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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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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MODANAFIL


Image result for MODAFINIL

Modafinil enantiomers.svg

MODANAFIL

Modafinil; 68693-11-8; Provigil; Modiodal; 2-[(diphenylmethyl)sulfinyl]acetamide; Modafinilum [Latin]
Molecular Formula: C15H15NO2S
Molecular Weight: 273.35 g/mol

Patent EP0966962 and Patent US2002043207.

Modafinil (INN,[6] USAN, BAN, JAN) is a wakefulness-promoting agent (or eugeroic) used for treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea.[7] It has also seen widespread off-label use as a purported cognition-enhancing agent. In English-speaking countries it is sold under the brand names Alertec, Modavigil, and Provigil. In the United States modafinil is classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns about possible addiction potential. In most other countries it is a prescription drug but not otherwise legally restricted.

Although the mechanism of action of modafinil was initially unknown, it now appears that the drug acts as a selective, relatively weak, atypical dopamine reuptake inhibitor. However, it appears that other additional mechanisms may also be at play.

Image result for MODAFINIL

History

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,[77] and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.

In 1998, modafinil was approved by the U.S. Food and Drug Administration[78] for the treatment of narcolepsy and in 2003 for shift work sleep disorder and obstructive sleep apnea/hypopnea[79] even though caffeine and amphetamine were shown to be more wakefulness promoting on the Stanford Sleepiness Test Score than modafinil.[80]

It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.

 

That’s how it went…

2-benzhydryl-sulfanylacetamide.

Diphenylbromomethane (4,95g = 0.02 moles) and thiourea (1,52g=0.02moles) were refluxed in 20mls water for 30mins. As the synth from Rh’s says, a clear solution must have been formed in 5 mins, but in the end we still had a lot of oil at the bottom (the reasion to blame was old, semidecomposed diphenylbromomethane – when we opened the can, it emitted HBr). We were too lazy to separate the oil , so 2.5g (0.04moles) KOH in 15mls water was added straight and the reflux continued for 30 more mins. A disgusting stench filled the lab.

Thus obtained solution of potassium salt of diphenylmercaptane was cooled to 50-60 C and 1.9g (0.02moles) of chloroacetamide was added thereto. The mixtr was left to its own devices for 2hours – the precipitated oil crystallized. The xtals were filtered, washed thrice w/water, thrice w/ether (removing all benzhydrol). After drying there was obtained 1.9g (37%) of  finely divided crystals with mp of 111 C.

With fresh diphenylbromomethane this will give not less than 80% – otherwise I’ll bee a reddish (this is an idiom which I am again unable to translatesmile).

Modafinil

Into the solution of 3.6g benzhydrylsulfanylacetamide (0.014moles) in 15mls of GAA there was added 3mls (~0.03moles) 30% hydrogene peroxide. The mixture was left at RT (15 Ñ in our case, better not to heat above) for 20 hrs. Then into the solution there was added 30mls aqua, scratching the walls with a glass rod. After 1 hr the precipitate was filtered, washed w/water twice, then w/ether and dried. Yield – 2,3g (61%), mp – 158-159 C. After some time the mother liquor yielded some more product but we were too lazy to work it up.

PATENT
Patent US2002183552

This is a part of the experimental section:

Preparation of isothiouronium Salt (IV).

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux {106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

Preparation of diphenylmethylthioacetamide.

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water {700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, O.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% (from diphenylmethanol.)]

20 gr. of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15 gr. of pure title compound.

Preparation of Modafinil.

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H2O2 solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H2O2 and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)].tongue

 

CLIP

Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel
Facile Synthesis and Potential Anti-Epileptic Activity

Nithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. Alexander
Neurochemical Research, Vol. 29, No. 8, August 2004 (© 2004), pp. 1481–1486

Abstract:

We report a facile procedure to synthesize racemic modafinil (diphenylmethylsulfinylacetamide), which is now being used in pharmacotherapy, and its achiral oxidized derivative (diphenylmethylsulfonyl acetamide). Modafinil is of interest more than for its potential anti-narcoleptic activity. It has also been reported to have neuroprotective properties and may potentially be effective in the enhancement of vigilance and cognitive performance. Finally, it may also protect from subclinical seizures that have been implicated as causative factors in autistic spectrum disorders and other neurodegenerative conditions. This agent can now be synthesized simply and in larger amounts than previously, making it more readily available for testing in various research modalities. The described procedure also lends itself to production of several other amides of potential interest. We are currently in the process of synthesizing and testing several new derivatives in this series. The anticonvulsant properties of modafinil and its sulfone derivative have not previously been extensively described in the literature. It may be of interest to note that the oxidized derivative of modafinil is also nontoxic and almost as effective as an anticonvulsant as the parent.

Experimental

Diphenylmethylthioacetic Acid (3)
Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed flask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H2O; the mixture was stirred under N2 for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH2Cl2 and saturated aqueous NaHCO3. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction filtration gave the 6.9 g of the acid (3, 46%), mp 125°C. Rf  0.2. Recrystallization from MeOH/H2O gave mp 126–128°C.

Diphenylmethylthioacetamide (4)
Diphenylmethylthioacetic acid (19.5 g, 0.076 mole)
in 114 ml of dry benzene was taken in a 250-ml roundbottomed
flask attached to a reflux condenser, under N2 gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and refluxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH2Cl2 and filtered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH4OH in H2O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na2SO4) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit2 110°C). Rf  0.8. Recrystallization from CH3OH/H2O gave mp 109–110°C.

Diphenylmethylsulfinylacetamide (modafinil, 1)
Diphenylthioacetamide (3.46 g, 0.013 mole) was  taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was filtered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. Rf  0.6. Recrystallization from hot MeOH gave mp 161–162°C

Diphenylmethylsufonylacetamide (2)
Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (reg. No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H2O2 and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H2O and set aside to cool in the refrigerator. Upon filtration and drying, 2.1 g (80%) of 2 was obtained as a white powder. Rf  0.89. The melting  point of sample after recrystallization from absolute EtOH was 195–197°C.

One aspect of our preparation of modafinil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H2O2, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al. (3) does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the modafinil. Our NMR data for the newly prepared modafinil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in modafinil are geminally
coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Modafinil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication (2,3).

RESULTS
The chemical pathway leading to modafinil may be
represented in Scheme 1.

see pdf for further information and references,

 

CLIP

Synthesis and determination of the absolute configuration of the enantiomers of modafinil
Thomas Prisinzanoa, John Podobinskia, Kevin Tidgewella, Min Luoa and Dale Swensonb
Tetrahedron: Asymmetry 15(6), 1053-1058 (2004) (../rhodium/pdf /modafinil.enantiomers.pdf)
DOI:10.1016/j.tetasy.2004.01.039

a Division of Medicinal & Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242-1112, USA
b Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA

Abstract
The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.

Graphical Abstract

Stereochemistry Abstract

(S)-(+)-(Diphenylmethanesulfinyl)acetic acid
C15H14O3S

[alpha]D22 + 40.2 (c=1.11, MeOH)
Source of chirality: resolution via diastereomeric salt formation with (R)-(+)-alpha-methylbenzylamine
Absolute configuration: S CLIP

http://www.wmich.edu/cas/experts/docs/2011posters/modafinil.pdf

 

Narcolepsy is a debilitating neurological disorder which is characterized by chronic sleepiness and is marked to be disorganization of sleep and wake patterns. Every six out of ten thousand people in Western Europe and North America are affected by this disorder. Modafinil (Provigil®) is approved by the Food and Drug Administration for the treatment of narcolepsy. It is commonly used in opposition to Ritalin®, however Ritalin® has an associated dependency issue. Modafinil, a central nervous system stimulant, has reported to have little abuse potential. Modafinil has the ability to act like wake-promoting sympathomimetic agents which includes amphetamine. At relevant pharmacological concentrations modafinil lacks binding ability to receptors for sleep/wake regulation, which includes the ones used for norepinephrine and serotonin. The precise mechanism of action of modafinil is unknown and is presently being researched. Modafinil contains a chiral sulfoxide moiety but is prescribed as a racemate. In collaboration with faculty from the Psychology department at Western Michigan University we were to synthesize modafinil for behavioral studies with animals. Therefore a large scale of pure modafinil was synthesized.

str0

 

The tetrahedral sulfur atom acts as a chiral center (being surrounded by two dissimilar carbon atoms, an oxygen atom and an electron lone pair (Figure 1). Unlike most analogous trisubstituted amines that undergo umbrella-like inversion at the nitrogen atom, sulfoxides are configurationally stable.

 

str1

The initial target of this synthesis was to prepare the 2-(diphenylmethylthio)acetamide (1) (Scheme I). The reaction of benzyhydral chloride and thiourea are reacted with potassium iodide, water, heat, 30% sodium hydroxide, 2-chloroacetamide and triethylamine. The procedure required the 2-(diphenylmethylthio) acetamide (1) to be recrystallized to remove any impurities with methanol:water solution 60:40 . After recrystallization (Figure 2) the ¹H NMR spectrum of the synthesized 2-(diphenylmethylthio)acetamide (1) provides evidence that the recrystallization did not purify the compound. In addition recrystallization significantly reduced the percent yield from 78.3-79.2% to 56%. If the compound were pure it would only show peaks at the following locations (ppm): 3.05 (s, 2H), 5.18 (s, 1H), 6.53 (s, 1H), 7.21-7.44(m, 10H).

 

str0

In preparing (±) modafinil (2) the procedure used acetic acid and hydrogen peroxide to form peracetic acid to react with 2-(diphenylmethylthio)acetamide (1) to form (±) modafinil (2) . The summation of experimentations of Scheme II eventually lead us to use of commercially available peracetic acid to obtain a more pure molecule of (±) modafinil (2). Over oxidation of the sulfone product can be seen if occurs at the peak (ppm):3.7-3.8 in a¹H NMR spectrum of (±) modafinil (2) . str1

 

 

str2

str0

To produce pure 2-(diphenylmethylthio)acetamide (1) elimination of the recrystallization step and 2-(diphenylmethylthio)acetamide (1) was then purified via column chromatography using dichloromethane:ether 80:20 as an eluent with the stationary phase (silica gel). After testing several of the fractions from the column using thin layer chromatography the fractions where able to be identified that contained 2- (diphenylmethylthio)acetamide (1). Once 2-(diphenylmethylthio)acetamide (1) was isolated it was oxidized with peracetic acid. The oxidation process was extended to three hours due to lack of desired product (±) modafinil (Figure 1).

With the procedure we used and modified through experimentation a new procedure was developed that increased the percent yield from 56% to 78.3-79.2%. We encountered a few problems that lead to the removal of the recrystallization step and the use of column chromatography was performed to purify 2-(diphenylmethylthio)acetamide (1) . Over- oxidation could have occurred but would have showed up at 3.7-3.8 (ppm), this did not occur in our experiment. The peak at 1.5 (ppm) is a water peak that was not fully removed during the rotovep procedure. After a precise and confident procedure was perfected then we were able to upscale the reaction and sythesize12gs of pure (±) modafinil.

 

FROM EROWID………

Benzhydrylsulphinylacetamide (Modafinil)2

Benzhydrylthioacetyl chloride

19.5g (0.076 mol) of benzhydrylthioacetic acid in 114 ml of benzene are placed in a three-necked flask provided with a condenser and a dropping funnel. The mixture is heated and 19 ml of thionyl chloride are added drop by drop. Once the addition is complete, the reflux is continued for about 1 hour, cooling and filtering are carried out and the benzene and the excess thionyl chloride and then evaporated. In this way, a clear orange oil is obtained.

Benzhydrylthioacetamide

35 ml of ammonia in 40 ml of water are introduced into a three-necked flask provided with a condenser and a dropping funnel and the benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene chloride is added drop by drop. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na2SO4, the solvent is evaporated and the residue is taken up in diisopropyl ether; in this way, the benzhydrylthioacetamide is crystallized. 16.8 g of product (yield 86%) are obtained. M.p. 110°C.

Modafinil (CRL 40,476)

14.39 g (0.056 mol) of benzhydrylthioacetamide are placed in a balloon flask and 60 ml of acetic acid and 5.6 ml of H2O2 (about 110 volumes, 33%) are added. The mixture is left in contact for one night at 40°C. and about 200 ml of water are then added; the CRL 40476 crystallizes. By recrystallization from methanol, 11.2 g of benzhydrylsulphinylacetamide are obtained. Yield: 73%. M.p. 164-66°C.

Novel Synthesis of Modafinil and its sulfone analog3

Our interest in synthesis of modified neuroactive compounds has led us to consider Modafinil (1), a stimulant and anti-narcoleptic agent that is finding increasing use in a number of neurological areas. The compound was originally prepared by a rather tedious route described in a procedure patented by L. Lafon2. More recently, its preparation has been reported by Mu et al.4 We believe that this compound has many interesting properties and possible alternative uses in addition to its recognized anti-narcoleptic actions.

Fig 1.
The chemical pathway leading to modafinil

Not having been able to obtain it from the patent holder, we proceeded to explore alternate synthetic pathways and settled on a convenient synthesis, which permitted us to produce this compound along with a primary derivative, the sulfone (2) in sufficient quantities for whole-animal studies. The current, more facile method starts with benzhydryl bromide and sodium thiolacetate in aqueous acetone, which reacts directly to form diphenylmethylthioacetic acid (3), possibly by an ionic mechanism. This resultant compound can be converted to its acid chloride that, in turn, may be used to acylate ammonia. The ensuing primary amide (4) may be gently oxidized by H2O2 to form the corresponding sulfoxide (Modafinil, 1) and, under more vigorous conditions, the modafinil sulfone (2), whose anticonvulsant and biological properties have not been described extensively in the literature. Additionally, this procedure is also uniquely suitable for large-scale preparation of Modafinil and its congeners.

