WO 2016042441, Mankind Research Centre, Silodosin, New patent

PATENTS Comments Off

Apr 012016

WO 2016042441, Mankind Research Centre, Silodosin, New patent

WO-2016042441

Mankind Research Centre

MANKIND RESEARCH CENTRE [IN/IN]; 191-E, Sector 4-II, IMT-Manesar, Haryana 122050 (IN)

A novel process for the preparation of considerably pure silodosin

GANGWAR, Kuldeep Singh; (IN).
KUMAR, Anil; (IN).
BHASHKAR, Bhuwan; (IN)

The present invention relates to a novel, improved, commercially viable and industrially advantageous process for the preparation of Silodosin of Formula (I), its pharmaceutically acceptable salts or solvates thereof. The invention relates to the preparation of considerably pure Silodosin with high yield.

Silodosin, l-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide of Formula (I) is an indoline antidysuric which has a selectively inhibitory effect against urethra smooth muscle constriction, and decreases urethra internal pressure without great influence on blood pressure. Silodosin is available under trade names RAPAFLO^® or UROREC^®. Silodosin was first disclosed in EP 0600675 as a therapeutic agent for the treatment of dysuria associated with benign prostatic hyperplasia, where a process for producing the compound is also disclosed.

Formula (I)

Since, Silodosin is an optically active compound having a complex chemical structure; its synthesis is relatively complex and requires a sequence of multiple steps.

US patent no. 6,310,086, discloses a process for preparing Silodosin analogue compound from reaction of (R)-3-{5-(2-aminopropyl)-7-cyano-2,3-dihydro-lH-indol-l-yl} propylbenzoate with 2-(2-ethoxyphenoxy)ethyl methanesulfonate and finally isolated as a crude compound which is purified by column chromatography. The said process has a major disadvantage of using column chromatography which is not feasible at plant scale production.

PCT application no. WO 2012147019, discloses the preparation of Silodosin as shown in scheme- 1, wherein the Ν,Ν-dialkyl impurity of Formula (Ila) formed during condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl}propyl benzoate of Formula (III) with 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methanesulfonate of Formula (IV); is removed through preparation of monotartarate salt to give compound of Formula (VI). The compound of Formula (VI) is base hydrolyzed followed by cyano hydrolysis to give crude Silodosin of Formula (VIII) which is then further purified by crystallization to get desired pure Silodosin.

Scheme- 1:

Major drawback of above said reaction process is that multiple isolations and crystallizations are required to get pure Silodosin.

Similarly, US 7,834,193 discloses monooxalate salt represented by Formula Via having 0.9% of dialkyl impurity represented by Formula Ila. The oxalate salt so obtained is subjected to alkaline hydrolysis followed by transformation of the nitrile to an amide.

Formula (Ila)

Similarly, PCT application no. WO 2012147107, discloses the method wherein Silodosin is prepared by condensation of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH-indol-l-yl} propyl benzoate with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate in solvent using base and phase transfer catalyst wherein, dialkyl impurity is formed up to 11%, followed by hydroxyl deprotection in protic solvent using base and phase transfer catalyst which is then subjected to purification to remove N,N-dialkyl impurity represented by Formula (lib) up to 0.6% through the preparation of acetate salt. This process suffers from a serious drawback i.e., accountable formation of dialkyl impurity and even after purification the impurity is reduced to only up to 0.6%. Secondly, the process requires multiple isolations and purifications ensuing into time engulfing workups and purifications and hence incurring solvent wastage. This makes process lengthy, uneconomical and tedious to be performed at plant scale.

Another PCT application no. WO 2012131710, discloses the preparation of Silodosin in which the chiral compound (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) is reacted with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate in isopropyl alcohol using sodium carbonate as base. The reaction is completed in 40-50h and about 9-11% of dimer is formed during condensation. After completion of reaction, it is subjected to hydroxyl deprotection and the crude compound so obtained is purified to remove the Ν,Ν-dialkyl impurity of Formula (lib). The pure compound is then reacted with hydrogen peroxide in dimethyl sulfoxide to give Silodosin. The major drawback of this process is that the process is a multistep process wherein the condensation reaction is long-drawn-out resulting into countable amount of dimer formation during the process.

Thus, the prior art methods of preparing Silodosin require multiple and repeated purifications to synthesize DMF (Drug Master File) grade Silodosin. None of the prior art produces compound of Formula (VI) or (VII) with Ν,Ν-dialkyl impurity of Formula (Ila) or (lib) in an amount less than 0.6% to 0.5% even after purification. Therefore to prepare highly pure Silodosin, there is a need to explore new synthetic schemes that could be more economical and scalable. The present invention provides a novel, improved, commercially viable and industrially advantageous process for the synthesis of Silodosin and its pharmaceutically acceptable salts or solvates thereof. The present invention focus on preparation of highly pure Silodosin in appreciable yields with minimal use of solvents wherein the Silodosin is isolated with purity >99.5% having Ν,Ν-dialkyl impurity less than 0.03% and other individual impurities below 0.1%.

Mankind Pharma: Formulating Strategy To Enter The Big League

Ramesh Juneja (seated), founder of Mankind Pharma, with brother Rajeev, who is senior director (marketing & sales)

Mankind Pharma Chairman and Founder RC Juneja

In accordance to one embodiment of the present invention, the process of the preparation of Silodosin represented by Formula (I)

comprises the steps of:

a) condensing chiral compound represented by Formula (III)

Formula (III)

wherein, Bz represents to Benzoyl group with compound represented by Formula (IV)

Formula (IV)

wherein, Ms represents to Methanesulfonyl group in presence of base and phase transfer catalyst in an organic solvent to give intermediate represented by Formula (V)

Formula (V)

wherein, n is an integer of 1 and 2 and Bz is as defined above, wherein the compound having n=2 is formed in an amount of less than 5%;

b) optionally isolating compound of Formula (V),

c) without purification converting it to de-protected compound represented by Formula (IX) in an organic solvent;

Formula (IX)

wherein, n is as defined above;

d) optionally isolating compound of Formula (IX), and

e) without purification converting it to compound represented by Formula (X)

Formula (X)

wherein n is as defined above;

f) subjecting compound of Formula (X) to purification by converting to acid salt for removal of Ν,Ν-dialkyl impurity represented by Formula (lie);

Formula (He)

g) hydrolysis of the said acid salt to get Silodosin of Formula (I) with purity >99.5%.

Examples

The invention is explained in detail in the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1

Preparation of Crude Silodosin:

Method A:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of toluene was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Cooled the reaction mass, added de-mineralized water and separated the toluene layer followed by distillation to get crude viscous mass. Added 110ml of dimethyl sulfoxide and a solution of 1.51g (0.0415 mol) of sodium hydroxide dissolved in 8.52ml of water followed by addition of 6.42g (0.0567 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at 20-25°C till completion and added sodium sulfite solution. Extracted the compound in ethylacetate, washed the organic layer with brine solution and concentrated to get 10.2g of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.2% as per HPLC.

Method B:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of toluene was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 110ml of dimethyl sulfoxide and added a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 10. lg of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.0% as per HPLC

Method C:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of dimethyl sulfoxide was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 2-3h. Added 100ml of water and 50ml of toluene and stirred the reaction mass at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure. To the crude mass so obtained was added 110ml of dimethyl sulfoxide and a solution of 4.4g of sodium hydroxide dissolved in 10ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 9.8 g of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.1% as per HPLC

Method D:

To the solution of 20g (0.055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 200ml of toluene was added 28.6g (0.165 mol) of dipotassium hydrogen phosphate and 16.4g (0.0522 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate followed by addition of 4.0g (0.11 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added de-mineralized water and stirred at room temperature for half an hour. Separated the toluene layer to which was added a solution of 8.8g of sodium hydroxide dissolved in 20ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 200ml of dimethyl sulfoxide and added a solution of 3.9g (0.0976 mol) of sodium hydroxide dissolved in 16ml of water followed by addition of 15g (0.132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 400ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 21. Og of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.8% as per HPLC

Method E:

To the solution of 2g (0.0055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 20ml of was dimethyl sulfoxide was added 2.87g (0.0165 mol) of dipotassium hydrogen phosphate and 1.64g (0.0052 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 0.29g (0.0011 mol) of 16-crown ether and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 0.88g of sodium hydroxide dissolved in 2ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 20ml of dimethyl sulfoxide and a solution of 0.38g (0.0231 mol) of sodium hydroxide dissolved in 1.6ml of water followed by addition of 1.5g (0.0132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 2.1g of crude Silodosin.

