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

Types of Pharmaceutical Patent - Product, Process, Formulation and Method

Types of Pharmaceutical Patent - Product, Process, Formulation and Method

Pharmaceutical Patents

Patents protecting the intellectual property of products in the industrial area are vital to the owners existence. This is particularly so for the research-based pharmaceutical industry. Thus the enormous costs that are invested in terms of time and money for research and development, will be protected by secure patents. It is estimated that the costs of developing a new chemical entity (NCE) can be as much as £800millions and rising. The fact that the industry has been successful in recent times has meant that it is running out of new areas to cover. Also finding drugs that show significant improvements over those already existing is becoming increasingly difficult and costly.

In the UK, the NHS is the major customer, though the National Institute for Clinical Excellence (NICE), try to ensure that new drugs have significant benefits before allowing NHS prescriptions to be issued. Once the drug is patented there are 20 years of exclusivity. However, before any drugs can be marketed there are extensive procedures covering testing and licensing prior to their use. In effect, on average, half the allotted time span is exhausted, but this has been, to some extent, rectified by pharmaceutical patent term extensions. Even with these shortcomings, the industry has been very profitable. Most of the big companies have much of their turnover tied up in very few products. So, with diminishing patent time other producers have entered the field without the encumbrance of large research and development costs.

Nevertheless, to continue to feed the growth of new products, their protective patents are a necessity. Without them innovation will disappear. By the same token, patents allow the originators to make a reasonable return on investment, but not to excess. It is the term ‘reasonable’ that is often called into question. When the exclusivity period has ended producers must be allowed to supply products at more reasonable costs. Therefore, it is essential that knowledge about patents and their expiries are known by both originators and those who may wish to produce those products in the post-patent period.

Patents can seem confusing to read and understand and have a particular language of their own. For instance, ‘prior art’ refers to the technical background information relating to the invention and ‘one skilled in the art’ is a person competent in the technology the invention covers. OPI stands for open to public inspection, ie the document is available for the general public to read.

Patents are national or regional. They have no force outside the territory where they are granted. It must also be remembered that some countries do not have patent laws and certain types of invention, such as pharmaceuticals, can be excluded from patent cover. Countries are constantly changing their patent laws and the trend is to a more uniform system. Where new laws are coming into force, they tend to be in line with the patent laws of the western industrialised nations. International agreements such as the General Agreement on Tariffs and Trade (GATT) can have a profound effect on patent laws, and more recently Trade Related Aspects of Intellectual Property Rights (TRIPS). The strength of any granted patent depends on many factors including the way patent laws are interpreted in a country; the same patent laws can and are interpreted quite differently in various countries.

Without knowledge of the basic principles, it is impossible to grasp and understand the more complex patent scenarios. Once lawyers become involved, the simplest concepts can suddenly seem extremely complex. It must be remembered that patents can be a ‘double-edged sword’. This price of obtaining exclusivity and a monopoly on your invention for a fixed period is disclosure. So, to quality for this state monopoly you have to disclose to the whole world exactly what you have done. Some may consider this too big a price to pay. 

There are several types of patent or patent claim that are particularly relevant to pharmaceuticals. These are:
 

Product patent or claim

This claims the active chemical substance as a new chemical entity and is generally regarded as being superior claim. If there is a product claim on the drug then none but the patent holder or licensee can make, sell or import the chemical for any use without infringing the product patent.

This type of patent claim is now allowed in most commercially important countries, although it is a fairly recent event in many others. For instance, Japan, Switzerland, Sweden and Italy introduced product patent for pharmaceuticals in the 1970’s, Austria in 1987, Portugal, Spain and Greece in 1992.

The novel drug is claimed either by chemical name or by chemical structure, or both. The drug may be claimed within a Markush structure. This comprises a core chemical structure with several optional chemical groups that may be attached to the core structure. This is known as a generic claim to a compound. A drug will be covered by the generic claim and there may be a specific claim to the chemical as well. Some Markush structures are so general that they can cover millions of actual chemicals.

Note that in patentees the term ‘composition of matter’ actually denotes a product claim.

Product by process patent or claim

This type of claim ‘claims’ a chemical or other process used to manufacture the drug whenever the drug is made by the patented process. It is the ‘next best’ type of claim as it also confers protection against importation of a product. However, the drug can be made and sold if another company can devise a commercially viable process not covered in the patent.

Process patent

This claims the chemical or other process used to manufacture the drug. The chemical product itself is not covered. Because of the difficulty of proving that another company is using the patented process, many countries have a ‘burden of proof reversal’ clause where the potential infringer has to prove that the patented process is not being used. In the USA, the patent law was amended to made importation of the product of a patented process an infringing act, although this is not generally the case.

Formulation patent

This claims the pharmaceutical dosage form on the drug, commonly also known as a composition but not to be confused with ‘composition of matter’ (see previously). It may take the form of a formulation of a particular drug or class of drugs, or a general formulation applicable to many drugs with different actions, such as slow release technologies, transdermal patches, etc. There may also be formulation process patents covering the manufacturing processes used to make the formulation.

Method of use

This covers the use of the drug to treat a disease. This type of claim is originally allowed in the USA and Germany, but is now being accepted in other countries including the UK. However, a careful wording of the claim in European patent application allows this type of claim. The European claim usually goes ‘... use of drug x to manufacture a pharmaceutical dosage form to treat ...’, thereby avoiding a direct method of treatment claim.

Remember that not all types of claim are allowed in all countries and some countries do not have patent laws.

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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO