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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Synthesis of isosorbide: an overview of challenging reactions


Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC01912B, Tutorial Review
C. Dussenne, T. Delaunay, V. Wiatz, H. Wyart, I. Suisse, M. Sauthier
This review gives an overview of the catalysts and technologies developed for the synthesis of isosorbide, a platform molecule derived from biomass (sorbitol and cellulose).

Synthesis of isosorbide: an overview of challenging reactions

 Author affiliations

Abstract

Isosorbide is a diol derived from sorbitol and obtained through dehydration reactions that has raised much interest in the literature over the past few decades. Thus, this platform chemical is a biobased alternative to a number of petrosourced molecules that can find applications in a large number of technical specialty fields, such as plasticizers, monomers, solvents or pharmaceuticals. The synthesis of isosorbide is still a technical challenge, as several competitive reactions must be simultaneously handled to promote a high molar yield and avoid side reactions, like degradation and polymerization. In this purpose, many studies have proposed innovative and varied methods with promising results. This review gives an overview of the synthesis strategies and catalysts developed to access this very attractive molecule, pointing out both the results obtained and the remaining issues connected to isosorbide synthesis.

STR1 STR2

Up to now, isosorbide has been used to access a large panel of molecules with relevant applicative properties and industrial reality (Scheme 2).12 Isosorbide dinitrate is used since several decades as vasodilator.13, 14 The dimethyl isosorbide is for example used as solvent in cosmetics15-17 and isosorbide diesters18-22 are actually industrially produced and commercialized as surfactants23-27 and PVC plasticizer28, 29 . The rigid scaffold associated to the bifunctionality of the molecule has attracted a strong interest in the field of polymers chemistry. Isosorbide and derivatives have thus been shown as suitable monomers for the industrial production of polycarbonates30, 31, polyesters32-41 or polyamides42-44, with attractive applicative properties. For example, isosorbide allows the increase of Tg, improves the scratch resistance and gives excellent optical properties to polymers. Polyesters and polycarbonates containing isosorbide have now commercial developments in food packaging, spray container, automotive, material for electronic devices … .

Conclusions

Isosorbide is a versatile platform molecule that shows key features to make it a credible alternative to petro-based products. The molecule is already available on large industrial scale (tens of thousands tons per years), which allows its development in commercial products such as active pharma ingredient, additive for cosmetic, speciality chemicals and polymers (ex: polycarbonates – polyesters). The development of more selective and higher yields syntheses of isosorbide are greatly needed to consolidate isosorbide production in view of a large expansion of its uses. Sorbitol conversion to isosorbide, relying on a starch route, is already a tough challenge. In a farther future, development of a credible path to isosorbide relying on cellulose source could even be thought of, provided that very versatile innovative catalysts will be developed in the next years. In all cases, a key issue is to develop catalysts that will avoid the massive production of “oligomeric/polymeric” by-products in order to access more sustainable processes by limiting the amounts of wastes produced during the synthesis. For this purpose, more selective homogeneous catalysts than the conventional Brønsted acids or alternative reaction conditions would be of strong interest. Selective and recyclable heterogeneous catalysts would be even more profitable as they would allow the continuous production of catalyst free isosorbide. This latter approach faces strong limitations due to the need of high reaction temperatures that often result in high amounts of side-products and the need of frequent and often tedious catalyst regeneration. Innovation concerning isosorbide synthesis is still an open field on which the design of efficient and robust catalysts, either homogeneous or heterogeneous, is a key issue. Such developments would pave the way to high scale effective processes considering altogether synthesis and purification of isosorbide.

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Image result for ISOSORBIDE SYNTHESIS

Image result for ISOSORBIDE SYNTHESIS

Isosorbide is a heterocyclic compound that is derived from glucose. Isosorbide and its two isomers, namely isoidide and isomannide, are 1,4:3,6-dianhydrohexitols. It is a white solid that is prepared from the double dehydration of sorbitol. Isosorbide is a non-toxic diolproduced from biobased feedstocks, that is biodegradable and thermally stable. It is used in medicine and has been touted as a potential biofeedstock.

Production

Hydrogenation of glucose gives sorbitol. Isosorbide is obtained by double dehydration of sorbitol:

(CHOH)4(CH2OH)2 → C6H10O2(OH)2 + 2 H2O

An intermediate in the dehydration is the monocycle sorbitan.[1]

Application

Isosorbide is used as a diuretic, mainly to treat hydrocephalus, and is also used to treat glaucoma.[2] Other medications are derived from isosorbide, including isosorbide dinitrate and isosorbide mononitrate, are used to treat angina pectoris. Other isosorbide-based medicines are used as osmotic diuretics and for treatment of esophageal varices. Like other nitric oxide donors (see biological functions of nitric oxide), these drugs lower portal pressure by vasodilation and decreasing cardiac output. Isosorbide dinitrate and hydralazineare the two components of the anti-hypertensive drug isosorbide dinitrate/hydralazine (Bidil).

Isosorbide is also used as a building block for bio based polymers such as polyesters.[3]

References

  1. Jump up^ M. Rose, R. Palkovits (2012). “Isosorbide as a Renewable Platform chemical for Versatile Applications—Quo Vadis?”. ChemSusChem5 (1): 167–176. PMID 22213713doi:10.1002/cssc.201100580.
  2. Jump up^ CID 12597 from PubChem
  3. Jump up^ Bersot J.C. (2011). “Efficiency Increase of Poly (ethylene terephthalate‐co‐isosorbide terephthalate) Synthesis using Bimetallic Catalytic Systems”. Macromol. Chem. Phys212 (19): 2114–2120. doi:10.1002/macp.201100146.
Isosorbide
Isosorbide.svg
Names
Other names

D-Isosorbide; 1,4:3,6-Dianhydro-D-sorbitol; 1,4-Dianhydrosorbitol
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.010.449
KEGG
PubChem CID
UNII
Properties
C6H10O4
Molar mass 146.14 g·mol−1
Appearance Highly hygroscopic white flakes
Density 1.30 at 25 °C
Melting point 62.5 to 63 °C (144.5 to 145.4 °F; 335.6 to 336.1 K)
Boiling point 160 °C (320 °F; 433 K) at 10 mmHg
in water (>850 g/L), alcoholsand ketones
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

From the net

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1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

1H Nuclear magnetic resonance (NMR) spectra of PTMG, isosorbide, HDI, and polyurethane.HDI: hexamethylene diisocyanate; PTMG: poly(tetramethylene glycol).

 

Image result for ISOSORBIDE SYNTHESIS

REF

http://www.rsc.org/suppdata/gc/c4/c4gc01822b/c4gc01822b1.pdf

Synthesis of five- and six-membered heterocycles by dimethyl carbonate with catalytic amount of nitrogen bicyclic bases

http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01822b#!divAbstract

F. Aricò, a,*S. Evaristoa and P. Tundoa,*

Catalytic amount of a nitrogen bicyclic base, i.e., DABCO, DBU and TBD is effective for the one-pot synthesis of heterocycles from 1,4-, 1,5-diols and 1,4-bifunctional compounds via dimethyl carbonate chemistry under neat conditions. Nitrogen bicyclic bases, that previously showed to enhance the reactivity of DMC in methoxycarbonylation reaction by BAc2 mechanism, are herein used for the first time as efficient catalysts for cyclization reaction encompassing both BAc2 and BAl2 pathways. This synthetic procedure was also applied to a large scale synthesis of cyclic sugars isosorbide and isomannide starting from D-sorbitol and D-mannitol, respectively. The resulting anhydro sugar alcohols were obtained as pure crystalline compounds that did not require any further purification or crystallization.

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Larger scale synthesis of isosorbide: In a round bottom flask equipped with a reflux condenser, D-sorbitol (0.05 mol, 1.00 mol. eq.), DMC (0.44 mol, 8.00 mol. eq.), DBU (2.70 mmol, 0.05 mol. eq.) and MeOH (20.00 mL) were heated at reflux while stirring. The progress of the reaction was monitored by NMR. After 48 hours the reaction was stopped, cooled at room temperature and the mixture was filtered over Gooch n°4. Finally, DMC was evaporated under vacuum and the product was obtained as pure in 98% yield (7.90 g, 0.05 mol). Characterization data were consistent with those obtained for the commercially available compound.

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File:Isosorbide dinitrate synthesis.png

 

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Increasing global access to the high-volume HIV drug nevirapine through process intensification


 

Increasing global access to the high-volume HIV drug nevirapine through process intensification

Green Chem., 2017, 19,2986-2991
DOI: 10.1039/C7GC00937B, Paper
Jenson Verghese, Caleb J. Kong, Daniel Rivalti, Eric C. Yu, Rudy Krack, Jesus Alcazar, Julie B. Manley, D. Tyler McQuade, Saeed Ahmad, Katherine Belecki, B. Frank Gupton
Fundamental elements of process intensification were applied to generate efficient batch and continuous syntheses of the high-volume HIV drug nevirapine.

Green Chemistry

Increasing global access to the high-volume HIV drug nevirapine through process intensification

Abstract

Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.

Preparation of Nevirapine (1).

Preparation of CYCLOR (7), Step 1A: To a solution of CAPIC (2, 15 g, 105 mmole, 1.0 equiv) in diglyme (75 mL) in a 500 mL 3-neck round-bottom flask fitted with overhead stirrer, thermocouple, and addition funnel was added NaH (7.56g, 189 mmole, 1.8 equiv). The reaction mixture was stirred at room temperature for 30 minutes and gradual evolution of H2 gas was observed. The temperature of the reaction mixture was slowly increased to 60 °C (10 °C/hr increments). A preheated (55 °C) solution of MeCAN (5, 21.19 g, 192.2 mmol, 1.05 equiv) in diglyme (22.5 mL) was added over a period of an hour to the reaction mixture kept at 60 °C. The reaction mixture was allowed to stir at 60 °C for 2 hours. If desired, 7 may be isolated at this stage. The reaction mixture is cooled to 0 – 10 °C and the pH is adjusted to pH 7-8 using glacial acetic acid and stirred for an hour. The precipitate is collected by vacuum filtration and dried under vacuum to a constant weight to afford CYCLOR (7) (29.89g, 94%).

1H NMR (300MHz, CHLOROFORM-d)  = 8.44 (dd, J = 1.8, 5.3 Hz, 1 H), 8.21 (d, J = 4.7 Hz, 1 H), 8.15 (br. s., 1 H), 7.87 (dd, J = 2.1, 7.9 Hz, 1 H), 7.54 (s, 1 H), 7.20 (d, J = 5.3 Hz, 1 H), 6.66 (dd, J = 4.7, 7.6 Hz, 1 H), 2.95 – 2.84 (m, 1 H), 2.35 (s, 3 H), 0.91 – 0.77 (m, 2 H), 0.62 – 0.47 (m, 2 H).

13C NMR (75MHz, CHLOROFORM-d)  = 166.8, 159.2, 153.2, 148.3, 146.9, 136.0, 129.9, 125.1, 111.1, 108.4, 77.4, 76.6, 23.8, 18.8, 7.0.

HRMS (ESI) C15H15ClN4O m/z [M+H] + found 303.0998, expected 303.1012.

Preparation of nevirapine (1), Step 1B: In a 150 mL, 3 neck flask, fitted with overhead stirrer, thermocouple and addition funnel, a suspension of NaH (7.14 g, 178.5 mmol, and 1.7 equiv) in diglyme (22.5 ml) was heated to 105 °C and crude CYCLOR (7) reaction mixture from Step 1 (preheated to 80 °C) was added over a period of 30 minutes while maintaining the reaction mixture at 115 °C. The reaction mixture was stirred for 2 hours at 117 °C for ~2 hours then cooled to room temperature. Water (30 mL) was added to quench the excess sodium hydride and the reaction was concentrated in vacuo to remove 60 mL of diglyme. To the resulting suspension was added water (125 mL), cyclohexane (50 mL) and ethanol (15 mL). The pH of the mixture was adjusted to pH 7 using glacial acetic acid (19.5 g, 3.09 mmol) at which precipitate formed. After stirring for 1 hour at 0 °C, the precipitate was collected via vacuum filtration and the filter cake was washed with ethanol: water (1:1 v/v) (2 x 20 mL). The solid was dried between 90-110°C under vacuum to provide nevirapine (25.4 g, 91% over two steps).

1H NMR (400MHz, CDCl3)  = 8.55 (dd, J = 2.0, 4.8 Hz, 1 H), 8.17 (d, J = 5.0 Hz, 1 H), 8.13 (dd, J = 2.0, 7.8 Hz, 1 H), 7.61 (s, 1 H), 7.08 (dd, J = 4.8, 7.8 Hz, 1 H), 6.95 (dd, J = 0.6, 4.9 Hz, 1 H), 3.79 (tt, J = 3.6, 6.8 Hz, 1 H), 2.37 (s, 3 H), 1.07-0.93 (m, 2 H), 0.59-0.50 (m, 1 H), 0.50-0.41 (m, 1 H).

13C NMR (101MHz, CDCl3)  = 168.4, 160.5, 153.9, 152.1, 144.3, 140.3, 138.8, 124.8, 121.9, 120.1, 118.9, 29.6, 17.6, 9.1, 8.8.

HRMS (ESI) C15H14N4O m/z [M+H] + found 267.1239, expected 267.1245.

Purification of nevirapine. To a cooled (0 °C) suspension of nevirapine (10g, 375.5 mmole) in water (43 ml) was added a 10 M solution of HCl (11.6 ml, 117.5 mmole) dropwise. The solution was allowed to stir for 30 minutes and activated carbon (0.3g) was added. After stirring for 30 minutes, the solution was filtered over Celite. The filtrate was transferred to flask and cooled to 0 °C. A 50% solution of NaOH was added dropwise until a pH of 7 is reached. A white precipitate appeared and the solution was stirred for 30 minutes and filtered. The solid was washed with water (3 x 10ml). The wet cake was dried between 90-110°C under vacuum to a constant weight to provide nevirapine (9.6 g, 96%).

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Enantioselective synthesis of a cyclobutane analogue of Milnacipran


(1R,2S)-2-(Aminomethyl)-N,N-diethyl-1 phenylcyclobutanecarboxamide (19)

1 H NMR (CDCl3) δ 7.36–7.33 (m, 4H), 7.25–7.21 (m, 1H), 3.51–3.43 (qd, J = 13.8 Hz, 6.8 Hz, 1H), 3.15–2.87 (m, 7H), 2.81–2.72 (m, 2H), 2.23–2.14 (m, 1H), 2.04–1.97 (m, 1H), 1.62 (tdd, J = 10.5 Hz, 5.7 Hz, 2.6 Hz, 1H), 1.07 (t, J = 7.1 Hz, 3H), 0.35 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (CDCl3) δ 172.7, 143.3, 128.8, 126.4, 125.3, 54.6, 44.4, 42.4, 41.0, 39.5, 31.1, 19.0, 12.2, 12.0 ppm;

IR (neat) 3364, 1622, 1437, 905, 728 cm−1 ;

[α] 20 D +1.5 (c 0.5, CHCl3) (lit.5 [α]D +0.84);

ESI-MS (ES+ ) 261 [M + H]+ ; HRMS m/z calcd for C16H25N2O: 261.1958, found: 261.1961;

chiral HPLC (CHIRALCEL OJ-RH 150 × 4.6 mm, H2O/MeOH 35 : 65, flow rate 1 mL min−1 , detection at 254 nm), tmajor = 8.5 min, tminor = 6.7 min, er 95 : 5. Of note, compound 19 was acetylated with acetic anhydride/NEt3 prior to HPLC analysis.

5 S. Cuisiat, A. Newman-Tancredi, O. Vitton and B. Vacher, WO patent, 112597, 2010

Enantioselective synthesis of a cyclobutane analogue of Milnacipran

Org. Chem. Front., 2017, Advance Article
DOI: 10.1039/C7QO00140A, Research Article
Dinh-Vu Nguyen, Edmond Gravel, David-Alexandre Buisson, Marc Nicolas, Eric Doris
An optically active cyclobutane analogue of Milnacipran was synthesized from phenylacetonitrile, and its cis-stereochemistry was controlled by an epimerization step.

Enantioselective synthesis of a cyclobutane analogue of Milnacipran

aService de Chimie Bioorganique et de Marquage (SCBM), CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France

Abstract

The asymmetric synthesis of a cyclobutane analogue of the antidepressant drug Milnacipran is reported. The optically active derivative incorporates a central cyclobutane ring in lieu of the cyclopropane unit classically found in Milnacipran. The two stereogenic centres borne by the cyclobutane were sequentially installed starting from phenylacetonitrile.

Graphical abstract: Enantioselective synthesis of a cyclobutane analogue of Milnacipran
//////////Enantioselective, cyclobutane analogue  Milnacipran

Review, Continuous Processing


Continuous Processing

Continuous production is a flow production method used to manufacture, produce, or process materials without interruption. Continuous production is called a continuous process or a continuous flow process because the materials, either dry bulk or fluids that are being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production.

Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Some chemical plants can operate for more than one or two years without a shutdown. Blast furnaces can run four to ten years without stopping.[1]

Production workers in continuous production commonly work in rotating shifts.

Processes are operated continuously for practical as well as economic reasons. Most of these industries are very capital intensive and the management is therefore very concerned about lost operating time.

Shutting down and starting up many continuous processes typically results in off quality product that must be reprocessed or disposed of. Many tanks, vessels and pipes cannot be left full of materials because of unwanted chemical reactions, settling of suspended materials or crystallization or hardening of materials. Also, cycling temperatures and pressures from starting up and shutting down certain processes (line kilns, boilers, blast furnaces, pressure vessels, etc.) may cause metal fatigue or other wear from pressure or thermal cycling.

In the more complex operations there are sequential shut down and start up procedures that must be carefully followed in order to protect personnel and equipment. Typically a start up or shut down will take several hours.

Continuous processes use process control to automate and control operational variables such as flow rates, tank levels, pressures, temperatures and machine speeds.[2]

Semi-continuous processes

Many processes such as assembly lines and light manufacturing that can be easily shut down and restarted are today considered semi-continuous. These can be operated for one or two shifts if necessary.

History

The oldest continuous flow processes is the blast furnace for producing pig iron. The blast furnace is intermittently charged with ore, fuel and flux and intermittently tapped for molten pig iron and slag; however, the chemical reaction of reducing the iron and silicon and later oxidizing the silicon is continuous.

Semi-continuous processes, such as machine manufacturing of cigarettes, were called “continuous” when they appeared.

Many truly continuous processes of today were originally batch operations.

The Fourdrinier paper machine, patented in 1799, was one of the earliest of the industrial revolution era continuous manufacturing processes. It produced a continuous web of paper that was formed, pressed, dried and reeled up in a roll. Previously paper had been made in individual sheets.

Another early continuous processes was Oliver Evans‘es flour mill (ca. 1785), which was fully automated.

Early chemical production and oil refining was done in batches until process control was sufficiently developed to allow remote control and automation for continuous processing. Processes began to operate continuously during the 19th century. By the early 20th century continuous processes were common.

Shut-downs

In addition to performing maintenance, shut downs are also when process modifications are performed. These include installing new equipment in the main process flow or tying-in or making provisions to tie-in sub-processes or equipment that can be installed while the process is operating.

Shut-downs of complicated processes may take weeks or months of planning. Typically a series of meetings takes place for co-ordination and planning. These typically involve the various departments such as maintenance, power, engineering, safety and operating units.

All work is done according to a carefully sequenced schedule that incorporates the various trades involved, such as pipe-fitters, millwrights, mechanics, laborers, etc., and the necessary equipment (cranes, mobile equipment, air compressors, welding machines, scaffolding, etc.) and all supplies (spare parts, steel, pipe, wiring, nuts and bolts) and provisions for power in case power will also be off as part of the outage. Often one or more outside contractors perform some of the work, especially if new equipment is installed.

Safety

Safety meetings are typically held before and during shutdowns. Other safety measures include providing adequate ventilation to hot areas or areas where oxygen may become depleted or toxic gases may be present and checking vessels and other enclosed areas for adequate levels of oxygen and insure absence of toxic or explosive gases. Any machines that are going to be worked on must be electrically disconnected, usually through the motor starter, so that it cannot operate. It is common practice to put a padlock on the motor starter, which can only be unlocked by the person or persons who is or are endangered by performing the work. Other disconnect means include removing couplings between the motor and the equipment or by using mechanical means to keep the equipment from moving. Valves on pipes connected to vessels that workers will enter are chained and locked closed, unless some other means is taken to insure that nothing will come through the pipes.

Continuous processor (equipment)

Continuous Production can be supplemented using a Continuous Processor. Continuous Processors are designed to mix viscous products on a continuous basis by utilizing a combination of mixing and conveying action. The Paddles within the mixing chamber (barrel) are mounted on two co-rotating shafts that are responsible for mixing the material. The barrels and paddles are contoured in such a way that the paddles create a self-wiping action between themselves minimizing buildup of product except for the normal operating clearances of the moving parts. Barrels may also be heated or cooled to optimize the mixing cycle. Unlike an extruder, the Continuous Processor void volume mixing area is consistent the entire length of the barrel ensuring better mixing and little to no pressure build up. The Continuous Processor works by metering powders, granules, liquids, etc. into the mixing chamber of the machine. Several variables allow the Continuous Processor to be versatile for a wide variety of mixing operations:[3]

  1. Barrel Temperature
  2. Agitator speed
  3. Fed rate, accuracy of feed
  4. Retention time (function of feed rate and volume of product within mixing chamber)

Continuous Processors are used in the following processes:

  • Compounding
  • Mixing
  • Kneading
  • Shearing
  • Crystallizing
  • Encapsulating

The Continuous Processor has an unlimited material mixing capabilities but, it has proven its ability to mix:

  • Plastics
  • Adhesives
  • Pigments
  • Composites
  • Candy
  • Gum
  • Paste
  • Toners
  • Peanut Butter
  • Waste Products

EXAMPLE…………….

Abstract Image

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Org. Process Res. Dev., 2014, 18 (11), pp 1427–1433
Figure

EXAMPLE…………….


Correia et al. have published a three-step flow synthesis of rac-Effavirenz. This short synthetic route begins with cryogenic trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO3)2 and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO3)2, Cu(OTf)2 was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date
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1H NMR (400 MHz, CDCl3, ppm) δ9.45 (s, 1H), 7.49 (s, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.43-1.36 (m, 1H); 0.93-0.85 (m, 4H);
STR1
13C NMR (100 MHz, CDCl3, ppm) δ 149.2, 133.2, 131.7, 129.2, 127.8, 122.1 (q, JC-F = 286 Hz), 116.3, 115.1, 95.9, 79.6 (q, JC-F = 35 Hz), 66.1, 8.8, 0.6;
STR1
19F NMR (376 MHz, CDCl3, ppm) δ -80.98.
1 T. J. Connolly; A. W.-Y Chan; Z. Ding; M. R. Ghosh; X. Shi; J. Ren, E. Hansen; R. Farr; M. MacEwan; A. Alimardanov; et al, PCT Int. Appl. WO 2009012201 A2 20090122, 2009.
2 (a) Z. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, (Lonza Ltd), PCT Int. Appl. WO2012097510, 2012; (b) D. D. Christ; J. A. Markwalder; J. M. Fortunak; S. S. Ko; A. E. Mutlib; R. L. Parsons; M. Patel; S. P. Seitz, PCT Int. Appl. WO 9814436 A1 19980409, 1998 (c) C. A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517−3521.
Angewandte Chemie International Edition
( Angew. Chem., Int. Ed. 2015,54, 4945−4948).

Volume 54, Issue 16April 13, 2015 Pages 4945–4948

A Concise Flow Synthesis of Efavirenz

  • DOI: 10.1002/anie.201411728
SUPP INFO
STR1
STR1

 NEXT EXAMPLE…………….

 

Wang et al. developed a flow process that uses metal catalyzed hydrogenation of NAB (2-nitro-2′-hydroxy-5′-methylazobenzene) to BTA (2-(2′-hydroxy-5′-methylphenyl)benzotriazole), a commonly used ultraviolet absorber. The major challenge in this process was to optimize the reduction of the diazo functionality over the nitro group and control formation of over reduction side products. The initial screen of metals adsorbed onto a γ-Al2O3 support indicated Pd to be superior to the other metals and also confirmed that catalyst preparation plays an important role in selectivity. To better understand the characteristics of the supported metal catalyst systems, the best performing were analyzed by TEM, XRD, H2-TPR, and N2 adsorption–desorption. Finally, solvents and bases were screened ultimately arriving at the optimized conditions using toluene, 2 equiv n-butylamine over 1% Pd/Al2O3, which provided 90% yield BTA in process with 98% conversion. The process can run over 200 h without a decrease in performance
( ACS Sustainable Chem. Eng. 2015, 3,1890−1896)
.
Abstract Image

The synthesis of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole from 2-nitro-2′-hydroxy-5′-methylazobenzene over Pd/γ-Al2O3 in a fixed-bed reactor was investigated. Pd/γ-Al2O3 catalysts were prepared by two methods and characterized by XRD, TEM, H2-TPR, and N2 adsorption–desorption. Employed in the above reaction, the palladium catalyst impregnated in hydrochloric acid exhibited much better catalytic performance than that impregnated in ammonia–water, which was possibly attributed to the better dispersion of palladium crystals on γ-Al2O3. This result demonstrated that the preparation process of the catalyst was very important. Furthermore, the reaction parameters were optimized. Under the optimized conditions (toluene, NAB/triethylamine molar ratio 1:2, 60 °C, 2.5 MPa hydrogen pressure, 0.23 h–1 liquid hourly space velocity), about 90% yield of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole was obtained. Finally, the time on stream performance of the catalyst was evaluated, and the reaction could proceed effectively over 200 h without deactivation of the catalyst.

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al2O3 by a Continuous Process

ACS Sustainable Chem. Eng., 2015, 3 (8), pp 1890–1896
DOI: 10.1021/acssuschemeng.5b00507
Publication Date (Web): July 06, 2015

NEXT EXAMPLE…………….

 

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

continuous flow processing of organometallic reagents

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

https://www.vapourtec.com/flow-chemistry-resource-centre/publications-citing-vapourtec/continuous-flow-processing-of-organometallic-reagents-using-an-advanced-peristaltic-pumping-system-and-the-telescoped-flow-synthesis-of-ez-tamoxifen/

NEXT EXAMPLE…………….

 

Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

A versatile multi-step continuous flow synthesis for the preparation of substituted pyrazoles is presented.

The automated synthesis utilises a metal-free ascorbic acid mediated reduction of diazonium salts prepared from aniline starting materials followed by hydrolysis of the intermediate hydazide and cyclo-condensation with various 1,3-dicarbonyl equivalents to afford good yields of isolated functionalised pyrazole products.

The synthesis of the COX-2 selective NSAID was demonstrated using this approach.

NEXT EXAMPLE…………….

 

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

NEXT EXAMPLE…………….

 

RAFT RAFT (Reversible Addition Fragmentation chain Transfer), a type of controlled radical polymerization, was invented by CSIRO in 1998 but developed in partnership with DuPont over a long term collaboration. Conventional polymerisation is fast but gives a wide distribution of polymer chain lengths. (known as a high polydispersity index ). RAFT is more versatile than other living polymerization techniques, such as atom transfer radical polymerization (ATRP) or nitroxide-mediated polymerization (NMP), it not only leads to polymers with a low polydispersity index and a predetermined molecular weight, but it permits the creation of complex architectures, such as linear block copolymers, comblike, star, brush polymers and dendrimers. Monomers capable of polymerizing by RAFT include styrenes, acrylates, acrylamides, and many vinyl monomers. CSIRO is the owner of the RAFT patents and is actively commercialising the technology. There are 12 licences in force and CSIRO is pursuing interest in a number of fields including human health, agriculture, animal health and personal care. RAFT is the dominant polymerization technique for the creation of polymer-protein or polymer-drug conjugates, permitting (for example) the combination of a polymer exhibiting high solubility with a drug molecule with poor solubility.. Though RAFT can be carried out in batch, it also lends itself to continuous flow processing, as this processing method offers an easy and reproducible scale-up route of the oxygen sensitive RAFT process. The possibility to effectively exclude oxygen using continuous flow reactors in combination with inline degassing methods offers advantages over batch processing at scales beyond the laboratory environment. Challenges associated with the high viscosity of the polymer product solution can be controlled using pressuriseable continuous flow reactor systems. http://www.csiro.au/products/RAFT.html
STR1

Examples………..

Cyclohexaneperoxycarboxylic acid (6,  has been developed as a safe, inexpensive oxidant, with demonstrated utility in a Baeyer−Villiger rearrangement.34 Solutions of cyclohexanecarboxylic acid in hexane and 50% aqueous H2O2 were continuously added to 45% H2SO4 at 50−70 °C and slightly reduced pressure. The byproduct H2O was removed azeotropically, and the residence time in the reactor was 3 h. Processing was adjusted to maintain a concentration of 6 at 17−19%, below the detonable level, and the product was kept as a stable solution in hexane. These operations enhanced the safety margin in preparing 6.

figure

Scheme .  Generation of cyclohexaneperoxycarboxylic acid

Examples………..

Abstract Image

The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4,d-erythronolactone at kilogram scale was used as an example. Fully continuousprocessing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Org. Process Res. Dev., 2012, 16 (5), pp 1003–1012

Examples………..

Abstract Image

Continuous Biocatalytic Processes

Org. Process Res. Dev., 2009, 13 (3), pp 607–616
Figure
Scheme . Biotransformation of sodium l-glutamate to γ-aminobutyric acid (GABA) by single-step α-decarboxylation with glutamate decarboxylase

PICS…………..

References

  1.  American Iron and Steel Institute
  2.  Benett, Stuart (1986). A History of Control Engineering 1800-1930. Institution of Engineering and Technology. ISBN 978-0-86341-047-5.
  3.  Ziegler, Gregory R.; Aguilar, Carlos A. (2003). “Residence Time Distribution in a Co-rotating, Twin-screw Continuous Mixer by the Step Change Method”. Journal of Food Engineering(Elsevier) 59 (2-3): 1–7.

Sources and further reading

  • R H Perry, C H Chilton, C W Green (Ed), Perry’s Chemical Engineers’ Handbook (7th Ed), McGraw-Hill (1997), ISBN 978-0-07-049841-9
  • Major industries typically each have one or more trade magazines that constantly feature articles about plant operations, new equipment and processes and operating and maintenance tips. Trade magazines are one of the best ways to keep informed of state of the art developments.

FDA approved a switchover from batch to the new technology for production of HIV drug Prezista, Darunavir on a line at its plant in Gurabo, Puerto Rico


Above is an Illustration example,

FDA urges companies to get on board with continuous manufacturing

The FDA gave Johnson & Johnson’s ($JNJ) Janssen drug unit the thumbs up last week for the continuous manufacturing process that it has been working on for 5 years. The agency approved a switchover from batch to the new technology for production of HIV drug Prezista on a line at its plant in Gurabo, Puerto Rico……http://www.fiercepharma.com/manufacturing/fda-urges-companies-to-get-on-board-continuous-manufacturing

Darunavir
Darunavir structure.svg
Darunavir ball-and-stick animation.gif

SEE……http://www.en-cphi.cn/news/show-29367.html

Just after opening a refurbished manufacturing facility in Cape Town, South Africa earlier this year, pharma giant Johnson & Johnson ($JNJ) recently opened the doors to its Global Public Health Africa Operations office there.

The company has invested $21 million (300 million rand) in the facilities. The global public health facility will focus on HIV, tuberculosis and maternal, newborn and child health, South Africa – The Good News reported.

“This (investment) tells us that South Africa has the capability to provide a facility for world-class manufacturing,” Rob Davies, minister of the Department of Trade and Industry told the publication.

Johnson & Johnson, which has operated in South Africa for more than 86 years, planned to close the Cape Town manufacturing plant by the end of 2008 but was persuaded to keep the facility open for local manufacturing to serve sub-Saharan business. By 2015, the plant was cited by J&J as the most-improved in cost competitiveness from 30 company plants worldwide.

Earlier this month, the FDA gave J&J’s Janssen drug unit the go-ahead to proceed with the continuous manufacturing process it’s been working on for 5 years. The agency approved a switchover from batch to the new technology for production of HIV drug Prezista, Darunavir on a line at its plant in Gurabo, Puerto Rico.

AN EXAMPLE NOT RELATED TO DARUNAVIR

References

May 20-21, 2014    (Link to 2016 Meeting Website)

Continuous Bioprocessing

https://iscmp.mit.edu/white-papers/white-paper-4

READ

Achieving Continuous Manufacturing: Technologies and Approaches for Synthesis, Work-Up and Isolation of Drug Substance

https://iscmp.mit.edu/white-papers/white-paper-1

//////

 

 

//////FDA, HIV drug,  Prezista, Darunavir, Gurabo, Puerto Rico

Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED


250px

 

WO2016016774, CRYSTALLINE FORMS OF CANAGLIFLOZIN

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

SANTRA, Ramkinkar; (IN).
NAGDA, Devendra, Prakash; (IN).
THAIMATTAM, Ram; (IN).
ARYAN, Satish, Kumar; (IN).
SINGH, Tarun, Kumar; (IN).
PRASAD, Mohan; (IN).
GANGULY, Somenath; (IN).
WADHWA, Deepika; (IN)

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus. A crystalline Form R1of canagliflozin emihydrate. The crystalline Form R1 of canagliflozin hemihydrate of claim 1, characterized by an X-ray powder diffraction peaks having d-spacing values at about 3.1, 3.7, 4.6, and 8.9 A

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus.

Canagliflozin hemihydrate, chemically designated as (l<S)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Its chemical structure is represented by Formula I.

Formula I

U.S. Patent Nos. 7,943,582 and 8,513,202 disclose crystalline forms of canagliflozin hemihydrate.

PCT Publication No. WO 2009/035969 discloses a crystalline form of

canagliflozin, designated as I-S.

PCT Publication No. WO 2013/064909 discloses crystalline complexes of canagliflozin with L-proline, D-proline, and L-phenylalanine, and the processes for their preparation.

PCT Publication No. WO 2014/180872 discloses crystalline non-stoichiometric hydrates of canagliflozin (HxA and HxB), and the process for their preparation.

PCT Publication No. WO 2015/071761 discloses crystalline Forms B, C, and D of canagliflozin.

Chinese Publication Nos. CN 103980262, CN 103936726, CN 103936725, CN 103980261, CN 103641822, CN 104230907, CN 104447722, CN 104447721, and CN 104130246 disclose different crystalline polymorphs of canagliflozin.

In the pharmaceutical industry, there is a constant need to identify critical physicochemical parameters of a drug substance such as novel salts, polymorphic forms, and co-crystals, that affect the drug’s performance, solubility, and stability, and which may play a key role in determining the drug’s market acceptance and success.

The discovery of new forms of a drug substance may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification. Accordingly, the present invention provides novel crystalline forms of canagliflozin having enhanced stability over known crystalline forms of canagliflozin.

 

EXAMPLES

Example 1 : Preparation of a crystalline Form Rl of canagliflozin hemihydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours to obtain a solid. The solid was further dried under vacuum at 60°C for 6 hours.

Yield: 4.71 g

Example 2: Preparation of a crystalline Form R2 of canagliflozin monohydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours at room temperature.

Yield: 4.71 g

Example 3 : Preparation of a crystalline Form R2 of canagliflozin monohydrate

Canagliflozin hemihydrate (0.15 g; Form Rl obtained as per Example 1) was suspended in de-ionized water (3 mL). The suspension was stirred at room temperature for 24 hours. The reaction mixture was filtered, then dried at room temperature under vacuum for 5 hours.

Yield: 0.143 g

Example 4: Preparation of a crystalline Form R3 of canagliflozin hydrate

Amorphous canagliflozin (100 g) was suspended in an aqueous solution of sodium formate (1224 g of sodium formate in 1600 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water

(2000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for one hour. De-ionized water (1000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for another one hour. The reaction mixture was filtered, then washed with de-ionized water (6000 mL), and then dried under vacuum for 30 minutes to obtain a solid. The solid was then dried under vacuum at 30°C to 35°C until a water content of 8% to 16% was attained.

Yield: 100 g

Sun Pharma's Dilip Shanghvi has become the stuff of legends

From top left: Abhay Gandhi (CEO-India Business-Sun Pharma), Kal Sundaram (CEO-TARO). Middle row (L-R): Israel Makov (chairman, Sun Pharma), Dilip Shanghvi (Founder and MD, Sun Pharma) Uday Baldota (CFO, Sun Pharma). Bottom: Kirti Ganorkar (Senior VP, Business development, Sun Pharma)

 

./////////////Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

Continuous ruthenium-catalyzed methoxycarbonylation with supercritical carbon dioxide


 

Catal. Sci. Technol., 2016, Advance Article
DOI: 10.1039/C5CY01883H, Paper
Stefan Christiaan Stouten, Timothy Noel, Qi Wang, Matthias Beller, Volker Hessel
The methoxycarbonylation of cyclohexene with carbon dioxide over a ruthenium catalyst was realized in a micro flow system under supercritical conditions.
Continuous ruthenium-catalyzed methoxycarbonylation with supercritical carbon dioxide
The methoxycarbonylation of cyclohexene with carbon dioxide over a ruthenium catalyst was realized in a micro flow system under supercritical conditions. Instead of the toxic and flammable carbon monoxide, this process utilizes carbon dioxide, thereby avoiding issues with bulk transportation of carbon monoxide as well as eliminating the need for safety precautions associated with the use of carbon monoxide. Obtained was a 77% yield of the ester product at 180 °C, 120 bar and with a 90 min residence time, which is over five times faster than for the same reaction performed under subcritical conditions in batch. An important factor for the performance of the system was to have a sufficiently polar supercritical mixture, allowing the catalyst to dissolve well. The optimal temperature for the reaction was 180 °C, as the activity of the system dropped considerably at higher temperatures, most likely due to catalyst deactivation.