One aspect of our preparation of modafinil needs further mention. When diphenylmethylthioacetamide (4) is being oxidized by H2O2, care must be taken to keep the reaction mixture cool, and workup should be done in a timely manner. Allowing the reaction to go to 24 h or longer at room temperature results in the formation of the sulfone (2). The paper by Mu et al.4 does not discuss this possibility. In our hands, the procedure stated therein led to the higher melting sulfone and not the modafinil. Our NMR data for the newly prepared modafinil preparation are in consonance with the data of the patented commercial product. It should be noted that the methylene protons in modafinil are geminally coupled and appear as a pair of doublets. This is due to the fact that the adjacent sulfoxide moiety is chiral, and therefore the methylene protons adjacent to it wind up being diastereotopic with different chemical shifts and coupling. In the sulfone 2, the methylene protons appear as a singlet due to the fact that the adjacent sulfone moiety is achiral, thus making the two protons equivalent. Modafinil 1 is, however, an equal mixture of enantiomers, as in the reported patent and publication2,4.

Experimental

The new compounds were prepared according to modified procedures published in the patent literature. Starting materials and solvents were obtained commercially from Fluka and/or Aldrich Chemical Corp. Thin layer chromatography (TLC) was performed on silica gel plates. Solvent system was EtOAc:MeOH:NH4OH, 100:10:3 by volume. Melting points are uncorrected.

Diphenylmethylthioacetic Acid (3)

Benzhydryl bromide (14.78 gm, 0.059 mole) was dissolved in 75 ml of acetone in a 250-ml round-bottomed flask. To this solution was added dropwise sodium mercaptoacetate (6.59 g, 0.058 mole) in about 60 ml of H2O; the mixture was stirred under N2 for 2 h at room temperature and was thereafter warmed at about 60–70°C for 1 h. The reaction mixture was evaporated to dryness and taken up in CH2Cl2 and saturated aqueous NaHCO3. The organic extract was rejected, and the aqueous phase was treated with acid to pH 2 and chilled. Suction filtration gave the 6.9 g of the acid (3, 46%), mp 125°C. Rf 0.2. Recrystallization from MeOH/H2O gave mp 126–128°C.

Diphenylmethylthioacetamide (4)

Diphenylmethylthioacetic acid 3 (19.5 g, 0.076 mole) in 114 ml of dry benzene was taken in a 250-ml roundbottomed flask attached to a reflux condenser, under N2 gas. To this was added thionyl chloride (19.5 ml, 0.097 mole) with a dropping funnel. The mixture was stirred at room temperature with a magnetic stirrer and refluxed for 1 h. Thereafter, the mixture was evaporated under low pressure to give a yellow oil that was taken up in about 100 ml of CH2Cl2 and filtered to yield a clear orange solution. This was chilled in ice water and added slowly to an ice-cold solution of concentrated NH4OH in H2O (40:40 ml). The ensuing mixture was stirred for 1 h and shaken well in a separatory funnel. The organic layer was dried (Na2SO4) and evaporated to dryness to give 14.39 g (54%) of the amide (4), mp 108–109°C (lit4 110°C). Rf 0.8. Recrystallization from CH3OH/H2O gave mp 109–110°C.

Diphenylmethylsulfinylacetamide (Modafinil, 1)

Diphenylmethylthioacetamide 4 (3.46 g, 0.013 mole) was taken in glacial acetic acid (14 ml) with stirring; to this was added 1.34 ml of 30% H2O2 with chilling in ice water. The mixture was left in the refrigerator for 4 h and thereafter worked up by treating it with 70 ml of ice-cold water. The precipitated material was filtered under suction and washed with ice-cold water to give 1.5 g of white crystals (43%), mp 159–160°C. Rf 0.6. Recrystallization from hot MeOH gave mp 161–162°C

Diphenylmethylsulfonylacetamide (2)

Diphenylmethylthioacetamide (2.5 g, 0.009 mole) (CAS No. 118779-53-6) was dissolved in about 12 ml of glacial acetic acid and 3 ml of 30% H2O2 and set aside overnight (16 h or more). The next day, the mixture was diluted with 100 ml of H2O and set aside to cool in the refrigerator. Upon filtration and drying, 2.1 g (80%) of 2 was obtained as a white powder. Rf 0.89. The melting point of sample after recrystallization from absolute EtOH was 195–197°C.

High-yield Synthesis of Modafinil from Benzhydrol5

A recent patent5 describes a very easy two-step route to the Modafinil precursor diphenylmethanethioacetamide from benzhydrol (diphenylmethanol) in 90% yield and with 95% purity. A 200g batch is made in a 2000 mL vessel using water as reaction medium and ethyl acetate for recrystallization of the product.

Diphenylmethylbromide is prepared in situ from benzhydrol and react it with thiourea in a one-pot reaction to form the corresponding isothiouronium salt. The crude salt is then reacted with chloroacetamide (by generating the thiolate cation in situ), and after filtration and washing, diphenylmethylthioacetamide is isolated in excellent yield and good purity. After oxidation of the thioacetamide with hydrogen peroxide, followed by recrystallization, the overall yield of Modafinil is 67% from the benzhydrol.

(Chimimanie’s Voice:) The synthesis works just as great without the nitrogen inert atmosphere (most patents do not use it at all), step two is only a hydrolysis of the thiouronium salt to the thiolate. You just have to put the salt, NaOH and heat till you got a homogenous solution, with no more solid material floating around. The following chloroacetamide SN2 reaction is a breeze too. Sometime a blue solution can bee obtained, it is nothing to worry about. In the final step, you just have to filter off the solid which did not dissolve when the crude thioacetamide is put in the GAA/H2O2, bee4 crashing the soluble one with water.
Do not forget to slurry the modafinil in EtOAc and then recrystallize it from aqueous MeOH, as the crystalline shape of modafinil is important for the kinetic and quality of effects, at least according to the patents EP0966962 and US2002043207.

Experimental

Preparation of isothiouronium Salt (IV)

Diphenylmethanol (130 g, 0.7 mole) and thiourea (65 g, 0.85 mole) are added in 0.5 L reactor charging with water (325 ml). The mixture is heated to 95°C. (an emulsion is obtained) and 48% HBr (260 gr. 3.22 mole, 4.6 equivalents) is then added gradually during 0.5 hour. The mixture is heated under reflux (106-107°C) for 0.5 hour and cooled to 80-85°C. At this temperature, the mixture is seeded with several crystals of the product and the mixture is stirred at that temperature for 0.5 hour and then cooled to 25°C. The colorless crystals are collected by filtration, washed with water (200 ml) yielding about 240 gr. of wet crude isothiouronium salt.

(Antoncho’s Voice:) Assholium successfully made Modafinil by this method, but there turned out to be a mistake in the original patent text – In the preparation of IV, the quantity of HBr stated here is excessive and leads to complete hydrolysis of the initially formed isothiouronium salt. The acid should bee added until the reaction mixture turns completely clear (about half as much as the patent says) – a sort of titration. Further addition will result in precipitation of heavy stinky oil, benzhydrylmethanethiol.

Preparation of diphenylmethylthioacetamide

A 2 L reactor was charged with diphenylmethylisothiouronium bromide crude wet obtained (240 gr.) and water (700 mL) under nitrogen. The suspension was heated to 60°C and 46% aqueous NaOH solution (98 ml, 1.68 mole, 2.4 eq.) was added. The reaction mixture was heated to 85°C and stirred until all the solid was dissolved. Then, it was cooled to 60°C and chloroacetamide (80 g, 0.84 mole, 1.2 eq.) was added in five portions hour at 60-70°C during one hour. The suspension is stirred at 70°C for 4-5 hours. The mixture was filtered while warm and the cake was washed with hot water (250 ml). Diphenylmethylthioacetamide crude wet is obtained [220 gr., HPLC assay: 78%, HPLC purity: 95%, yield: 95% from diphenylmethanol]. 20g of the product was recrystallized twice from ethyl acetate, dried in vacuo to give 15g of pure title compound.

Preparation of Modafinil

A 1.0 L reactor was charged with diphenylmethylthioacetamide crude wet (220 gr.) obtained above and glacial acetic acid (610 mL). The mixture was heated to 40°C and stirred until full dissolution is achieved. 5.8% H2O2 solution (500g, 1.2 eq) was added dropwise during 0.5 hours at 40-45°C. The reaction mixture was stirred at 40-45°C for 4 hours. Then sodium metabisulfite (18.3g) in 610 mL water was added in order to quench the unreacted H2O2 and the suspension was stirred for 0.5 hours. Then the reaction mixture was cooled to 15°C and filtered. The cake was washed with water (610 mL) and dried on air to obtain crude wet Modafinil (205 g). Reslurry in refluxing ethyl acetate, followed by recrystallization from methanol:water (4:1) solution afforded pure Modafinil [125 g, HPLC assay: 99.9%, HPLC purity: 99.9%, yield: 67% (from diphenylmethanol)].

References

  1. US Pat 4,066,686
  2. L. Lafon, US Pat 4,177,290 (1979); L. Lafon, Eur. Pat. 283,362 (1988)
  3. Nithiananda Chatterjie, James P. Stables, Hsin Wang, and George J. Alexander, Anti-Narcoleptic Agent Modafinil and Its Sulfone: A Novel Facile Synthesis and Potential Anti-Epileptic Activity, Neurochemical Research, 29(8), 1481–1486 (2004)
  4. Mu, B., Lei, G., He, X., and Du, X., Synthesis of central stimulant modafinil. Zhongguo Yaowu Huaxue Zazhi, 9(2), 132–134 (1999)
  5. US Pat. 6,649,796 (2002)
Modafinil
Modafinil enantiomers.svg

(R)-(−)-modafinil (armodafinil; top)
(S)-(+)-modafinil (bottom)
Clinical data
Trade names Provigil, others (see below)
AHFS/Drugs.com Monograph
MedlinePlus a602016
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Dependence
liability
Psychological: Very low[1]
Physical: Negligible[1]
Addiction
liability
Very low to low[2]
Routes of
administration
Oral (tablets)
ATC code N06BA07 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: Schedule F
  • UK: POM (Prescription only)
  • US: Schedule IV
Pharmacokinetic data
Bioavailability Not determined due to the aqueous insolubility
Protein binding 62%
Metabolism Hepatic (primarily via amide hydrolysis;[3] CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 involved [4]
Biological half-life 15 hours (R-enantiomer),
4 hours (S-enantiomer)[5]
Excretion Urine (80%)
Identifiers
Synonyms CRL-40476; Diphenylmethylsulfinylacetamide
CAS Number 68693-11-8 Yes
PubChem (CID) 4236
IUPHAR/BPS 7555
DrugBank DB00745 Yes
ChemSpider 4088 Yes
UNII R3UK8X3U3D Yes
KEGG D01832 Yes
ChEBI CHEBI:31859 
ChEMBL CHEMBL1373 Yes
ECHA InfoCard 100.168.719
Chemical and physical data
Formula C15H15NO2S
Molar mass 273.35 g/mol
3D model (Jmol) Interactive image
Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication
Shivam Maurya, Dhiraj Yadav, Kemant Pratap, Atul Kumar
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Shivam Maurya,ab   Dhiraj Yadav,a   Kemant Pratapab and  Atul Kumar*ab  
 *Corresponding authors
aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
E-mail: dratulsax@gmail.comatul_kumar@cdri.res.in
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02623K

Atul Kumar

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI
Central Drug Research Institute
Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, MOD) is a key psychostimulant drug used for the treatment of narcolepsy and other sleep disorders that has a very low addiction liability. Recently, MOD has been clinically investigated for the treatment of cocaine addiction and used by astronauts in long-term space missions. We have developed a synthetic strategy for “smart drug” Modafinil. An efficient atom and step economic (EASE) synthesis has been carried out by the direct reaction of benzhydrol and 2-mercaptoacetamide using the recyclable heterogeneous catalyst Nafion-H along with post-sulfoxidation. This protocol exhibits improved sustainability credentials. We have also developed a superior pre-sulfoxidation approach for the synthesis of Modafinil.
Modafinil Physical State – White solid; M.p. 158-159ºC,
IR (KBr): 3383, 3314, 3256, 1690, 1 1616, 1494, 1376, 1027, 702 cm-1;
H NMR (CDCl3) δ(ppm): 3.14(d, J=14.3 Hz, 1H); 3.48(d, J=14.3 Hz, 1H); 5.24(s, 1H); 5.88(br s, 1H); 7.09(br s, 1H); 7.29-7.43(m, 7H); 7.43-7.51(m, 3H);
13C NMR (CDCl3) δ(ppm): 52.00, 71.61, 128.80, 128.98, 129.10, 129.58, 129.62, 134.30, 134.74, + 166.46; Molecular formula C15H15NO2S;
ESI-MS (m/z): 274.1 (M+H) .

Dr. Atul Kumar

Senior Principal Scientist

str0

 

////////////

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil


Green Chemistry International

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication
Shivam Maurya, Dhiraj Yadav, Kemant Pratap, Atul Kumar
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Shivam Maurya,ab  Dhiraj Yadav,a  Kemant Pratapab and  Atul Kumar*ab  
 *Corresponding authors
aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
E-mail: dratulsax@gmail.com, atul_kumar@cdri.res.in
bAcademy of Scientific and Innovative Research, New Delhi 110001, India
Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02623K

Atul Kumar

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI

Central Drug Research Institute

View original post 206 more words

CPP 115


str0

(+)-(1S,4S)-4-Amino-3-(difluoromethylene)-1-cyclopentanecarboxylic acid

640897-20-7 CAS

PHASE 1

NORTHWESTERN UNIVERSITY .INNOVATORS

Sponsor:
CPP-115 free base; UNII-5TD9324Z2U; CHEMBL146927; 640897-20-7; (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid; (+)-(1S,4S)-4-Amino-3-(difluoromethylene)-1-cyclopentanecarboxylic acid
Molecular Formula: C7H9F2NO2
Molecular Weight: 177.151 g/mol

Catalyst Pharmaceutical Partners

  • Originator Northwestern University
  • Developer Catalyst Pharmaceutical Partners
  • Class Aminobutyric acids; Antiepileptic drugs; Small molecules
  • Mechanism of Action 4-aminobutyrate transaminase inhibitors
  • Orphan Drug Status Yes – Infantile spasms
  • On Fast track Drug abuse
  • Cocaine Dependency

Highest Development Phases

  • Phase I Gilles de la Tourette’s syndrome; Infantile spasms; Partial epilepsies
  • Preclinical Drug abuse

Most Recent Events

  • 19 Sep 2016 Efficacy data from a phase I trial in Infantile spasms released by Catalyst Pharmaceuticals
  • 16 Dec 2015 Top-line adverse events and pharmacodynamics data from a phase Ib trial in Healthy volunteers released by Catalyst Pharmaceuticals
  • 13 Oct 2015Catalyst Pharmaceuticals receives patent allowance for CPP 115 in USA

Image result for SILVERMAN, Richard, BRichard B. Silverman, Ph.D.,
John Evans Professor of Chemistry, Northwestern University, Evanston, Illinois, USA.

Click here for structure editor

UNII-0285I2MVUA.png

CPP 115 HCl salt, cas 760947-97-5

UNII-0285I2MVUA; CPP-115; 760947-97-5; (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid hydrochloride; Cyclopentanecarboxylic acid, 3-amino-4-(difluoromethylene)-, hydrochloride, (1S,3S)-; 0285I2MVUA
Molecular Formula: C7H10ClF2NO2
Molecular Weight: 213.609 g/mol

Responsible Party:Catalyst Pharmaceuticals, Inc.ClinicalTrials.gov Identifier:NCT01493596     History of ChangesOther Study ID Numbers:CPP-115-0001 Study First Received:November 28, 2011Last Updated:May 10, 2012Health Authority:United States: Food and Drug Administration

Cpp-115: An Investigational Drug For Epilepsy

The fact that 1 in 12 people will have a seizure in their lifetime raises alarming signals to mitigate, prevent and cure epilepsy. The etiology is still unclear, but one of the pharmaceutical strategies to treat seizures is to replenish the local concentrations of GABA (gamma-aminobutyric acid, an inhibitory neurotransmitter in the human brain) that is degraded by an enzyme called GABA aminotransferase (GABA-AT). Mere consumption of GABA capsules is not effective, due to its inability to cross the blood-brain barrier (BBB). Therefore, an alternative strategy that involved stopping the function of GABA-AT was envisioned. Sabril is a first-in-class, FDA-approved antiepileptic drug; however, its daily dosage limit (1g – 3g) and adverse side effects, which include vision defects, call for further innovation.

Prof. Richard Silverman and his lab members at Northwestern University embarked on a scientific journey to identify BBB-penetrating antiepileptic compounds that would not cause visual defects. Through computational modeling and several cycles of optimization they discovered CPP-115 (chemical name: (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid; kinact/KI = 52 mM.min-1.)1 Mechanistically, CPP-115 binds to GABA-AT, undergoing product transformation that kills GABA-AT’s function. In rat studies, CPP-115 suppressed spasms at a much lower dose (0.1 mg/kg) than Sabril (>200 mg/kg) and exhibited better tolerance without visual defects.

CPP-115 (licensed to Catalyst Pharmaceuticals) elicited no cross-inhibition. It is metabolically more stable, with favorable PK characteristics (including rapid absorption and clearance). In a randomized, double-blind, single ascending dose phase I(a) study, CPP-115 was very well tolerated in all six doses (n=55 patients; maximum dose 500 mg, therapeutic dose 80 mg/day).2 Phase I(b) studies conducted in double-blind, placebo-controlled conditions demonstrated the safety and tolerability of CPP-115 in healthy volunteers. Intriguingly, an increase in brain GABA levels (150% to over 200%) was detected, accentuating CPP-115’s antiepileptic potential.2 Further clinical trials are currently in progress. CPP-115, with 12 years of unexpired patent life, has been granted orphan-drug designation in both the U.S. and EU for treating infantile spasms.

CPP-115 is one of a group of novel GABA-aminotransferase inhibitors discovered by scientists at Northwestern University. In 2009 Catalyst entered into a strategic collaboration with Northwestern University and in-licensed the worldwide rights to these inhibitors.

CPP-115 binds to GABA-AT (GABA-aminotransferase, also known as GABA transaminase or GABA-T), causing increased levels of GABA, gamma-aminobutyric acid, the chief inhibitory neurotransmitter in humans. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone.

In preclinical studies CPP-115 has been shown to have potentially significant advantages compared to the only approved and marketed current GABA-AT inhibitor (vigabatrin). CPP-115 may not cause the visual field defects associated with chronic administration of vigabatrin and it has been shown to be at least 200 times more potent in both in-vitro and animal model studies. The increased potency could enable the development of superior or alternative dosage forms and routes of administration. Catalyst hopes these important benefits will allow it to develop CPP-115 for a broad range of other central nervous system indications, such as infantile spasms, epilepsy, Tourette Syndrome and Post Traumatic Stress Disorder (PTSD). Additionally, Catalyst is exploring other selected diseases in which modulation of GABA levels might be beneficial. Catalyst believes that it controls all current intellectual property for GABA-aminotransferase inhibitors.

CPP-115 has received orphan drug designation in both the US and the EU for infantile spasms. Catalyst has begun the clinical development of CPP-115 by completing a randomized, double-blind, single ascending dose Phase I(a) study in normal healthy volunteers to evaluate the human safety characteristics of CPP-115, including CNS side effects and respiratory and cardiovascular safety. The Company reported results which indicated that CPP-115 was well tolerated at all six doses administered up to 500 mg, well above the anticipated therapeutic dose of up to 80 mg/day.

The hydrochloride salt of CPP-115 (PubChem CID 71252718) has been granted orphan drug designation by the EMA for the treatment of West syndrome, an epileptic disorder of young children which causes developmental problems. West syndrome is a long-term debilitating disease which may be life threatening as it can lead to severe damage to motor and cognitive functions. CPP-115 may have additional therapeutic applications for treating other neurological disorders, including drug addiction [4]. A single Phase I clinical trial has assessed CPP-115 as a treatment for cocaine addiction [3], but development has not progressed further.

Image result for CPP 115

Patent

WO 2016073983

NORTHWESTERN UNIVERSITY [–/US]; 633 Clark Street Evanston, IL 60208 (US)
Inventors: SILVERMAN, Richard, B.; (US).
ILAN, Yaron; (IL)

Example 8

[0067] (IS, 4S)-6-Difluoromethylenyl-2-(4′-methoxybenzyl)-2- azabicyclo[2.2.1]heptan-3-one (13). At -78 °C, T uLi (1.7 M in pentane, 1.73 mL, 2.94 mmol) was slowly added to a stirred solution of diethyl (difluoromethyl)phosphonate (0.48 mL, 2.94 mmol) in anhydrous THF (15 mL). After being stirred for 0.5 h at -78 °C, 12 (0.60g, 2.45 mmol) in anhydrous THF (20 mL) was slowly added via syringe. Stirring continued for 1 h at – 78 °C , then the solution was allowed to warm to room temperature and heated to reflux for 24 h. Compound 12 is known and available in the art, and can be prepared as described in Qiu, J.; Silverman, R.B. A New Class of Conformationally Rigid Analogues of 4-Amino-5- halopentanoic Acids, Potent Inactivators of γ-Aminobutyric Acid Aminotransferase. J. Med. Chem. 2000, 43, 706-720. After the reaction had cooled down, THF was evaporated, and saturated NH4C1 solution (20 mL) was added to the residue, which was extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine (2 x 20 mL), dried over anhydrous Na2S04, and concentrated under reduced pressure. The residue was purified by flash column

chromatography, eluting with hexanes/ethyl acetate (2: 1) to give 13 (0.47 g, 68%) as a colorless oil: 1H NMR (400 MHz, CDC13) δ 7.18 (d, J 8.4 Hz, 2H), 6.07 (d, J 8.4 Hz, 2H), 4.63 (d, J 14.8 Hz, 1H), 4.14 (s, 1H), 3.80 (s, 3H), 3.78 (d, J 14.8 Hz, 1H), 3.00 (s, 1H), 2.50 (dt, J 15.2, 3.6 Hz, 1H), 2.27 (dd, J 15.2, 2.4 Hz, 1H), 2.00 (d, J 9.2 Hz, 1H), 1.53 (d, 9.6 Hz, 1H); 13C NMR (100 MHz, CDC13) δ 177.37, 159.13, 152.19 (dd, J 285.7, 281.2 Hz), 129.59, 128.47, 1 14.13, 88.95 (dd, J 25.6, 22.2 Hz), 58.38 (d, J 5.3 Hz), 55.50, 45.60, 44.59, 40.96, 27.43; 19F NMR (376 MHz, CDC13) δ 42.64 and 41.01 (2 dd, J 60.2, 2.3 Hz, 2F). HRMS (EI) Ci5Hi5N02F2 calcd M

279.1071 , found M 279.10701.

Example 10

 (IS, 3S)-3-Amino-4-difluoromethylenyl-l-cyclopentanoic acid (15) (i.e., compound 10, CPP-115, Figure 2). To lactam 14 (20.0 mg, 0.13 mmol) was added 4 mL of 4 N HCl. The solution was stirred at 70 °C for 10 h. After being washed with ethyl acetate (3 x 4 mL), the water layer was evaporated under reduced pressure to give a yellow solid. Recrystallization with ethanol/ether gave a white solid, which was then loaded on a cation- exchange column (AG50W-X8) and eluted with 0.2 N ammonium hydroxide to give the free amino acid 15 as a white solid (16 mg, 72%). 1H NMR (400 MHz, D20) δ 4.44 (s, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.57 (dd, J 16.4, 3.6 Hz, 1H), 2.34 (m, 1H), 2.02 (d, J 14.8 Hz, 1H); 13C NMR (126 MHz, D20) δ 186.08, 155.30 (t, J 288.7 Hz), 92.19 (m), 53.16 (d, J 3.8 Hz), 48.01, 37.89, 32.45; 19F NMR (376 MHz, D20) δ -8.43 and -9.02 (2d, J 46.3 Hz, 2F); MS (ESI) C7H9N02F2 calcd M+H 178, found M+H 178.

PATENT

US 6794413

https://www.google.com/patents/US6794413

C7H11O2N, H% 7.85 C% 59.56 N% 9.92, found H% 7.88 C% 59.23 N% 9.62.

Example 5

(1S, 4S)-6-Difluoromethylenyl-2-(4′-methoxybenzyl)-2-azabicyclo [2.2.1]heptan-3-one (13). At −78° C., tBuLi (1.7 M in pentane, 1.73 mL, 2.94 mmol) was slowly added to a stirred solution of diethyl (difluoromethyl)phosphonate (0.48 mL, 2.94 mmol) in anhydrous THF (15 mL). After being stirred for 0.5 h at −78° C., 12 (0.60 g, 2.45 mmol) in anhydrous THF (20 mL) was slowly added via syringe. Stirring continued for 1 h at −78° C., then the solution was allowed to warm to room temperature and heated to reflux for 24 h. Compound 12 is known and available in the, art, and can be prepared as described in Qiu, J.; Silverman, R. B. A New Class of. Conformationally Rigid Analogues of 4-Amino-5-halopentanoic Acids, Potent Inactivators of γ-Aminobutyric Acid Aminotransferase. J. Med. Chem. 2000, 43, 706-720. After the reaction had cooled down, THF was evaporated, and saturated NH4Cl solution (20 mL) was added to the residue, which was extracted with EtOAc (3×20 mL). The organic layer was washed with brine (2×20 mL), dried4over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with hexanes/ethyl acetate (2:1) to give 13 (0.47 g, 68%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J 8.4 Hz, 2H), 6.07 (d, J 8.4 Hz, 2H), 4.63 (d, J 14.8 Hz, 1H), 4.14 (s. 1H), 3.80 (s, 3H), 3.78 (d, J 14.8 Hz, 1H), 3.00 (s, 1H), 2.50 (dt, J 15.2, 3.6 Hz, 1H), 2.27 (dd, J 15.2, 2.4 Hz, 1H), 2.00 (d, J 9.2 Hz, 1H) 1.53 (d, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.37, 159.13, 152.19 (dd, J 285.7, 281.2 Hz), 129.59, 128.47, 114.13, 88.95 (dd, J 25.6, 22.2 Hz), 58.38 (d, J 5.3 Hz), 55.50, 45.60, 44.59, 40.96, 27.43; 19F NMR (376 MHz, CDCl3) δ 42.64 and 41.01 (2 dd, J 60.2, 2.3 Hz, 2F). HRMS (EI) C15H15NO2F2 calcd M 279.1071, found M 279.10701.