Ν,Ν-dialkyl impurity is 2.2% as per HPLC

Method F:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of was acetonitrile was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 2.0g (0.0055 mol) of tetra butyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 110ml of dimethyl sulfoxide and a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 9.5g of crude Silodosin.

Ν,Ν-dialkyl impurity is 3.1% as per HPLC

Method G:

To the solution of lOg (0.0275 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-l-yl)propyl benzoate) in 100ml of was Dimethyl sulfoxide was added 14.3g (0.0826 mol) of dipotassium hydrogen phosphate and 8.20g (0.0261 mol) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate followed by addition of 4.0g (0.0055 mol) of tetra butyl ammonium iodide and stirred the reaction mass at 85-90°C for 10-12h. Added a solution of 4.4g of sodium hydroxide dissolved in 10ml of water and stirred the reaction at ambient temperature till completion. Added de-mineralized water and toluene and stirred at room temperature for half an hour. Separated the toluene layer and concentrated under reduced pressure and to the solid mass so obtained were added 110ml of dimethyl sulfoxide and a solution of 1.95g (0.0488 mol) of sodium hydroxide dissolved in 7.95ml of water followed by addition of 7.5g (0.066 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 210ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 10.4g of crude Silodosin.

Ν,Ν-dialkyl impurity is 1.83% as per HPLC

Example 2

Purification of Crude Silodosin:

To the lOg (0.0080 mol) of crude mass of Silodosin was added 110ml of isopropyl alcohol followed by addition of 1.75g of oxalic acid at ambient temperature. Stirred the solution 6-8h and filtered the precipitates. Added ethyl acetate and water in the ratio of 1: 1 to the above solid followed by addition of 5ml of liquor ammonia. Stirred the reaction mass at ambient temperature for 15 min and separated the layers. Concentrated the organic layer to ¼ of its volume and left undisturbed overnight. Filtered the precipitates and recrystallized with ethyl acetate followed by drying under reduced pressure to get 5.1g of pure Silodosin. The amount of impurities and the percent impurity of the Silodosin obtained was as follows:

Ν,Ν-dialkyl impurity: undetectable amount

Other impurities: 0.03 to 0.09%

Silodosin purity: 99.65% (HPLC)

////WO 2016042441, Mankind Research Centre, Silodosin, New patent

New patent, WO 2016042573, Acitretin, Emcure Pharmaceuticals Ltd

PATENTS Comments Off

Apr 012016

Acitretin

PDT PATENT US4105681

WO-2016042573

Process for preparation of acitretin

Emcure Pharmaceuticals Ltd

EMCURE PHARMACEUTICALS LIMITED [IN/IN]; an Indian company at EMCURE HOUSE, T-184, MIDC., Bhosari, Pune – 411 026 Maharashtra (IN)

GURJAR MUKUND KESHAV; (IN).
JOSHI SHASHIKANT GANGARAM; (IN).
BADHE SACHIN ARVIND; (IN).
KAMBLE MANGESH GORAKHANATH; (IN).
MEHTA SAMIT SATISH; (IN)

The present invention Provides a process for preparation of {(2E, 4E, 6E, 8E) -9- (4-methoxy-2,3,6-trimethyl) phenyl-3,7-dimethyl-nona-2,4,6 , 8} tetraenoate, acitretin year intermediate of formula (VI) with trans isomer ≥97%, comprenant of Reacting 3-formyl-Crotonic acid butyl ester of formula (V) Substantially free of impurities, with 5- (4-methoxy- 2,3,6-trimethylphenyl) -3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide of formula (IV) and isolating resulting compound of formula (VI) Treating the filtrate with iodine for isomerization of the Undesired cis intermediate and finally Obtaining acitretin (I), with trans isomer Desired ≥97%.

Samit Satish Mehta holds the position of the President – Research & Development

Acitretin of formula (I), chemically known as (2E,4E,6E,8E)-9-(4-methoxy-2,3,6- trimethyl)phenyl-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid, is a second generation retinoid a roved by USFDA in 1996, for the treatment of psoriasis.

Acitretin (I)

The process for preparation of acitretin (I) was first disclosed in US 4,105,681 wherein the intermediate, 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide was reacted with 3-formyl-crotonic acid butyl ester in presence of sodium hydride as base and dimethylformamide as solvent. The resultant ester derivative was obtained with a trans is (E/Z) ratio of around 55:45 which was subjected to hydrolysis in presence of potassium hydroxide and ethyl alcohol to obtain acitretin.

Use of hazardous, highly pyrophoric and moisture sensitive reagent like sodium hydride, along with cumbersome work-up and successive crystallizations to obtain the desired isomer rendered the process unviable for commercial scale.

Indian patent application 729/MUM/2012 discloses use of organic bases such as triethyl amine or pyridine for the reaction of 3-formyl-crotonic acid butyl ester and 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l -triphenyl phosphonium bromide for the synthesis of acitretin. The process utilizes a large excess of the organic base (2.85:1.0) with respect to the reactant phosphonium bromide derivative. Further, there is no mention of the ratio of cis and trans geometric isomers of the product thus obtained either at the intermediate or final stage. The trans: cis (E/Z) ratio of the intermediate significantly impacts the final yield and purity of the product as several purifications and crystallizations are required to obtain the desired trans isomer.

The present inventors have experimentally observed that use of organic base in such large quantities severely hampers the removal of the undesired side product triphenyl phosphonium oxide formed in significant amounts. Also, the intermediate is obtained with a very modest trans: cis (E/Z) ratio.

WO2012/155796 discloses another method wherein alkali metal alkoxides are used as bases in the reaction of 5-(4-methoxy-2,3,6-trimethylphenyl)-3 -methyl -penta-2,4-diene-l -triphenyl phosphonium bromide with 3-formyl-crotonic acid. The obtained reaction mass, after adjusting pH to 7-8 with acid, is directly subjected to catalytic isomerization using catalysts such as Pd(OAc)₂ or Pd(NH₃)₂Cl_2. The reaction mixture so obtained is quenched with water, neutralized and filtered to get the desired product, which is further recrystallized from ethyl acetate. Although this procedure avoids the hydrolysis step and attempts in-situ isomerization, however the use of expensive, soluble palladium catalyst which cannot be recycled from the reaction mass coupled with lengthy reaction time of 25-30 hours and large solvent volumes make the process unviable.

It may be noted that in the synthesis of acitretin, the key reaction of 5-(4-methoxy-2,3,6-trimethylphenyl)-3 -methyl-penta-2 ,4-diene- 1 -triphenylphosphoniumbromide with 3 -formyl crotonic acid or its ester in presence of either strong inorganic bases such as sodium hydride, alkali metal alkoxides or organic bases like triethylamine is common to almost all synthetic routes disclosed in the prior art. Hence, all these routes suffer from the inherent problems of formation of undesired impurities including cis-isomeric compounds and their separation from the desired all-trans product which necessitates various purification methods ranging from column chromatography, multiple crystallizations etc.

Thus, there still exists a need for a convenient, easy-to-scale up process for synthesis of acitretin (I) which avoids use of pyrophoric strong bases and provides a robust method which affords acitretin having desired isomeric purity in high yield.

5-(4-methoxy,2,3,6 trimethylphenyl)- 3-formyl crotonic acid butyl glyoxalate L(+) tartaric acid

3-methyl-penta-2,4-dien-1-triphenyl butyl ester (V) dibutyl ester

phosphonium bromide (IV)

Acitretin (I)

Satish Mehta,CEO, Above and here Inspiring the participants

EXAMPLES

Example 1: Preparation of 4-(4-methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (II)

Acetone (6000 ml) was added to 4-methoxy-2,3,6 trimethyl benzaldehyde (500.3 g) and the mixture was stirred at 20-30°C. Aqueous solution of sodium hydroxide (134.8 g in 500 ml water) was gradually added to it and the resulting mixture was heated to 45-50°C with continued stirring. After completion of the reaction, as monitored by HPLC, the reaction mass was cooled and acetic acid was added till pH 4.5 to 5.5. Distillation of acetone, followed by addition of cyclohexane to the residue, followed by washing with water, separation and concentration of the organic layer gave 4-(4-methoxy-2,3,6 trimethylphenyl)-but-3-en-2-one of formula (II).

