AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

RG 6080

 phase 1, Uncategorized  Comments Off on RG 6080
Jul 152016
 

STR1

RG-6080

Sulfuric acid, mono[(1R,​2S,​5R)​-​2-​[[(2-​aminoethoxy)​amino]​carbonyl]​-​7-​oxo-​1,​6-​diazabicyclo[3.2.1]​oct-​6-​yl] ester

Phase I

A β-lactamase inhibitor potentially for the treatment of bacterial infections.

RG-6080; FPI-1459; OP-0595

CAS No. 1452458-86-4

Molecular Formula C9 H16 N4 O7 S
Formula Weight 324.31
  • Originator Fedora Pharmaceuticals
  • Developer Meiji Seika Pharma
  • Class Antibacterials; Azabicyclo compounds
  • Mechanism of Action Beta lactamase inhibitors
  • Phase IBacterial infections

Most Recent Events

  • 13 Jan 2015 OP 0595 licensed to Roche worldwide, except Japan ,
  • 30 Nov 2014 Meiji Seika Pharma completes a phase I trial in Healthy volunteers in Australia (NCT02134834)
  • 01 May 2014 Phase-I clinical trials in Bacterial infections (in volunteers) in Australia (IV)

 

 

SYNTHESIS

WO 2015046207,

STR1

 

CONTD…………………..

 

 

STR1

CONTD………………………………..

STR1

 

Patent

WO 2015053297

The novel heterocyclic compound in Japanese Patent 4515704 (Patent Document 1), preparation and shown for their pharmaceutical use, sodium trans-7-oxo-6- (sulfooxy) as a representative compound 1,6-diazabicyclo [3 .2.1] discloses an octane-2-carboxamide (NXL104). Preparation in regard to certain piperidine derivatives which are intermediates Patent 2010-138206 (Patent Document 2) and JP-T 2010-539147 (Patent Document 3) are shown at further WO2011 / 042560 (Patent Document 4) NXL104 to disclose a method for producing the crystals.
　In Patent 5038509 (Patent Document 5) (2S, 5R) -7- oxo -N- (piperidin-4-yl) -6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane – 2- carboxamide (MK7655) is shown, discloses the preparation of certain piperidine derivatives with MK7655 at Patent 2011-207900 (Patent Document 6) and WO2010 / 126820 (Patent Document 7).
　The present inventors also disclose the novel diazabicyclooctane derivative represented by the following formula (VII) in Japanese Patent Application 2012-122603 (Patent Document 8).
Patent Document 1: Japanese Patent No. 4515704 Pat
Patent Document 2: Japanese Patent Publication 2010-138206 Pat
Patent Document 3: Japanese patent publication 2010-539147 Pat
Patent Document 4: International Publication No. WO2011 / 042560 Patent
Patent Document 5: Japanese Patent No. 5038509 Pat
Patent Document 6: Japanese Patent Publication 2011-207900 Pat
Patent Document 7: International Publication No. WO2010 / 126820 Patent
Patent Document 8: Japanese Patent application 2012-122603 Pat.
[Chemical formula 1] (In the formula, R 3 are the same as those described below)

Reference Example
5 of 5 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
Formula 43]
step 1 tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate 　(IV-1)(2S, 5R)-6-(benzyloxy) -7-oxo-1,6-diazabicyclo [3.2.1] octane-2-carboxylic acid (4 .30g, dehydrated ethyl acetate (47mL) solution of 15.56mmol) was cooled to -30 ℃, isobutyl chloroformate (2.17g, washing included dehydration ethyl acetate 1mL), triethylamine (1.61g, washing included dehydration ethyl acetate 1 mL), successively added dropwise, and the mixture was stirred 1 hour at -30 ° C.. To the reaction solution tert- butyl 2-dehydration of ethyl acetate (amino-oxy) ethyl carbamate (3.21g) (4mL) was added (washing included dehydration ethyl acetate 1mL), raising the temperature over a period of 1.5 hours to 0 ℃, It was further stirred overnight. The mixture of 8% aqueous citric acid (56 mL), saturated aqueous sodium bicarbonate solution (40 mL), sequentially washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, filtered, concentrated to 5 mL, up to 6mL further with ethanol (10 mL) It was replaced concentrated. Ethanol to the resulting solution (3mL), hexane the (8mL) in addition to ice-cooling, and the mixture was stirred inoculated for 15 minutes. The mixture was stirred overnight dropwise over 2 hours hexane (75 mL) to. Collected by filtration the precipitated crystals, washing with hexane to give the title compound 5.49g and dried in vacuo (net 4.98 g, 74% yield). HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 50/50, 1.0 mL / min, UV 210 nm, Retweeted 4.4 min; 1 H NMR (400 MHz, CDCl 3 ) [delta] 1.44 (s, 9H), 1.56-1.70 (m, 1H), 1.90-2.09 (m, 2H), 2.25-2.38 (m, 1H), 2.76 (d, J = 11.6 Hz, 1H), 3.03 (br.d., J = 11.6 Hz , 1H), 3.24-3.47 (m, 3H), 3.84-4.01 (m, 3H), 4.90 (d, J = 11.6 Hz, 1H), 5.05 (d, J = 11.6 Hz, 1H), 5.44 (br. . s, 1H), 7.34-7.48 (yd, 5H), 9.37 (Br.S., 1H); MS yd / z 435 [M + H] + .
Step 2
tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate
(V-1) tert-butyl {2 – [({[( 2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl ] carbonyl} amino) oxy] ethyl} carbamate (3.91 g, to a methanol solution (80 mL) of 9.01mmol), 10% palladium on carbon catalyst (50% water, 803 mg) was added, under hydrogen atmosphere and stirred for 45 minutes . The reaction mixture was filtered through Celite, after concentrated under reduced pressure to give 3.11g of the title compound (quantitative).
HPLC: COSMOSIL 5C18 MS-II 4.6 × 150 mm, 33.3 mM phosphate buffer / MeCN = 75/25, 1.0 mL / min, UV 210 nm, Retweeted 3.9 from min; 1 H NMR (400 MHz, CD 3 OD) [delta] 1.44 (s, 9H) , 1.73-1.83 (m, 1H), 1.86-1.99 (m, 1H), 2.01-2.12 (m, 1H), 2.22 (br.dd., J = 15.0, 7.0 Hz, 1H), 3.03 (d, J= 12.0 Hz, 1H), 3.12 (br.d., J = 12.0 Hz, 1H), 3.25-3.35 (m, 2H), 3.68-3.71 (m, 1H), 3.82-3.91 (m, 3H); MS M / Z 345 [M Tasu H] Tasu .
Step 3
Tetrabutylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl } amino) oxy] ethyl} carbamate
(VI-1) tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct 2-yl] carbonyl} amino) oxy] ethyl} carbamate (3.09g, in dichloromethane (80mL) solution of 8.97mmol), 2,6- lutidine (3.20mL), sulfur trioxide – pyridine complex (3 .58g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate solution, washed the aqueous layer with chloroform, tetrabutylammonium hydrogen sulfate to the aqueous layer and (3.47 g) chloroform (30 mL) was added and stirred for 10 minutes. The aqueous layer was extracted with chloroform, drying the obtained organic layer with anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 5.46g (91% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 80/20, 1.0ML / Min, UV210nm, RT 2.0 Min; 1 H NMR (400 MHz, CDCl 3 ) Deruta 1.01 (T, J = 7.4 Hz, 12H), 1.37-1.54 (m , 8H), 1.45 (s, 9H), 1.57-1.80 (m, 9H), 1.85-1.98 (m, 1H), 2.14-2.24 (m, 1H), 2.30- 2.39 (m, 1H), 2.83 (d, J = 11.6 Hz, 1H), 3.20-3.50 (m, 11H), 3.85-3.99 (m, 3H), 4.33-4.38 (m, 1H), 5.51 (br s , 1H), 9.44 (Br.S., 1H); MS yd / z 425 [M-Bu 4 N + 2H] + .
Step 4 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VII-1)
tetra butylammonium tert- butyl {2 – [({[( 2S, 5R) -7- oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (5.20g, 7.82mmol) in dichloromethane (25mL) solution of ice-cold under trifluoroacetic acid (25mL), and the mixture was stirred for 1 hour at 0 ℃. The reaction mixture was concentrated under reduced pressure, washed the resulting residue with diethyl ether, adjusted to pH7 with aqueous sodium bicarbonate, subjected to an octadecyl silica gel column chromatography (water), after freeze drying, 1.44 g of the title compound obtained (57% yield).
HPLC: COSMOSIL 5C18 MS-II 4.6X150mm, 33.3MM Phosphate Buffer / MeCN = 99/1, 1.0ML / Min, UV210nm, RT 3.1 Min; 1 H NMR (400 MHz, D 2O) Deruta 1.66-1.76 (M, 1H), 1.76-1.88 (m, 1H ), 1.91-2.00 (m, 1H), 2.00-2.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 3.15 (t, J = 5.0 Hz , 2H), 3.18 (br d , J = 12.0 Hz, 1H), 3.95 (dd, J = 7.8, 2.2 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H), 4.07 (dd, J = 6.4 3.2 Hz &, 1H); MS yd / z 325 [M + H] + .

 

PATENT

WO 2015046207

Example
64 tert-butyl {2 – [({[( 2S, 5R) -6- hydroxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy ] ethyl} carbamate (V-1)
[of 124]

tert- butyl {2 – [({[(2S, 5R) -6- benzyloxy-7-oxo-1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl } carbamate (example 63q, net 156.42g, 360mmol) in methanol solution (2.4L) of 10% palladium carbon catalyst (50% water, 15.64g) was added, under an atmosphere of hydrogen, stirred for 1.5 hours did. The catalyst was filtered through celite, filtrate was concentrated under reduced pressure until 450mL, concentrated to 450mL by adding acetonitrile (1.5 L), the mixture was stirred ice-cooled for 30 minutes, collected by filtration the precipitated crystals, washing with acetonitrile, and vacuum dried to obtain 118.26g of the title compound (net 117.90g, 95% yield). Equipment data of the crystals were the same as those of the step 2 of Reference Example 3.

Example
65 (2S, 5R)-N- (2-aminoethoxy) -7-oxo-6- (sulfooxy) 1,6-diazabicyclo [3.2.1] octane-2-carboxamide (VI-1)
[of 125]

 

　tert- butyl {2 – [({[(2S, 5R) -1,6- -6- hydroxy-7-oxo-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate (example 64,537.61g, 1.561mol) in acetonitrile (7.8L) solution of 2,6-lutidine (512.08g), sulfur trioxide – pyridine complex (810.3g) was added, at room temperature in the mixture was stirred overnight. Remove insolubles and the mixture was filtered, the filtrate concentrated to 2.5 L, diluted with ethyl acetate (15.1L). The mixture was extracted with 20% phosphoric acid 2 hydrogencarbonate aqueous solution (7.8L), the resulting aqueous layer into ethyl acetate (15.1L), added tetrabutylammonium hydrogen sulfate (567.87g), was stirred for 20 min. The organic layer was separated layers, dried over anhydrous magnesium sulfate (425 g), after filtration, concentration under reduced pressure, substituted concentrated tetrabutylammonium tert- butyl with dichloromethane (3.1L) {2 – [({[(2S, 5R ) -7-oxo-6 (sulfooxy) 1,6-diazabicyclo [3.2.1] oct-2-yl] carbonyl} amino) oxy] ethyl} carbamate was obtained 758g (net 586.27g, Osamu rate 84%).

 

　The tetra-butyl ammonium salt 719g (net 437.1g, 0.656mol) in dichloromethane (874mL) solution was cooled to -20 ℃, dropping trifluoroacetic acid (874mL) at 15 minutes, 1 the temperature was raised to 0 ℃ It was stirred time. The reaction was cooled to -20 ° C. was added dropwise diisopropyl ether (3.25L), and the mixture was stirred for 1 hour the temperature was raised to 0 ° C.. The precipitate is filtered, washed with diisopropyl ether to give the title compound 335.36g of crude and vacuum dried (net 222.35g, 99% yield).

