µl MeOH-d4 Referencing: centre of the solvent peak: 3.31 ppm