Yield: 80-84%

Example 2: Preparation of 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene- 1-triphenyl phosphonium bromide (IV)

4-(4-Methoxy-2,3,6-trimethylphenyl)-but-3-en-2-one (II; 500 g) dissolved in toluene (2000 ml) was gradually added to a mixture of vinyl magnesium bromide (3500 ml; 1 molar solution in THF) and lithium chloride (4.8 g) and stirred at 20-30 C till completion of the reaction as monitored by HPLC. The reaction mixture was quenched with water and concentrated hydrochloric acid was added till the pH was between 3 and 4. The organic layer was separated and concentrated to give residue containing 5-(4-methoxy-2,3,6 trimethylphenyl)-3 -methyl -penta l,4-dien-3-ol (III). Methyl isobutyl ketone (3500 ml) was added to the residue, followed by gradual addition of triphenyl phosphine hydrobromide (745.3 g) at room temperature. The reaction mixture was heated to 50-60°C till completion of the reaction. The reaction mixture was cooled and filtered to give 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide of formula (IV).

Yield: 1000 g (76%)

Example 3: Preparation of 3-formyl crotonic acid butyl ester (V)

Dibutyl-L- tartrate (500 g) was dissolved in isopropanol (3500 ml) at room temperature, and water (750 ml) was added to it. The reaction mixture was cooled to 15-25°C and sodium metaperiodate (448.5 g) was gradually added to it with stirring. The reaction was continued at 20-30°C till completion of the reaction based on GC analysis. The reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in toluene (1000 ml), stirred and filtered to obtain the filtrate containing butyl glyoxylate. Propionaldehyde (221.0 g) was added to the filtrate and heated to around 60°C, followed by gradual addition of piperidine (26.4 g, dissolved in toluene). The reaction mixture was further heated and stirred at 110-120°C till completion of the reaction, as monitored by GC. After completion, the reaction mass was cooled, washed with aqueous sulfuric acid, water and finally with aqueous sodium bicarbonate solution. The organic layer was concentrated and the residue was distilled to give 3-formyl crotonic acid butyl ester (V)

Yield: 230-280 g (35-43%)

Example 4. Preparation of butyI{(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethyl) phenyl-3,7-dimethyl-nona-2,4,6,8}tetraenoate (VI)

Sodium carbonate (297. lg), was added to the mixture of 5-(4-Methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl-phosphoniumbromide (IV; 1000 g) in toluene (5000 ml) followed by gradual addition of 3-formyl crotonic acid butyl ester (330 g) at room temperature. The stirred reaction mixture was heated to 60-70°C till completion of the reaction as monitored by HPLC. The reaction mass was cooled, quenched with water. The organic layer was separated, concentrated and n-heptane was added to the residue. The mass was stirred, filtered and 40% aqueous methanol (2000 ml) was added to it with stirring. Layer separation, concentration of the organic layer, and crystallization of the resulting residue from isopropyl alcohol, optionally with seeding followed by filtration gave crop I of butyl {{(2E,4E,6E,8E)— 9-(4-methoxy-2,3,6 trimethyl)phenyl-3,7 dimethyl -nona-2,4,6,8} tetraenoate (VI),.

Yield: 45-50%;

Cis: Trans isomer ratio (2.0:98.0)

The filtrate was concentrated, the residue was dissolved in toluene (2000 ml) and treated with iodine (4.5 g) at room temperature. After completion of the reaction, as monitored by HPLC, the reaction mixture was stirred with aqueous sodium thiosulfate solution. Separation and concentration of the organic layer and crystallization of the resulting residue from isopropyl alcohol, optionally with seeding, gave crop II of butyl {{(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethyl)phenyl-3,7-dimethyl-nona-2,4,6,8} tetraenoate (VI).

Yield (crop II): 15 to 20%.

Cis: Trans isomer ratio (2.0:98.0)

Total yield (crop I+II): 60-70%.

Example 5: Preparation of acitretin (I)

Aqueous solution of potassium hydroxide (155.2 g in 600 ml water) was added to a solution of butyl {(2E,4E,6E,8E)-9-(4-methoxy-2,3 ,6-trimethyl) phenyl-3 ,7-dimethyl-nona- 2,4,6,8}tetraenoate, VI (300.0 g) in ethanol (1800 ml) at 25-30°C and the reaction mixture was stirred at reflux temperature till completion of the reaction. After completion, as monitored by HPLC, the reaction mixture was quenched with water, and hydrochloric acid was added till pH was between 2.5 and 3.5. The mass was heated at 70°C, stirred, cooled to 40-50°C and filtered. Recrystallization of the resulting solid from tetrahydrofuran gave acitretin (I).

Yield: 154.0 g (60%)

Desired trans isomer: > 98%

India’s hockey stars Sardara Singh and Sandeep Singh with Emcure Pharmaceuticals COO, Arun Khanna

HE Dr. Kenneth Kaunda, First President of Zambia interacting with Mr. A. K. Khanna, COO & ED, Emcure at Emcure booth at AIDS 2012 conference, Washington

Mr. Sunil Mehta is an Executive Director and Senior Director (Projects)

Arun Khanna is the Chief Operating Officer and Executive Director on the Board of Emcure Pharmaceuticals Limited.

//////New patent, WO 2016042573, Acitretin, Emcure Pharmaceuticals Ltd

New patent, Lomitapide mesylate , Zydus Cadila Healthcare Ltd, US 20160083345,

PATENTS Comments Off

Apr 012016

Lomitapide mesylate

Was developed and launched by Aegerion, under license from the University of Pennsylvania (which acquired rights from BMS).

US-20160083345

Sanjay Jagdish DESAI
Brij KHERA
Jagdish Maganlal PATEL
Harshita Bharatkumar SHAH
Arunkumar Shyam Narayan UPADHYAY
Sureshkumar Narbheram AGRAVAT

Polymorphic forms of lomitapide and its salts and processes for their preparation

Zydus Cadila Healthcare Ltd

The present invention relates to various polymorphic forms of lomitapide or its salts and processes for preparation thereof. The present invention provides Lomitapide mesylate in solid amorphous form and process for preparation thereof. The invention also provides an amorphous solid dispersion of lomitapide mesylate. Further, various crystalline forms of lomitapide mesylate like A, B and C and process for preparation thereof are provided. The invention also provides crystalline forms of lomitapide free base, in particular Form I and Form-II and their preparation. The invention further provides compositions comprising various forms of lomitapide and its salts.

A novel amorphous form of lomitapide mesylate (having >98% of purity and 0.5% of residual solvent and particles size D90 of >250 µm, D50 of >100 µm and D10 of >50 µm), a process for it preparation and a composition comprising it is claimed. Also claimed is an amorphous solid dispersion of lomitapide mesylate and a carrier (eg hydroxypropylmethyl cellulose acetate succinate). Further claimed are crystalline forms of lomitapide mesylate (designated ad Forms A, B, C, I, II and free base of lomitapide in amorphous form), processes for their preparation and compositions comprising them. Lomitapide is known to act as a microsomal triglyceride transfer protein inhibitor, useful for treating familial hypercholesterolemia.

Lomitapide is a synthetic lipid-lowering agent for oral administration. It is a microsomal triglyceride transfer protein inhibitor approved as Juxtapid® in US and as Lojuxta® in Europe as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-highdensity lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). The approved drug product is a mesylate salt of lomitapide, chemically known as N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4′(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-1-piperidinyl]butyl]-9H-fluorene-9carboxamide methanesulfonate [“lomitapide mesylate” herein after] and has the structural formula

(MOL) (CDX)

As per the approved label for Juxtapid® (US) “Lomitapide mesylate is a white to off-white powder that is slightly soluble in aqueous solutions of pH 2 to 5. Lomitapide mesylate is freely soluble in acetone, ethanol, and methanol; soluble in 2-butanol, methylene chloride, and acetonitrile; sparingly soluble in 1-octanol and 2-propanol; slightly soluble in ethyl acetate; and insoluble in heptane”.