Example 6

(1S, 4S)-6-Difluoromethylenyl-2-azabicyclo[2.2.1]heptan-3-one (14). Compound 13 (86.9 mg, 0.31 mmol) was dissolved in CH3CN (1.75 mL). A solution of ceric ammonium nitrate (512 mg, 0.93 mmol) in water (0.87 mL) was slowly added. The resulting solution was stirred at room temperature for 4 h. The reaction mixture was then diluted with ethyl acetate (20 mL), washed with brine (2×10 mL), and dried over anhydrous Na2SO4. After being concentrated under reduced pressure, the residue was purified by flash column chromatography, eluting with hexanes/ethyl acetate (1:1) to give the desired product as a colorless oil (33.6 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 5.48 (br s, 1H), 4.40 (s, 1H), 2.93 (s, 1H), 2.54 (dd, J 15.2, 2.8 Hz, 1H), 2.32 (d, J 15.2 Hz, 1H), 2.15 (d, J 9.6 Hz, 1H), 1.64 (d, J 10.0 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ 42.85 and 40.00 (2d, J 60.2 Hz, 2F); HRMS (EI) C7H7NOF2 calcd M 159.0496, found M 159.04673.

Example 7

(1S, 3S)3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid (15). To lactam 14 (20.0 mg, 0.13 mmol) was added 4 mL of 4 N HCl. The solution was stirred at 70° C. for 10 h. After being washed with ethyl acetate (3×4 mL), the water layer was evaporated under reduced pressure to give a yellow solid. Recrystallization with ethanol/ether gave a white solid, which was then loaded on a cation-exchange column (AG50W-X8) and eluted with 0.2 N ammonium hydroxide to give the free amino acid 15 as a white solid (16 mg, 72%). 1H NMR (400 MHz, D2O) δ 4.44 (s, 1H), 2.92 (m, 1H), 2.74 (m, 1H), 2.57 (dd, J 16.4, 3.6 Hz, 1H), 2.34 (m 1H), 2.02 (d, J 14.8 Hz, 1H); 13C NMR (126 MHz, D2O) δ 186.08, 155.30 (t, J 288.7 Hz), 92.19 (m), 53.16 (d, J 3.8 Hz), 48.01, 37.89, 32.45; 19F NMR (376 MHz, D2O) δ −8.43 and −9.02 (2d, J 46.3 Hz, 2F); MS (ESI) C7H9NO2F2 calcd M+H 178, found M+H 178.

paper

Journal of Medicinal Chemistry (2003), 46(25), 5292-5293

Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor

Department of Chemistry, Department of Biochemistry, Molecular Biology, and Cell Biology, and Drug Discovery Program, Northwestern University, Evanston, Illinois 60208-3113
J. Med. Chem., 2003, 46 (25), pp 5292–5293
DOI: 10.1021/jm034162s
Publication Date (Web): November 11, 2003
Copyright © 2003 American Chemical Society

Abstract

Abstract Image

Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate γ-aminobutyric acid aminotransferase (GABA-AT). A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mercaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.

1 to 6 of 6
Patent ID Patent Title Submitted Date Granted Date
US2015196522 METHODS OF USING (1S, 3S)-3-AMINO-4-DIFLUOROMETHYLENYL-1-CYCLOPENTANOIC ACID 2015-03-02 2015-07-16
US8969413 Methods of using (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid 2011-02-25 2015-03-03
US2014336256 METHOD OF TREATING TOURETTE’S DISORDER WITH GABA-AMINOTRANSFERASE INACTIVATORS 2014-07-25 2014-11-13
US2011237554 Combination therapies: inhibitors of GABA transaminase and NKCC1 2011-09-29
US7381748 Compounds and related methods for inhibition of gamma-aminobutyric acid aminotransferase 2008-06-03
US6794413 Compounds and related methods for inhibition of gamma-aminobutyric acid aminotransferase 2004-09-21

RICHARD B. SILVERMAN

PROFESSOR

Research Statement

The research in my group can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents, particularly for neurodegenerative diseases. Numerous drugs are known to function as specific inhibitors of particular enzymes. When little is known about the enzyme’s molecular mechanism of action, chemical model studies are designed to determine reasonable nonenzymatic pathways applicable to the enzyme. Based on the proposed mechanism of enzyme action, inhibitors are designed and synthesized. Organic synthesis is a primary tool for this work. The enzymes are isolated from either mammalian tissue or from overexpressed cells containing recombinant enzymes. Active site labeling studies utilize MALDI TOF and electrospray ionization mass spectrometry as well as radiolabeled inactivators and peptide mapping. We also are synthesizing compounds to act as receptor antagonists for important receptors related to neurodegenerative diseases.

Recent Publications

Lee, H.; Doud, E. H.; Wu, R.; Sanishvili, R.; Juncosa, J. I.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115). J. Am. Chem. Soc. 2015, 137, 2628-2640.

Zigmond, E.; Ya’acov, A. B.; Lee, H.; Lichtenstein, Y.; Shalev, Z.; Smith, Y.; Zolotarov, L.; Ziv, E.; Kalman, R.; Le, H. V.; Lu, H.; Silverman, R. B.; Ilan, Y. Suppression of hepatocellular carcinoma by inhibition of overexpressed ornithine aminotransferase. ACS Med. Chem. Lett. 2015, 6, 840-844.

Tang, W.; Li, H.; Doud, E. H.; Chen, Y.; Choing, S.; Plaza, C.; Kelleher, N. L.; Poulos, T. L.; Silverman, R. B. Mechanism of inactivation of neuronal nitric oxide synthase by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid. J. Am. Chem. Soc. 2015, 137, 5980-5989.

Le, H. V.; Hawker, D. D.; Wu, R.; Doud, E.; Widom, J.; Sanishvili, R.; Liu, D.; Kelleher, N. L.; Silverman, R. B. Design and mechanism of tetrahydrothiophene-based GABA aminotransferase inactivators. J. Am. Chem. Soc. 2015, 137, 4525-4533.

Huang, H.; Li, H.; Yang, S.; Chreifi, G.; Martásek, P.; Roman, L. J.; Meyskens, F. L.; Poulos, T. L.; Silverman, R. B. Potent and Selective Double-headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma. J. Med. Chem. 2014, 57, 686-700.

Trippier, P. C.; Zhao, K. T.; Fox, S. G.; Schiefer, I. T.; Benmohamed, R.; Moran, J.; Kirsch, D. R.; Morimoto, R. I.; Silverman, R. B. Proteasome Activation is a Mechanism for Pyrazolone Small Molecules Displaying Therapeutic Potential in Amyotrophic Lateral Sclerosis. ACS Chem. Neurosci. 2014, 5, 823-829.

Holden, J. K.; Li, H.; Jing, Q.; Kang, S.; Richo, J.; Silverman, R. B.; Poulos, T. L. Structural and biological studies on bacterial nitric oxide synthase inhibitors. Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 18127-18131.

Kang, S.; Cooper, G.; Dunne, S. F.; Dusel, B.; Luan, C.-H.; Surmeier, D. J.; Silverman, R. B. CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson’s disease. Nature Commun 2012, 3, 1146.

Silverman, R. B. The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms. J. Med. Chem. 2012, 55, 567-575.

Chen, T.; Benmohamed, R.; Kim, J.; Smith, K.; Amante, D.; Morimoto, R. I.; Kirsch, D. R.; Ferrante, R. J.; Silverman, R. B. ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives to Block Mutant SOD1 Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis. J. Med. Chem. 2012, 55, 515-527.

Selected Honors/Awards

  • 2014 Fellow of the National Academy of Inventors
  • 2014 Northwestern University Trustee Medal for Faculty Innovation and Entrepreneurship
  • 2014 iCON Innovator Award (iBIO Institute)
  • 2014 Elected to American Academy of Arts & Sciences
  • 2014 Excellence in Medicinal Chemistry Prize of the Israel Chemical Society
  • 2013 Fellow of the Royal Society of Chemistry (UK)
  • 2013 Centenary Prize of the Royal Society of Chemistry
  • 2013 Bristol-Myers Squibb-Edward E. Smissman Award of the American Chemical Society (ACS)
  • 2013 Roland T. Lakey Award from Wayne State University
  • 2012 Sato Memorial International Award of the Pharmaceutical Society of Japan
  • 2011 Fellow of the ACS
  • 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances of the ACS
  • 2011 Alumni Hall of Fame, Central High School of Central High School of Philadelphia
  • 2009 Medicinal Chemistry Hall of Fame of the American Chemical Society
  • 2009 Perkin Medal, Society of Chemical Industry
  • 2008 Alumni Fellow Award, Pennsylvania State University
  • 2003 Arthur C. Cope Senior Scholar Award of the American Chemical Society
  • 2000 Northwestern University Alumni Association Excellence in Teaching Award
  • 1999 E. LeRoy Hall Award for Teaching Excellence
  • 1999 Excellence in Chemistry Education Award from the Northwestern University Chapter of Alpha Chi Sigma Chemistry Fraternity
  • 1990 Fellow of the American Association for the Advancement of Science
  • 1985 Fellow of the American Institute of Chemists
  • 1982 NIH Research Career Development Awardee
  • 1981 Alfred P. Sloan Research Fellow
  • 1976 Du Pont Young Faculty Fellow
  • Silverman describes the structure of pregabalin.
    Silverman describes the structure of pregabalin.

In recognition of his outstanding work in applied chemistry, the Society of Chemical Industry 2009 Perkin Medal has been awarded to Richard B. (Rick) Silverman, the John Evans Professor of Chemistry at Northwestern University. The Perkin Medal, which was first awarded just over one century ago, is recognized as one of the chemical industry’s most prestigious awards.

Silverman’s research primarily focuses on medicinal chemistry: studying the molecular basis of drug action, reaction mechanisms of enzymes, and design and synthesis of pharmaceutical agents. He has worked to deepen understanding of several diseases, including epilepsy, cancer, Parkinson’s, and cerebral palsy.

Among Silverman’s many scientific accomplishments, designing pregabalin and discovering the medicinal properties of that compound stand out for catapulting him and Northwestern to pharmaceutical fame and fortune. Pregabalin, a γ-aminobutyric acid analog, is the active substance in Lyrica, a pain and epilepsy medication commercialized by drug giant Pfizer.

In 2007, after Northwestern collected more than $70 million in royalties for the drug, the university sold a portion of its royalty rights for an additional $700 million (C&EN, March 10, 2008, page 56). Around the same time, Silverman and his family donated a portion of their earnings from the drug to fund construction of a new Northwestern science building. The facility, which is scheduled to open this fall, will house chemistry, biology, and engineering research groups devoted to biomedical science.

Silverman has published more than 250 papers in organic chemistry, medicinal chemistry, and enzymology. He is also the author of three books, including “The Organic Chemistry of Drug Design and Drug Action,” and holds 40 patents.

The Perkin Medal is named for Sir William Henry Perkin (1838–1907), who was honored by SCI in 1906 for developing the first synthetic dye, Perkin mauve. This year’s medal will be presented at SCI’s Perkin Medal banquet in Philadelphia in September.

The Legacy Of Lyrica

November 18, 2013

Northwestern’s Richard Silverman, professor of chemistry, developed pregabalin, the chemical that Pfizer now markets as Lyrica.  The drug is one of the two approved treatments for fibromyalgia, epilepsy, and the most effective treatment for seizures as well.

In his laboratory, Silverman’s research team studied chemicals made in the brain. Of particular interest was GABA, a neurotransmitter that inhibits certain brain functions. When GABA levels fall too low in some people, it can trigger epileptic seizures. His group studied enzymes that affect GABA levels, looking for ways to keep GABA elevated.  In 1989, the Parke-Davis unit of Warner-Lambert was interested in the research findings. Among the 17 chemical analogs that Silverman sent to Parke-Davis, only pregabalin showed effects in mice.

Serendipity played a huge part in shaping this success story, as most chemicals that affect cells in lab experiments do not survive inside an animal. Another outcome of the research was that the compound was effective for a reason entirely different from Silverman’s initial goal of producing more GABA. In another stroke of luck, the molecule happened to be of the right shape to be transported directly into the brain with nearly 90 percent efficacy.

Lyrica has been a tremendous medical and commercial success that has validated the nearly 15 year process from invention to market launch in 2005. In 2004 Lyrica was approved for use in adults for the treatment of various peripheral neuropathic pain indications as well as therapy for partial epilepsy in more than 60 countries outside of the United States. In 2006 Lyrica was also approved for the treatment of generalized anxiety disorder in Europe. The drug brought in $1.2 billion in sales in 2006 and in 2010 was approved in Europe to treat central neuropathic (nerve) pain. This is expected to push profits from the blockbuster drug to climb even higher.

Northwestern sold a sizeable amount of royalty interest in 2007 to Royalty Pharma, a company that specializes in acquiring cash-generating intellectual property, for $700 million to help the university’s endowment. This deal has been termed the largest sale ever of a royalty stream for a pharmaceutical product.

