New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd, Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467

Tedizolid phosphate

Suzhou MiracPharma Technology Co Ltd; Zheren Pharmaceutical Nanjing Co Ltd

WO-2016058467   click for patent

SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1 Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN).
ZHEREN PHARMACEUTICAL NANJING CO., LTD [CN/CN]; Qiaolin Industry Park 32-71, Pukou District Nanjing, Jiangsu 211806 (CN)

Disclosed is a method for preparing tedizolid phosphate (I), and the preparation step thereof comprises producing the tedizolid phosphate (I) by means of a coupling reaction of a compound of formula II and a compound of formula III. The preparation method uses easily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.

Process for preparing tedizolid phosphate (TD-P), useful for treating bacterial infection. The present filing represents the first PCT and first filing to be seen from Suzhou Miracpharma and Zheren Pharmaceutical, respectively, that focuses on tedizolid; however this case was first seen as a Chinese national filing (assigned to Suzhou Miracpharma), published in February 2015. The drug was developed and launched by Dong-A ST and licensees Cubist Pharmaceuticals and Bayer, for treating acute bacterial skin and skin structure infections.

Tedizolid phosphate by Charpy Manchester (Cubist) pharmaceutical companies to develop a oxazolidinone antibiotics. Tedizolid phosphate in June 2014 to obtain FDA approval in the United States, the trade name Sivextro. The drug was first approved by the FDA in the second generation oxazolidinone antibiotics, and linezolid compared to the previous generation, Sivextro some bacteria in vitro inhibitory activity 2-8 times higher security to a certain extent also improved. Because compound Tedizolid not have standard Chinese translation, so the applicant where it is transliterated as "Thai to acetazolamide."

Thailand phosphate to acetazolamide (Tedizolid phosphate) Chemical name: {(5R) -3- [3- fluoro-4- [6- (2-methyl--2H- tetrazol -5-yl) pyridine-3 yl] phenyl] -2-oxazolone -5-yl} methanol phosphate (I), having the formula:

Preparation of phosphate Thailand to acetazolamide has been reported, PCT Patent No. WO2005058886, No. WO2010042887 and "European Journal of Medicinal Chemistry" 2011 on 1027 - 1039 Section 46 were reported to temozolomide and phosphate Thai analog synthesis and related intermediates. Comparative summary of these methods, which are synthetic route from Intermediate A and Intermediate B (or intermediate B ') by an aryl coupling reaction to achieve.

Wherein 2- (2-methyl-tetrazol-5-yl) -5-bromopyridine (Intermediate A) is generated by a tetrazolium derivative azide reaction of 2-cyano-5-bromopyridine, and then the use of methyl iodide or dimethyl sulfate, etc. methylating reagent for tetrazole ring methylation reaction, to give 2- (2-methyl-tetrazol-5-yl) -5-bromopyridine (intermediate A ) and (1-methyl-tetrazol-5-yl) -5-bromo pyridine (by-product) in a mixture of 2, by column chromatography or recrystallization to give the intermediate separator A.

Intermediate B or B 'by R-3- (3- fluoro-4-iodo-phenyl) -2-oxo-5-oxazolidinyl methanol formed organoboron reagent or an organotin reagent, the reagent is Stille or Suzuki coupling reactions, realize intermediate a coupling.

This shows that the existing preparation method has the steps for preparing long, difficult to obtain raw materials and high costs weaknesses; preparation and use of organotins on equipment and environmental requirements are high, there is environmental pollution risks. In addition, intermediate B or B 'structure halogens fluorine and iodine exist, reducing the selective formation of organometallic reagents, so that an increase in side effects, product quality is difficult to be effectively controlled.

Example One:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid (II) (2.15g, 10.5mmol) , R-3- (3- fluoro - 4-iodo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (4.17g, 10mmol) , tetrakis (triphenylphosphine) palladium (0.23g, 0.2mmol), 1M phosphoric acid 15mL of toluene solution of potassium 30mL, warmed to reflux, maintained the reaction at reflux for 10-12 hours, TLC the reaction was complete. Ethyl acetate was added 30mL, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized, and dried in vacuo to give a white The solid phosphoric acid to Thailand acetazolamide (I) 3.82g, yield% 84.9, ¹ the H NMR (of DMSO-d6): D 8.92 (S, IH), 8.20 (m, 2H), 7.74 (T, IH), 7.66 ( dd, 1H), 7.50 (dd , 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (m, 1H), FAB-MS m / Z: 451 [the m the H +] ⁺ .

 

Example Two:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester (II) (3.01g, 10.5mmol), R-3- (3 - fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (3.69g, 10mmol), [1,1'- bis (diphenylphosphino) ferrocene Fe] dichloropalladium / dichloromethane complex (0.15g, 0.2mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 50mL, heated to 110 ℃, the reaction was stirred for 4-5 hours , TLC the reaction was complete. Ethyl acetate was added 50mL, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized, and dried in vacuo to give a white Thai solid phosphoric acid to acetazolamide (I) 4.02g, yield 89.3%.

Example Three:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) -5-bromo - pyridine (IV) (2.4g, 10mmol), alcohol-based dual which diborane ( 1.27g, 5mmol), 1,1'- bis (diphenylphosphino) ferrocene palladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 30mL , heated to 110 deg.] C, the reaction was stirred for 4 hours. Cooled to room temperature, still under nitrogen, was added to the system for R-3- (3- fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (3.69 g, 10mmol), 1,4- dioxane and 20mL 5M potassium phosphate 0.5mL, again heated to 100 ℃, the reaction was stirred for 4 hours, TLC the reaction was complete. Ethyl acetate was added 50mL, filtered and the filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized vacuo Thai dried to give a white solid phosphoric acid to acetazolamide (I) 3.34g, yield 74.2%.

IV (Preparation of the intermediate II) Example:

In a three-necked reaction flask 2- (2-methyl-tetrazol-5-yl) -5-bromo - pyridine (IV) (2.4g, 10mmol) was dissolved in 25mL anhydrous tetrahydrofuran, cooled to -55 deg.] C, was added dropwise isopropylmagnesium chloride (1M, 15ml), dropwise after completion of the reaction was stirred for 30 minutes. To the reaction system was added trimethylborate (1.25g, 12mmol), stirring was continued for 4-5 hours the reaction. At low temperature with saturated ammonium chloride solution to quench the reaction, and the reaction solution was poured into dilute hydrochloric acid and 30mL 1N reaction at room temperature for 1 hour. Extracted three times with ethyl acetate, the combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the resulting solid is washed with petroleum ether, and then recrystallized from water to give a white solid of 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid (II) 1.6g, 78.0% yield, m the MS-FAB / Z: 206 [the m the H +] ⁺ .

Embodiment 5 (preparation of intermediate II):

In a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) -5-bromo - pyridine (IV) (2.4g, 10mmol) , alcohol-based dual which diborane (1.27g, 5mmol ), 1,1'-bis (diphenylphosphino) ferrocene palladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 50mL, heated to 110 ℃, the reaction was stirred for 8-10 hours to complete the reaction by TLC. Extracted three times with ethyl acetate, the combined organic phases were washed with brine, dried over anhydrous sodium sulfate. Concentrated, ethyl acetate and n-hexane (1:4) recrystallized to give an off-white solid 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester (II) 2.48g, yield 86.4 %, the MS-FAB m / Z: 288 [the m the H +] ⁺ .

Six (preparation of intermediate III) Example:

Under nitrogen, in a three-necked reaction flask R- glycidyl tosylate (TG) (2.28g, 10mmol) and N, N- dimethylformamide 25mL, stirred and dissolved, was added cesium carbonate (0.33 g, 1mmol) and 3-fluoro-4-bromo - phenyl isocyanate (V) (2.15g, 10mmol) , was heated to 100 ℃, after 1 hour, TLC detection completion of the reaction. Recovery of the solvent under reduced pressure, the residue was dissolved with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted twice with methylene chloride, concentrated under reduced pressure to give an oil which was R-3- (3- fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol p-toluenesulfonate (the VI), without further purification, 1N hydrochloric acid was added directly to the reaction at 50 ℃ 5 hours and extracted three times with dichloromethane The combined organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 30mL of triethyl phosphate was added at room temperature, phosphorus oxychloride (2.2mL, 24mmol), stirred for 2-3 hours. 30mL of ethyl acetate was added, stirred for half an hour, poured into 50g of ice-water, and stirring was continued for 2 hours at 0 deg.] C, and a solid white precipitate was filtered, the filter cake washed with acetone and dried to give an off-white solid R-3- (3-fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) 2.45g, yield 66.4%, FAB-MS m / z: 369 [m + H ] ⁺ .

Six (preparation of intermediate III) Example:

 

Under nitrogen, in a three-necked reaction flask R- glycidyl tosylate (TG) (2.28g, 10mmol) and tetrahydrofuran 50mL, stirred and dissolved, was added lithium iodide (0.14g, 1mmol) and 3- fluoro-4 - phenyl isocyanate (V) (2.63g, 10mmol) , was heated to reflux. after 2 hours, TLC detection completion of the reaction. Recovery of the solvent under reduced pressure, the residue was dissolved with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted twice with methylene chloride, concentrated under reduced pressure to give an oil which was R-3- (3- fluoro-4 - phenyl) -2-oxo-5-oxazolidinyl methanol p-toluenesulfonate (the VI), without further purification, 1N hydrochloric acid was added directly to the reaction at 50 ℃ 5 hours and extracted three times with dichloromethane The combined organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 30mL of triethyl phosphate was added at room temperature, phosphorus oxychloride (2.2mL, 24mmol), stirred for 2-3 hours. 30mL of ethyl acetate was added, stirred for half an hour, poured into 50g of ice-water, and stirring was continued for 2 hours at 0 deg.] C, and a solid white precipitate was filtered, the filter cake washed with acetone and dried to give an off-white solid R-3- (3-fluoro-4-iodo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) 2.65g, yield 63.7%, FAB-MS m / z: 417 [m + H ] ⁺ .

 

//////New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd,  Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467

NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE

WO2016055918) NOVEL STABLE POLYMORPHS OF ISAVUCONAZOLE OR ITS SALT THEREOF

WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)

KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

The present invention relates to novel stable novel stable polymorphs of Isavuconazole or its salt thereof, having purity more than 90 % when measured by HPLC. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5-difluoro- phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol.

Isavuconazole, Isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.

The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-l -(lH-l,2,4-triazol-l-yl)-2-(2,5-difluorophenyl)43utan-2-ol; and has the structural formula I:

Formula I

The '353 described the process for the preparation Isavuconazole, involve the use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol (referred herein after "diol base") in an oil form, which is difficult to isolate and purify. The use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base, without purification, reflects the purity of Isavuconazole and Isavuconazonium sulfate. However, the reported process not feasible industrially.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for preparation of Isavuconazole or its salt thereof in enhanced yield as well as purity. In a particular present invention directs to novel stable polymorphs of Isavuconazole or its salt thereof.

Examples

Example-1: Preparation of Amorphous Isavuconazole

In a round bottomed flask charged ethanol (250 ml), thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 °C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product.

Yield: 26.5 gm

HPLC purity: 92.7%

Example-2: Preparation of crystalline Isavuconazole Base

Charged methylene dichloride (250 ml) and 25.0 gm Isavuconazole Hydrobromide compound of formula-II into 1.0 L flask and stirred. Added aqueous solution of sodium bi carbonate in to the reaction mass to obtained clear solution. The layers were separated and organic layer was washed with dilute hydrochloric acid solution followed by saturated solution of sodium chloride. Finally, Organic layer was concentrated under vacuum to get titled product.

Yield: 18.5 gm

HPLC Purity: 97%

Example-3: Preparation of crystalline Isavuconazole Hydrobromide

Charged isopropanol alcohol (250 ml) followed by thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) into 1.0 L flask. The reaction mixture was stirred and heated to 50 C, after completion of reaction the precipitated material was filtered and washed with isopropanol alcohol (25 ml). The wet cake is dried under vacuum for 4-5 hrs at 40 C to obtain off-white solid product.

Yield: 26.5 gm

HPLC Purity: 97.3%

Exaniple-4: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Dissolved crude 50 gm 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol base compound in 150 ml of ethyl acetate. Oxalic acid dihydrate 25 gm was added into the reaction mixture and stirred. Heat the reaction mixture for 1 hour at 50-55 °C. The reaction mixture was cooled to 25°C to 35°C. Toluene 300 ml was added into the reaction mixture to precipitate the solid. The precipitate was washed with toluene and dried under vacuum to obtain the solid crystalline form of titled compound.

Yield: 58 g

HPLC Purity: 76%

Exaniple-5: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate salt

Exemplified procedure in example 1 with the replacement ethyl acetate solvent with tetrahydrofuran and antisolvent toluene with petroleum ether were used to get the title compound.

Exaniple-6: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 with the replacement ethyl acetate solvent with isopropyl acetate and antisolvent toluene with diisopropyl ether were used to get the title compound.

Exaniple-7: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and toluene or heptane was used as antisolvent to get the title compound.

Example-8: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and isolation of the product were done by means of partial removal of the solvent under vacuum.

Example-9: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein ethyl acetate is replaced with isopropyl acetate and further, the reaction mass was stirred at lower temperatures to about 10°C to about 15°C for 3-5 hours and subsequently precipitated product was isolated and dried.

Example-10: Synthesis of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base

Stirring the suspension of 260 ml water and 65 gm 2-(2,5-difluoro-phenyl)-l-[l,2,4] triazol-l-yl-butane-2,3-diol oxalate salt were added. The reaction mixture pH was adjusted by addition of 10 % aqueous sodium carbonate solution. The pH was maintained to about pH 7 to about 8, 300 ml dichloro methane was added into the reaction mixture with stirring. The layers were separated and dichloromethane layer was collected. Aqueous layer was extracted with 150 ml dichloromethane. Dichloromethane layer was combined and washed with water. Dichloromethane was distilled out to get titled compound.

Yield: 35 gm

Purity: 87%

Wockhardt Ltd chairman Habil Khorakiwala.

/////////NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE

The top five biggest patent losses in 2016 are AstraZeneca, Daiichi Sankyo, Merck, Abbott and ViiV.

The top five biggest patent losses in 2016 per holder after AstraZeneca are Daiichi Sankyo, Merck, Abbott and ViiV.
read
 http://www.genengnews.com/insight-and-intelligence/the-major-pharmaceuticals-losing-patent-protection-in-2016/77900599/

NOTES, Data exclusivity, Tecfidera, Dimethyl fumarate

  Dimethyl fumarate

The CHMP has now completed its assessment and considers that dimethyl fumarate is different from Fumaderm
2. Therefore, the active substance of Tecfidera, dimethyl fumarate, is a new active substance. This conclusion is based on the review of the scientific evidence, and in line withclarification provided by the European Commission that:

i) a new active substance under Directive 2001/83/EC is a chemical substance not previouslyauthorised as a medicinal product in the European Union (Annex I to the Notice to applicants Volume 2A, Procedures for marketing authorisation, Chapter 1, Marketing authorisations, June 2013) and,ii) dimethyl fumarate is part of the medicinal product Fumaderm authorised in 1994 in Germany, but it has not been previously authorised as a medicinal product in the Euopean Union

.

The fact that tecfidera is new active substance under Directive 2001/83/EC it is eligible for 10 yrs exclusivity in EU

Tecfidera MA on 30 January 2014..........10 yrs from this date

Biogen Idec has won regulatory protection for its top-selling multiple sclerosis drug Tecfidera in Europe, paving the way for its launch in markets that could account for a large proportion of future sales.
The European Medicines Agency said on Friday it had granted the oral medicine a "new active substance" (NAS) designation, securing Biogen 10 years protection through data exclusivity that will stop generic firms from launching copycat versions.
In March, Tecfidera was approved in the United States and also recommended for approval in Europe - but its EU launch has been delayed, pending a resolution of uncertainty over data protection.
Without this protection, Biogen would have to rely on relatively weak patents relating the drug's use, which analysts believe might not prevent generic rivals launching cheaper copies in key markets like Germany.



Tecfidera was recommended on 25 March by Europe’s Committee for Medicinal Products for Human Use (CHMP) as a known active substance, rather than a new active substance. A Biogen spokesperson said it was entitled to 10 years’ exclusivity for Tecfidera in the EU under the “Independent Development” principle and its stand-alone data package. The EMA’s guidance on exclusivity will be announced when the final approval decision is given.
If Tecfidera is not granted exclusivity through new active substance status or the Independent Development principle, Biogen will only have patent protection in the EU rather than protection against competitors using its MS data for generic regulatory filings of Tecfidera. The company’s latest EU patent (EP 1131065) expires in 2019 and is directed to formulations of dimethyl fumarate and its uses for autoimmune diseases including MS, according to company documents.

Germany (Fumaderm)
Drug: BG00012

Other Names:

• dimethyl fumarate
• Tecfidera®

The proverbial thorn in Biogen Idec’s paw is a little used product called Fumaderm – which is approved in Germany for the treatment of psoriasis. A ‘chemical cousin’ of Tecfidera (Fumaderm is a compounded form of dimethyl fumarate – the active ingredient in Biogen Idec’s new MS treatment), Fumaderm generated sales of just $60 million in 2012 – a figure that Tecfidera is expected to surpass during its first three months of availability in the US market alone.
The similarities between Tecfidera and Fumaderm would appear to have guided Biogen Idec away from the pursuit of new active substance (NAS) status for Tecfidera – which ordinarily provides new product approvals a minimum of eight years data exclusivity and two years market exclusivity

Biogen Idec wins EU battle on Tecfidera exclusivity

Oral MS drug gains New Active Substance status

Biogen Idec has been buoyed by victory in its longstanding battle to secure market exclusivity for its oral multiple sclerosis (MS) drug Tecfidera in the EU.

Shares in the US biopharma company climbed around 10 per cent on Friday after the Committee for Medicinal Products for Human Use (CHMP) agreed that the active ingredient in Tecfidera - dimethyl fumarate - should be classed as a New Active Substance (NAS) in the EU.
Biogen Idec has delayed the introduction of Tecfidera in Europe while the matter was resolved, and can now move ahead with a launch, secure in the knowledge that it has gained 10 years of regulatory exclusivity for the fast-growing product.
Tecfidera was approved in the US in March, becoming the third orally-active MS treatment to reach the market after Novartis' Gilenya (fingolimod) and Sanofi's Aubagio (teriflunomide), and has romped away in its first few months on the market, racking up around $500m in sales in its first six months.
The drug was awarded a European patent on May 29 that protects it from generic competition until 2028, but has also been pushing for regulatory data protection and NAS status, which will confer an additional level of protection against patent challenges.
Biogen Idec said in a statement that Tecfidera's EU approval has been delayed while the regulatory status of the drug is resolved, but now - with a CHMP positive opinion already in the bag - it can now be referred to the European Commission for a final ruling on the marketing application.
"We are ready to introduce Tecfidera in EU countries shortly after anticipated approval," said the company's executive vice president of R&D Douglas Williams.
Analysts have predicted that the drug could lead the market for oral MS therapies as they become established in favour of injectable interferon-based treatments, with sales of $3bn-a-year or more in 2016.

The European Commission granted a marketing authorisation valid throughout the European Union for Tecfidera on 30 January 2014  ie dimethyl fumarate

read http://drugpatentsint.blogspot.in/2015/01/data-exclusivity-for-medicinal-products.html





FUMADERM An oral preparation containing dimethyl fumarate and monoethyl fumarate salts

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

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/cm² and 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

New patent, WO 2016042573, Acitretin, Emcure Pharmaceuticals Ltd

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