As per Public Assessment Report for Lojuxta® (Europe) “Polymorphism has been observed for lomitapide mesylate. Of the different solid-state forms, hydrates, and solvates identified in the polymorph studies, only 2 desolvated solid-state forms, Form I and Form II, were identified in batches after drying to final drug substance.” The report further states, under the heading Manufacture, that “The final particle size distribution is controlled during the crystallisation step” (emphasis added) suggesting that the approved drug product lomitapide mesylate is a crystalline compound

U.S. Pat. No. 5,712,279 A discloses the lomitapide compound and a process for its preparation. It also discloses a process for preparation of lomitapide monohydrochloride.

U.S. Pat. No. 5,883,109 A discloses lomitapide mesylate specifically but no solid form was disclosed.

The reference article Synthesis and Applications of Isotopically Labelled Compounds, Vol. 8, Pg. 227-230 (2004) discloses the preparation of Deuterium labelled [d₄]BMS-201038, [³H]BMS-201038, [¹⁴C]BMS-201038 wherein BMS-201038 is lomitapide mesylate.

International (PCT) Publication No. WO 2015/121877 A2 discloses lomitapide crystalline Form I and Form II as well as amorphous form of Lomitapide mesylate and processes for their preparation.

There is still a need to provide a novel polymorph of lomitapide or its salts which is suitable for pharmaceutical preparations. Therefore, the present invention provides new crystalline forms of lomitapide free base and lomitapide mesylate. The present invention also provides amorphous form of lomitapide free base and lomitapide mesylate, which is stable and useful for pharmaceutical preparations.

EXAMPLES

Example-1

Preparation of Lomitapide Mesylate

In a 250 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 10 g lomitapide and 20 mL methanol were added and stirred to obtain a solution. 1.5 g methane sulfonic acid dissolved in 20 mL water was added slowly to the above solution under stirring. The reaction mixture was stirred till maximum salt formation was achieved. 50 mL water was added to the mixture, stirred for 15-20 min, filtered and washed with water. The product was dried further to obtain lomitapide mesylate.

EXAMPLE 2

Preparation of Amorphous Form of Lomitapide Mesylate

10 g lomitapide mesylate, 50 mL acetone and 150 mL ethyl acetate were heated in a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel at 50-55° C. and stirred to obtain clear solution. The solution was subjected to spray drying in JISL Mini spray drier LSD-48 with feed pump running at 30-35 rpm, inlet temperature 50-55° C., out let temperature 45-50° C., aspiration rate 1200-1300 rpm, hot air supply 1.8-2.2 Kg/cm²and vacuum for conveying the dry product 80 mmHg. The product was collected from cyclone and characterized to an amorphous form by x-ray powder diffraction. The product was further dried to obtain the amorphous form of lomitapide mesylate

/////////////New patent, Lomitapide mesylate , Zydus Cadila Healthcare Ltd, US 20160083345, Amorphous

WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, New patent

PATENTS, Uncategorized Comments Off

Feb 082016

(S) – propylene glycol and water, 1: 1 crystalline complex

PATENT

WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME

HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)

KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)

The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.

long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.

Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.

In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.

Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.

[Formula 1]

While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.

In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.

[Formula 2]

Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).

However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.

In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.

However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.

Best Mode for Carrying out the Invention

Hereinafter, the present invention will be described in detail.

Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).

[Formula 3]

The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.

It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.

The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.

In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.

It describes a method for producing crystalline complex according to the present invention;

Step 1: Mannitol solution prepared

Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.

The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.

The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.

The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.

The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .

Step 2: Preparation of an alcohol solution

Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.

In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.

The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C ₁ ~ C ₄ alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .

The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.

Step 3: heat-up phase

Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.

The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.

The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.

Step 4: obtained crystalline complexes

Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.

The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.

Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.

The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.

Mode for the Invention

Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.

Example 1. Preparation of the crystalline complex

The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).

Experimental Example 1. Structural analysis

Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using ¹ yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.

¹ H NMR (400㎒, DMSO-d ₆ ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)

The ^first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).

[Formula 4]

Experimental Example 2. OK crystalline crystalline complexes

By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.

Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .

Experimental Example 3. HPLC analysis

To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.

TABLE 1

column	Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
The mobile phase	_{A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)}
Test Solution	Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
Column temperature	25 ℃
Wavelength detector	UV, 220nm
Dose	3 ㎕
Flow rate	0.7 mL / min
Operating hours	40 min

Table 2

Gradient systems
Time (min)	Mobile phase A (%)	Mobile phase B (%)
0	75	25
0-25	35	65
25-26	30	70
26-29	30	70
29-35	75	25
35-40	75	25

As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.

Claims

To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]

According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.

According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.

1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]

[Claim 5]

According to claim 4, wherein the solvent is the production of water, the crystalline complex.

According to claim 4, wherein the alcohol is a C ₁ ~ C _4, a method of producing a crystalline complex comprising at least one kind of alcohol.

According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.

According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.

FIGURES

Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.

2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.

3 is of the crystalline complex in accordance with an embodiment of the present invention ¹ shows the H-NMR measurement results.

[Figure 1]

[Figure 2]

[Figure 3]

CEO, YOUNG KIL CHANG

/////////WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LT, NEW PATENT

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

NEW PATENT WO2015188782, METHOD FOR PREPARING SOFOSBUVIR

PATENTS Comments Off

Dec 302015

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

Step (a):

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ8.25 & 7.94 (1: 1);

¹ HNMR (CDCl ₃ , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

¹³ C NMR (CDCl ₃ , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ as internal standard): δ3.54ppm;

¹³ C NMR (CDCl ₃ , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

¹ HNMR (CDCl ₃ , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(4) nucleophile as NaN ₃ , phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN ₃ (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N ₃ ).

¹ HNMR (CDCl ₃ , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

³¹ PNMR- (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO ₄ dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

¹ HNMR (CDCl ₃ , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

³¹ PNMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

¹ HNMR (CDCl ₃ , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH ₃ ) ₂ ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH ₃ ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH ₃ ), 1.25-1.23 (t, 6H, CH- (CH ₃ ) ₂ );

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(2) X is N ₃

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na ₂ CO ₃ and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

P ³¹ NMR (CDCl ₃ , 300 Hz, H ₃ PO ₄ internal standard): δ3.56.

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Zydus Cadila Healthcare Ltd, WO 2015102017, lorcaserin

PATENTS, PROCESS, Uncategorized Comments Off

Jul 132015

Processes for the preparation of lorcaserin

Zydus Cadila Healthcare Ltd

WO 2015102017, 09 July2015

Applicants:	CADILA HEALTHCARE LIMITED [IN/IN]; Zydus Tower, Satellite Cross Roads Ahmedabad – 380 015 Gujarat (IN)
Inventors:	DWIVEDI, Shriprakash Dhar; (IN). SHAH, Alpeshkumar Pravinchandra; (IN). GAJJAR, Samir Rameshbhai; (IN). KHERA, Brij; (IN)

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol

Useful for treating obesity.

The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed. Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.

In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT_2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)

U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.

U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form

I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.

The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.

International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.

International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.

U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.

International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.

see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.

100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.

Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Example-9: Preparation of crystalline Form I lorcaserin hydrochloride

50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

New Horizons Pluto Flyby

/////////

Sofosbuvir new patent…WO 2015097605, Mylan

PATENTS, PROCESS Comments Off

Jul 102015

WO 2015097605

Mylan Laboratories Ltd.

Process for the preparation of sofosbuvir

02 July 2015

The present disclosure relates to processes for the preparation of sofosbuvir or of its pharmaceutically acceptable salts. The present disclosure also provides intermediates useful in the synthesis of sofosbuvir.

Kaushik, Vipin Kumar; Vakiti, Srinivas; Ravi, Vijaya Krishna; Tirumalaraju, Bhavanisankar

Nucleoside phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

Sofosbuvir (PSI-7977) is a nucleotide analog inhibitor of HCV NS5B polymerase, which is developed by Pharmasset and used for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.

SOVALDI® tablets contain sofosbuvir, which is chemically named as (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2yl)methoxy)-(phenoxy)phosphorylamino) propanoate and is represented by the following chemical structure:

Formula-1

Sofosbuvir and a process for the preparation are disclosed in U.S. Patent No. 7,964,580 B2 and PCT Publication No. WO 2008/121634 A2, which are hereby incorporated by reference.

The present disclosure provides a novel process for the preparation of sofosbuvir or its pharmaceutically acceptable salts that employs novel intermediates.

SUMMARY OF THE DISCLOSURE

A first aspect of the present disclosure is to provide a process for the preparation of sofosbuvir or its pharmaceutically acceptable salts.

In one embodiment, the present disclosure provides a process for the preparation of sofosbuvir or its pharmaceutically acceptable salts that includes the steps of:

a) reacting the compound of formula 4 with a compound of formula 5 to get a compound of formula 3;

b) hydrolyzing the compound of formula 3 to get a compound of formula 2; and

3 2

c) optionally deprotecting the compound of formula 2 to get sofosbuvir of formula 1 or its pharmaceutically acceptable salts.

wherein R is hydrogen or any hydroxy protecting group and X is a leaving group such as tosylate, camphorsulfonate, mesylate, trifluoroacetate, trifluorosulfonate, an aryloxide, heteroaryl oxide or an aryloxide or heteroaryl oxide substituted with at least one electron-withdrawing group.

In another embodiment, the present disclosure provides a novel intermediate of formula 3a.

In an additional embodiment, the present disclosure provides a crystalline compound of formula 3a, which is characterized by a powdered X-ray diffraction pattern as shown in Figure 1.

In September 2014, Gilead entered into non-exclusive licensing agreements with various generic companies (including Mylan) to manufacture and supply generic sofosbuvir. In April 2015, Mylan launched its generic version of the drug as MyHep, in India

scheme-II.

Sofosbuvir

Scheme-II

In another embodiment the present disclosure provides a process for the preparation of sofosbuvir as shown in below scheme-Ill.

Example 3: Preparation of sofosbuvir (formula 1).

N-Benzoyl Sofosbuvir (6 g) was added to 70% w/w aqueous acetic acid (90 mL) and the contents were stirred at 90-95 °C. After completion of the reaction, which was monitored by qualitative HPLC, the reaction mass was cooled to ambient temperature, diluted with water and filtered through a Hyflo filter. Thereafter, obtained filtrate was extracted with ethyl acetate which was further washed with ~4%w/w aqueous hydrochloric acid followed by ~9%w/w aqueous sodium carbonate solution. Finally, the ethyl acetate layer was washed with water and dried. The dried layer was concentrated under reduced pressure at 60-65 °C. Thereafter, the concentrated mass was dissolved in a mixture of 5% isopropanol in methylene dichloride and isopropyl ether was added to precipitate the product. After stirring at 0-5 °C for 2 hours, the product was filtered, washed with methylene dichloride/isopropyl ether mixture, which was recrystallized with methylene dichloride/isopropyl ether mixture to yield sofosbuvir as white crystals (3 g)……https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015097605&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Mylan launches Sovaldi tablets in India

http://www.dalaltimes.com/article/india-inc/mylan-launches-sovaldi-tablets-in-india-94699.aspx

Sovaldi is indicated for the treatment of chronic hepatitis-C infection as a component of a combination antiviral treatment

Pharma giant Mylan NV today said its subsidiary Mylan Pharmaceuticals has launched Gilead Sciences’ Sovaldi (sofosbuvir 400mg tablets) in the country.

Sovaldi is indicated for the treatment of chronic hepatitis-C infection as a component of a combination antiviral treatment.

It is estimated that around 12 million people are chronically infected with hepatitis-C in India, Mylan said in a release.

In February this year, Gilead appointed Mylan as its exclusive distributor of Sovaldi in India.

Mylan president Rajiv Malik said they have a history of partnering with Gilead to tackle key public health issues in India and around the world, beginning with expanding access to high quality and affordable HIV/AIDS antiretrovirals.

“We are proud to continue our work together with the launch of Sovaldi as it supports our joint commitment to meeting the unmet medical needs of patients in India,” Malik said.

Gregg Alton, Executive Vice-President, Corporate and Medical Affairs, Gilead Sciences said it makes an important milestone in the company’s ongoing effort to make its hepatitis-C medicines accessible to as many patients, in as many places, as quickly as possible.Sovaldi is sold by Mylan’s dedicated sales force as part of its Hepato Care segment.

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What is 35 U.S. Code § 112 – Specification, ………..it is so easy to understand, try

PATENTS, regulatory Comments Off

Feb 032015

U.S. Code› Title 35 › Part II › Chapter 11 › § 112………more explanation see below

Law is easy, …. learn with me and explained by cornell

I picked this up from site………..http://www.law.cornell.edu/uscode/text

Cock can teach you

thanks to cornell

Cornell law school

http://www.law.cornell.edu/uscode/text

U.S. Code: Table of Contents U.S. Code›

U.S. Code: Title 35 – PATENTS Title 35 ›

35 U.S. Code Part II – PATENTABILITY OF INVENTIONS AND GRANT OF PATENTS Part II ›

35 U.S. Code Chapter 11 – APPLICATION FOR PATENT Chapter 11 ›

§ 112. specification explained in this article

http://www.uspto.gov/web/offices/pac/mpep/mpep-9015-appx-l.html

(a) In General.— The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

(b) Conclusion.— The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.

(c) Form.— A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.

(d) Reference in Dependent Forms.— Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

(e) Reference in Multiple Dependent Form.— A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.

(f) Element in Claim for a Combination.— An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

35 U.S.C. 112 Specification.

[Editor Note: Applicable to any patent application filed on or after September 16, 2012. See 35 U.S.C. 112 (pre-AIA)for the law otherwise applicable.]

(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
(c) FORM.—A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(e) REFERENCE IN MULTIPLE DEPENDENT FORM.—A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.
(f) ELEMENT IN CLAIM FOR A COMBINATION.—An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

(Amended July 24, 1965, Public Law 89-83, sec. 9, 79 Stat. 261; Nov. 14, 1975, Public Law 94-131, sec. 7, 89 Stat. 691; amended Sept. 16, 2011, Public Law 112-29, sec. 4(c), 125 Stat. 284, effective Sept. 16, 2012.)

35 U.S.C. 112 (pre-AIA) Specification.

[Editor Note: Not applicable to any patent application filed on or after September 16, 2012. See 35 U.S.C. 112 for the law otherwise applicable.]

The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.

A claim may be written in independent or, if the nature of the case admits, in dependent or multiple dependent form.

Subject to the following paragraph, a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.

A claim in multiple dependent form shall contain a reference, in the alternative only, to more than one claim previously set forth and then specify a further limitation of the subject matter claimed. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of the particular claim in relation to which it is being considered.

An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.

(Amended July 24, 1965, Public Law 89-83, sec. 9, 79 Stat. 261; Nov. 14, 1975, Public Law 94-131, sec. 7, 89 Stat. 691.)

SO EASY TO UNDERSTAND 35 U.S.C. § 112

Cornell law school

Cornell seal beneath the tower of Myron Taylor Hall

Interior of Cornell Law School quad

View of Cornell Law School from Central Avenue

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The Cornell Law Library is one of 12 national depositories for print records of briefs filed with the U.S. Supreme Court.

Entrance to Myron Taylor Hall, Cornell Law’s principal building for instruction

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Ithaca
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LEARN A CASE STUDY WITH DR ANTHONY, SO EASY TO UNDERSTAND 35 U.S.C. § 112

case study on this

The Attack of 35 U.S.C. § 112

http://www.google.com/patents/US8598219

September 2, 2014, Accord Healthcare, Inc. (“Accord”) filed what appears to be the second-ever Post-Grant Review (“PGR”) (see Petition). This PGR was for U.S. Patent No. 8,598,219 (“the ‘219 Patent”), which is jointly assigned to Helsinn Healthcare S.A. and Roche Palo Alto, LLC (collectively “Helsinn”).

Helsinn Healthcare Sa, Roche Palo Alto Llc

As a reminder, PGRs are the third type of post-issuance review procedures established by the America Invents Act (“AIA”) — the other two being Inter Partes Review and Covered Business Method Patent Review (IPR and CBM, for short). However, the reason that only one other PGR has been filed to date is because this type of proceeding only applies to patents that were examined pursuant to the new First Inventor to File scheme established by the AIA.

And because such applications could only be filed on or after March 16, 2013, there are only a limited number of such patents that are presently eligible for PGR. One of the other significant differences between IPRs and PGRs is that the latter is not limited to certain types of prior art validity attacks (such as 102 or 103), but instead any type of validity challenge available in District Court is essentially available in front of the Patent Trial and Appeals Board (“PTAB”).

This includes attacks under 35 U.S.C. § 112, such as allegations of a lack of enablement, a lack of written description, and a failure to distinctly claim the invention. Accord took full advantage of this in its petition for PGR2014-00010, in which Accord alleged that Helsinn’s patent related to liquid pharmaceutical formulations of palonosetron should not have been issued by the Patent Office.

Accord Healthcare

The ‘219 patent had been asserted in several Hatch-Waxman litigations involving ALOXI®, which is a palonosetron formulation indicated to help prevent nausea and vomiting following chemotherapy. Palonosetron hydrochloride, the active pharmaceutical ingredient, has the following structural formula:

The ‘219 patent is a member of a family of patents directed to formulations of palonosetron hydrochloride. Importantly, this patent was filed as a continuation-in-part application on May 23, 2013, with a letter that asserted that claim 9 only had support because of a newly added example, and therefore was subject to the AIA. Only claims 1-5 and 8 of the ‘219 patent are the subject of this petition, with claim 1 reading:

1. A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:
palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;
from 0.005 mg/mL to 1.0 mg/mL EDTA;
and from 10 mg/mL to 80 mg/mL mannitol,
wherein said formulation is stable at 24 months when stored at room temperature.

Claim 8 is the only other challenged independent claim, and it reads identically, except for a stability limitation of 18 months when stored at room temperature. This patent issued on December 3, 2013, and the PGR petition was filed within the requisite nine months.

CLAIMS(8)………..http://www.google.com/patents/US8598219

What is claimed is:

palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;

from 0.005 mg/mL to 1.0 mg/mL EDTA; and

from 10 mg/mL to 80 mg/mL mannitol,

wherein said formulation is stable at 24 months when stored at room temperature.

2. The pharmaceutical formulation of claim 1, wherein said EDTA is in an amount of 0.5 mg/mL.

3. The pharmaceutical formulation of claim 1, wherein said mannitol is in an amount of 41.5 mg/mL.

4. The pharmaceutical formulation of claim 1, wherein said solution further comprises a citrate buffer.

5. The pharmaceutical formulation of claim 4, wherein said citrate buffer is at a concentration of 20 millimolar.

6. The pharmaceutical formulation of claim 1, wherein said solution is buffered at a pH of 5.0 ±0.5.

7. The pharmaceutical formulation of claim 1, wherein said EDTA is in an amount of 0.5 mg/mL, wherein said mannitol is in an amount of 41.5 mg/mL, wherein said solution further comprises a citrate buffer at a concentration of 20 millimolar, and wherein said solution is buffered at a pH of 5.0 ±0.5.

8. A pharmaceutical single-use, unit-dose formulation for intravenous administration to a human to reduce the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising a 5 mL sterile aqueous isotonic solution, said solution comprising:

palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its free base;

from 0.005 mg/mL to 1.0 mg/mL EDTA; and

from 10 mg/mL to 80 mg/mL mannitol, wherein said formulation is stable at 18 months when stored at room temperature.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

The petition pointed out that during the prosecution of the ‘219 patent and its family, the Patent Office had rejected the claimed formulations as obvious. In response, the applicants submitted a declaration from inventor Daniele Bonadeo (“the Bonadeo declaration”) and argued that one of skill in the art would not have combined the features of the invention as a matter of routine optimization. Instead of routine, the applicants continued, the claimed formulations were obtained after a sequence of experiments, each of which built upon the others like building blocks.

If the experimental sequence had varied, the applicants alleged that they would have obtained a different formulation. The Bonadeo declaration explained that the first two parameters studied were palonosetron concentration and pH. None of the studies described in this declaration, however, occurred at a pH other than 5.0, which makes sense because palonosetron was described as extremely stable at this pH.

Considering that the ‘219 patent ultimately issued, the applicants were apparently successful in overcoming these obviousness rejections. In other words, the applicants convinced the examiner that a person of ordinary skill in the art would not have found it obvious to combine the teachings in the prior art to derived the claimed inventions.

The positions taken by the applicant, however, were utilized by the petitioner, Accord, to allege that a person of ordinary skill in the art would not have, for example, found the specification enabling. This highlights the problem that PGRs pose for patent applicants. Before such procedure, arguments could be made without much fear that they would be coopted by the Office for making alternative rejections. And, if the Office did, there would still an opportunity to provide a response or amend the claims. Even if such arguments were made in district court litigation, the patent would at least enjoy a presumption of validity.

Now, all applicants must take extreme caution in making any arguments, because anything said can (and probably will) be used against them at the PTAB.

What follows is an identification of the 35 U.S.C. § 112 arguments made by Accord. Considering that the patent owner has not yet filed any response, and the PTAB has not weighed in, no position is taken here as to the merits of these arguments.

Written Description – Stability

Accord first alleged that the ‘219 was unpatentable for failing to provide an adequate description of the claimed subject matter being stable at 18 or 24 months when stored at room temperature, as required by 35 U.S.C. § 112(a). Specifically, the petition asserted that the specification does not show that the inventors were in possession of any formulation that would have achieved the stability limitations of the claims.

Instead, the argument went, the patent contained general statements that it is possible to increase the stability of the formulations, but did not provide any examples with stability beyond a couple of weeks. Accord included a declaration from Dr. Arnold J. Repta, which explained how a person of ordinary skill in the art would have understood the teaching of the specification. However, Dr. Repta did not include any additional testing of the formulations taught in the application in his declaration.

Enablement

The second assertion made in the petition was that the ‘219 patent does not enable a pH range for the claimed formation outside of about 4.0 to 6.0, and therefore it is not enabled as required by 35 U.S.C. § 112(a). This is because, according the petition, the only relevant formulation in the specification was disclosed as having a pH of 5.0±0.5. Moreover, the specification was alleged to claim that palonosetron is most stable at pH 5.0.

Accord also cited to the Bonadeo Declaration, which was submitted during prosecution by the applicants, which alleged claimed that palonosetron formulations containing mannitol or EDTA required a pH of 4-6. Therefore, according to the petition, because the challenged claims do not recite any pH limitations, they were broader than the teaching of the specification.

“Regards as the Invention”

35 U.S.C § 112(b) requires that a patent “conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.” Accord challenged the claims of the ‘219 patent as not including the invention as regarded by the inventors. Specifically, the petition alleges that the Bonadeo Declaration made clear that palonosetron was extremely stable at a pH of 5.0, and that there was no hint that a pH outside of the range of about 4.0 or 6.0 would be suitable. A similar argument was made about the language found in the specification. The petitioner concluded by pointing out that, even though the inventors believed that the inventive formation should be in a range of 4.0 to 6.0, such a limitation was not included in the claims.

Written Description – pH Range

Finally, Accord made a similar argument when alleging that the specification did not support claims that did not include a pH range of 4.0 to 6.0. Citing to the Gentry Gallery, Inc. v. Berkline Corp., 134 F.3d 1473 (Fed. Cir. 1998), line of cases, the petitioner alleged that the pH range was an essential or critical feature which was omitted from that claims. In other words, Accord alleged that the broad claims without a pH limitation were invalid because the “entirety of the specification” demonstrates that the invention was of much narrower scope.

Of course, similar to an IPR, the patent owner now has a chance to submit a preliminary response to the petition. The standard used for instituting a PGR differs from that required for an IPR. Instead of the “reasonable likelihood” standard, a PGR will only be instituted when it is more likely than not that at least one of the claims challenged is unpatentable. In essence, this should be a slightly more stringent standard, because with both positions being equally likely, an IPR petition would have a reasonable likelihood of demonstrating claims as unpatentable, but a PGR petition would not be more likely than not to demonstrate unpatentable claims.

However, it remains to be seen if less PGRs are instituted than IPRs. We will continue to monitor PGR2014-00010, and provide updates as warranted.

SO EASY TO UNDERSTAND 35 U.S.C. § 112

TRIPS Agreement

PATENTS, Uncategorized Comments Off

Jan 232015

WTO members (where the TRIPS agreement applies)

Parties to the Agreement where also the membership of the European Union applies

“TRIPS” redirects here. For the microprocessor, see TRIPS architecture. For the German racing driver, see Wolfgang von Trips. For other uses, see Trip.

TRIPS Agreement
Annex 1C to the Agreement establishing the World Trade Organization
Agreement on Trade-Related Aspects of Intellectual Property Rights
WTO members (where the TRIPS agreement applies) Parties to the Agreement where also the membership of the European Union applies
Type	Annex to the Agreement establishing the World Trade Organization
Effective	1 January 1996
Parties	158 (All WTO members)^[1]
Languages	English, French and Spanish
Agreement on Trade-Related Aspects of Intellectual Property Rights at Wikisource

The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) is an international agreement administered by the World Trade Organization (WTO) that sets down minimum standards for many forms of intellectual property (IP) regulation as applied to nationals of other WTO Members.^[2] It was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994.

The TRIPS agreement introduced intellectual property law into the international trading system for the first time and remains the most comprehensive international agreement on intellectual property to date. In 2001, developing countries, concerned that developed countries were insisting on an overly narrow reading of TRIPS, initiated a round of talks that resulted in the Doha Declaration. The Doha declaration is a WTO statement that clarifies the scope of TRIPS, stating for example that TRIPS can and should be interpreted in light of the goal “to promote access to medicines for all.”

Specifically, TRIPS requires WTO members to provide copyright rights, covering content producers including performers, producers of sound recordings and broadcasting organizations; geographical indications, including appellations of origin; industrial designs;integrated circuit layout-designs; patents; new plant varieties; trademarks; trade dress; and undisclosed or confidential information. TRIPS also specifies enforcement procedures, remedies, and dispute resolution procedures. Protection and enforcement of all intellectual property rights shall meet the objectives to contribute to the promotion of technological innovation and to the transfer and dissemination of technology, to the mutual advantage of producers and users of technological knowledge and in a manner conducive to social and economic welfare, and to a balance of rights and obligations.

Background and history

TRIPS was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994. Its inclusion was the culmination of a program of intenselobbying by the United States, supported by the European Union, Japan and other developed nations. Campaigns of unilateral economic encouragement under the Generalized System of Preferences and coercion under Section 301 of the Trade Act played an important role in defeating competing policy positions that were favored by developing countries, most notably Korea and Brazil, but also including Thailand, India and Caribbean Basin states. In turn, the United States strategy of linking trade policy to intellectual property standards can be traced back to the entrepreneurship of senior management at Pfizer in the early 1980s, who mobilized corporations in the United States and made maximizing intellectual property privileges the number one priority of trade policy in the United States (Braithwaite and Drahos, 2000, Chapter 7).

After the Uruguay round, the GATT became the basis for the establishment of the World Trade Organization. Because ratification of TRIPS is a compulsory requirement of World Trade Organization membership, any country seeking to obtain easy access to the numerous international markets opened by the World Trade Organization must enact the strict intellectual property laws mandated by TRIPS. For this reason, TRIPS is the most important multilateral instrument for the globalization of intellectual property laws. States like Russia and China ^[3] that were very unlikely to join the Berne Convention have found the prospect of WTO membership a powerful enticement.

Furthermore, unlike other agreements on intellectual property, TRIPS has a powerful enforcement mechanism. States can be disciplined through the WTO’s dispute settlementmechanism.

The requirements of TRIPS

TRIPS requires member states to provide strong protection for intellectual property rights. For example, under TRIPS:

Copyright terms must extend at least 20 years, unless based on the life of the author. (Art. 12 and 14)^[4]^{[not in citation given]}
Copyright must be granted automatically, and not based upon any “formality,” such as registrations, as specified in the Berne Convention. (Art. 9)
Computer programs must be regarded as “literary works” under copyright law and receive the same terms of protection.
National exceptions to copyright (such as “fair use” in the United States) are constrained by the Berne three-step test
Patents must be granted for “inventions” in all “fields of technology” provided they meet all other patentability requirements (although exceptions for certain public interests are allowed (Art. 27.2 and 27.3)^[5] and must be enforceable for at least 20 years (Art 33).
Exceptions to exclusive rights must be limited, provided that a normal exploitation of the work (Art. 13) and normal exploitation of the patent (Art 30) is not in conflict.
No unreasonable prejudice to the legitimate interests of the right holders of computer programs and patents is allowed.
Legitimate interests of third parties have to be taken into account by patent rights (Art 30).
In each state, intellectual property laws may not offer any benefits to local citizens which are not available to citizens of other TRIPS signatories under the principle of national treatment (with certain limited exceptions, Art. 3 and 5).^[6] TRIPS also has a most favored nation clause.

Many of the TRIPS provisions on copyright were copied from the Berne Convention for the Protection of Literary and Artistic Works and many of its trademark and patent provisions were modeled on the Paris Convention for the Protection of Industrial Property.

Access to essential medicines[

The most visible conflict has been over AIDS drugs in Africa. Despite the role that patents have played in maintaining higher drug costs for public health programs across Africa, this controversy has not led to a revision of TRIPs. Instead, an interpretive statement, the Doha Declaration, was issued in November 2001, which indicated that TRIPs should not prevent states from dealing with public health crises. After Doha, PhRMA, the United States and to a lesser extent other developed nations began working to minimize the effect of the declaration.^[7]

A 2003 agreement loosened the domestic market requirement, and allows developing countries to export to other countries where there is a national health problem as long as drugs exported are not part of a commercial or industrial policy.^[8] Drugs exported under such a regime may be packaged or colored differently in order to prevent them from prejudicing markets in the developed world.

In 2003, the Bush administration also changed its position, concluding that generic treatments might in fact be a component of an effective strategy to combat HIV. Bush created the PEPFAR program, which received $15 billion from 2003–2007, and was reauthorized in 2008 for $48 billion over the next five years. Despite wavering on the issue ofcompulsory licensing, PEPFAR began to distribute generic drugs in 2004-5.

Software and business method patents

Main article: Software patents under TRIPs Agreement

Another controversy has been over the TRIPS Article 27 requirements for patentability “in all fields of technology”, and whether or not this necessitates the granting of softwareand business method patents.

Implementation in developing countries

The obligations under TRIPS apply equally to all member states, however developing countries were allowed extra time to implement the applicable changes to their national laws, in two tiers of transition according to their level of development. The transition period for developing countries expired in 2005. The transition period for least developed countries to implement TRIPS was extended to 2013, and until 1 January 2016 for pharmaceutical patents, with the possibility of further extension.^[9]

It has therefore been argued that the TRIPS standard of requiring all countries to create strict intellectual property systems will be detrimental to poorer countries’ development.^[10] Many argue^[who?] that it is, prima facie, in the strategic interest of most if not all underdeveloped nations to use the flexibility available in TRIPS to legislate the weakest IP laws possible.^[11]

This has not happened in most cases. A 2005 report by the WHO found that many developing countries have not incorporated TRIPS flexibilities (compulsory licensing, parallel importation, limits on data protection, use of broad research and other exceptions to patentability, etc.) into their legislation to the extent authorized under Doha.^[12]

This is likely caused by the lack of legal and technical expertise needed to draft legislation that implements flexibilities, which has often led to developing countries directly copying developed country IP legislation,^[13] or relying on technical assistance from the World Intellectual Property Organization (WIPO), which, according to critics such as Cory Doctorow, encourages them to implement stronger intellectual property monopolies.