Department of Chemical Engineering and Chemistry

ir. S.C. (Stefan) Stouten –

Stouten, ir. S.C.
Address:
Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN
Department:
Department of Chemical Engineering and Chemistry
Section:
Micro Flow Chemistry and Process Technology
Positioncategory:
doctoral candidate (PhD) (PhD Stud.)
Position:
doctoral candidate
Room:
STW 0.
Email:
s.stouten@tue.nl

 

 

 

Volker Hessel

prof.dr. V. (Volker) Hessel

Hessel, prof.dr. V.
Address:
Technische Universiteit Eindhoven
P.O. Box 513
5600 MB EINDHOVEN
Chair:
Micro Flow Chemistry and Process Technology
Department:
Department of Chemical Engineering and Chemistry
Section:
Micro Flow Chemistry and Process Technology
Positioncategory:
Professor (HGL)
Position:
Full Professor
Room:
STW 1.45
Tel:
+31 40-247 2973
Tel (internal):
2973
Email:
v.hessel@tue.nl

////////Continuous,  ruthenium-catalyzed,  methoxycarbonylation, supercritical carbon dioxide, flow reactor

Ezetimibe NMR


syn2

Ezetimibe

 

 

 

 

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
J. Org. Chem., 2013, 78 (14), pp 7048–7057
Figure

Ezetimibe (1)

 ezetimibe 1 (1.08 g, 80%) as a white solid.
Mp 164–166 °C [lit.(11) 155–157 °C];
99% ee;
[α]20D −28.1 (c 0.15, MeOH) [lit.(11) −32.6 (c 0.34, MeOH)];
1H NMR (600 MHz, DMSO-d6) δ 9.49 (1H, s), 7.28–7.24 (2H, m), 7.19–7.16 (4H, m), 7.11–7.07 (4H, m), 6.75–6.71 (2H, m), 5.25 (1H, d, J 4.3 Hz), 4.77 (1H, d, J 2.2 Hz), 4.49–4.59 (1H, m), 3.07–3.04 (1H, m) 1.84–1.66 (4H, m);
13C NMR (150 MHz, CDCl3) δ 167.8, 162.3, and 160.7 (d, JC–F 240.3 Hz), 159.3, 157.9, 157.7, 142.5, 134.4, 128.7, 128.3, 128.0, 127.9, 118.7, and 118.6 (d, JC–F 8.1 Hz), 116.3, 116.2, 115.2, and 115.0 (d, JC–F 20.7 Hz), 71.5, 60.0, 59.9, 36.8, 24.9;
HRMS (EI, TOF) m/z calcd for C24H21F2NO3 [M] 409.1489 found 409.1478. Anal. Calcd for C24H21F2NO3: C 70.41, H 5.17, F 9.28, N 3.42. Found: C 70.46, H 5.23, F 9.24, N 3.34.

(3S,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3′-hydroxypropyl)azetidin-2-one (20)

Method 1

To a cooled (0 °C) solution of lactone 19 (2.0 g, 4 mmol) in 160 mL of dry diethyl ether was added 12 mL of 1 M solution of t-BuMgCl in diethyl ether. After 2 h, 30 mL of aq NH4Cl was added. The aqueous layer was extracted with ether (160 mL), the organic layer was washed with satd NaHCO3 (50 mL) and dried (MgSO4), and the solvent was removed under reduced pressure. Crude product 20 (1.64 g, 82%) obtained as a yellowish solid was used in the next step without further purification. An analytic sample was obtained by chromatography on silica gel (hexanes/ethyl acetate 7:3). Mp 130–133 °C [lit.(11) 132–134 °C]; [α]20D −42.2 (c 1.2, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.42–7.20 (11H, m), 7.02–6.90 (6H, m), 5,04 (2H, s), 4.72–4.68 (1H, m), 4.55 (1H, d J 2.2 Hz), 3.07 (1H, dt J 7.1, 2.2 Hz), 2.05–1.93 (3H, m) 1.89–1.82 (2H, m); 13C NMR (150 MHz, CDCl3) δ 167.6, 163.0, and 161.4 (d, JC–F 244.2 Hz), 159.8 and 158.1 (d, JC–F 241.8 Hz), 159.0, 140.0, 139.9, 136.6, 133.9, and 133.8 (d, JC–F 2.9 Hz), 129.6, 128.6, 128.1, 127.5, 127.4 and 127.4, (d, JC–F 8.0 Hz), 127.2, 118.4, 118.3, 115.8, 115.8, and 115.7 (d, JC–F 22.0 Hz), 115.5, 115.4, and 115.3 (d, JC–F 21.3 Hz), 73.3, 70.1, 61.1, 60.3, 36.5, 25.0; HRMS (ESI, TOF) m/z calcd for C31H27F2NO3Na [M + Na]+ 522.1851, found 522.1862; IR (KBr) v 3441, 1743, 1609, 1510 cm–1. Anal. Calcd for C31H27F2NO3: C 74.53, H 5.45, N 2.80, F 7.61. Found: C 74.40, H 5.53, N 2.74, F 7.56.
Abstract Image
Org. Process Res. Dev., 2009, 13 (5), pp 907–910
DOI: 10.1021/op900039z
Figure

Preparation of 1-(4-Fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone 1 (Ezetimibe)

 of compound 1. 1H NMR (300 MHz, DMSO-d6, δ) 1.72−1.84 (m, 4H), 3.08 (m, 1H), 4.45 (m, 1H), 4.8 (d, 1H, J = 2.0 Hz), 5.25 (d, 1H, J = 4.8), 6.75 (d, 2H, J = 8.4 Hz), 7.05−7.4 (m, 10H, Ar), 9.48 (s, 1H); IR: 3270.0, 2918, 1862, 1718.4, 1510 cm−1. MS: m/z 409.2 (M+). Anal. Calcd for C15H17NO5: C, 70.41; H, 5.17; N, 3.42. Found: C, 70.38; H, 5.27; N, 3.34.

Preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 10

compound 9 as a white solid. 1H NMR (200 MHz, DMSO-d6, δ) 1.6−1.9 (m, 4H), 2.0−2.2 (bs, 1H), 3.0−3.2 (m, 1H), 4.4−4.6 (m, 1H), 4.74 (m, 1H), 5.05 (s, 2H), 6.95−7.9 (m, 17H, Ar); IR: 3492, 2922, 2852, 1719 cm−1; MS: m/z 499.3 (M+).
 ….

Synthesis of ezetimibe and desfluoro ezetimibe impurity.

Scheme 1.

Synthesis of ezetimibe and desfluoro ezetimibe impurity.

Comparison of 1H, 13C and 19F NMRs of ezetimibe and desfluoro ezetimibe ...

Fig. 4.Structures of ezetimibe, desfluoro impurity and intermediates.

Fig. 2.

Structures of ezetimibe, desfluoro impurity and intermediates.

 

 

Comparison of 1H, 13C and 19F NMRs of ezetimibe and desfluoro ezetimibe impurity.

Table 2.1H and 13C NMR assignments for Eze-1 and desfluoro Eze-1.

