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

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

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

WO 2012044577 A1.......Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases

 
  Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)

 



 Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)




 WO 2012044577 A1.......Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
 http://www.google.com/patents/WO2012044577A1?cl=en

In another embodiment, the compound of Formula I is Compound 1 :

Compound 1

or a pharmaceutically acceptable salt thereof. Compound I is known as N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide. WO 2005/030140 describes the synthesis of N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140.

[0013] In another embodiment, the compound of Formula I is Compound 2:

Compound 2
  Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)

or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro-4- ({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4- fluorophenyl)cyc!opropane- 1,1 -dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC50 value of about 0.6 nanomolar (nM). PC1YUS09/064341, which claims priority to U.S. provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis of Compound I.

Indian Court Upholds Breaking Of Bayer Patent

 

 

Indian Court Upholds Breaking Of Bayer Patent

Intellectual Property: Supreme Court decision is likely to increase Western pressure on India to tighten patent laws

The Supreme Court of India has dismissed Bayer’s appeal of a decision by the Indian patent office authorizing forced licensing of the cancer drug Nexavar. The ruling will likely increase Western pressure on India to tighten its patent rules.

In 2012, India’s controller general for patents issued a compulsory license of Nexavar, a liver and kidney cancer treatment known generically as sorafenib tosylate. The license allows the Indian drugmaker Natco Pharma to sell generic Nexavar in India after paying a 6% sales royalty to Bayer. The firm’s price for the drug is about $175 a month, 3% of Bayer’s price.

see

http://cen.acs.org/articles/92/i51/Indian-Court-Upholds-Breaking-Bayer.html

NEW PATENT.......WO 2014199244 ....Crystalline imatinib mesylate process

WO-2014199244
 Crystalline imatinib mesylate process
Shilpa Medicare Ltd

Inventors:	PIPAL, Bhagat Raj VEERESHAPPA, Mr. SHARMA, Manish CHATURVEDI, Akshay, Kant
Title:	CRYSTALLINE IMATINIB MESYLATE PROCESS
Abstract:	The present invention relates to a process for preparation of crystalline non-needle shaped Form-SA of Imatinib mesylate (I).(Formula I) (I) The invention also relates to crystalline Form-SA obtained by the process of the present invention, the said Form-SA being substantially pure, stable, non-needle shaped and characterized by X-ray powder diffraction pattern comprising of atleast five 20° peaks selected from 10.67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 ± 0.05 2Θ°. The invention further relates to pharmaceutical compositions comprising non-needle shaped crystalline Form-SA of Imatinib mesylate, useful for the treatment of cancer.

http://patentscope.wipo.int/search/mobile/detail.jsf;jsessionid=90CD8A71CE44807F360D11B3517E5EA5.wapp2nA?docId=WO2014199244&recNum=624&office=&queryString=&prevFilter=&sortOption=Pub+Date+Desc&maxRec=2561913

Olivetol-cyclodextrin complexes and regio-selective process for preparing delta 9-tetrahydrocannabinol US 20060194761 A1

Olivetol-cyclodextrin complexes and regio-selective process for preparing delta 9-tetrahydrocannabinol
US 20060194761 A1

http://www.google.com/patents/US20060194761

Green chemistry synthesis of the malaria drug amodiaquine and analogs thereof WO 2013138200 A1

Amodiaquine

http://www.google.com/patents/WO2013138200A1?cl=en

An exemplary method for producing amodiaquine is:

[0013] In an aspect, analogs can be suitably prepared, such as by using a different secondary diamine. For example, an exemplary di-alkyl analog of amodiquine is a di- isopropyl analog that can be prepared using di-isopropyl amine instead of di-ethylamine, and such di-isopropyl analog is represented by the formula:

[0014] A di-aryl substituted analog can be prepared in a similar fashion using an aryl- substituted secondary amine instead of a secondary di-alkylamine. An exemplary di-aryl analog of amodiquine can be prepared using a di-aryl amine, such as diphenyl amine instead of diethylamine, and such diphenyl analog is represented by the formula:

It will be appreciated that different alkyl-substituted or aryl-substituted analogs of amodiaquine can be prepared by selecting a suitable secondary amine.

[0015] Another illustrative synthesis involves using a 3-aminophenol. For example, such a synthesis can be illustrated as follows:

1. Acetic acid, reflux, 3 h

2. CH₂0, iPr₂NH, acetic acid, 14 h

[0016] In a similar fashion, an analog having a di-aryl phenyl group is obtainable as follows:

[0017] In one of its aspects, an illustrative one-pot synthesis is described in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0018] In one of its aspects a method described herein advantageously utilizes a one- pot process for preparing a compound, or its pharmaceutical salts, and preferably the compound is represented by the formula:

EXAMPLE 1

[0074] To a mixture of 4-aminophenol (11.4 grams, 0.104 mol) and 4,7- dichloroquinoline (19.8 grams, 0.10 mol), acetic acid was added (60 ml, 3.0 volumes w/v relative to 4,7-dichloroquinoline) with stirring at room temperature and the resulting mixture was heated with stirring at 110°C for about one hour. The mixture was cooled to 20°C and formaldehyde (14.06 grams of a 32% aqueous solution, 0.150 mol, 1.5 mol eq) and diethylamine (10.95 grams, 0.150 mol, 1.5 mol eq were sequentially added to the same reaction vessel). The reaction mixture was then heated and reaction occurred at 50°C for four hours. The mixture was cooled in an ice water bath and 22 mL of 37% aqueous hydrochloric acid solution (containing 0.264 mol of HC1) was added at a rate so that the internal temperature did not exceed 40°C. Stirring was continued for an additional 2 hours to complete the precipitation of the desired product as yellow crystals The precipitated crystals were collected by filtration and dried at room temperature to a constant weight to obtain 42.7 grams of amodiaquine dihydrochloride dihydrate (92% yield) in a purity of greater than 99% as determined by HPLC analysis. [0075]

WO2011073322A1 *	Dec 16, 2010	Jun 23, 2011	Institut National De La Sante Et De La Recherche Medicale (Inserm)	7-chloro-quinolin-4-amine compounds and uses thereof for the prevention or treatment of diseases involving formation of amyloid plaques and/or where a dysfunction of the app metabolism occurs
US3855286 *	Sep 27, 1972	Dec 17, 1974	Ciba Geigy Corp	N-carboxymethyl-n-(2-hydroxybenzyl) aspartic acid and derivatives thereof

* Cited by examiner

NON-PATENT CITATIONS

Reference
1	*	DELARUE-COCHIN ET AL.: 'Synthesis and antimalarial activity of new analogues of amodiaquine' EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, [Online] vol. 43, 2008, pages 252 - 260 Retrieved from the Internet: <URL:www.sciencedirect.com> [retrieved on 2013-05-07]
2		GUO ET AL.: 'Chiral Bronsted Acid-Catalyzed Direct Asymmetric Mannich Reaction' J. AM. CHEM. SOC., [Online] vol. 129, 2007, pages 3790 - 3791 Retrieved from the Internet: <URL:http://www.do.ufgd.edu.br> [retrieved on 2013-05-07]  amcrasto@gmail.com http://newdrugapprovals.org/ DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE Join me on Linkedin Join me on Facebook FACEBOOK Join me on twitter      Join me on google plus Googleplus  amcrasto@gmail.com