Banerjee and Nayak^[14] shows that TRIPS has a positive effect on R&D expenditure of Indian pharmaceutical firms.

Post-TRIPS expansion

The neutrality of this article is disputed. Relevant discussion may be found on the talk page. Please do not remove this message until the dispute is resolved. (May 2011)

In addition to the baseline intellectual property standards created by the TRIPS agreement, many nations have engaged in bilateral agreements to adopt a higher standard of protection. These collection of standards, known as TRIPS+ or TRIPS-Plus, can take many forms.^[15] General objectives of these agreements include:

The creation of anti-circumvention laws to protect Digital Rights Management systems. This was achieved through the 1996 World Intellectual Property Organization Copyright Treaty (WIPO Treaty) and the WIPO Performances and Phonograms Treaty.
More stringent restrictions on compulsory licenses for patents.
More aggressive patent enforcement. This effort has been observed more broadly in proposals for WIPO and European Union rules on intellectual property enforcement. The 2001 EU Copyright Directive was to implement the 1996 WIPO Copyright Treaty.
The campaign for the creation of a WIPO Broadcasting Treaty that would give broadcasters (and possibly webcasters) exclusive rights over the copies of works they have distributed.

Panel reports

According to WTO 10th Anniversary, Highlights of the first decade, Annual Report 2005 page 142,^[16] in the first ten years, 25 complaints have been lodged leading to the panel reports and appellate body reports on TRIPS listed below.

The WTO website has a gateway to all TRIPS disputes (including those that did not lead to panel reports) here [1].

2005 Panel Report:^[17]
- European Communities – Protection of Trademarks and Geographical Indications for Agricultural Products and Foodstuffs.
2000 Panel Report:^[18] Part 2^[19] and 2000 Appellate Body Report^[20]
- Canada – Term of Patent Protection.
2000 Panel Report, Part 1:^[21] and Part 2^[22]
- United States – Section 110(5) of the US Copyright Act.
2000 Panel Report:^[23]
- Canada – Patent Protection of Pharmaceutical Products.
2001 Panel Report:^[24] and 2002 Appellate Body Report^[25]
- United States – Section 211 Omnibus Appropriations Act of 1998.
1998 Panel Report:^[26]
- India – Patent Protection for Pharmaceutical and Agricultural Chemical Products.
1998 Panel Report:^[27]
- Indonesia – Certain Measures Affecting the Automobile Industry.

Criticism

Since TRIPS came into force it has received a growing level of criticism from developing countries, academics, and non-governmental organizations. Some of this criticism is against the WTO as a whole, but many advocates of trade liberalization also regard TRIPS as bad policy. TRIPS’s wealth concentration effects (moving money from people in developing countries to copyright and patent owners in developed countries) and its imposition of artificial scarcity on the citizens of countries that would otherwise have had weaker intellectual property laws, are common bases for such criticisms.

Peter Drahos writes that “It was an accepted part of international commercial morality that states would design domestic intellectual property law to suit their own economic circumstances. States made sure that existing international intellectual property agreements gave them plenty of latitude to do so.”^[28]

Daniele Archibugi and Andrea Filippetti^[29] argue that the importance of TRIPS in the process of generation and diffusion of knowledge and innovation has been overestimated by both their supporters and their detractors. Claude Henry and Joseph E. Stiglitz^[30] argue that the current intellectual property global regime may impede both innovation and dissemination, and suggest reforms to foster the global dissemination of innovation and sustainable development.

References

Jump up^ “WTO TRIPS implementation”. International Intellectual Property Alliance. Retrieved22 May 2012.
Jump up^ See TRIPS Art. 1(3).
Jump up^ Farah, Paolo Davide & Cima, Elena (2010) ‘SSRN.com China’s Participation in the World Trade Organization: Trade in Goods, Services, Intellectual Property Rights and Transparency Issues” in Aurelio Lopez-Tarruella Martinez (ed.), El comercio con China. Oportunidades empresariales, incertidumbres jurídicas, Tirant lo Blanch, Valencia (Spain) 2010, pp. 85–121. ISBN 978-84-8456-981-7.
Jump up^ “intellectual property (TRIPS) – agreement text – standards”. WTO. 1994-04-15. Retrieved 2012-04-16.
Jump up^ World Trade Organization, “Part II — Standards concerning the availability, scope and use of Intellectual Property Rights; Sections 5 and 6”, Agreement on Trade-Related Aspects of Intellectual Property Rights
Jump up^ World Trade Organization, “Part I — General Provisions and Basic Principles”,Agreement on Trade-Related Aspects of Intellectual Property Rights
Jump up^ cf. Timmermann, Cristian, and Henk van den Belt. 2013. Intellectual property and global health: from corporate social responsibility to the access to knowledge movement. Liverpool Law Review 34 (1):47-73. also available at http://edepot.wur.nl/252885
Jump up^ World Trade Organization (1 September 2003), Implementation of paragraph 6 of the Doha Declaration on the TRIPS Agreement and public health
Jump up^ World Trade Organisation, IP – http://www.wto.org/english/tratop_e/trips_e/tripfq_e.htm
Jump up^ IP Justice policy paper for the WIPO development agenda, IP Justice
Jump up^ Trade and Health. McGill-Queen’s University Press. 2007. p. 33. |first1= missing|last1= in Authors list (help)
Jump up^ Musungu, Sisule F.; Oh, Cecilia (August 2005), The use of flexibilities in TRIPS by developing countries: can they promote access to medicines?, Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH)
Jump up^ Finger, J. Michael (2000). “The WTO’s special burden on less developed countries”(PDF). Cato Journal 19 (3).
Jump up^ Banerjee and Nayak, Effects of Trade Related Intellectual Property Rights on the R&D Expenditure of Indian Pharmaceutical Industry,2014 ‘Journal of Pharmaceutical Health Services Research.
Jump up^http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195390124.001.0001/acprof-9780195390124-chapter-8
Jump up^ World Trade Organization (2005). “Annual Report 2005”.
Jump up^ “2005 News items – Panel reports out on geographical indications disputes”. WTO. 2005-03-15. Retrieved 2012-04-16.
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/1391da.pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/1391db.pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/170abr_e.pdf
Jump up^ http://www.wto.org/english/news_e/news00_e/1234da.pdf
Jump up^ http://www.wto.org/english/news_e/news00_e/1234db.pdf
Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/canada-pharmaceuticals(panel)(full).pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/176r_e.pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/176abr_e.pdf
Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/india-patents(panel)(ec)(full).pdf
Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/indonesia-autos(panel)(full).pdf
Jump up^ Drahos with Braithwaite, Information Feudalism, New Press 2002, p38
Jump up^ Archibugi, D. and Filippetti, A. (2010) ‘The globalization of intellectual property rights: Four learned lessons and four thesis‘, Journal of Global Policy, 1: 137-49.
Jump up^ Henry, C. and Stiglitz, J. (2010) ‘Intellectual Property, Dissemination of Innovation and Sustainable Development‘, Journal of Global Policy, 1: 237-51.

Source

Braithwaite and Drahos, Global Business Regulation, Cambridge University Press, 2000
Westkamp, ‘TRIPS Principles, Reciprocity and the Creation of Sui-Generis-Type Intellectual Property Rights for New Forms of Technology’ [2003] 6(6) The Journal of World Intellectual Property 827-859, ISSN: 1422-2213
Banerjee and Nayak, ‘Effects of trade related intellectual property rights on the research and development expenditure of Indian pharmaceutical industry’ [2014] 5 Journal of Pharmaceutical Health Services Research 89-94.

External links

TRIPS agreement (PDF version)
Agreement on Trade-Related Aspects of Intellectual Property Rights (html version)
World Trade Organization links
- World Trade Organization – Official Text
- World Trade Organization – TRIPs gateway
Audio presentation by Professor Susan Sell, George Washington University, on intellectual property rights in the global context.
WTO TRIPS Agreement profile on database of Market Governance Mechanisms

The Korean Intellectual Property Office (KIPO) is the patent office and intellectual property office of South Korea. In 2000, the name of the office was changed from “Korean Industrial Property Office” to “Korean Intellectual Property Office”.^[1] It is located in Daejeon Metropolitan City.^[2]