 

　The title compound of crude were obtained (212.99g, net 133.33g) and ice-cold 0.2M phosphate buffer solution of pH5.3 mix a little at a time, alternating between the (pH6.5,4.8L). The solution was concentrated under reduced pressure to 3.6L, it was adjusted to pH5.5 at again 0.2M phosphate buffer (pH6.5,910mL). The solution resin purification (Mitsubishi Kasei, SP207, water ~ 10% IPA solution) is subjected to, and concentrated to collect active fractions, after lyophilization, to give the title compound 128.3 g (96% yield). Equipment data of the crystals were the same as those of step 3 of Reference Example 3.

PATENT

US 20140288051

WO 2014091268

WO 2013180197

US 20130225554

///////////RG-6080, 1452458-86-4, FPI-1459,  OP-0595, Phase I ,  β-lactamase inhibitor, bacterial infections, Fedora parmaceuticals, Meiji Seika Pharma

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Chemistry in Water

 Uncategorized  Comments Off on Chemistry in Water
Jul 152016
 

Chemistry in Water

1
Isley et al. reported the use of the nonionic amphiphile TPGS-750-M (2 wt %) in water to facilitate nucleophilic aromatic substitution reactions (SNAr) with oxygen, nitrogen, and sulfur nucleophiles. The team eliminated the use of dipolar aprotic organic solvents traditionally required for SNAr reactions, such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP).
Moderate to high yields at ambient or slightly elevated temperatures (up to 45 °C) were observed, and a diverse substrate scope with respect to thermal stability was established. The team additionally demonstrated the ability to recycle the water/micelle mixture by extracting the product with organic solvent. Recycling of the aqueous media resulted in improving the E-factor and reducing aqueous waste ( Org. Lett. 2015, 17,4734−4737)., Supporting Info

Nucleophilic Aromatic Substitution Reactions in Water Enabled by Micellar Catalysis

† Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
‡ Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland
Org. Lett., 2015, 17 (19), pp 4734–4737
DOI: 10.1021/acs.orglett.5b02240
STR1
2
Wang et al. described the development of a copper-catalyzed hydroxylation of aryl halides in water. The syntheses of phenols generally require the use of energy intensive and/or harsh reaction conditions which can impact the substrate scope. This methodology utilized a hydroxylated phenanthroline ligand to improve solubility in water. Optimization of this method through screening resulted in the selection of copper(I) oxide (Cu2O) as the copper source and tetrabutyl-ammonium hydroxide (TBAOH) at 110 °C. The TBAOH was proposed to function as both phase transfer catalyst and nucleophile, resulting in high yields and excellent selectivity toward phenol versus biphenyl ether.
The scope of this method with substituted aryl halides was demonstrated, affording excellent yields and high selectivity for para-substituted electron-rich and electron-deficient aryl bromides, as well as meta-substituted bromo-halides. Functional groups such as carboxyl and hydroxyl groups were also tolerated. The team additionally demonstrated a one-pot synthesis of either alkyl aryl ethers or benzofuran by trapping the in situ generated phenol with an alkyl bromide or through intramolecular cyclization ( Green Chem. 2015, 17, 3910−3915).
Graphical abstract: Copper-catalyzed hydroxylation of aryl halides: efficient synthesis of phenols, alkyl aryl ethers and benzofuran derivatives in neat water

Copper-catalyzed hydroxylation of aryl halides: efficient synthesis of phenols, alkyl aryl ethers and benzofuran derivatives in neat water

Yangxin Wang,ab   Chunshan Zhoua and   Ruihu Wang*a  
*Corresponding authors
aState Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, China
E-mail: ruihu@fjirsm.ac.cn
bUniversity of Chinese Academy of Sciences, Beijing, China
Green Chem., 2015, 17, 3910-3915
DOI: 10.1039/C5GC00871A , supporting info,
 An efficient catalytic protocol for hydroxylation of aryl halides in water is proposed to prepare phenols, ethers and benzofuran derivatives.
A thorough study of environmentally friendly hydroxylation of aryl halides is presented. The best protocol consists of hydroxylation of different aryl bromides and electron-deficient aryl chlorides by water solution of tetrabutylammonium hydroxide catalyzed by Cu2O/4,7-dihydroxy-1,10-phenanthroline. Various phenol derivatives can be obtained in excellent selectivity and great functional group tolerance. This methodology also provides a direct pathway for the formation of alkyl aryl ethers and benzofuran derivatives in a one-pot tandem reaction.
3
Jung et al. reported the use of a continuous flow reactor to synthesize propargylamines in an atom economic fashion using stoichiometric quantities of reagents, water as solvent, and generating only CO2 and water as byproducts. The team exploited the use of a pressurized tube reactor to achieve temperatures above the boiling point of water, enabling excellent yields (≥88%) and reasonable residence time (2 h).
This procedure improved the atom economy of previously reported methods for this transformation by eliminating the use of transition metal catalysts and excess of reagents. The substrate scope was demonstrated for multiple alkynyl carboxylic acids and secondary amines ( Tetrahedron. Lett. 2015, 56, 4697−4700).
image
Tetrahedron Letters

Volume 52, Issue 36, 7 September 2011, Pages 4697–4700

Basic alumina supported tandem synthesis of bridged polycyclic quinolino/isoquinolinooxazocines under microwave irradiation

  • Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
4
Wang et al. reported the synthesis of an easily accessible diammonium functionalized Ru-alkylidene complex capable of ring-closing metathesis (RCM) and cross metathesis (CM) reactions in water. The NHBoc penultimate intermediate was isolated as an air-stable, nonhygroscopic Ru-alkylidene complex. Acidic cleavage of the Boc groups with trifluoroacetic acid (TFA) in dichloromethane generated the diammonium catalyst as a green solid after removal of volatiles under reduced pressure. The diammonium catalyst (5 mol %) achieved modest to high conversion to cyclic RCM products in D2O at ambient to elevated temperatures (up to 80 °C). Lowering the catalyst loading to 0.1 mol % established a turnover number (TON) of >900.
Homocoupling of allyl alcohol and long chain alkenylammonium salts provided the desired diammonium cross products in high yield/conversion. Short chain alkenyl-ammonium salts were poor substrates for the CM reaction.
Catalyst deactivation was attributed to the ammonium:free amine equilibration in water followed by Lewis basic nitrogen coordination to the Ru-center (Green Chem. 2015, 17, 3407−3414).
Graphical abstract: A simple and practical preparation of an efficient water soluble olefin metathesis catalyst

A simple and practical preparation of an efficient water soluble olefin metathesis catalyst

*Corresponding authors
aSchool of Chemistry, Monash University, Clayton 3800, Australia
E-mail: andrea.robinson@monash.edu
Green Chem., 2015,17, 3407-3414

DOI: 10.1039/C5GC00252D, supp info

5
The same research group additionally reported the divergent functionalization of L-tyrosine to generate a family of tyrosine-derived Ru-alkylidene RCM catalysts. This common ligand precursor approach was utilized to successfully create not only a hydrophilic/water-soluble PEG Ru-alkylidene, but a hydrophobic alkane Ru-alkylidene for solvent-free catalysis and a solid-phase supported Ru-alkylidene to access a potentially recyclable precatalyst system.
The PEG Ru-alkylidene complex displayed poor solubility in water at 40 °C under ultrasonication, providing the desired model RCM product in only 25% conversion. >95% conversion was achieved by utilizing a 1:1 water–MeOH solvent system at 40 °C with 2.5 mol % catalyst loading. It was rationalized in the Green Chemistry report (vide supra) that functionalization of the benzylidene ligand to increase aqueous solubility may be problematic due to the dissociation of the labile ligand during the catalytic cycle, whereas functionalization of nondissociating NHC ligand could sustain the desired solubility throughout the reaction.
The hydrophobic alkane Ru-alkylidene provided solvent-free RCM and CM products in high conversion. The solid-phase Ru-alkylidene also provided the desired RCM products in high conversion and demonstrated stable performance after multiple catalyst recovery/reuse operations. Sustained leaching of Ru metal into the reaction media was monitored and observed for the recycled solid-phase catalyst method. However, this iterative loss of metal did not negatively impact conversion ( J. Org. Chem. 2015, 80, 7205−7211).

Divergent Approach to a Family of Tyrosine-Derived Ru−Alkylidene Olefin Metathesis Catalysts

divergent

Authors

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson
Published Journal of Organic Chemistry
Graphical abstract divergent
Abstract

A simple and generic approach to access a new family of Ru−alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda−Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.
Citation

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson, J. Org. Chem., 2015, 80(14), 7205–7211
Pdf Article
Doi 10.1021/acs.joc.5b01091
6
Bhowmick et al. published a review “Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions”. This review addressed the various types of organocatalysts based on (1) l-proline, (2) 4-hydroxy-l-proline, (3) amino acid derivatives, (4) enzymes, and (5) other miscellaneous catalysts applied to the aldol reaction in aqueous media. In general, the intermolecular asymmetric aldol reaction has been shown to perform poorly in pure aqueous media and is typically performed in organic solvents such as DMF, DMSO, etc.
However, structural modifications to l-proline and 4-hydroxy-l-proline have generated catalysts capable of asymmetric aldol reactions in aqueous media.
Examples provided in this review highlight (a) instances of enhanced reactivity using water as a solvent, cosolvent, or additive, (b) formation of enzyme mimics that use hydrophobic forces to reinforce substrate/catalyst binding, (c) the use of aqueous media to interrogate proposed transition state geometries, and (d) the pH dependence of organocatalyzed aldol reactions. Limitations presented in the review include (a) substrate specific catalyst activities, (b) multistep/low-yielding synthesis of the organocatalysts, (c) slow catalysis rate in pure aqueous media, (d) high catalyst loading, and (e) poor to moderate selectivity (Tetrahedron: Asymmetry 2015, 26, 1215−1244).
Image for unlabelled figure
Tetrahedron: Asymmetry

Volume 26, Issues 21–22, 1 December 2015, Pages 1215–1244

Tetrahedron: Asymmetry Report Number 159

Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions

  • Division of Organic Synthesis, Department of Chemistry, Visva-Bharati (A Central University), Bolpur, West Bengal 731 235, India
7
Hot water’s ability to promote unexpected reactions without any other reagents or catalysts.

Chinese and Japanese chemists have highlighted hot water’s ability to promote unexpected reactions without any other reagents or catalysts. The work should expand our understanding of how to harness the physicochemical properties of water to potentially replace more complex reagents and catalysts.

Above its critical point at 374°C and 218atm the properties of water change quite dramatically, explains Hiizu Iwamura from Nihon University in Tokyo. But even below that point, as water is heated, hydrogen bonding and hydrophobic interactions are disrupted. ‘This means that organic compounds get more soluble and salts become insoluble in hot pressurised water,’ Iwamura says. Dissociation of water into hydroxide (OH–) and hydronium (H3O+) ions also increases, he adds, so there are higher concentrations of these ions available to act as catalysts for reactions.

Iwamura was synthesising triaroylbenzene molecules for a previous project on molecular magnets, using base-catalysed Michael addition reactions, when he first became interested in whether the reactions might work in water. He teamed up with a chemical engineer colleague, Toshihiko Hiaki, who is more familiar with working at the required temperatures and pressures. Together, they found that 4-methoxy-3-buten-2-one could be transformed into 1,3,5-triacetylbenzene in pressurised water at 150°C, with no other additives (see reaction scheme).1

Meanwhile, Jin Qu and her team at Nankai University in Tianjin have been investigating water-promoted reactions at lower temperatures, without the need for pressurised vessels, which Qu says is more accessible for many researchers and makes monitoring reactions easier. ‘In 2008, one of my students found he could hydrolyse epoxides in pure water at 60°C, in 90% yields,’ she explains. ‘At first I thought it was not very interesting, just a hydrogen-bonding effect, but as we found more examples I got more interested.’

More than a thermal effect

When Qu’s team hydrolysed an epoxide made from (-)-α-pinene, they found that at room temperature they got (-)-sobrerol, the product they expected. But at 60°C or higher, the sobrerol began to racemise, giving a mixture of the (+)- and (-)-forms (see reaction scheme). ‘We couldn’t understand why this was happening at first,’ says Qu, but eventually it became clear that the allylic alcohol group in the sobrerol, which is much less reactive than the epoxide in pinene, was also being hydrolysed. The same reactions happen at room temperature if acid is added, Qu says, but don’t happen in propanol or other alcoholic and hydrogen-bonding solvents heated to the same temperatures, so it is not simply a thermal effect.

Qu points out that these observations, along with those of Iwamura’s team, show that molecules that might usually be considered unreactive in water can undergo useful transformations. And these reactions can take place without other reagents or solvents, which would create extra waste streams. Also, owing to the decreased solubility of the organic product molecules when the solutions are cooled back to room temperature, they are often easy to purify as well.

Iwamura suggests that there are many other simple acid- and base-catalysed reactions that might be suitable for reacting in hot water. However, reactions with thermally unstable molecules, or those requiring delicate selectivity, are unlikely to be so effective at higher temperatures, he adds. He also makes a distinction between Qu’s work – in which the water molecules are directly involved in the reaction – and his own group’s, in which the water acts as the reaction medium and provides the catalyst. ‘Our reaction did not take place in water heated at reflux,’ Iwamura adds.

However, Hiaki points out that the potential environmental benefits of reduced waste streams will have little impact on industrial chemistry if the reactions remain confined to batch processes. ‘High temperature and pressure is detrimental for the scale up to commercial chemical plants,’ he says. For that reason, the team is developing a flow microreactor system that should be more industry compatible.REFERENCES, 1 T Iwado et al, J. Org. Chem., 2012, DOI: 10.1021/jo301979p, 2 Z-B Xu and J Qu, Chem. Eur. J., 2012 DOI: 10.1002/chem.201202886

 8
Hydration: A process which adds water.

In this hydration reaction, 1-methylcyclohexene (an alkene) is reacted with aqueous H3O+ (formed from water and a strong acid such as H2SO4), resulting in Markovnikov addition of water across the pi bond. The product is an alcohol.


Syn, anti-Markovnikov addition of water to an alkene can be achieved via a hydroboration-oxidation reaction.

–to be added– –to be added–
CuSO4 (anhydrous) CuSO4 . 5 H2O

Anhydrous CuSO4 (colorless) absorbs water vapor from the air, hydrating it to CuSO4 . 5 H2O (copper sulfate pentahydrate; blue).

///////////Chemistry in Water
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Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

 flow synthesis, SYNTHESIS  Comments Off on Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam
Jul 152016
 
Abstract Image

A method for synthesizing chiral lactams from chiral oxaziridines in continuous flow is described. The oxaziridines are readily available from cyclic ketones. Photolysis of the oxaziridines using the Booker-Milburn flow system provides conversion to the chiral lactams in good yield and short residence times. Application of this chemistry toward the synthesis of a chiral bicyclic lactam is described.

Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00213

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00213

John Cochran

Manager, Custom Synthesis Group at Vertex Pharmaceuticals

https://www.linkedin.com/in/john-cochran-00a86299

Experience

Research Fellow II (Manager, Custom Synthesis Group)

Vertex Pharmaceuticals

– Present (16 years 7 months)Boston, MA

– Supervised 10 chemists (6 Ph.D., 2 M.S., 2 B.S)

– Synthesized starting materials, intermediates, and preclinical tox lots for medicinal chemistry on
multigram to kilogram scale.

– Synthesized standards for various assays

– Performed kilo-scale enzymatic reactions

– Used flow chemistry on kilo scale

– Worked with several outsourcing firms in Europe and Asia

– Designed and updated an internal group website used to communicate with stakeholders

– Experienced with DOE and reaction optimization

Medicinal Chemist

Vertex Pharmaceuticals

– (3 years 11 months)Cambridge, MA

– Supervised 4 chemists (2 M.S., 2 B.S.)

– Managed a lead generation team that synthesized hundreds of very potent and selective heterocyclic leads on several kinase programs including JNK3, GSK3, LCK, SYK, and JAK3.

– Chemistry Head of the p38 2nd-generation program.

– Designed and synthesized very potent and selective inhibitors of p38

– Designed synthetic routes for previously unknown substitution patterns on pyridine

– Made presentations to external collaborators on the program.

– Produced two clinical candidates that were substantially more potent and had much better physical
properties than the 1st-generation inhibitors.

– Filed several patents concerning the 1st-generation compounds and related scaffolds

Postdoctoral Research Associate

Emory University

– (2 years 2 months)Atlanta, GA

– Designed and researched a proposal to use Pummerer chemistry to synthesize furans and to apply
the methodology to lignin synthesis

– Authored and investigated a proposal to synthesize 2-aminofurans using Pummerer or diazo
chemistry and to use them to make highly substituted anilines, phenols, indoles, and the general
framework found in the Amaryllidaceae, Erythrina, Lycopodium, and Aspidospermina classes of
alkaloids.

– Designed the synthetic strategy for indole synthesis using a vinylogous Pummerer rearrangement.

– Authored and supervised the research on a proposal to use Pummerer chemistry to synthesize
aromatic glides that can be used to make complex polycyclic systems.

– Supervised two graduate students working on the 2-aminofuran project and one graduate student on the vinylogous Pummerer project.

Industrial Chemist

Tennessee Valley Authority

– (6 years)Muscle Shoals, AL

– Synthesized potential urease inhibitors in gram to several hundred gram quantities using high
temperature and high pressure equipment

– Performed gas-phase reactions in fluidized bed reactors containing transition-metal catalysts to find
an efficient industrial process for making dicyandiamide

– Characterized compounds and analyzed their decomposition kinetics using 1H and 31P NMR, HPLC,
and GC.

– Authored and researched a proposal to modify urea crystal morphology in fluid fertilizers

– Developed software for receiving and analyzing data from various instrumentation.

Education

University of Wisconsin-Madison

Doctor of Philosophy (Ph.D.), Organic Chemistry

Synthesized heterocyclophanes and studied their binding interactions with small neutral molecules in nonaqueous media. Complexation studies were performed with 1H , 13C, variable temperature, and 2D NMR, UV spectroscopy, and X-ray diffraction.

University of North Alabama

Bachelor of Science (B.S.), Industrial Chemistry

///////John E. Cochran, vertex, Chiral Bicyclic Lactam

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NEW PATENT, WO 2016108172, OSPEMIFENE AND FISPEMIFENE, OLON S.P.A.

 PATENTS  Comments Off on NEW PATENT, WO 2016108172, OSPEMIFENE AND FISPEMIFENE, OLON S.P.A.
Jul 142016
 

 

Ospemifene.svg

Ospemifene is useful for treating menopause-induced vulvar and vaginal atrophy; while fispemifene is useful for treating symptoms related with male androgen deficiency and male neurological disorders.

In July 2016, Newport Premium™ reported that Olon was potentially interested in ospemifene and holds an active US DMF for ospemifene since September 2015. Olon’s website also lists ospemifene under R&D APIs portfolio.

WO2016108172

PROCESS FOR THE PREPARATION OF OSPEMIFENE AND FISPEMIFENE

OLON S.P.A. [IT/IT]; Strada Rivoltana, Km. 6/7 20090 Rodano (MI) (IT)

CRISTIANO, Tania; (IT).
ALPEGIANI, Marco; (IT)

 

WO2016108172

Process for preparing ospemifene or fispemifene, by reacting a phenol with an alkylating agent.

Ospemifene, the chemical name of which is 2-{4-[(lZ)-4-chloro-l,2-diphenyl-l-buten-l-yl]phenoxy}ethanol (Figure), is a non-steroidal selective oestrogen-receptor modulator (SERM) which is the active ingredient of a medicament recently approved for the treatment of menopause-induced vulvar and vaginal atrophy.

The preparation of ospemifene, which is disclosed in WO96/07402 and WO97/32574, involves the reaction sequence reported in Scheme 1 :

Ospemifene

Scheme 1

The first step involves alkylation of 1 with benzyl-(2-bromoethyl)ether under phase-transfer conditions. The resulting product 2 is reacted with triphenylphosphine and carbon tetrachloride to give chloro-derivative 3, from which the benzyl protecting group is removed by hydrogenolysis to give ospemifene.

A more direct method of preparing ospemifene is disclosed in WO2008/099059 and illustrated in Scheme 2.

Ospemifene

Scheme 2

Intermediate 5 (PG = protecting group) is obtained by alkylating 4 with a compound X-CH2-CH2-O-PG, wherein PG is a hydroxy protecting group and X is a leaving group (specifically chlorine, bromine, iodine, mesyloxy or tosyloxy), and then converted to ospemifene by removing the protecting group.

Alternatively (WO2008/099059), phenol 4 is alkylated with a compound of formula X-CH2-COO-R wherein X is a leaving group and R is an alkyl, to give a compound of formula 6, the ester group of which is then reduced to give ospemifene (Scheme 3)

Ospemifene

Scheme 3

Processes for the synthesis of ospemifene not correlated with those reported in schemes 2 and 3 are also disclosed in the following documents: CN104030896, WO2014/060640, WO2014/060639, CN103242142 and WO201 1/089385.

Fispemifene, the chemical name of which is (Z)-2-[2-[4-(4-chloro-l,2-diphenylbut-l-enyl)phenoxy]ethoxy]ethanol (Figure) is a non-steroidal selective oestrogen-receptor modulator (SERM), initially disclosed in WOO 1/36360. Publications WO2004/108645 and WO2006/024689 suggest the use of the product in the treatment and prevention of symptoms related with male androgen

deficiency. The product is at the clinical trial stage for the treatment of male neurological disorders.

According to an evaluation of the synthesis routes for ospemifene and fispemifene described in the literature, those which use compound 4 (Schemes 2 and 3) are particularly interesting, as 4 is also a key intermediate in the synthesis of toremifene, an oestrogen-receptor antagonist (ITMI20050278).

Leaving group X of the compound of formula 7 is preferably a halogen, such as chlorine, bromine or iodine, or an alkyl or arylsulphonate such as mesyloxy or tosyloxy.

In one embodiment of the invention, in the compound of formula 7, X is a leavmg group as defined above and Y is -(OCH2CH2)nOH wherein n is zero, and the reaction of 7 with 4 provides ospemifene, as reported in Scheme 4.

Scheme 4

In another embodiment of the invention, in the compound of formula 7, X and Y, taken together, represent an oxygen atom, the compound of formula 7 is ethylene oxide, and the reaction of 7 with 4 provides ospemifene, as reported in Scheme 5.

Scheme 5

In another embodiment of the invention, X is a leaving group as defined above and n is 1, and the reaction of 7 with 4 provides fispemifene, as reported in Scheme 6.

Scheme 6

The reaction between phenol 4 and alkylating reagent 7, wherein X is a leaving group as defined above and Y is the -(OCHbCEh^OH group as defined above, can be effected in an aprotic solvent preferably selected from ethers such as tetrahydrofuran, dioxane, dimethoxyethane, tert-butyl methyl ether, amides such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide and N-methylpyrrolidone, nitriles such as acetonitrile, and hydrocarbons such as toluene and xylene, in the presence of a base preferably selected from alkoxides, amides, carbonates, oxides or hydrides of an alkali or alkaline-earth metal, such as potassium tert-butoxide, lithium bis-trimethylsilylamide, caesium and potassium carbonate, calcium oxide and sodium hydride.

The reaction can involve the formation in situ of an alkali or alkaline earth salt of phenol 4, or said salt can be isolated and then reacted with alkylating reagent 7. Examples of phenol 4 salts which can be conveniently isolated are the sodium salt and the potassium salt. Said salts can be prepared by known methods, for example by treatment with the corresponding hydroxides (see preparation of the potassium salt of phenol 4 by treatment with aqueous potassium hydroxide as described in document ITMI20050278), or from the corresponding alkoxides, such as sodium methylate in methanol for the preparation of the sodium salt of phenol 4, as described in the examples of the present application.

Example 1

Sodium hydride (4.2 g) is loaded in portions into a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (10 g) in tetrahydrofuran (120 ml) in an inert gas environment, and the mixture is maintained under stirring at room temperature for 1 h. 2-Iodoethanol (11 ml) is added dropwise, and the reaction mixture is refluxed for about 9 h. Water is added, and the mixture is concentrated and extracted with ethyl acetate. The organic phase is washed with sodium carbonate aqueous solution and then with water, and then concentrated under vacuum. After crystallisation of the residue from methanol-water (about 5: 1), 9.9 g of crude ospemifene is obtained.

Example 2

A solution of sodium methylate in methanol (6.25 ml) is added to a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (10 g) in methanol (100 ml) in an inert gas environment, and maintained under stirring at room temperature for 1 h. The mixture is concentrated under vacuum and taken up with tetrahydrofuran (100 ml). A solution of 2-iodoethanol (3.5 ml) in tetrahydrofuran (30 ml) is added dropwise, and the reaction mixture is refluxed for about 3 h. Water is added, and the mixture is concentrated and extracted with ethyl acetate. The organic phase is washed with a saturated sodium hydrogen carbonate aqueous solution, and finally with water. The resulting solution is then concentrated under vacuum and crystallised from methanol-water to obtain 5.8 g of crude ospemifene.

Example 3

Potassium tert-butylate (2.0 g) is added to a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (5 g) in tert-butanol (75 ml) in an inert gas environment, and maintained under stirring at room temperature for 1 h. The solvents are concentrated under vacuum, and the concentrate is taken up with tetrahydrofuran (50 ml). A solution of 2-iodoethanol (1.7 ml) in tetrahydrofuran (15 ml) is added in about 30 minutes, and the reaction mixture is then refluxed for about 2 h. The process then continues as described in Example 1, and 2.9 g of crude ospemifene is obtained.

Example 4

A 50% potassium hydroxide aqueous solution (4.4 ml) is added to a solution of 4-(4-chloro-l,2-diphenyl-buten-l-yl)phenol (2 g) in toluene (20 ml) in an inert gas environment, and maintained under stirring at room temperature for 15

minutes. 2-Iodoethanol (2.2 ml) is added in about 30 minutes, and the reaction mixture is refluxed and maintained at that temperature for about 7 h. After the addition of water, the phases are separated. The organic phase is washed with a saturated sodium hydrogen carbonate aqueous solution, and finally with water. The organic phase is then concentrated under vacuum. After crystallisation of the residue from methanol-water (about 5:1), 0.85 g of crude ospemifene is obtained.

 

//////NEW PATENT, WO 2016108172, OSPEMIFENE,  FISPEMIFENE, OLON S.P.A.

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EDQM announces revision of general chapter Monocyte Activation Test (2.6.30)

 regulatory  Comments Off on EDQM announces revision of general chapter Monocyte Activation Test (2.6.30)
Jul 142016
 

On 23 June, the EDQM in Strasbourg announced the revision of the pharmacopoeial general chapter 2.6.30 on Monocyte Activation Test.

see  http://www.gmp-compliance.org/enews_05440_EDQM-announces-revision-of-general-chapter-Monocyte-Activation-Test–2.6.30-_15500,15298,15853,15541,Z-MLM_n.html

During the last two years, the chapters of the European Pharmacopoeia relating to the detection of Endotoxins and Pyrogens were successively updated or revised, e.g. 5.1.10. “Guidelines for Using the Test for Bacterial Endotoxins” or 2.6.8.” Pyrogens” (see Pharmeuropa – Comments concerning revised texts about Bacterial Endotoxins). There, amongst others, the EDQM announced that the chapter 2.6.8. now includes a reference to 2.6.30. “Monocyte Activation Test” as a potential replacement for the test for pyrogens.

Last week, the EDQM published the information that  during its 155th Session held in Strasbourg on 21-22 June 2016, the European Pharmacopoeia (Ph. Eur.) Commission adopted a revision of the general chapter Monocyte Activation Test (2.6.30).

It has been a goal of the Ph. Eur. Commission since nearly 30 years to consider the goals of the European Convention (ETS 123) to protect vertebrate animals used for experimental and other scientific purposes and to minimise the number of animal testing in the revisions of their documents.

The Monocyte Activation Test (MAT) is used to detect or quantify substances that activate human monocytes or monocytic cells to release endogenous mediators which have a role in the human fever response. The MAT is suitable, after product-specific validation, as a replacement for the rabbit pyrogen test (RPT). The revision of 2.6.30 should lead to a further reduction in the use of laboratory animals. It includes the results of the consultation of industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories.

The revised general chapter Monocyte Activation Test (2.6.30) will be published in the Ph. Eur. Supplement 9.2 and will come into effect in July 2017.

For more information, please see the  EDQM announcement European Pharmacopoeia Commission adopts revised general chapter on Monocyte-activation test to facilitate reduction in testing on laboratory animals.

In this context, please pay attention to “Monocyte Activation Test – MAT – A Joint Workshop of the Paul-Ehrlich-Institut (PEI) and ECA” on 7. September 2016 at the Paul-Ehrlich-Institut in Langen, Germany.

During the last two years, the chapters of the European Pharmacopoeia relating to the detection of Endotoxins and Pyrogens were successively updated or revised, e.g. 5.1.10. “Guidelines for Using the Test for Bacterial Endotoxins” or 2.6.8.” Pyrogens” (see Pharmeuropa – Comments concerning revised texts about Bacterial Endotoxins). There, amongst others, the EDQM announced that the chapter 2.6.8. now includes a reference to 2.6.30. “Monocyte Activation Test” as a potential replacement for the test for pyrogens.

Last week, the EDQM published the information that  during its 155th Session held in Strasbourg on 21-22 June 2016, the European Pharmacopoeia (Ph. Eur.) Commission adopted a revision of the general chapter Monocyte Activation Test (2.6.30).

It has been a goal of the Ph. Eur. Commission since nearly 30 years to consider the goals of the European Convention (ETS 123) to protect vertebrate animals used for experimental and other scientific purposes and to minimise the number of animal testing in the revisions of their documents.

The Monocyte Activation Test (MAT) is used to detect or quantify substances that activate human monocytes or monocytic cells to release endogenous mediators which have a role in the human fever response. The MAT is suitable, after product-specific validation, as a replacement for the rabbit pyrogen test (RPT). The revision of 2.6.30 should lead to a further reduction in the use of laboratory animals. It includes the results of the consultation of industry representatives, academics, regulatory authorities and Official Medicines Control Laboratories.

The revised general chapter Monocyte Activation Test (2.6.30) will be published in the Ph. Eur. Supplement 9.2 and will come into effect in July 2017.

For more information, please see the  EDQM announcement European Pharmacopoeia Commission adopts revised general chapter on Monocyte-activation test to facilitate reduction in testing on laboratory animals.

In this context, please pay attention to “Monocyte Activation Test – MAT – A Joint Workshop of the Paul-Ehrlich-Institut (PEI) and ECA” on 7. September 2016 at the Paul-Ehrlich-Institut in Langen, Germany.

/////Monocyte Activation Test

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Drafts of revised USP plastic packaging chapters <661.1> and <661.2>: removal of the biological reactivity test for oral and topical dosage forms

 regulatory  Comments Off on Drafts of revised USP plastic packaging chapters <661.1> and <661.2>: removal of the biological reactivity test for oral and topical dosage forms
Jul 142016
 

In a recent Pharmacopeial Forum two revised USP general chapters have been published for comment. With these drafts, the USP expert committee is removing the requirement for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms. Read more about the draft chapters of <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.testing for packaging materials and systems for oral and topical dosage forms. Read more about the draft chapters of <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use.

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http://www.gmp-compliance.org/enews_05453_Drafts-of-revised-USP-plastic-packaging-chapters–661.1–and–661.2–removal-of-the-biological-reactivity-test-for-oral-and-topical-dosage-forms_15493,15615,Z-PKM_n.html

 

In Pharmacopeial Forum 42(4) [Jun-Jul 2016] drafts of two revised USP general chapters <661.1> Plastic Materials of Construction and <661.2> Plastic Packaging Systems for Pharmaceutical Use have been published for comment. Deadline for comments is September 30, 2016. With these drafts, the USP General Chapters – Packaging and Distribution Expert Committee is removing the requirement for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms.

The Expert Committee is removing the requirement for <87> testing at this time, while the effort to revise the general chapters <87> and Biological Reactivity Tests, In Vivo <88> proceeds. Depending on the revisions of <87> and <88> the two packaging chapters may be revised to align with those chapters.

The new requirement (since May 2016) for <87> Biological Reactivity Tests, In Vitro testing for packaging materials and systems for oral and topical dosage forms has been highly discussed, since this testing is not required for the mentioned dosage forms according to EMA guideline on plastic immediate packaging materials (December 2005) and US FDA container closure guidance (May 1999). In case of oral and topical dosage forms both guidances require “only” compliance to food regulations (EU: regulation 10/2011, US: indirect food additives guidelines) or, if applicable, (preferably) to pharmacopoeial monographs (if the material or system is described in a pharmacopoeial chapter).

The principle of these two guidances is that materials considered safe for food contact are also safe for topical and oral dosage form packaging systems.

The new requirement (Biological Reactivity Tests, In Vitro) could have led to delays in releasing new oral or topical products on the market. Additionally, one might have had to re-evaluate already existing oral and topical products packaging systems on the market. Therefore, the present decision to revise the two packaging chapters regarding the requirement for <87>Biological Reactivity Tests, In Vitro seems to be justified.

Furthermore, the Expert Committee is proposing the addition of four new polymers [polyamide 6, polycarbonate, poly(ethylene-vinyl acetate), and polyvinyl chloride, plasticized] with test methods and specifications to general chapter <661.1>. To support the addition of these new polymers, polymer descriptions have been added to Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact <1661>, which appeared in PF 42(3) [May–June 2016].

In addition, the test for Spectral Transmission in Containers—Performance Testing <671> is being moved into general chapter <661.2> as requirement for light resistant containers.

On the basis of comments received, the scope of both chapters was revised for clarification.

After registration on the USP Pharmacopeial Forum website you can read the complete drafts of the two general chapters <661.1> and <661.2>.

 

Frequently Asked Questions: Plastic Materials of Construction <661.1> and Plastic Packaging Systems for Pharmaceutical Use <661.2>

  1. How do the newly revised General Chapters <661.1> and <661.2> impact currently marketed packaged pharmaceutical products?
  2. If a packaging system or component that gained regulatory approval with one product is used as a packaging system for a new product, would <661.1> and/or <661.2> testing be required?
  3. If a material of construction for a packaging system or component that has received regulatory approval is changed, is <661.1> and/or <661.2> testing required?
  4. Why does USP require <87> Biological Reactivity Tests, In Vitro testing for solid oral dosage forms?

  1. How do the newly revised General Chapters <661.1> and <661.2> impact currently marketed packaged pharmaceutical products?

    In order to market a drug product, defined as a dosage form plus its associated packaging system, the product must be evaluated for its suitability for use by the relevant regulatory authority. The purpose of <661.1> is to increase the likelihood that a packaging system will be suited for use by providing data about its material(s) of construction, whereas the purpose of <661.2> is to establish that the packaging system is suited for use. Because suitability for use has already been established for marketed products via regulatory review, <661.1> and <661.2> testing has no additional value in terms of establishing suitability for use. Thus, a packaging system and its materials of construction that have been evaluated by a regulatory authority and are used with a marketed dosage form are considered to already meet the requirements of <661.2> and <661.1> (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).

     

  2. If a packaging system or component that gained regulatory approval with one product is used as a packaging system for a new product, would <661.1> and/or <661.2> testing be required?

    If a packaging system (and its materials of construction) that is used with one marketed dosage form is used with a second, compositionally similar dosage form, and if the conditions of use are similar for the two dosage forms, neither <661.1> nor <661.2> testing is required. This is because the information used to establish the suitability for use with the approved product is relevant to and is typically sufficient for establishing the suitability for use with the new product.

    If the new drug product is compositionally different from the approved product, and/or the conditions of use are different, then <661.1> testing would not be required. This is because generally, <661.1> testing is not dependent on the dosage form composition or the conditions of use.

    The exception to this statement is when a packaging system for a marketed “low-risk” dosage form is used for a new “high-risk” dosage form. A dramatic change in the nature of the dosage form would require <661.1> testing. This is because <661.1> testing of materials used with “high-risk” dosage forms is more extensive than <661.1> testing of materials used with “low-risk” dosage forms. In this scenario, those tests that are required for both low- and high-risk dosage forms do not need to be repeated (for example, Identity, Physicochemical Tests, Extractable Metals, and <87> Biological Reactivity Tests, In Vitro). Those tests that are unique to the high-risk dosage forms (e.g., <88> Biological Reactivity Tests, In Vivo as appropriate and Plastic Additives) would need to be performed.

    A similar analysis is true for <661.2> testing of the packaging system. Biological Reactivity and Physicochemical Tests are not specifically linked to a dosage form or conditions of contact, thus the packaging system would not need to be tested for these attributes regardless of any differences in the composition or conditions of use between the approved and new drug products. However, as the generation and toxicological safety assessment of an extractables profile is influenced by the composition of the dosage form and the conditions of use, it may be necessary to perform the Chemical Safety Assessment (extractables profiling and toxicological safety) in <661.2>. Under <661.2>, any decision not to perform this Chemical Safety Assessment would need to be justified on a case-by-case basis.

    When a packaging system for a marketed “high-risk” dosage form is used for a new “low-risk” dosage form, <661.1> and <661.2> testing is not necessary. In this case, whatever information was used to establish the suitability for use with the “high-risk” dosage form would also establish the suitability for use with the “low-risk” dosage form, as the “high-risk” information would generally represent a worst case scenario for the “low-risk” situation (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).

     

  3. If a material of construction for a packaging system or component that has received regulatory approval is changed, is <661.1> and/or <661.2> testing required?

    As all materials of construction are required to meet <661.1>, it is expected that the new, different material would have to have been tested per <661.1>. Note that the new material would not be one of the legacy materials whose <661.1> compliance is “covered” by the fact that the product is being marketed.

    Use of a new and different material of construction in a packaging system can reasonably be anticipated to have an effect on the suitability for use of that packaging system. Thus, the new packaging system should be tested per <661.2>.

    Nevertheless, neither <661.1> nor <661.2> is intended to establish prescriptive requirements associated with exercising change control. Organizations are responsible for establishing their own change control practices, subject to approval by the appropriate regulatory authority. It is expected that those change control practices that do not specifically utilize <661.1> and <661.2> will include a justification for such practices, specifically focusing on the potential effect(s) that the change may have on user safety and product quality (see <1661> Evaluation of Plastic Packaging Systems and Their Materials of Construction with Respect to Their User Safety Impact and Table 1).

    Table 1. Guidance for Situations where <661.1> and <661.2> Testing would be Applicable

    Situation Required Testing
    General Situation Specific Circumstances <661.1> <661.2>
    Packaging system used with a currently marketed pharmaceutical product — No No
    New packaging system that has not gained regulatory approval for use with a to-be-marketed pharmaceutical product — Yes Yes
    Changes to a packaging system used with a currently marketed pharmaceutical product A new material is introduced into the packaging system Yes (for the new material) Yes
    A material of construction in the packaging system is changed in either composition or process Yes (for the changed material) Yes
    The packaging system is changed, in either composition or process, in a manner that does not involve a change in its materials or to its materials (for example, changing the thicknesses of individual layers in a multi-layered film) No Yes
    Packaging system used with a currently marketed pharmaceutical product is to be applied to a different pharmaceutical product Dosage form and conditions of use are similar for the current and different pharmaceutical products No No
    Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from a “high risk” to “low risk” dosage form) No No
    Dosage form and/or conditions of use are different from the current pharmaceutical products (moving from a “low risk” to “high risk” dosage form) Yes Yes

    Note: The provisions in <661.2> for packaging systems must be met for components whose testing has been deemed to be necessary.

     

  4. Why does USP require <87> Biological Reactivity Tests, In Vitro testing for solid oral dosage forms?

    In general, the amount and type of testing required to verify the suitability of packaging systems and their materials of construction should be consistent with the risk that the system or material could be unsuitable. In addition, the risk that packaging systems would be unsuited for use for solid oral dosage forms is lower than the risk associated with other dosage forms. Recognizing these generalizations, <661.1> has different testing requirements and/or specifications for these two groups of dosage forms. Because some of the tests required in <661.1> are applicable regardless of dosage form (for example, Identity, Physicochemical Tests, and Extractable Metals), such tests are applied with no difference to both groups of dosage forms. Although both groups of dosage forms are required to address Biological Reactivity, <661.1> requires only Biological Reactivity Tests, In Vitro <87> for oral and topical dosage forms while requiring both Biological Reactivity Tests, In Vitro <87> and Biological Reactivity Tests, In Vivo <88> (as applicable) for all other dosage forms. Both groups are required to address Plastic Additives, but solid oral dosage forms address this aspect by making proper reference to FDA’s Indirect Food Additive regulations while the other dosage forms address this issue by specified Plastic Additives testing.

    A cornerstone of suitability for use assessment of packaging systems and their materials of construction is the concept of orthogonal assessment. This is because individual means of assessment are generally insufficiently robust or broad enough in scope to provide rigorous and complete assessments on their own. Thus orthogonal assessments are performed to essentially “fill in the gaps” in the individual assessments.

Q: What types of “plastic packaging systems” are used in the pharmaceutical industry?

A: Plastic packaging systems for pharmaceutical use include bags, bottles, vials, cartridges, metered-dose inhalers, prefillable syringes, pouches and closures for capsules and tablets. Plastic materials commonly used in these systems include polyethylene, polypropylene, polyolefins, and polyvinyl chloride, among others.

Plastic packaging systems can include—not only the container that holds a particular drug product—but also gaskets, rubber stoppers, tubing and other components that may be part of the overall system used to store and/or deliver a drug to the patient.

Q: What are the key quality considerations for manufacturers of plastic packaging systems for drug products?

A: As drug products are manufactured, packaged, and stored, they come into direct contact with packaging systems and their plastic materials of construction. Such contact may result in interactions between the drug product and its packaging system. The packaging systems must protect and be compatible with drug products and not compromise their stability, efficacy or safety. In turn, the ingredients of a drug product should not be absorbed onto the surface or migrate into the body of the plastic packaging system.

The use of well-characterized plastic materials of construction and the appropriate testing of packaging systems help to determine if adverse interactions are taking place. Manufacturers should be able to provide a rationale for using a particular raw material of a packaging system and characterize that material to know what can possibly come out of it (e.g., additives, extractable  metals). This is key to determining potential interactions with a drug product.

Q: What are extractables and leachables?

A: Extractables are organic and inorganic chemical compounds that can be extracted from packaging material under laboratory conditions. They can be released from a pharmaceutical packaging/delivery system, a packaging component or a packaging material of construction. Depending on the specific purpose of a particular extraction study, laboratory conditions (e.g., solvent, temperature) may accelerate or exaggerate the normal conditions of storage and use for a packaged dosage form. Extractables themselves (or substances derived from extractables) have the potential to leach into a drug product under normal conditions or storage and use and, thus, become leachables.

Leachables are extractables derived from drug packaging or delivery systems that may migrate into the drug product over the course of a drug product’s shelf life. Leachables can affect the stability and efficacy of the drug product, and in some extreme cases, introduce some patient safety risks.

Q: How can USP help?

A: The U.S. Pharmacopeial Convention (USP) is a nonprofit scientific organization that develops and revises public standards that help promote global drug quality. USP’s standards encompass drug substances, excipients, drug products and their delivery and packaging systems. These standards are available for use by industry, academia, regulators, healthcare professionals and other stakeholders.

USP’s published official standards—in the form of specifications for identity, strength, quality and purity in drug product, drug substance and excipient monographs as well as information and procedures in general chapters—appear in the compendia, U.S. Pharmacopeia—National Formulary (USP–NF).

Q: What USP standards are available to support work with plastic packaging systems, as well as extractables and leachables?

A: USP has developed the following standards specifically for plastic packaging systems:

  • General Chapter <661> Plastic Packaging Systems and their Materials of Construction: Testing rationale for plastic materials of construction and packaging systems used in the pharmaceutical industry. The use of well-characterized materials to construct a packaging system is a primary means of ensuring that the packaging system is suitable for its intended use since properties and characteristics of the materials can be matched to the performance requirements of the packaging system. (Current official standard, published in USP 38–NF 33.)
  • General Chapter <661.1> Plastic Materials of Construction: Tests, procedures and acceptance criteria for plastic materials of construction used in pharmaceutical packaging systems. Proper characterization of materials of construction facilitates the identification of and use of appropriate materials for pharmaceutical packaging systems. (New standard, becomes official May 1, 2016, published in USP 39–NF 34.)
  • General Chapter <661.2> Plastic Packaging Systems for Pharmaceutical Use: Safety aspects of a drug product’s packaging system based on appropriate chemical assessments, includes performing extractables testing, leachables testing, and toxicology assessment. (New standard, becomes official May 1, 2016, published in USP 39–NF 34.)
  • General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems*: Framework for the design, justification and execution of an extractables assessment for pharmaceutical packaging and delivery systems. Establishes critical dimensions of an extractables assessment and discusses practical and technical aspects of each. Also examines critical dimensions of an extraction study—laboratory generation of the extract (extraction) and testing the extract (characterization). (Current official standard, published in USP 38–NF 33, S1.)
  • General Chapter <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems*: Framework for the design, justification and implementation of assessments for drug-product leachables derived from pharmaceutical packaging and delivery systems. Covers: 1) the requirement for leachables studies; 2) fundamental concepts for leachables studies; 3) the basis of thresholds for leachables and general guidance and application of these thresholds; 4) design and implementation of leachables studies; 5) leachables method development and validation; 6) correlation of results from extractables assessment and routine extractables testing with leachables studies; and 7) establishment of leachables specification including acceptance criteria. (Current official standard, published in USP 38–NF 33, S1.)

*This chapter is for informational purposes, it does not establish specific conditions, analytical methods, specifications, or acceptance criteria for any particular dosage forms or packaging system or drug product combination. The principles and best practices outlined in this general chapter represent a unified interpretation of sound science and are applicable to situations in which extractables or leachables assessment is required for pharmaceutical application. 

Q: Does USP have plans to develop future standards for plastic packaging systems?

A: Yes, USP is currently developing a brand new chapter <661.3> Plastic Materials for Pharmaceutical Manufacturing Systems which will cover plastic components and systems used in the manufacturing of a drug products. The chapter is scheduled to be published for public review and comment in Pharmacopeial Forum 42 (3) May 2016.

In addition, we will be hosting a workshop June 20–21 on Material Biocompatibility and Standard for Plastic Manufacturing Systems/Components at our facility in Rockville, MD.

We encourage all interested parties to take advantage of these two new resources to learn more and contribute to the development of new USP standards for drug packaging systems.

//////////////////Drafts, revised USP,  plastic packaging chapters <661.1> and <661.2>,  removal of the biological reactivity test for oral and topical dosage forms

 

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EMA reviews Medicines manufactured at U.S. Company

 regulatory  Comments Off on EMA reviews Medicines manufactured at U.S. Company
Jul 142016
 

Following the issuance of two Non-Compliance Reports for two sites of the US based company, EMA has started a review of medicines manufactured by Pharmaceutics International Inc., USA.

The European Medicines Agency (EMA) has started a review of medicines manufactured by Pharmaceutics International Inc., USA. This follows the issuance of two Non-Compliance Reports for two sites of the US based company after an inspection in February 2016 conducted by the MHRA (the medicines regulatory agency in the United Kingdom) which highlighted several shortcomings in relation to good manufacturing practice (GMP).

Pharmaceutics International Inc. manufactures the centrally authorised medicine Ammonaps (sodium phenylbutyrate) and is also the registered manufacturing site for some other medicines that have been authorised through national procedures in the European Union (EU).

This inspection which was a follow-up to an inspection in June 2015 aimed to assess whether corrective measures agreed previously had been appropriately implemented. It found that shortcomings remained, which included insufficient measures to reduce the risk that traces of one medicine could be transferred to another (cross-contamination), as well as problems with the way data were generated and checked and deficiencies in the systems for ensuring medicines’ quality (quality assurance).

EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.

There is no evidence that patients have been put at risk by this issue. However, as a precautionary measure, medicines from this site will no longer be supplied to the EU unless they are considered to be ‘critical’ to public health. Criticality will be assessed by national medicines regulatory agencies for their territories, taking into account alternatives and any impact of shortages on patients. In case where a medicine manufactured at this site is considered not critical in a member state it will no longer be supplied in this member state and any medicine remaining on the market will be recalled.

Source: EMA Press Release

Pharmaceutics International Inc., USA

/////////// EMA,  Medicines,  manufactured, U.S. Company, Pharmaceutics International Inc., USA

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Cipla to invest in South Africa’s first biosimilars production facility

 INDIA, MONOCLONAL ANTIBODIES  Comments Off on Cipla to invest in South Africa’s first biosimilars production facility
Jul 142016
 

Cipla to invest in South Africa’s first biosimilars production facility
Indian-based pharmaceutical and biotechnology company Cipla will invest more than R1.3bn ($19.34m) in the first advanced biotech manufacturing facility in South Africa for the production of biosimilars.

Indian-based pharmaceutical and biotechnology company Cipla will invest more than R1.3bn ($19.34m) in the first advanced biotech manufacturing facility in South Africa for the production of biosimilars.

The investment will be carried out by South African subsidiary Cipla BioTec…………………cont

read at

http://www.pharmaceutical-technology.com/news/newscipla-invest-south-africas-first-biosimilars-production-facility-4945516?WT.mc_id=DN_News

Cipla Managing director and global CEO Subhanu Saxena

 

Dr Y.K. Hamied,

Department of Trade and Industries Special Economic Zone of Dube Tradeport, DURBAN, SOUTHAFRICA

 

///Cipla, South Africa, biosimilars,  production facility, Dube Tradeport, Cipla BioTec Pvt Ltd, Durban, SOUTHAFRICA

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Besifloxacin hydrochloride (Besivance)

 Uncategorized  Comments Off on Besifloxacin hydrochloride (Besivance)
Jul 132016
 

Besifloxacin.png

Besifloxacin

SS 734, BOL 303224A, ISV-403

MW 430.301, MF C19H21ClFN3O3

141388-76-3 CAS

7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

(R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

(R) -7- (3- amino-hexahydro-azepin -1H- mushroom-1-yl) -8-chloro-1-cyclopropylmethyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

Synthesis of the molecule (R)-(+)-7-(3-amino-2,3,4,5,6,7-hexahydro-1H-azepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is disclosed in U.S. Pat. No. 5,447,926,

Besifloxacin is a fourth generation fluoroquinolone-type opthalmic antibiotic for the treatment of bacterial conjunctivitis. FDA approved on May 28, 2009. by Bausch & Lomb, for the treatment of non-viral bacterial conjunctivitis

Besifloxacin, (+)-7-[(3R)-3-aminohexahydro-1H-azepin-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride, developed by SS Pharmaceutical (SSP) Co.Ltd. was a fourth-generation fluoroquinolone antibiotic . Besifloxacin hydrochloride eye drop was used to treat bacterial conjunctivitis caused by aerobic and facultative Gram-positive microorganisms and aerobic and facultative Gram-negative microorganisms

Besifloxacin.png

Besifloxacin (INN/USAN) is a fourth-generation fluoroquinolone antibiotic. The marketed compound is besifloxacin hydrochloride. It was developed by SSP Co. Ltd., Japan, and designated SS734. SSP licensed U.S. and European rights to SS734 for ophthalmic useto InSite Vision Incorporated (OTCBB: INSV) in 2000. InSite Vision developed an eye drop formulation (ISV-403) and conducted preliminary clinical trials before selling the product and all rights to Bausch & Lomb in 2003.[1]

The eye drop was approved by the United States Food and Drug Administration (FDA) on May 29, 2009 and marketed under the trade name Besivance.[2]

Name Dosage Strength Route Labeller Marketing Start Marketing End
Besivance suspension 6 mg/mL ophthalmic Bausch & Lomb Incorporated 2009-05-28 Not applicable Us
Besivance suspension 0.6 % ophthalmic Bausch & Lomb Inc 2010-01-27 Not applicable Canada
Besivance suspension 6 mg/mL ophthalmic Physicians Total Care, Inc. 2011-07-13 Not applicable Us

405165-61-9 CAS

Besifloxacin Hydrochloride

Besifloxacin hydrochloride is a fourth-generation fluoroquinolone antibiotic.
IC50 Value:
Target: Antibacterial
Besifloxacin has been found to inhibit production of pro-inflammatory cytokines in vitro. Besifloxacin is a novel 8-chloro-fluoroquinolone agent with potent, bactericidal activity against prevalent and drug-resistant pathogens.besifloxacin is the most potent agent tested against gram-positive pathogens and anaerobes and is generally equivalent to comparator fluoroquinolones in activity against most gram-negative pathogens. Besifloxacin demonstrates potent, broad-spectrum activity, which is particularly notable against gram-positive and gram-negative isolates that are resistant to other fluoroquinolones and classes of antibacterial agents.

Clinical Information of Besifloxacin Hydrochloride

Product Name Sponsor Only Condition Start Date End Date Phase Last Change Date
Besifloxacin Hydrochloride Bucci Laser Vision Institute Bacterial infection 31-MAY-11 31-DEC-11 Phase 4 05-JUN-13
Bucci Laser Vision Institute 31-MAY-11 31-DEC-11 Phase 4 03-JUN-13
Innovative Medical Services 30-SEP-10 31-OCT-12 Phase 4 11-SEP-13
Ophthalmology Consultants, Ltd Cataract 30-SEP-10 28-FEB-11 Phase 4 11-SEP-13
University of Louisville Blepharitis 31-AUG-11 31-OCT-11 Phase 4 01-DEC-11

Pharmacodynamics

Besifloxacin is a fluoroquinolone that has a broad spectrum in vitro activity against a wide range of Gram-positive and Gram-negativeocular pathogens: e.g., Corynebacterium pseudodiphtheriticum, Moraxella lacunata, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus hominis, Streptococcus mitis, Streptococcus oralis, Streptococcus pneumoniae and Streptococcus salivarius. Besifloxacin has been found to inhibit production of pro-inflammatory cytokines in vitro.[3] The mechanism of action of besifloxacin involves inhibition of two enzymes which are essential for the synthesis and replication of bacterial DNA: the bacterialDNA gyrase and topoisomerase IV.

Medical Use

Besifloxacin is indicated in the treatment of bacterial conjunctivitis caused by sensitive germs,[4] as well as in the prevention of infectious complications in patients undergoing laser therapy for the treatment of cataracts.[5][6]

Adverse Effects

During the treatment, the most frequently reported ocular adverse reaction was the appearance of conjunctival redness (approximately 2% of patients). Other possible adverse reactions, reported in subjects treated with besifloxacin were: eye pain, itching of the eye, blurred vision, swelling of the eye or eyelid.

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

 

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PATENT

WO 2010111116

https://www.google.com/patents/WO2010111116A1?cl=en

 

PATENT

CN 104592196

https://www.google.com/patents/CN104592196A?cl=en

STR1

The method comprises performing condensation reaction of 1-​cyclopropyl-​6,​7-​dichloro-​1,​4-​dihydro-​4-​oxy-​3-​quinoline carboxylic acid with (R)​-​3-​aminohexahydroazepine in the presence of org. base in org. solvent I at 45°C-​solvent b.p. temp. under refluxing, washing with acid, vacuum concg. to obtain (R)​-​7-​(3-​amino-​hexahydro-​1H-​azepine-​1-​yl)​-​1-​cyclopropyl-​6-​fluoro-​1,​4-​dihydro-​4-​oxy-​3-​quinoline carboxylic acid, dissolving in 5-​10 fold org. solvent II, reacting with thionyl chloride at 0-​40°C, and vacuum concg. to obtain (R) -7- (3- amino-hexahydro-azepin -1H- mushroom-1-yl) -8-chloro-1-cyclopropylmethyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride

Preparation method of the present invention provides hydrochloride Besifloxacin, comprising the steps of:

(1), in three _6 flask of 1-cyclopropyl, 6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 10g of acetonitrile added 100mL, was added (R ) -3-amino-hexahydro-aza mushroom 4.73g and 7.2mL of triethylamine was heated at reflux for 5h TLC plate detection point, the reaction was complete spin dry plus 100mL dissolved in chloroform and then 200mL 1M hydrochloric acid and washed twice with saturated brine The organic phase to pH 4-6, the organic phase was poured into the jar and dried to obtain the single (R) -7- (3- amino-hexahydro-azepin -1H- leather-yl) cyclopropyl-6 -1_ fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid in chloroform solution; spin-dried to give (R) -7- (3- amino-hexahydro-azepin -1H- leather-yl) cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid.

(2), obtained in the previous step (R) -7- (3_ atmosphere atmosphere -1H- gas hybrid group six leather-1-yl) cyclopropyl-6-fluoro-1,4 _1_ dihydro-4-oxo-3-quinolinecarboxylic acid in chloroform solution was cooled to 0 ° C, was slowly added dropwise under constant stirring 18mL S0C12, temperature does not exceed 5 ° C added, the mixture was stirred at 0 ° C after 2h l to room temperature, TLC detection, after completion of the reaction was evaporated to dryness to column chromatography to give (R) -7- (3- amino-hexahydro-azepin -1H- mushroom-1-yl) -8-chloro-1-cyclopropylmethyl -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride 5. 12g.

 

PATENT

US 20110144329

https://www.google.com/patents/US20110144329

EXAMPLE 1Preparation of Besifloxacin Free Base Solid

Besifloxacin free base was prepared from besifloxacin hydrochloride addition salt.

An amount of about 5 g of besifloxacin HCl (HCl addition salt of besifloxacin made, for example, by the method of U.S. Pat. No. 5,447,926; which is incorporated herein by reference in its entirety) was added to about 750 ml of water. The besifloxacin HCl was allowed to dissolve in said water. Twenty milliliters of 1N NaOH solution were added slowly to the besifloxacin aqueous solution while stirring (final pH 10.2). Besifloxacin free base started to precipitate. Eight milliliters of 1N HCl solution were added slowly while stirring (final pH of 9.7). The resulting mixture was allowed to mix for 2 hours while besifloxacin free base continued to precipitate. At the end of 2 hours, the precipitated besifloxacin free base was filtered through a Millipore type RA 1.2 μm filter. The besifloxacin free base thus collected was dried in a vacuum oven at room temperature. 4.35 g of besifloxacin free base was recovered.

FIG. 1 shows a UV absorption spectrum of besifloxacin free base starting material of Example 1.

FIG. 3 shows an IR spectrum of free base starting material of Example 1.

PATENT

https://www.google.com/patents/CN103044397A?cl=en

Figure CN103044397AD00041

Example 6 (R) -7_ (3- amino-hexahydro–1H- diazepan-1-yl) -8_ chloro-1-cyclopropyl-6-fluoro-1,4- Hydrogen oxo – quinoline-3-carboxylic acid (Besifloxacin). [0021] The reaction vessel was added chloroform (50ml) as a reaction solvent, in the case of a solid material was added with stirring (III) (3. 59g, O. Olmol), until the intermediate (III) is completely dissolved, was added dropwise under ice- chlorosulfonic acid, stirred for I hour under ice-cooling, gradually warmed to room temperature, stirred for 6 hours, and then reacted at reflux temperature for 6 hours. After completion of the reaction by TLC, the reaction solution was cooled to 0 ° C, white solid was precipitated, filtered, washed with a small amount of dichloromethane to give a crude product besifloxacin (3. 65g, 93. 01%). [0022] Example 7 (R) -7_ (3- amino-hexahydro–1H- diazepan-1-yl) -8_ chloro-1-cyclopropyl-6-fluoro-1,4- Hydrogen oxo – quinoline-3-carboxylic acid (Besifloxacin). [0023] The reaction vessel was added chloroform (50ml) as a reaction solvent, in the case of a solid material was added with stirring (III) (3. 59g, 0. Olmol), until the intermediate (III) is completely dissolved, was added dropwise under ice- chlorosulfonic acid was stirred for I hour under ice-cooling, gradually warmed to room temperature, stirred for 6 hours, and then reacted at reflux temperature for 12 hours. After completion of the reaction by TLC, the reaction solution was cooled to 0 ° C, the precipitated white solid was filtered , washed with a little dichloromethane to give Besifloxacin crude (3. 05g, 77. 22%).

PAPER

Molbank 2013, 2013(2), M801; doi:10.3390/M801
Short Note
(R)-7-(Azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid Hydrochloride
Zhengjun Xia, Zaixin Chen *  and Shuitao Yu
Supplementary File 3:Support Information (PDF, 340 KB)
Download PDF [188 KB, 27 May 2013; original version 22 May 2013]
R&D Center, Jiangsu Yabang Pharmaceutical Group, Changzhou 213200, China
In this paper (R)-7-(azepan-3-ylamino)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1was isolated and identified as the N-substituted regioisomer of besifloxacin, which has been synthesized from the reaction of 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 with (R)-tert-butyl 3-aminoazepane-1-carboxylate 2in acetonitrile as solvent in 37% yield. The chemical structure of compound 1 was established on the basis of 1H-NMR, 13C-NMR, mass spectrometry data and elemental analysis

REGIOMER OF BESIFLOXACIN

 

Besifloxacin.pngBESIFLOXACIN

 

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References

  1.  “InSite Vision Reaches Agreement to Sell ISV-403 to Bausch & Lomb” (Press release). InSite Vision. 2003-12-19. Retrieved 2009-08-15.
  2.  “Bausch & Lomb Receives FDA Approval of Besivance, New Topical Ophthalmic Antibacterial for the Treatment of Bacterial Conjunctivitis (“Pink Eye”)” (Press release). Bausch & Lomb. 2009-05-29. Retrieved 2009-05-29.
  3.  Zhang JZ, Ward KW (January 2008). “Besifloxacin, a novel fluoroquinolone antimicrobial agent, exhibits potent inhibition of pro-inflammatory cytokines in human THP-1 monocytes”. J. Antimicrob. Chemother. 61 (1): 111–6. doi:10.1093/jac/dkm398. PMID 17965029.
  4.  Malhotra R, Ackerman S, Gearinger LS, Morris TW, Allaire C (December 2013). “The safety of besifloxacin ophthalmic suspension 0.6 % used three times daily for 7 days in the treatment of bacterial conjunctivitis”. Drugs in R&D 13 (4): 243–52. doi:10.1007/s40268-013-0029-1. PMC 3851703. PMID 24142473. Retrieved 2015-01-06.
  5.  Majmudar PA, Clinch TE (May 2014). “Safety of besifloxacin ophthalmic suspension 0.6% in cataract and LASIK surgery patients”. Cornea33 (5): 457–62. doi:10.1097/ICO.0000000000000098. PMC 4195578. PMID 24637269. Retrieved 2015-01-06.
  6.  Nielsen SA, McDonald MB, Majmudar PA (2013). “Safety of besifloxacin ophthalmic suspension 0.6% in refractive surgery: a retrospective chart review of post-LASIK patients”. Clinical Ophthalmology (Auckland, N.Z.) 7: 149–56. doi:10.2147/OPTH.S38279. PMC 3552478. PMID 23355771. Retrieved 2015-01-06.

 

CLIPS

Besifloxacin hydrochloride (Besivance) Besifloxacin is a fourth-generation fluoroquinolone antibiotic which is marketed as besifloxacin hydrochloride. It was originally developed by the Japanese firm SSP Co. Ltd and designated SS734. SSP then licensed U.S. and European rights of SS734 for ophthalmic use to InSite Vision, Inc., in 2000, who then developed an eye drop formulation (ISV-403) and conducted preliminary clinical trials before selling the product and all rights to Bausch & Lomb in 2003.

The eye drop was approved by the United States Food and Drug Administration (FDA) on May 29, 2009 and marketed under the trade name Besivance.24a

Besifloxacin has been found to inhibit production of pro-inflammatory cytokines in vitro. The synthesis of besifloxacin commences with commercially available ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate (13, Scheme3).24b

Condensation of this ketoester with triethyl orthoformate resulted in a mixture of vinylogous esters 14. Substitution with cyclopropanamine converts 14 to the vinylogous amide 15 as an unreported distribution of cis- and trans-isomers. This mixture was treated with base at elevated temperature to give 16.

Presumably, the trans-isomer isomerizes to the cis-isomer, which subsequently undergoes an intramolecular nucleophilic aromatic substitution with concomitant saponification to construct quinolone acid 16.

Quinolone 16 is then subjected to another nucleophilic substitution involving readily available iminoazepine 17 and the displacement reaction proceeds regioselectively to furnish the atomic framework of besifloxacin (18).

Acidic methanolysis of 18 at elevated temperature gave besiflozacin (III).

str1

24. (a) Bertino, J. S.; Zhang, J.-Z. Expert Opin. Pharmacother. 2009, 10, 2545; (b) Harms, A. E.; Arul, R.; Soni, A. K. U.S. 2009561283 A1, 2009.

US5447926 * Sep 16, 1994 Sep 5, 1995 Ss Pharmaceutical Co., Ltd. Quinolone carboxylic acid derivatives
Citing Patent Filing date Publication date Applicant Title
CN104458945A * Nov 27, 2014 Mar 25, 2015 广东东阳光药业有限公司 Separation and measurement method of besifloxacin hydrochloride and isomer of besifloxacin hydrochloride
CN102659761A * Apr 27, 2012 Sep 12, 2012 常州亚邦制药有限公司 Method for preparing besifloxacin hydrochloride
US5385900 * Nov 8, 1993 Jan 31, 1995 Ss Pharmaceutical Co., Ltd. Quinoline carboxylic acid derivatives
Reference
1 * 黄山等: “克林沙星的 2, 4, 5-三氟苯甲酸路线合成“, 《中国医药工业杂志》, vol. 31, no. 8, 31 December 2000 (2000-12-31)
Citing Patent Filing date Publication date Applicant Title
CN103709100A * Dec 31, 2013 Apr 9, 2014 南京工业大学 Preparation method of 8-chloroquinolone derivatives
Besifloxacin
Besifloxacin.png
Besifloxacin-3D-balls.png
Systematic (IUPAC) name
7-[(3R)-3-Aminoazepam-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Clinical data
Trade names Besivance
AHFS/Drugs.com Monograph
MedlinePlus a610011
License data
Routes of
administration		 Ophthalmic
Legal status
Legal status
Identifiers
CAS Number 141388-76-3
ATC code S01AE08 (WHO)
PubChem CID 10178705
ChemSpider 8354210
UNII BFE2NBZ7NX Yes
ChEMBL CHEMBL1201760
Chemical data
Formula C19H21ClFN3O3
Molar mass 393.84 g·mol−1
Patent Number Pediatric Extension Approved Expires (estimated)
US5,447,926 No 1995-09-05 2012-09-05 Us
US5447926 No 1996-04-13 2016-04-13 Us
US6,685,958 No 2004-02-03 2021-06-20 Us
US6,699,492 No 2004-03-02 2019-03-31 Us
US6685958 No 2001-06-29 2021-06-29 Us
US6699492 No 1999-03-31 2019-03-31 Us
US8415342 No 2010-11-07 2030-11-07 Us
US8481526 No 2011-01-09 2031-01-09 Us
US8604020 No 2010-03-12 2030-03-12 Us
US8937062 No 2009-11-13 2029-11-13 Us

 

  1. O’Brien TP: Besifloxacin ophthalmic suspension, 0.6%: a novel topical fluoroquinolone for bacterial conjunctivitis. Adv Ther. 2012 Jun;29(6):473-90. doi: 10.1007/s12325-012-0027-7. Epub 2012 Jun 20. [PubMed:22729919 ]
  2. Proksch JW, Granvil CP, Siou-Mermet R, Comstock TL, Paterno MR, Ward KW: Ocular pharmacokinetics of besifloxacin following topical administration to rabbits, monkeys, and humans. J Ocul Pharmacol Ther. 2009 Aug;25(4):335-44. doi: 10.1089/jop.2008.0116. [PubMed:19492955 ]

  3. Besifloxacin Hydrochloride

    [1]. Wang Z, Wang S, Zhu F, Chen Z, Yu L, Zeng S. Determination of enantiomeric impurity in besifloxacin hydrochloride by chiral high-performance liquid chromatography with precolumn derivatization. Chirality. 2012 Jul;24(7):526-31. doi: 10.1002/chir.22042.
    Abstract
    Besifloxacin hydrochloride is a novel chiral broad-spectrum fluoroquinolone developed for the treatment of bacterial conjunctivitis. R-besifloxacin hydrochloride is used in clinics as a consequence of its higher antibacterial activity. To establish an enantiomeric impurity determination method, some chiral stationary phases (CSPs) were screened. Besifloxacin enantiomers can be separated to a certain extent on Chiral CD-Ph (Shiseido Co., Ltd., Japan), Chiral AGP, and Crownpak CR (+) (Daicel Chemical IND., Ltd., Japan). However, the selectivity and sensitivity were both unsatisfactory on these three CSPs. Therefore, Chiral AGP, Chiral CD-Ph, and Crownpak CR (+) were not used in the enantiomeric impurity determination of besifloxacin hydrochloride. The separation of enantiomers of besifloxacin was further performed using a precolumn derivatization chiral high-performance liquid chromatography method. 2,3,4,6-Tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate was used as the derivatization reagent. Besifloxacin enantiomer derivates were well separated on a C(18) column (250 × 4.6 mm, 5 μm) with a mobile phase that consisted of methanol-KH(2)PO(4) buffer solution (20 mM; pH 3.0) (50:50, v/v). Selectivity, sensitivity, linearity, accuracy, precision, stability, and robustness of this method were all satisfied with the method validation requirement. The method was suitable for the quality control of enantiomeric impurity in besifloxacin hydrochloride.

    [2]. Hussar DA. New drugs: golimumab, besifloxacin hydrochloride, and artemether/lumefantrine. J Am Pharm Assoc (2003). 2009 Jul-Aug;49(4):570-4.

    [3]. Nafziger AN, Bertino JS Jr. Besifloxacin ophthalmic suspension for bacterial conjunctivitis. Drugs Today (Barc). 2009 Aug;45(8):577-88.
    Abstract
    Besifloxacin hydrochloride ophthalmic suspension 0.6% (Besivance) is a recently approved fluoroquinolone for the topical treatment of bacterial conjunctivitis. The drug is rapidly bactericidal against common bacterial pathogens causing conjunctivitis, i.e., coagulase-negative Staphylococcus, Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae as well as against other less common organisms. In addition to being a potent agent against Gram-positive and Gram-negative pathogens including those resistant to other fluoroquinolones, besifloxacin has balanced DNA gyrase and topoisomerase IV activity, which should slow the development of resistance. Topical administration achieves high sustained concentrations in human tears and good ocular tissue penetration in animals while demonstrating an excellent safety profile. Besifloxacin’s pharmacokinetic and pharmacodynamic characteristics meet the criteria for successful eradication of many Gram-positive and Gram-negative bacteria while demonstrating minimal systemic exposure. The biochemical properties, achievement of target pharmacokinetic/pharmacodynamic goals and the restriction of besifloxacin to topical ophthalmic use should result in slower development of bacterial resistance, making besifloxacin a new, appealing option for empiric therapy in acute bacterial conjunctivitis.

    [4]. Proksch JW, Ward KW. Ocular pharmacokinetics/pharmacodynamics of besifloxacin, moxifloxacin, and gatifloxacin following topical administration to pigmented rabbits. J Ocul Pharmacol Ther. 2010 Oct;26(5):449-58.
    Abstract
    PURPOSE: The purpose of this investigation was to evaluate the ocular pharmacokinetic/pharmacodynamic (PK/PD) relationship for besifloxacin, moxifloxacin, and gatifloxacin using rabbit ocular PK data, along with in vitro minimum inhibitory concentration (MIC90) values against methicillin- and ciprofloxacin-resistant Staphylococcus aureus (MRSA-CR) and Staphylococcus epidermidis (MRSE-CR).METHODS: Rabbits received a topical instillation of Besivance? (besifloxacin ophthalmic suspension, 0.6%), Vigamox (moxifloxacin hydrochloride ophthalmic solution, 0.5% as base), or Zymar (gatifloxacin ophthalmic solution, 0.3%), and ocular tissues and plasma were collected from 4 animals/treatment/collection time at 8 predetermined time intervals during the 24h after dosing. Ocular levels of each agent were measured by LC/MS/MS, and PK parameters (Cmax, Tmax, and AUC????) were determined. AUC????/MIC?? ratios were calculated for tears, conjunctiva, cornea, and aqueous humor using previously reported MIC??values for MRSA-CR and MRSE-CR.RESULTS: All of the fluoroquinolones tested demonstrated rapid penetration into ocular tissues after a single instillation. Besifloxacin demonstrated the highest exposure in tear fluid, while exposure in conjunctiva was comparable for all 3 compounds. Peak concentrations of all fluoroquinolones in aqueous humor were at or below ~1g/mL. In comparison with their MIC??values against MRSE-CR and MRSA-CR, besifloxacin achieved an AUC????/MIC?? ratio of ~800 in tears, compared with values of ≤10 for moxifloxacin and gatifloxacin. In cornea, conjunctiva, and aqueous humor, the AUC????/MIC?? ratios were <10 for all compounds. However, in these tissues AUC????/MIC?? ratios for besifloxacin were 1.5- to 38-fold higher than moxifloxacin and gatifloxacin….

    [5]. Comstock TL, Paterno MR, Usner DW, Pichichero ME. Efficacy and safety of besifloxacin ophthalmic suspension 0.6% in children and adolescents with bacterial conjunctivitis: a post hoc, subgroup analysis of three randomized, double-masked, parallel-group, multicenter clinical trials. Paediatr Drugs. 2010 Apr 1;12(2):105-12. doi: 10.2165/11534380-000000000-00000.
    Abstract
    BACKGROUND: Acute conjunctivitis is the most frequent eye disorder seen by primary care physicians and one that often affects children. Besifloxacin is a new topical fluoroquinolone, the first chlorofluoroquinolone, for the treatment of bacterial conjunctivitis.OBJECTIVE: To examine the efficacy and safety of besifloxacin ophthalmic suspension 0.6% in patients aged 1-17 years with bacterial conjunctivitis.METHODS: This was a post hoc analysis of a subgroup of pediatric patients aged 1-17 years who had participated in three previously reported, randomized, double-masked, parallel-group, multicenter, clinical trials evaluating the safety and efficacy of besifloxacin in the treatment of bacterial conjunctivitis. The studies were conducted in a community setting (clinical centers). All three clinical trials included children (aged > or = 1 year) with a clinical diagnosis of bacterial conjunctivitis in at least one eye, based on the presence at baseline of grade 1 or greater purulent conjunctival discharge and conjunctival injection, and pin-hole visual acuity of at least 20/200 in both eyes for verbal patients. Two trials were vehicle controlled; the third trial was comparator controlled (moxifloxacin hydrochloride ophthalmic solution 0.5% as base). In all studies, besifloxacin ophthalmic suspension 0.6% was administered as one drop in the affected eye(s) three times daily, at approximately 6-hourly intervals, for 5 days. The main outcome measures were clinical resolution and microbial eradication at visit 2 (day 4 +/- 1 in one study; day 5 +/- 1 in the other two studies) and visit 3 (day 8 or 9). Data from the two vehicle-controlled studies were combined for the assessments to provide greater statistical power.RESULTS: This analysis included 815 pediatric patients aged 1-17 years (447 with culture-confirmed bacterial conjunctivitis). Clinical resolution was significantly greater (p < 0.05) in the besifloxacin group than in the vehicle group at both visit 2 (53.7% vs 41.3%) and visit 3 (88.1% vs 73.0%). Similarly, microbial eradication was significantly higher with besifloxacin than with vehicle at visit 2 (85.8% vs 56.3%) and visit 3 (82.8% vs 68.3%). No significant differences in clinical resolution and microbial eradication were noted between besifloxacin and moxifloxacin. Besifloxacin was well tolerated, with similar incidences of adverse events in the besifloxacin, vehicle, and moxifloxacin groups.CONCLUSION: Besifloxacin ophthalmic suspension 0.6% was shown to be safe and effective for the treatment of bacterial conjunctivitis in children and adolescents aged 1-17 years.

///////Besifloxacin hydrochloride, Besivance, Besifloxacin, SS734, 141388-76-3, 405165-61-9, BOL 303224A, ISV-403, Bausch & Lomb, treatment of non-viral bacterial conjunctivitis

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Virtue Insight invites you to the 9th Biosimilars Congregation 2016, 22nd Sept 2016, The Lalit Hotel, Mumbai, India

 CONFERENCE  Comments Off on Virtue Insight invites you to the 9th Biosimilars Congregation 2016, 22nd Sept 2016, The Lalit Hotel, Mumbai, India
Jul 132016
 

STR1

9th Biosimilars Congregation 2016 during 22nd September 2016 Mumbai,  INDIA

22nd September 2016, The Lalit Hotel, Mumbai, India

Link http://www.virtueinsight.com/pharma/9th-Biosimilars-Congregation-2016/

ANINDITA DAS

ANINDITA DAS

Dr. Reddy’s Laboratories

MANISH VERMA

MANISH VERMA

Sanofi

DEBOLINA PARTAP

DEBOLINA PARTAP

Wockhardt

PARIKSHIT CHAUDHARI

PARIKSHIT CHAUDHARI

Nestle

HANMANT BARKATE

HANMANT BARKATE

Intas Pharmaceuticals

CONFERENCE INTRODUCTION:-

Virtue Insight invites you to the 9th Biosimilars Congregation 2016 during 22nd September 2016 Mumbai – India. This 9th Biosimilars Congregation 2016 brings together scientists, researchers and CROs from around the world. Biologics are a highly effective class of medicines that are based on naturally occurring proteins and produced using living cells. Current concepts of drugs and biologics, Unique considerations for biologics, Early clinical development essentials, Cancer therapeutics, Comparability for Biologics, Biosimilar approvals are the points of discussion in this session.

9th Biosimilars Congregation 2016 conference will bring together top pharmaceutical, biotechnology and regulatory representatives under one roof that will address the key issues of the industry. Hence, this global event will look at the multiple facets of biosimilars, ranging from the evolving regulatory landscapes, biosimilar guidelines to the legal and economic aspects and current challenges in biosimilar development. This biosimilar conference will focus on multiple aspects of biosimilar product development to successfully deliver safe, biosimilar products to the market place. By attending this biologics conference you will gain a comprehensive outlook on the key issues surrounding biosimilars. This event will provide an important platform for biosimilars stakeholders to discuss and share best practices in expediting development in Biosimilars 2016 and onwards.

 

KEY THEMES DISCUSSED IN THIS CONFERENCE:-

  • Global biopharma policy & market trends
  • The future of biosimilars in India
  • The evolving biosimilar sector: Trends and Implications
  • Complex biological models in biosimilar development
  • Viable extrapolation strategies for biosimilars with special emphasis on TNF antagonists
  • Effectively communicate the value of biosimilar products to raise confidence in the class
  • Improving characterization of biosimilars with technology
  • Create a robust patient services and reimbursement support program for biosimilar products
  • The future of the biosimilar industry – mapping the evolution and development of the biosimilar sector
  • Forecasting the financial growth of biosimilars in the global healthcare marketplace
  • Planning of a biosimilar development project – what to consider from the very beginning
  • Clinical development strategies for biosimilars
  • Gaining Better Market Access: Is Commercial CMO Acceptable for the Biosimilars Market?
  • Regulatory Updates and Development
  • Be part of a major networking opportunity

 

WHO WILL YOU MEET:-

CSOs, CMOs, Vice Presidents, Presidents, Heads, Directors, Team Leaders, and Senior Scientists from the following roles:

  • Biopharmaceuticals/ Biotherapeutics
  • Follow on Biologics/Follow on Proteins
  • Biologics/Biotechnology/ Biogenerics
  • Legal Affairs
  • Intellectual Property
  • Health Economics
  • Pricing and Reimbursement
  • Clinical Immunology
  • Principal Scientist
  • Chief Scientific Officer
  • Process Control and Analytical Technologies
  • Analytical Characterisation
  • Regulatory Compliance
  • Pharmacovigilance
  • Drug Safety & Risk Management
  • Quality Affairs/ Quality Control
  • New Product Development
  • Process Science
  • Portfolio Management
  • Research & Development
  • Business Development
  • Business Operations
  • Scientific Affairs
  • Commercial Affairs

 

WHY SHOULD YOU ATTEND?

Get more from the event, with a broader scope bringing the whole communications value chain together? Enjoy and make the best out of ourdedicated networking drinks time, meet the leading international vendors showcasing the products of tomorrow in the co-located exhibition.Expand your knowledge of the latest business models and strategies in the high-level conference. Whether you are on the branded or generic side, you cannot afford to miss this opportunity to benchmark your tactics and strategies against the industry leaders who will be the first to traverse the pathway. Devise an immediate action plan for your biosimilar prosecution and litigation strategies in light of the barriers to entry, research and development costs, and regulatory hurdles, which are balanced against an enormous potential for increased profit margin

Fen Castro

Fen Castro

Head – Productions

Virtue Insight

Tel (India) –       + 91 44 64614333

Mobile (India) –  + 91 9003 26 0693

Tel (UK) –          + 44 2036120886

Fen Castro fen@virtuefirms.com
Cc: Siddhaarth siddhaarth@virtueinsight.co.in

Link http://www.virtueinsight.com/pharma/9th-Biosimilars-Congregation-2016/

 

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