To learn more about Lyrica visit the product website at www.lyrica.com.

Originally Appeared:

////////Cocaine Dependency, CPP 115, PHASE 1, CATALYST, NORTHWESTERN UNIVERSITY, ORPHAN DRUG, 640897-20-7, 760947-97-5

C1C(CC(=C(F)F)C1N)C(=O)O

Selection and justification of starting materials: new Questions and Answers to ICH Q11 published


DRUG REGULATORY AFFAIRS INTERNATIONAL

 

The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.

http://www.gmp-compliance.org/enews_05688_Selection-and-justification-of-starting-materials-new-Questions-and-Answers-to-ICH-Q11-published_15619,15868,S-WKS_n.html

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The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.

On 30 November 2016 the ICH published a Questions and Answers…

View original post 2,105 more words

PIMODIVIR, VX 787


Pimodivir.pngFigure imgf000331_0001

PIMODIVIR

VX-787, JNJ-63623872, JNJ-872, VRT-0928787, VX-787, VX 787,  VX787,  JNJ-872, JNJ 872, JNJ872, VRT-0928787, VRT 0928787, VRT0928787, pimodivir

(2S,3S)-3-{[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino}bicyclo[2.2.2]octane-2-carboxylic acid

(2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridm-3-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

(2S,3S)-3-((5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic Acid

MF C20H19F2N5O2, MW 399.4018

CAS 1629869-44-8

PHASE 2

Originator Vertex Pharmaceuticals
Developer Janssen Pharmaceuticals
Mechanism Of Action Viral polymerase inhibitor, Viral protein inhibitor
Who Atc Codes J05A-X (Other antivirals)
Ephmra Codes J5B4 (Influenza antivirals)
Indication Influenza A
Paul Charifson, Michael P. Clark, Upul K. Bandarage, Randy S. Bethiel, John J. Court,Hongbo Deng, Ioana Drutu, John P. Duffy, Luc Farmer, Huai Gao, Wenxin Gu, Dylan H. Jacobs, Joseph M. Kennedy, Mark W. Ledeboer, Brian Ledford, Francois Maltais,Emanuele Perola, Tiansheng Wang, M. Woods Wannamaker, Less «
INNOVATOR Vertex Pharmaceuticals Incorporated

Pimodivir (also known as VX-787, JNJ-872 and VRT-0928787) is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. VX-787 binds the cap-binding domain of the PB2 subunit with a KD (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC).

The cell-based EC50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs).

Image result for PIMODIVIR

Pimodivir hydrochloride hemihydrate
RN: 1777721-70-6
UNII: A256039515, Bicyclo(2.2.2)octane-2-carboxylic acid, 3-((5-fluoro-2-(5-fluoro-1H-pyrrolo(2,3-b)pyridin-3-yl)-4-pyrimidinyl)amino)-, hydrochloride, hydrate (2:2:1), (2S,3S)-

Molecular Formula, 2C20-H19-F2-N5-O2.2Cl-H.H2-O, Molecular Weight, 889.7348

C20 H19 F2 N5 O2 . Cl H . 1/2 H2 O
Bicyclo[2.2.2]octane-2-carboxylic acid, 3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-pyrimidinyl]amino]-, hydrochloride, hydrate (2:2:1), (2S,3S)-

Janssen Pharmaceuticals, under license from Vertex Pharmaceuticals, was developing pimodivir (first disclosed in WO2010148197), a PB2 inhibitor, for treating influenza A virus infection. In December 2016, pimodivir was reported to be in phase 2 clinical development.

Influenza spreads around the world in seasonal epidemics, resulting in the deaths of hundreds of thousands annually – millions in pandemic years. For example, three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing influenza virus to humans from other animal species.

Influenza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within about 6 feet) infected persons. Transmission might also occur through direct contact or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune systems might be infectious for 10 or more days after onset of symptoms. [00103] Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus and Thogoto virus.

The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are: HlNl (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2 , H7N3 and H10N7. [00105] The Influenza virus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

The Influenza virus C genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children. [00107] Influenza A, B and C viruses are very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NSl, NS2(NEP), PA, PBl, PB1-F2 and PB2.

[HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins have been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1. [00109] Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.

Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral medications. Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people that have asthma, diabetes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific influenza strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective. [00111] Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.

Also, because of the absence of RNA proofreading enzymes, the RNA- dependent RNA polymerase of influenza vRNA makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant — antigenic drift. The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.

Thus, there is still a need for drugs for treating influenza infections, such as for drugs with expanded treatment window, and/or reduced sensitivity to viral titer

U.S. Patent No. 8,829,007 discloses compounds that inhibit the replication of influenza viruses, including (2S,3S)-3-((5-fluoro-2-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid (also known as VX-787). Boroylated intermediates are useful for preparing these compounds that inhibit the replication of influenza viruses. M. P. Clark et al., J. Med. Chem., 2014, 57-6668-6678. These borylated intermediates were previously prepared by incorporating a bromine at the position of the molecule to be borylated. For example, Clark reports preparing 5-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine from 3-bromo-5-fluoro-lH-pyrrolo[2,3-b]pyridine.

Methods for preparing borylated compounds are described in U.S. Patent Publication Nos. 2008/0146814 and 2008/0167476.

Improved methods for preparing 3-boryl 7-azaindole compounds, such as 3-boryl-5-halo-7-azaindole compounds, in high yield and with no or few impurities are needed

Synthetic Scheme 1

Figure imgf000087_0001

(a) CHC13; (b) NaOMe, MeOH; (c) DPPA, Et3N, BnOH; (d) H2, Pd/C;

Synthetic Scheme 2

Figure imgf000088_0001

(a) Et3N, CH3CN; (b) cone. H2S04; (c) 9M H2S04; (d) Ag2C03, HOAc, DMSO, 100 °C; (e) X- phos, Pd2(dba)3, K3PO4, 2-methyl THF, H20, 120 °C (f) LiOH, THF, MeOH, 70 °C

Synthetic Scheme 3

Figure imgf000091_0001

(a) Et3N, THF; (b) chiral SFC separation; (c) 5-fluoro- l -(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-

SYNTHESIS

PAPER

Journal of Medicinal Chemistry (2014), 57(15), 6668-6678

http://pubs.acs.org/doi/abs/10.1021/jm5007275

Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2

Vertex Pharmaceuticals Inc., 50 Northern Ave, Boston, Massachusetts 02210, United States
Vertex Pharmaceuticals (Canada) Inc., 275 Armand-Frappier, Laval, Quebec H7V 4A7, Canada
§ Arrowhead Research Corporation, 465 Science Drive, Suite C, Madison, Wisconsin 53711, United States
Sage Therapeutics, 215 First Street, Cambridge, Massachusetts 02141, United States
J. Med. Chem., 2014, 57 (15), pp 6668–6678
DOI: 10.1021/jm5007275
Publication Date (Web): July 14, 2014
Copyright © 2014 American Chemical Society
*Phone: 617-961-7727. E-mail: michael_clark@vrtx.com.

Abstract

Abstract Image

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A.Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105−114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Figure

aReagents and conditions: (a) CHCl3, 78%; (b) NaOMe, MeOH, 4 days, 85%; (c) DPPA, Et3N, BnOH, 77%; (d) H2, Pd/C, THF/MeOH, 99%; (e) 2,4-dichloro-5-fluoropyrimidine, iPr2NEt, THF, 77%; (f) SFC chiral separation; (g) 56, Pd2(dba)3, K3PO4, 2-MeTHF, water, 120 °C, 95%; (h) HCl, dioxane, MeCN, 95%; (i) NaOH, THF, MeOH, 95%.

(2S,3S)-3-((5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic Acid

1H NMR (300 MHz, DMSO-d6) δ 12.71 (br s, 1H), 8.58 (s, 1H), 8.47 (dd, J = 9.6, 2.8 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.39–8.34 (m, 1H), 4.89–4.76 (m, 1H), 2.94 (d, J = 6.9 Hz, 1H), 2.05 (br s, 1H), 1.96 (br s, 1H), 1.68 (complex m, 7H); 13C NMR (300 MHz, DMSO-d6) δ 174.96, 157.00, 155.07, 153.34, 152.97, 145.61, 142.67, 140.65, 134.24, 133.00, 118.02, 114.71, 51.62, 46.73, 28.44, 28.00, 24.90, 23.78, 20.88, 18.98; LCMS gradient 10–90%, 0.1% formic acid, 5 min, C18/ACN, tR = 2.24 min, (M + H) 400.14; HRMS (ESI) of C20H20F2N5O2 [M + H] calcd, 400.157 95; found, 400.157 56.

PATENT

WO2010148197

(1070) (2S,3S)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridm-3-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Figure imgf000331_0001

Compound 1070 was made in a similar fashion as described above for compounds 946 and 947.

Figure imgf000330_0001

946 (+/-) 947 (+/-)

[001117] (946) (+/-)-2,3-*r«/ts-CTt</ø-3-(2-(5-chloro-1H-pyrrolo [2,3-b] pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylic acid & (947) (+/-)-2,3-rr««s-^xo-3-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylic acid

To a stirred solution of starting methyl esters, 53d, (0.076 g, 0.183 mmol) (84 : 16 = endo : exo) in THF (0.60 mL) and MeOH (0.10 mL), was added NaOH (0.10 mL of 2 M, 0.201 mmol). The reaction progress was monitored by TLC. After 30 min, additional NaOH (0.18 mL of 2 M solution, 0.37 mmol) and MeOH (0.18 mL) was added. The mixture was stirred at room temperature for a further 16 hours. The mixture was neutralized with HCl (IM) and concentrated in vacuo. Purification by preparative HPLC provided 52 mg of the major isomer (946) and 1 lmg of the minor isomer (947) as the hydrochloric acid salts.

(946) major {endo) isomer: 1H NMR (300 MHz, MeOD) δ 8.82 (d, J= 2.2 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J= 2.2 Hz, 1H), 8.31 (d, J= 5.6 Hz, 1H), 5.11 (m, 1H), 2.85 (br s, 1H), 2.68 (br s, 1H), 2.62 (d, J = 4.8 Hz, 1H), 1.92 (d, J = 10.1 Hz, 1H) and 1.77 – 1.51 (m, 5H) ppm; LC/MS R, = 3.51, (M+H) 402.32.

(947) minor (exo) isomer: 1H NMR (300 MHz, MeOD) δ 8.87 (d, J = 2.1 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 5.7 Hz, 1H), 4.73 (d, J = 3.3 Hz, 1H), 3.12 (m, 1H), 2.76 (br s, 1H), 2.56 (d, J= 4.2 Hz, 1H), 1.86 (d, J= 9.5 Hz, 2H), 1.79 – 1.49 (complex m, 2H) and 1.51 (embedded d, J= 10.4 Hz, 2H) ppm; LC/MS R, = 3.42, (M+H) 402.32.

[001118] (1184) (2S,3S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid

Figure imgf000330_0002

Compound 1184 was made in a similar fashion as described above for compounds 946 and 947

PATENT

WO-2016191079

EXPERIMENTAL

Example 1: Synthesis of 3-BPin-5-bromo-7-azaindole

Chemical Formula: C7H5BrN2 Chemical Formula: Ci3H16BBrN202

Molecular Weight: 197.03 Molecular Weight: 322.99

5-fluoro-7-azaindole (1 g) and THF (10 mL) were added to a small screw-top vial fitted with a septum, argon inlet and exit needle. The flask was sparged with argon for -10 minutes. The iridium catalyst [Ir(OMe)COD]2 (0.168 mg) and 2,2′-bipyridyl (0.080 mg) were added as solids and the flask was covered with the septum and sparged with argon again for -10-15 minutes. When the catalyst was added, the reaction turned a dark red/purple. The argon was then turned off, and HBPin (1.5 mL) was added via syringe. The reaction bubbled, releasing hydrogen. The hydrogen was allowed to bubble out through the bubbler outlet and once bubbling stopped, the reaction was capped and placed in an oil bath heated to 80° C.

After approx. 20 hours, the flask was allowed to cool to room temperature and a sample was pulled from the reaction flask for HPLC analysis. The reaction was then quenched with methanol (10 mL) and allowed to stir for -5 minutes before it was concentrated in vacuo to afford a dark residue (2.44 g). The residue was dissolved in methyl t-butyl ether (MTBE) (50 mL) and filtered through a silica plug (20 g, 150 mL frit). The cake was washed with MTBE (3 x 20 mL) and the filtrate was collected and concentrated in vacuo to afford 1.5 g of an off-white solid. The solid residue was taken up in 10 mL of isopropanol (IPA) and heated until it dissolved. The flask was allowed to cool to room temperature, at which point some crystals had precipitated out of solution. The flask was placed in the freezer overnight to afford white crystals.

The crystals were filtered in vacuo, washed with cold hexanes, and dried on a rotovap (yield: 0.5 g). The crystals were taken up again in hexanes (10 mL) and heated to reflux, but the crystals would not dissolve in the hexanes. Thus, the hexanes were removed on the rotovap, and the crystals were taken up in IPA (10 mL) and heated to reflux until the crystals dissolved. The flask was allowed to cool to room temperature, and then placed in the freezer overnight to crystallize, affording 300 mg (7.8 %) of product.