Positiona 1H–δ ppm


13C–δ ppm (DEPT)


Eze-1b Desfluoro Eze-1b Eze-1b Desfluoro Eze-1b
1 10.15 (br, OH) 10.13 (br, OH)
2 161.3 (C) 161.3 (C)
3 6.87 (d, J=8.5 Hz, 2H) 6.87 (dd, J=8.4, 1.8 Hz, 2H) 116.3 (2CH) 116.3 (2CH)
4 7.74 (d, J=8.5 Hz, 2H) 7.75 (dd, J=8.4, 1.8 Hz, 2H) 131.4 (2CH) 131.4 (2CH)
5 128.1 (C) 128.2 (C)
6 8.43 (s, 1H) 8.43 (s, 1H) 160.8 (CH) 160.8 (CH)
7 149.0 (d, 4J=2.6 Hz, C) 152.7 (C)
8 7.15–7.26 (m, 4H) 7.36 (dd, J=8.1, 7.5 Hz, 2H) 123.3 (d, 3J=8.4 Hz, 2CH) 121.6 (2CH)
9 7.17 (d, J=7.8 Hz, 2H) 116.5 (d, 2J=22 Hz, 2CH) 129.8 (2CH)
10 7.18 (t, J=6.3 Hz, 1H) 160.8 (d, 1J=242 Hz, C) 126.0 (CH)
Assignments: s: singlet; d: doublet; t: triplet; m: multiplet; br: broad singlet. Mean values used for coupled signals.

aNumbering of all compounds shown in Fig. 2 and copies of NMR spectra are presented in Appendix A.
bSolvent is DMSO-d6.

 

R-Enantiomer in Ezetimibe

R-Enantiomer in Ezetimibe

ABOVE 1H NMR OF R ENANTIOMER

Isolation and Characterization of R-Enantiomer in Ezetimibe

by K Chimalakonda – ‎2013 – ‎Related articles
HPLC1H and 13C NMR. The purity of isolated R-Isomer is about 98%. Keywords: Isolation; Characterization; (R)-Isomer; Ezetimibe; Supercritical Fluid  …
 

http://file.scirp.org/Html/10-2200417_36901.htm

1H NMR VALUES FOR R ENANTIOMER

 
13C NMR OF R ENANTIOMER
 
 



13C NMR VALUES OF R ENANTIOMER



 
 
 
IR OF R ENANTIOMER

Ezetimibe for reference
Ezetimibe
Ezetimibe
Ezetimibe.svg
Systematic (IUPAC) name
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
Clinical data
Trade names Zetia
AHFS/Drugs.com monograph
MedlinePlus a603015
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 35–65%
Protein binding >90%
Metabolism Intestinal wall, hepatic
Half-life 19–30 hours
Excretion Renal 11%, faecal 78%
Identifiers
CAS number 163222-33-1 Yes
ATC code C10AX09
PubChem CID 150311
DrugBank DB00973
ChemSpider 132493 Yes
UNII EOR26LQQ24 Yes
KEGG D01966 Yes
ChEBI CHEBI:49040 Yes
ChEMBL CHEMBL1138 Yes
Chemical data
Formula C24H21F2NO3 
Molecular mass 409.4 g·mol−1
Physical data
Melting point 164 to 166 °C (327 to 331 °F)
 Yes (what is this?)  (verify)

1H NMR OF R ENANTIOMER PREDICTED

Ezetimibe NMR spectra analysis, Chemical CAS NO. 163222-33-1 NMR spectral analysis, Ezetimibe H-NMR spectrum

13C NMR OF R ENANTIOMER PREDICTED

Ezetimibe NMR spectra analysis, Chemical CAS NO. 163222-33-1 NMR spectral analysis, Ezetimibe C-NMR spectrum
cosy

.

Ezetimibe has the chemical name 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (hereinafter referred to by its adopted name “ezetimibe”) and is structurally represented by Formula I.
Figure US20070049748A1-20070301-C00001
Ezetimibe is in a class of lipid lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related phytosterols. It is commercially available in products sold using the trademark ZETIA as a tablet for oral administration containing 10 mg of ezetimibe, and in combination products with simvastatin using the trademark VYTORIN.
U.S. Pat. No. 6,096,883 discloses generically and specifically ezetimibe and its related compounds along with their pharmaceutical compositions. The patent also describes a process for the preparation of ezetimibe.
The process described in the patent involves the use of methyl-4-(chloroformyl) butyrate and also involves isolation of the compound (3R,4S)-1-(4-fluorophenyl)-3-[3-(chloroformyl)-3-oxo-propyl]-4-(4-benzyloxyphenyl)-2-azetidinone as an intermediate. Chlorinated compounds are unstable and difficult to handle in large scale productions. The process described in the patent also involves the purification of intermediates using column chromatography, thus making the process difficult to be scaled up.
Processes for preparation of ezetimibe and its intermediates have also been described in U.S. Pat. Nos. 6,207,822, 5,856,473, 5,739,321, and 5,886,171, International Application Publication No. WO 2006/050634, and in Journal of Medicinal Chemistry 1998, 41, 973-980, Journal of Organic Chemistry 1999, 64, 3714-3718, and Tetrahedron Letters, 44(4), 801-804.

http://www.google.com/patents/US20070049748

EXAMPLE 10 PREPARATION OF 1-(4-FLUOROPHENYL)-3(R)-[3-(4-FLUOROPHENYL)-3(S)-HYDROXYPROPYL]-4(S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (FORMULA I)

50 g of (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(s)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone and 475 ml of methanol were taken into a round bottom flask. A mixture of 15 g of 5% palladium on carbon and 25 ml of water was added to it. The reaction mass was flushed with hydrogen gas and a hydrogen pressure of 3 to 5 kg/cm2 was applied. The reaction mass was stirred for 3 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the pressure was released and the reaction mass was filtered through perlite. The filter bed was washed with 100 ml of methanol. The filtrate was distilled completely at 70° C., and 400 ml of isopropanol was added to it. The reaction mass was heated to 45° C. and maintained for 10 minutes. The reaction mass was then allowed to cool to 28° C. 400 ml of water was added to the reaction mass and stirred for 1 hour, 20 minutes. The separated compound was filtered and washed with 100 ml of water. The wet cake was taken into another round bottom flask and 500 ml of chlorobenzene and 40 ml of methanol were added to it. The reaction mass was heated to 65° C. and maintained for 15 minutes. 25 ml of water was added to the reaction mass and stirred for 2 hours. The separated compound was filtered and washed with 100 ml of chlorobenzene. The wet cake was taken into another round bottom flask and 375 ml of chlorobenzene, and 30 ml of methanol were added to it. The reaction mass was heated to 62° C. and maintained for 10 minutes. The reaction mass was then cooled to 28° C. and 20 ml of water was added to it. The reaction mass was stirred for 20 minutes and then filtered and washed with 100 ml of chlorobenzene. The wet cake was taken into another round bottom flask and 400 ml of isopropanol was added to it. The reaction mass was heated to 46° C. and maintained for 15 minutes. 800 ml of water was added to the reaction mass at 45 to 46° C. and stirred for one hour. The separated solid was filtered and washed with water. The process of recrystallization in a combination of isopropanol and water was repeated and the obtained compound was dried at 70° C. for 5 hours to get 19.8 g of the title compound. (Yield 49.2%)
Purity by HPLC: 99.68%.