Example 2: Synthesis of 3-BPin-5-bromo-N-tosyl-7-azaindole

Chemical Formula: Ci4HiiBrN202S Chemical Formula: C 0H22BBrN2O4S Molecular Weight: 351.22 Molecular Weight: 477.18

A 250 mL 1-neck round bottom flask equipped with a thermocouple and argon inlet was sparged with argon for 15 minutes. 5-bromo-N-tosyl-7-azaindole (4.0 g), B2Pin2 (2.90 g), [Ir(OMe)COD]2 (0.114 g), 2,2’bipyridyl (0.054 g) and hexane (50 mL) were then added. The flask was again inerted with 3 vacuum purges. The resulting brown slurry was then heated to 60° C incrementally (setpoints: 45° C, 55° C, 58° C and 60° C) and stirred overnight.

After 15 hours at 60 ° C, HPLC of the reaction mixture indicated 3.0% starting material remaining and 94% product. After 18 hours at 60 ° C, HPLC of the reaction mixture indicated 2.7% starting material and 5% product.

The slurry was then cooled to room temperature and vacuum filtered. The solids were recombined with the mother liquor and concentrated to afford a solid. The solid was dissolved in dichloromethane (50 mL) and filtered through silica (5 g on a 60 mL frit). The plug was washed with dichloromethane (2 x 50 mL). The filtrate and washes were combined and concentrated by rotovap to approx. 50 mL. Hexane (50 mL) was added and the solution was again concentrated to approx. 50 mL. Hexane (50 mL) was again added and the solution was concentrated. Product that “bumped” was rinsed back into the flask with dichloromethane. The solution was concentrated to approx. 50 mL and hexane (35 mL) was added. The solution was then concentrated to approx. 50 mL. The slurry was vacuum filtered and the solids were washed with cold hexane, then dried by rotovap, to afford 4.7 g (88.7% of product. HPLC indicated approx. 97% purity.

Example 3: Synthesis of 3-BPin-5-fluoro-N-tosyl-7-azaindole

Chemic

Mol
ecular Weight: 290.31

Chemical Formula: C20H22BFN2O4S

Molecular Weight: 416.27

A I L 3 -necked flask equipped with mechanical stirring, argon inlet, thermocouple, and heating mantle was sparged with argon for 15 minutes. 5-fluoro-N-tosyl-7-azaindole (50.0 g), B2Pin2 (43.7 g), [IrClCOD]2 (2.89 g), dppe (3.43 g), and heptane (500 mL) were then added to the flask. The resulting slurry was then heated to 95 C for 53 hours with stirring.

The slurry was then cooled to room temperature and the solids were collected by vacuum filtration, washed with cold hexane, and dissolved in dichloromethane (450 mL). The solution was filtered through silica (100 g on a 600 mL frit) and the plug was washed with 5 x 100 mL dichloromethane. The filtrate and washes were combined and concentrated by rotovap. Hexane (400 mL) was then added and the solution was concentrated to approx 200 mL. The slurry was then filtered and the solids washed with cold hexane, dried by rotovap to afford 56.97 g (79.6 %) of product. HPLC indicated a purity of >99%.

Example 4: Synthesis of N-Boc-3-BPin-5-fluoro-7-azaindole

Mo 204

N-Boc-5-fluoro-7-azaindole (5.0 g), B2Pin2 (5.38 g), and hexane (50 mL) were added to a 250 mL 2-neck round bottom equipped with a condenser, magnetic stirring, heating mantle and nitrogen inlet. A colorless solution resulted with stirring. The flask was sparged with 3 nitrogen/vacuum cycles. The iridium catalyst [Ir(OMe)COD]2(0.21 g) and 2,2′-bipyridyl (0.10 g) were added as solids and another nitrogen/vacuum cycle was used to inert the flask. The resulting black solution was heated to 60° C. After 1 hour, TLC (eluting with DCM) of the reaction solution indicated that no starting material remained. The solution was cooled to room temperature and filtered through silica (10 g on a 60 mL frit). The plug was washed with dichloromethane (4 x 100 mL). The fractions were combined and concentrated by rotovap until a precipitate began to form. Dichloromethane was then added until a solution resulted and hexane (50 mL) was added. The solution was concentrated cold <25° C to approx. 50 mL. Hexane (50 mL) was added and the solution was concentrated to approx. 75 mL. The resulting white solids were collected by vacuum filtration, washed with cold hexane and dried by rotovap, to afford 4.6 g (60.5%) of product.

Example 5: Synthesis of 3-BPin-7-azaindole

Chemical Formula: C7H6N2 Chemical Formula: C13H17BN202

Molecular Weight: 118.14 Molecular Weight: 244.10

7-azaindole (5.0 g) and THF (50 mL) were added to an argon-inert small screw-top vial fitted with a septum, argon inlet and bubbler outlet. The flask was sparged with argon. The iridium catalyst [Ir(OMe)COD]2 (1.4 g) and 2,2’bipyridyl (1.4 g) were then added and the flask was again sparged with argon. The HBPin (12. 3 mL) was added by syringe and gas evolution was observed. The screwtop was sealed and the vial was placed in an oil bath and heated to 80° C for 16 hours.

The vessel was then allowed to cool to room temperature. The cap was removed and sampled while under an argon stream. The reaction appeared to stall at 50% completion. The cap was removed and 20 mL of methanol was added with visible degassing. The combined reaction solution was concentrated to an oil by rotovap (17.28 g). The crude product was dissolved in 50mL of MTBE and filtered through 50g of silica. The plug was washed with 3 x 50 mL of MTBE and the filtrate was concentrated by rotovap (13g of crude product). The crude product was dissolved in 13 mL of refluxing IPA, cooled to room temperature, and placed in the freezer. No crystals were observed.

Example 6: Synthesis of 3-BPin-5-fluoro-7-azaindole

Chemical Formula: C7H5FN2 Chemical Formula: Ci3H-ieBFN202 Molecular Weight: 136.13 Molecular Weight: 262.09

5-fluoro-7-azaindole (1.0 g) and THF (10 mL) were added to an argon-inert small screw-top vial fitted with a septum, argon inlet and bubbler outlet. The flask was sparged with argon. The iridium catalyst [Ir(OMe)COD]2 (0.24 g) and 3,4,7, 8-tetramethyl-l,10-phenanthroline (0.11 g) were then added and the flask was again sparged with argon. HBPin (2.13 mL) was added by syringe and gas evolution was observed. The screwtop was sealed and the vial was placed in an oil bath and heated to 80° C overnight.

The vial was then removed from the oil bath and allowed to cool to room temperature. The reaction was quenched by the addition of methanol (20 mL, very little gas evolution noted). The solution was then concentrated by rotovap to afford a dark oil (3.57 g). The oil was dissolved in MTBE (50 mL) and filtered though silica. The plug was washed with MTBE (4 x 25 mL) and the clear, yellow filtrate was concentrated by rotovap to an oil (2.7 g).

Upon standing overnight, solids precipitated out of the crude oil. The oil was then dissolved in refluxing hexane (3 mL, ~1 mL/g) and the solution was allowed to cool to room temperature then placed in the freezer.

The resulting white solids were collected by vacuum filtration, washed three times with cold hexane, and dried by rotovap (0.58 g crude product). HPLC indicated 92.2% purity. The crude solids were dissolved in refluxing IPA (1.2 mL, ~2 mL/g) and the resulting yellow solution was allowed to cool to room temperature (during which time crystals precipitated) then placed in the freezer. The resulting crystals were collected by vacuum filtration, washed three times with cold hexane (3x), and dried by rotovap to afford 0.33 g (17.1%) of product.

PATENT

WO2015073491

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015073491&redirectedID=true

Example 2: Preparation of Compound (l)and 2-MeTHF solvate of Compound (1)

Compound (1) can be prepared as described in WO 2010/148197. For example, an amorphous free base Compound (1) was prepared according to WO 2010/148197, followed by usual chiral separation and purification: SCF chiral chromatography with a modifier that included Et2NH (which generated Et2NH salt of Compound (1)) and then ion-exchange resin treatment. Alternatively, Compound (1) can be made by the following procedures as a 2-MeTHF solvate:

Preparation of Compound 2a (2- Amino-3-bromo-5-fluoropyridine)

1a 2a

To a slurry of 2-amino-5-fluoropyridine (6 kg, 53.6 mol) in water (24 L) at 14 °C was added over 10 minutes 48% hydrobromic acid (18.5 kg, 110 mol). The reaction was exothermic and the temperature went up to 24 °C. The mixture was re-cooled to 12 °C then bromine (9 kg, 56.3 mol) was added in nine portions over 50 minutes (exothermic, kept at 20 °C). The mixture was stirred at 22 °C overnight, and monitored by ‘HNMR of a quenched aliquot (quenched 5 drops in to mix of 1 ml 20% K2CO3, 0.3 ml 10% Na2S203 and 0.7 ml DCM. Organic layer evaporated and assayed). The mixture was cooled to 10 °C then quenched by addition of sodium bisulfite (560 g, 5.4 mol) in water (2 L), and further cooled to 0 °C. This mixture was added to a cold (-4 °C) mixture of DCM (18 L) and 5.4M sodium hydroxide (35 L, 189 mol). The bottom -35 L was filtered through a pad of Celite and then the phase break was made. The aqueous layer was re-extracted with DCM (10 L). The organics were filtered through a pad of 3 kg magnesol, washing with DCM (8 L). The filtrate was evaporated, triturated with hexane and filtered.

Despite the in-process assay indicating 97% completion, this initial product from all four runs typically contained -10% SM. These were combined and triturated in hexane (2 L per kg material) at 50 °C, then cooled to 15 °C and filtered to afford Compound 2a (30.0 kg, -95% purity, 149 mol, 67%). Mother liquors from the initial trituration and the re-purification were chromatographed (20 kg silica, eluent 25-50% EtOAc in hexane) to afford additional Compound 2a (4.7 kg, -99% purity, 24.4 mol, 11%).

Preparation of Compound 3a

To an inert 400-L reactor was charged 2a (27.5 kg, 96% purity, 138 mol), Pd(PPh3)4 (1044 g, 0.90 mol) and Cul (165 g, 0.87 mol), followed by toluene (90 kg). The mixture was de-oxygenated with three vacuum-nitrogen cycles, then triethylamine (19.0 kg, 188 mol) was added. The mixture was de-oxygenated with one more vacuum-nitrogen cycle, then

TMS-acetylene (16.5 kg, 168 mol) was added. The mixture was heated to 48 °C for 23 hours (the initial exotherm took the temperature to 53 °C maximum), then cooled to 18 °C. The slurry was filtered through a pad of Celite and washed with toluene (80 kg). The filtrate was washed with 12% Na2HP04 (75 L), then filtered through a pad of silica (25 kg), washing with 1 :1 hexane:MTBE (120 L). This filtrate was evaporated to a brown oil and then dissolved in NMP for the next step. Weight of a solution of Compound 3a – 58 kg, ~50wt%, 138 mol,

100%. 1H NMR (CDCI3, 300 MHz): δ 7.90 (s, 1H); 7.33-7.27 (m, 1H); 4.92 (s, NH2), 0.28 (s, 9H) ppm.

Preparation o Compound 4a

3a 4a

To an inert 400-L reactor was charged potassium t-butoxide (17.5 kg, 156 mol) and NMP (45 kg). The mixture was heated to 54 °C then a solution of Compound 3a (29 kg, 138 mol) in NMP (38 kg) was added over 2.75 hours and rinsed in with NMP (6 kg)

(exothermic, maintained at 70-77 °C) . The reaction was stirred at 74 °C for 2 hours then cooled to 30 °C and a solution of tosyl chloride (28.5 kg, 150 mol) in NMP (30 kg) added over 1.5 hours and rinsed in with NMP (4 kg). The reaction was exothermic and maintained at 30-43 °C. The reaction was stirred for 1 hour while cooling to 20 °C then water (220 L) was added over 35 minutes (exothermic, maintained at 18-23 °C). The mixture was stirred at 20 °C for 30 minutes then filtered and washed with water (100 L). The solids were dissolved off the filter with DCM (250 kg), separated from residual water and the organics filtered through a pad of magnesol (15 kg, top) and silica (15 kg, bottom), washing with extra DCM (280 kg). The filtrate was concentrated to a thick slurry (-50 L volume) then MTBE (30 kg) was added while continuing the distillation at constant volume (final distillate temperature of 51 °C). Additional MTBE (10 kg) was added and the slurry cooled to 15 °C, filtered and washed with MTBE (40 L) to afford Compound 4a (19.13 kg, 95% purity, 62.6 mol, 45%). Partial concentration of the filtrate afforded a second crop (2.55 kg, 91% purity, 8.0 mol, 6%). 1H NMR (CDCI3, 300 MHz): δ 8.28-8.27 (m, 1H); 8.06-8.02 (m, 2H); 7.77 (d, J= 4.0 Hz, 1H); 7.54-7.50 (m, 1H); 7.28-7.26 (m, 2H); 6.56 (d, J= 4.0 Hz, 1H); 2.37 (s, 3H) ppm.

Preparation of Compound 5a

4a 5a

To a slurry of N-bromosuccinimide (14.16 kg, 79.6 mol) in DCM (30 kg) at 15 °C was charged a solution of Compound 4a (19.13 kg, 95% purity, and 2.86 kg, 91% purity, 71.6 mol) in DCM (115 kg), rinsing in with DCM (20 kg). The mixture was stirred at 25 °C for 18 hours, and then cooled to 9 °C and quenched by addition of a solution of sodium

thiosulfate (400 g) and 50% sodium hydroxide (9.1 kg) in water (130 L). The mixture was warmed to 20 °C and the layers were separated and the organics were washed with 12% brine (40 L). The aqueous layers were sequentially re-extracted with DCM (4 x 50 kg). The organics were combined and 40 L distilled to azeotrope water, then the solution was filtered through a pad of silica (15 kg, bottom) and magensol (15 kg, top), washing with DCM (180 kg). The filtrate was concentrated to a thick slurry (-32 L volume) then hexane (15 kg) was added. Additional hexane (15 kg) was added while continuing the distillation at constant volume (final distillate temperature 52 °C). The slurry was cooled to 16 °C, filtered and washed with hexane (25 kg) to afford Compound 5a (25.6 kg, 69.3 mol, 97%). 1H NMR (CDC13, 300 MHz): δ 8.34-8.33 (m, 1H); 8.07 (d, J= 8.2Hz, 2H); 7.85 (s, 1H); 7.52-7.49 (m, 1H); 7.32-7.28 (m, 2H); 2.40 (s, 3H) ppm.

Preparation of Compound 6a: BEFTA1 Reaction

6a

To an inert 400-L reactor was charged Compound 5a (25.6 kg, 69.3 mol), bis(pinacolato)diboron (19 kg, 74.8 mol), potassium acetate (19 kg, 194 mol), palladium acetate (156 g, 0.69 mol) and triphenylphosphine (564 g, 2.15 mol), followed by dioxane (172 kg), that had been separately de-oxygenated using vacuum-nitrogen cycles (x 3). The mixture was stirred and de-oxygenated using vacuum-nitrogen cycles (x 2), then heated to 100 °C for 15 hours. The mixture was cooled to 35 °C then filtered, washing with 30 °C THF (75 kg). The filtrate was evaporated and the residue dissolved in DCM (-90 L). The solution was stirred with 1 kg carbon and 2 kg magnesol for 45 minutes then filtered through a pad of silica (22 kg, bottom) and magensol (10 kg, top), washing with DCM (160 kg). The filtrate was concentrated to a thick slurry (-40 L volume) then triturated at 35 °C and hexane (26 kg) was added. The slurry was cooled to 20 °C, filtered and washed with a mix of DCM (5.3 kg) and hexane (15 kg), then hexane (15 kg) and dried under nitrogen on the filter to afford Compound 6a (23.31 kg, 56.0 mol, 81%) as a white solid. 1H-NMR consistent with desired product, HPLC 99.5%, palladium assay 2 ppm. 1H NMR (CDC13, 300 MHz): δ 8.25 (s, 1H); 8.18 (s, 1H); 8.09-8.02 (m, 2H); 7.91-7.83 (m, 1H); 7.30-7.23 (m, 2H); 2.39 (s, 3H); 1.38 (s, 12H) ppm.

Preparation of Compounds 8a and 9a

9a

[0247] Compound 8a: Anhydride 7a (24.6 kgs, Apex) and quinine (49.2 kgs, Buchler) were added to a reactor followed by the addition of anhydrous PhMe (795.1 kgs). The reactor was then cooled to -16 °C and EtOH (anhydrous, 41.4 kgs) was added at such a rate to maintain the internal reactor temperature < -12 °C. The maximum reaction temp recorded for this experiment was -16 °C. The reaction mixture was then stirred for 16 h at -16 °C. A sample was removed and filtered. The solid was dried and evaluated by 1H-NMR which showed that no anhydride remained. The contents of the reactor were filtered. The reactor and subsequent wet cake were washed with PhMe (anhydrous, 20 kgs). The resulting solid was placed in a tray dryer at < 45 °C with a N2 sweep for at least 48 h. In this experiment, the actual temperature was 44 °C and the vacuum was -30 inHG. Material was sampled after 2.5 d drying and showed 3% PhMe by NMR. After an additional 8 hrs, the amt of PhMe analyzed showed the same 3% PhMe present and the drying was stopped. The weight of the white solid was 57.7 kgs, 76% yield. 1 H-NMR showed consistent with structure and Chiral SFC analysis showed material >99% ee.

Compound 9a: The reactor was charged with quinine salt 8a (57.7 kgs) and PhMe (250.5 kgs, Aldrich ACS grade, >99.5%) and the agitator was started. The contents were cooled to <15 °C and was treated with 6N HCI (18 kgs H20 were treated with 21.4 kgs of cone. HCI) while keeping the temperature <25 °C. The mixture was stirred for 40 min and visually inspected to verify that no solids were present. Stirring was stopped and the phases were allowed to settle and phases were separated. The aqueous phases were extracted again with PhMe (160 kgs; the amount typically used was much less, calc. 43 kgs. However, for efficient stirring due to minimal volume, additional PhMe was added. The organic phases were combined. Sample the organic phase and run HPLC analysis to insure product is present; for information only test.

To the organic phases were cooled to <5 °C (0-5 °C) and was added sodium sulfate (anhydrous, 53.1 kgs) with agitation for 8 hrs (in this instance 12 hrs). The contents of the reactor containing the organic phase were passed through a filter containing sodium sulfate (31 kgs, anhydrous) and into a cleaned and dried reactor. The reactor was rinsed with PhMe (57.4 kgs), passed through the filter into reactor 201. The agitator was started and an additional amount of PhMe (44 kgs) was added and the reaction mixture cooled to -20 °C. At that temperature PhMe solution of potassium tert-pentoxide was added over 2 h while keeping the temperature between -15 and -22 °C. The reaction mixture was held at -20 °C for an additional 30 min before being sampled. Sampling occurred by removing an aliquat with immediate quenching into 6N HC1. The target ratio here is 96:4 (trans is).

Having achieved the target ratio, the reactor was charged with acetic acid (2.8 kgs) over 6 min. The temperature stayed at – 20 °C. The temperature was then adjusted to -5 °C and aqueous 2N HC1 (65.7 kgs water treated with 15.4 kgs of cone HC1) was added. The contents were warmed to 5 °C +/- 5 °C, agitated for 45 min before warming to 20 °C +/- 5 °C with stirring for 15 min. The agitator was stopped and the phases allowed to settle. The aqueous layer was removed (temporary hold). The organic phase was washed with water (48 kgs, potable), agitated for 15 min and phases allowed to settle (at least 15 min) and the aqueous layer was removed and added to the aqueous layer. 1/3 of a buffer solution (50 L) that was prepared (7.9 kgs NaH2P04, 1.3 kgs of Na2HP04 and 143.6 kgs water) was added to the organic phase and stirred for at least 15 min. Agitation was stopped and phases were allowed to separate for at least 15 min. The lower layer was discarded. Another portion of the buffered solution (50 L) was used to wash the organic layer as previously described. The wash was done a third time as described above.

Vacuum distillation of the PhMe phase (150 L) was started at 42 °C/-13.9 psig and distilled to an oil of 20 L volume. After substantial reduction in volume the mixture was transferred to a smaller vessel to complete the distillation. Heptanes (13.7 kgs) was added and the mixture warmed to 40 +/- 5 °C for 30 min then the contents were cooled to 0-5 °C over 1.5 h. The solids were filtered and the reactor washed with approximately 14 kgs of cooled (0-5 °C) heptanes. The solids were allowed to dry under vacuum before placing in the oven at <40 °C under house vac (-28 psig) until LOD is <1%. 15.3 kgs, 64%, 96% HPLC purity. 1H NMR (400 MHz, CDC13) δ 11.45 (br. s, 1H), 6.41 (t, J= 7.2 Hz, 1H), 6.25 (t, J=

7.2 Hz, 1H), 4.18 (m, 2H), 3.27 (m, 1H), 3.03 (m, 1H), 2.95 (m, 1H), 2.77 (m, 1H), 1.68 (m,

1H), 1.49 (m, 1H), 1.25 (t, J= 7.2Hz), 1.12 (m, 1H).

Preparation of Compound 10a

9a 10a

A three neck flask equipped with a mechanical stirrer, temperature probe, reflux condenser, addition funnel and nitrogen inlet was charged with Compound 9a (145.0 g, 1 equiv) and anhydrous toluene (Aldrich, cat# 244511) (1408 g, 1655 ml) under an atmosphere of nitrogen. Then triethylamine (Aldrich, cat# 471283) (140 g, 193 ml,

2.14 equiv) was added in portions over 5 minutes to the stirred solution during which an exotherm to a maximum temperature of 27 °C was observed. Data acquisition by ReactIR was started. The reaction mixture was then heated to 95 °C over 70 minutes. Then diphenyl phosphoryl azide (Aldrich, cat# 178756) (176.2 g; 138.0 ml, 0.99 equiv) was added by addition funnel in portions over a total time of 2.25 hours.

Following completion of the addition of diphenyl phosphoryl azide (addition funnel rinsed with a small amount of toluene), the resulting mixture was heated at 96 °C for an additional 50 minutes. A sample of the reaction mixture diluted in toluene was analyzed by GC/MS which indicated consumption of diphenyl phosphoryl azide. Then benzyl alcohol (Aldrich, cat# 108006) (69.9 g, 67.0 ml, 1.0 equiv) was added by addition funnel over 5-10 minutes. The resulting mixture was then heated at 97 °C overnight (for approximately 19 hours). A sample of the reaction mixture diluted in toluene by GC/MS indicated formation of product (m/e =330). The reaction mixture was then cooled to 21 °C after which water (870 g, 870 ml) was added in portions (observed slight exotherm to maximum temperature of 22 °C). The reaction mixture was first quenched by addition of 500 g of water and mechanically stirred for 10 minutes. The mixture was then transferred to the separatory funnel containing the remaining 370 g of water and then manually agitated. After agitation and phase separation, the organic and aqueous layers were separated (aqueous cut at pH of -10). The organic layer was then washed with an additional portion of water (870 g; 1 x 870 ml). The organic and aqueous layers were separated (aqueous cut at pH of ~10). The collected organic phase was then concentrated to dryness under reduced pressure (water bath at 45-50 °C) affording 215 g of crude Compound 10a (approximate volume of 190 ml). The 1H NMR and GC/MS conformed to compound 10a (with residual toluene and benzyl alcohol).

Preparation o Compound 11a

10a 11a

HCI in ethanol preparation: A three neck flask equipped with a temperature probe, nitrogen inlet and magnetic stirrer was charged with ethanol (1000 ml, 773 g) under a

nitrogen atmosphere. The solution was stirred and cooled in a dry ice/acetone bath until an internal temperature of- 12 °C was reached. Then anhydrous HC1 (~ 80 g, 2.19 moles) was slowly bubbled in the cooled solution (observed temperature of -24 to -6 °C during addition) over 2 hours. Following the addition, the solution was transferred to a glass bottle and allowed to warm to ambient temperature. A sample of the solution was submitted for titration giving a concentration of 2.6 M. The solution was then stored in the cold room (approximately 5 °C) overnight.

Hydrogenation/HCl salt formation: A glass insert to a 2 gallon Parr autoclave was charged with palladium on carbon (Pd/C (Aldrich, cat# 330108), 10 % dry basis; (50 % wet), 13.11 g, 0.01 equiv on the basis of Compound 10a) under a nitrogen atmosphere and then moistened with ethanol (93 g; 120 ml). Then a solution of crude Compound 10a (212 g, 1 eq) in ethanol (1246 g; 1600 ml) was added to the glass insert (small rinse with ethanol to aid with transfer). The glass insert was placed in the autoclave after which HC1 in ethanol (prepared as described above; 2.6 M; 1.04 equiv based on Compound 10a; 223 g; 259 ml) was added. The autoclave was sealed and then purged with hydrogen (3 x at 20 psi). The hydrogenation was then started under an applied pressure of hydrogen gas (15 psi) for 3 hours at which time the pressure of hydrogen appeared constant. Analysis of an aliquot of the reaction mixture by 1H NMR and GC/MS indicated consumption of starting

material/formation of product. The resulting mixture was then filtered over a bed of Celite (192 g) after which the Celite bed was washed with additional ethanol (3 x; a total of 1176 g of ethanol was used during the washes). The filtrate (green in color) was then concentrated under reduced pressure (water bath at 45 °C) to ~ 382 g ((-435 ml; 2.9 volumes based on theoretical yield of Compound 11a. Then isopropyl acetate (1539 g; 1813 ml (12 volumes based on theoretical yield of Compound 11a was added to the remainder. The resulting solution was distilled under vacuum with gradual increase in temperature.

The distillation was stopped after which the remaining solution (370 g, -365 ml total volume; brownish in color) was allowed to stand at ambient temperature over the weekend. The mixture was filtered (isopropyl acetate used to aid with filtration) and the collected solids were washed with additional isopropyl acetate (2 x 116 ml; each wash was approximately 100 g). The solid was then dried under vacuum at 40 °C (maximum observed temperature of 42 °C) overnight to afford 1 18 g (78.1 % over two steps) of Compound 11a. The 1H NMR of the material conformed to the structure of Compound 11a, and GC/MS indicated 99% purity.