EXAMPLE 11 PURIFICATION OF 1-(4-FLUOROPHENYL)-3(R)-[3-(4-FLUOROPHENYL)-3(S)-HYDROXYPROPYL]-4(S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (FORMULA I)

15.0 g of ezetimibe obtained above and 120 ml of isopropanol were taken into a round bottom flask and the reaction mass was heated to 48° C. The reaction mass was filtered through a perlite bed in the hot condition to make the solution particle free. The filtrate was taken into another round bottom flask and heated to 47° C. 240 ml of water was added at 47° C. After completion of the addition, the reaction mass was maintained at 47° C. for 1 hour. The separated solid was filtered and washed with 30 ml of water. The wet compound was dried at 70° C. for 8 hours to get 13.4 g of the title compound. (Yield 89%)
Purity by HPLC: 99.92.
benzyl ezetimibe impurity: less than 0.0003 area-%,
benzyl ezetimibe diol impurity: 0.004 area-%,
lactam cleaved alcohol impurity: 0.003 area-%,
lactam cleaved acid impurity: 0.01 area-%,
ezetimibe diol impurity: less than 0.0007 area-%.
Residual solvent content by gas chromatography:
Isopropyl alcohol: 1454 ppm
All other solvents: Less than 100 ppm.
WO1997045406A1 * May 28, 1997 Dec 4, 1997 Schering Corp 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
WO2004099132A2 May 5, 2004 Nov 18, 2004 Ram Chander Aryan Process for the preparation of trans-isomers of diphenylazetidinone derivatives
WO2008032338A2 * Sep 10, 2007 Mar 20, 2008 Reddy Maramreddy Sahadeva Improved process for the preparation of ezetimibe and its intermediates
EP0720599A1 Sep 14, 1994 Jul 10, 1996 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US20070049748 Aug 25, 2006 Mar 1, 2007 Uppala Venkata Bhaskara R Preparation of ezetim
Citing Patent Filing date Publication date Applicant Title
US7470678 Jul 1, 2003 Dec 30, 2008 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684 Apr 25, 2007 Nov 30, 2010 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265 Jun 19, 2006 Jan 4, 2011 Astrazeneca Ab N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine, used as anticholesterol agents
US7871998 Dec 21, 2004 Jan 18, 2011 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048 Jun 21, 2006 Feb 22, 2011 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502 Jun 21, 2006 Mar 15, 2011 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US8013150 * Feb 17, 2006 Sep 6, 2011 Msn Laboratories Ltd. Process for the preparation of ezetimibe
US8383810 Dec 12, 2011 Feb 26, 2013 Merck Sharp & Dohme Corp. Process for the synthesis of azetidinones
US20110130378 * May 26, 2009 Jun 2, 2011 Lek Pharmaceuticals D.D. Ezetimibe process and composition
US20110183956 * Jul 29, 2009 Jul 28, 2011 Janez Mravljak Process for the synthesis of ezetimibe and intermediates useful therefor
EP2128133A1 May 26, 2008 Dec 2, 2009 Lek Pharmaceuticals D.D. Ezetimibe process and composition
WO2008096372A2 * Feb 6, 2008 Aug 14, 2008 Pranav Gupta Process for preparing highly pure ezetimibe using novel intermediates
WO2009150038A1 May 26, 2009 Dec 17, 2009 Lek Pharmaceuticals D.D. Process for the preparation of ezetimibe and composition containing it
WO2009157019A2 * Jun 23, 2009 Dec 30, 2009 Ind-Swift Laboratories Limited Process for preparing ezetimibe using novel allyl intermediates
WO2005021497A2 * Aug 27, 2004 Mar 10, 2005 Eduardo J Martinez Tethered dimers and trimers of 1,4-diphenylazetidn-2-ones
WO2006127893A2 * May 25, 2006 Nov 30, 2006 Microbia Inc Processes for production of 4-(biphenylyl)azetidin-2-one phosphonic acids
WO2008096372A2 * Feb 6, 2008 Aug 14, 2008 Pranav Gupta Process for preparing highly pure ezetimibe using novel intermediates
US20070049748 * Aug 25, 2006 Mar 1, 2007 Uppala Venkata Bhaskara R Preparation of ezetimibe
/////

Process Development for Low Cost Manufacturing


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Process Development for Low Cost Manufacturing on 23-24 nov 2015 , Hyderabad, INDIA

23.11.2015 – 24.11.2015

 

Hotel Green Park – Hyderabad, India
View Brochure
or click
https://scientificupdate.co.uk/index.php/training/scheduled-training-courses/details/213-Low-Cost-Manufacturing.html?utm_source=Scientific+Update+News&utm_campaign=d31c03d4e3-India_Courses_Hyderabad7_22_2015&utm_medium=email&utm_term=0_08c5e1fb69-d31c03d4e3-78584097

Chemical process research and development is recognised as a key function during the commercialisation of a new product particularly in the generic and contract manufacturing arms of the chemical, agrochemical and pharmaceutical industries.

The synthesis and individual processes must be economic, safe and must generate product that meets the necessary quality requirements.

This 2-day course presented by highly experienced process chemists will concentrate on the development and optimisation of efficient processes to target molecules with an emphasis on raw material cost, solvent choice, yield improvement, process efficiency and work up, and waste minimisation.

Process robustness testing and reaction optimisation via stastical methods will also be covered.

A discussion of patent issues and areas where engineering and technology can help reduce operating costs.

The use of engineering and technology solutions to reduce costs will be discussed and throughout the course the emphasis will be on minimising costs and maximising returns.

 

    • Young Chemists who have just started work in industry as development chemists
    • Organic Chemists/Medicinal Chemists in Research and Development who would like to gain an appreciation of development and scale up and who are perhaps contemplating moving into chemical development.
    • Development and Production Chemists in industry who would like to improve their efficiency and gain an insight into alternative approaches to chemical development.
    • Chemical Engineers who wish to understand a chemist’s approach to chemical development of batch processes. (Engineers would, however, need a good grounding in organic chemistry)
    • Students who are about to enter the industry and can obtain company sponsorship.
    • Experienced Chemists looking to refresh and/or augment their knowledge of chemical development
    • Analytical Chemists who wish to gain a broader appreciation of process chemistry
    • Managers who might benefit from a comprehensive and up to date overview of chemical development

    • Introduction
      Route selection, raw material choice
      • Choosing the best route
      • Using the cheapest raw materials and reagents, back integration of raw material supply
      • Reducing the number of steps vs. reagent choice / yield and cost

      Solvent selection
      • Solvent cost, recyclability
      • Solvent reactivity and solvent swapping
      • Solvent choice for reaction and work up

      Reaction optimisation
      • Reaction understanding
      • Improving conversion, selectivity
      • Telescoping

      Process optimisation
      • Reaction quench
      • Work up
      • Product isolation (crystallisation, filtration and drying)

      Statistical methods of optimisation
      • Design of experiments
      • Factorial and fractional factorial design
      • Response surface analysis
      • Robustness testing

      Regulatory and Quality issues
      • Impurity control and tracking
      • Process validation and QbD
      • Vessel cleaning

      Patent issues
      • Patents basics
      • Patent definition
      • Where patents are in force
      • How to work around patents

      Use of technology and engineering
      • Flow chemistry
      • SMB chromatography
      • Separation technologies

      At the end of the course participants will have gained:

      • A logical investigative approach to chemical development and optimisation
      • An insight into the factors involved in development and scaleup
      • A preliminary knowledge of statistical methods of optimisation
      • Improved ability to decide which parts of the chemical process to examine in detail.
      • Ideas for efficient resource allocation
      • Improved troubleshooting and problem solving ability
      • A basic outline of the patent system
      • An appreciation of how to assess the main cost contributors in a process

    • https://scientificupdate.co.uk/images/eventlist/brochures/7649_su_23-24_nov_2015_doe_hyderabad(v2f)_1433342973.pdf

///////////

Indian Generics 2016


The generic APIs market is expected to continue to rise faster than the branded/innovative APIs, by 7.7%/year to reach $30.3 billion in 2016. Asia-Pacific is expected to show the fastest growth rates (10.8%/year). The 24 fastest growing markets will include 11 in Asia-Pacific, seven in Eastern Europe and CIS, four in Africa-Middle East and two in Latin America (Figure ).

Figure  – Top growth markets for generic APIs to 2016

By 2016, China will account for 27.7% of the global generic API merchant market, while the US will have fallen to 23.8%; the mature markets as a whole will see their share fall from 41.8% in 2012 to 36.9%. India will be the third largest, with a 7.2% share.

 

 

 

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