Preparation of Compound 13a

2a

Procedure A: A mixture of 5-fluoro-2,4-dichloropyrimidine (12a, 39.3 g, 235 mmol, 1.1 equiv), and HCI amine salt (11a, 50 g, 214 mmol) was treated with CH2C12(169 mL) and the mixture was warmed to 30 °C. The mixture was then treated slowly with DIEA (60.8 g, 82 mL, 471 mmol, 2.2 equiv) via syringe pump over 3 h. Peak temp was up to 32 °C. The reaction was stirred for 20 h, the reaction mixture was judged complete by HPLC and cooled to rt. The resulting reaction mixture was washed sequentially with water (21 1 mL, pH = 8-9), 5% NaHS04 (21 1 mL, pH = 1-2) then 5% aq. NaCl (211 mL, pH = 5-6).

The organic phase was then distilled under reduced pressure to 190 mL. PhMe was charged (422 mL) and temperature set at 70 -80 °C and internal temp at 60-65 °C until vol back down to 190 mL. The mixture was allowed to cool to approximately 37 °C with stirring – after approximately 10 min, crystallization began to occur and the temperature was observed to increase to approximately 41 °C. After equilibrating at 37 “C, the suspension was charged with n-heptane (421 mL) over 3.5 h followed by cooling to 22 °C over 1 h. The mixture was allowed to stir overnight at that temperature before filtering. The resulting solid on the filter was washed with a 10% PhMe in n-heptane solution (2 x 210 mL). The solid was then dried in the oven under vacuum with an N2 purge at 50 °C overnight. The resulting solid weighed 62 g (88% yield).

Procedure B: A three neck flask equipped with a mechanical stirrer, temperature probe, reflux condenser, nitrogen inlet and addition funnel was charged with Compound 11a (51.2 g) and Compound 12a (40.2 g) under an atmosphere of nitrogen. Dichloromethane (173 ml, 230 g) was added and the resulting mixture was stirred while warming to an internal temperature of 30 °C. Then N,N-diisopropylethylamine (85 ml, 63.09 g) was slowly added by addition funnel over 2.5-3 hours during which time an exotherm to a maximum observed temperature of 33.5 °C was observed. After complete addition, the resulting solution was stirred at 30-31 °C overnight under a nitrogen atmosphere (for approximately 19 hours).

A 100 μΐ sample of the reaction mixture was diluted with dichloromethane up to a total volume of 10 ml and the solution mixed well. A sample of the diluted aliquot was analyzed by GC/MS which indicated the reaction to be complete by GC/MS; observed

formation of product (m/e = 328)). The reaction mixture was cooled to 26 °C and transferred to a separatory funnel (aided with dichloromethane). The mixture was then sequentially washed with water (211 ml, 211 g; pH of aqueous cut was -8; small rag layer was transferred with aqueous cut), 5 % aqueous NaHS04 ((prepared using 50 g of sodium bisulfate monohydrate (Aldrich cat. # 233714) and 950 g water) 211 ml, 216 g; pH of aqueous cut was ~2) and then 5 % aqueous NaCl ((prepared using 50 g of sodium chloride (Aldrich cat. # S9888) and 950 g water) 211 ml, 215 g; pH of aqueous cut was -4-5). The collected organic phase was then concentrated under reduced pressure (water bath at 35 °C) to -190 ml (2.7 volumes based on theoretical yield of Compound 13a after which toluene (Aldrich cat. # 179418, 422 ml, 361 g) was added. The resulting mixture was concentrated under reduced pressure (water bath at 55-65 °C) to -190 ml (2.7 volumes based on theoretical yield of Compound 13a. Analysis of a sample of the solution at this stage by 1H NMR indicated the absence of dichloromethane. The remaining mixture was allowed to cool to 37 °C (using water bath at 37 °C on rotovap with agitation). During this time pronounced crystallization was observed. The mixture was then mechanically stirred and heated to approximately 37 °C (external heat source set to 38 °C) after which n-heptane (430 ml, 288 g; Aldrich cat# H2198) was slowly added by addition funnel over 3 hours. Following the addition, heating was stopped and the resulting slurry mechanically stirred while cooling to ambient temperature overnight. The resulting mixture was then filtered and the collected solids were washed with 10 % toluene in n-heptane (2 x 210 ml; each wash was prepared by mixing 21 ml (16 g) of toluene and 189 ml (132 g) of n-heptane). Vacuum was applied until very little filtrate was observed. The solids were then further dried under vacuum at 50 °C under a nitrogen bleed to constant weight (3.5 hours) giving 64.7 g (90 %) of Compound 13a. Analysis of a sample of the solid by Ή NMR showed the material to conform to structure and LC analysis indicated 99.8 % purity using the supplied LC method.

Preparation of Compound 14a

The ethyl ester 13a (85 g, 259 mmol) was dissolved in THF (340 mL) and treated with a solution of LiOH (2M, 389 mL, 778 mmol) over 10 min (temp from 21 to 24 °C). The mixture was warmed to 45 °C with stirring for 17 h at which time the reaction was judged complete by HPLC (no SM observed). The reaction mixture was cooled to rt and CH2C12 was added (425 mL). A solution of citric acid (2 M, 400 mL) was then added slowly over 45 min (temp up to 26 °C). It was noted that during the charge some white solids were formed but quickly dissolved with stirring. The reaction mixture was stirred for an additional 15 min before phases were allowed to separate. After the phases were split, the aqueous phase pH was measured pH = 4.0. The organic phase was washed (15 min stir) with water (255 mL) -phases were allowed to separate. The lower layer (organic) containing the desired product was then stored in the fridge overnight.

The organic phase was concentrated under reduced pressure (pot set to 65 °C) to 150 mL (est. 1.76 vol wrt SM). IPA (510 mL) was charged and distilled under reduced pressure (85 °C chiller temp setting) to 255 mL (3 vol). The level of solvent was brought to approximately 553 mL (6.5 vol) by the addition of IPA (298 mL). Water (16 mL) was then added and the reaction mixture warmed to reflux (77 °C) with good agitation which dissolved solids precipitated on the walls of the vessel. Reaction mixture was then cooled slowly to 65 °C (over 60 min) and held there – all material still in solution (sample pulled for residual solvent analysis). The reaction was further cooled to 60 °C and the reaction mixture appeared slightly opaque. After stirring for 15 min further cooled to 55 °C. While more product precipitates, the mixture is still thin and easily stirred. Water (808 mL) was added very slowly (2.5-3 hrs) while maintaining the temperature around 55 C. The mixture was then cooled to 22 °C over 2 h and allowed to stir overnight. Material was then filtered and washed with a mixture of water: IPA (75:25, 2 x 255 mL). The acid was dried in a vac oven at 55 °C overnight. Obtained 69 g of acid 14a, 88% yield of a white solid. The material analyzed >99% purity by HPLC.

Preparation o f Compound 15a: Suzuki Coupling

To 14a (91.4 g, 305 mmol), 6a (158.6 g, 381 mmol, 1.25 equiv.), Pd(OAc)2 (0.34 g, 1.5 mmol, 0.5 mol%), X-Phos (1.45 g, 3.0 mmol, 1.0 mol%), and K2C03 (168.6 g,

1220 mmol, 4 equiv.) was added THF (731 mL, 8 volumes) and water (29 mL, 0.32 vol). The reaction mixture was sparged with N2 for 30 min, then warmed to 65-70 °C and stirred for 5 h. HPLC analysis of the reaction mixture showed 99.3% conversion. The reaction mixture was cooled to 22-25 °C and water was added. The mixture was stirred, the phases

were allowed to separate, and the aqueous phase was decanted. A solution of 18 wt% NaCl in water (half-saturated aqueous NaCl) was added to the organic phase and the pH of the mixture was adjusted to 6.0-6.5 using 2N HC1. The phases were allowed to separate and the aqueous phase was decanted. The organic phase was concentrated to a minimum volume and acetonitrile was added. The process was repeated one more time and acetonitrile was added to bring the final volume to 910 mL (10 vol). The slurry was warmed to 80-85 °C for 6 h, then cooled to 20-25 °C. The slurry was stirred for 2 h, then filtered. The solids were rinsed with acetonitrile to give 15a (161 g, 89% yield).

Preparation of Compound (1): Detosylation Step

To 15a (25 g, 45.2 mmol) was added THF (125 ml, 5 vol), then MP-TMT resin (6.25 g, 25 wt%). The mixture was stirred at 20-25 °C for 16 h and filtered, rinsing with 1 vol THF. The resin treatment process and filtration were repeated. The THF solution was concentrated to 5 vol. To the mixture at 22-25 °C was added an aqueous solution of 2M LiOH (90.3 mL, 4 equiv). The reaction mixture was warmed to 40-45 °C and stirred for 5 h. HPLC analysis showed 99.7% conversion. The reaction mixture was cooled to 22-25 °C and MTBE (50 mL, 2 vol) was added. Phase separation occurred. The lower aqueous phase was collected. The aqueous phase was extracted with MTBE. The lower aqueous phase was collected. To the aqueous phase was added 2-MeTHF and the mixture was stirred. The pH of the mixture was adjusted to 6.0-6.5, and the lower aq. phase was decanted. The organic phase was washed with pH 6.5 buffer. The organic phase was concentrated to 85 mL, diluted with 2-MeTHF (150 mL), and concentrated to a final volume of 180 mL. The resultant slurry was warmed to 70-75 °C and stirred until complete dissolution, then cooled to 45-50 °C to give slurry. The slurry was stirred for 1 h, then heptane (180 mL) was added. The slurry was cooled to 20-25 °C over 1 h and stirred for 16 h. The batch was filtered, rinsing the solids with heptane. The solids were dried to give crude Compound (l)-2-MeTHF solvate, 79% yield.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015073476

Preparation of Compound (1): Detosylation Step

[0214] To 15a (25 g, 45.2 mmol) was added THF (125 ml, 5 vol), then MP-TMT resin (6.25 g, 25 wt%). The mixture was stirred at 20 °C – 25 °C for 16 h and filtered, rinsing with 1 vol. THF. The resin treatment process and filtration were repeated. The THF solution was concentrated to 5 vol. To the mixture at 22 °C – 25 °C was added an aqueous solution of 2M LiOH (90.3 mL, 4 equiv.). The reaction mixture was warmed to 40 °C – 45 °C and stirred for 5 h. HPLC analysis showed 99.7% conversion. The reaction mixture was cooled to 22 °C -25 °C and MTBE (50 mL, 2 vol) was added. Phase separation occurred. The lower aqueous phase was collected. The aqueous phase was extracted with MTBE. The lower aqueous phase was collected. To the aqueous phase was added 2-MeTHF and the mixture was stirred. The pH of the mixture was adjusted to 6.0 – 6.5, and the lower aq. phase was decanted. The organic phase was washed with pH 6.5 buffer. The organic phase was concentrated to 85 mL, diluted with 2-MeTHF (150 mL), and concentrated to a final volume of 180 mL. The resultant slurry was warmed to 70 °C – 75 °C and stirred until complete dissolution, then cooled to 45 °C – 50 °C to give slurry. The slurry was stirred for 1 h, then heptane (180 mL) was added. The slurry was cooled to 20 °C – 25 °C over 1 h and stirred for 16 h. The batch was filtered, rinsing the solids with heptane. The solids were dried to give crude Compound (l 2-MeTHF solvate, 79% yield.

PAPER

Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2

J. Med. Chem., 2014, 57 (15), pp 6668–6678

DOI: 10.1021/jm5007275

http://pubs.acs.org/doi/abs/10.1021/jm5007275

Vertex Pharmaceuticals Inc51

1H NMR (300 MHz, DMSO-d6) δ 12.71 (br s, 1H), 8.58 (s, 1H), 8.47 (dd, J = 9.6, 2.8 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.39–8.34 (m, 1H), 4.89–4.76 (m, 1H), 2.94 (d, J = 6.9 Hz, 1H), 2.05 (br s, 1H), 1.96 (br s, 1H), 1.68 (complex m, 7H);
13C NMR (300 MHz, DMSO-d6) δ 174.96, 157.00, 155.07, 153.34, 152.97, 145.61, 142.67, 140.65, 134.24, 133.00, 118.02, 114.71, 51.62, 46.73, 28.44, 28.00, 24.90, 23.78, 20.88, 18.98;
LCMS gradient 10–90%, 0.1% formic acid, 5 min, C18/ACN, tR = 2.24 min, (M + H) 400.14;
HRMS (ESI) of C20H20F2N5O2 [M + H] calcd, 400.157 95; found, 400.157 56.
Article
June 18, 2014

Vertex Licenses VX-787 to Janssen Pharmaceuticals for the Treatment of Influenza

Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that it has entered into a licensing agreement with Janssen Pharmaceuticals, Inc. for the worldwide development and commercialization of VX-787, a novel medicine discovered by Vertex for the treatment of influenza. As part of the agreement, Vertex will receive an up-front payment of $30 million from Janssen and has the potential to receive additional development and commercial milestone payments as well as royalties on future product sales. Vertex completed a Phase 2a study of VX-787 in 2013 that showed statistically significant improvements in viral and clinical measurements of influenza infection. VX-787 is designed to directly inhibit replication of the influenza virus.

“With a deep history in developing new medicines for viral infections and diseases, Janssen is well-positioned to advance the global development of VX-787 for the treatment of influenza,” said Jeffrey Leiden, M.D., Ph.D., Chairman, President and Chief Executive Officer of Vertex. “This collaboration provides important support for the continued development of VX-787 in influenza and contributes to our financial strength to enable continued investment in our key development programs for cystic fibrosis and in research aimed at discovering new medicines.”

About the Collaboration

Under the terms of the collaboration, Janssen will have full global development and commercialization rights to VX-787. Vertex will receive a $30 million up-front payment from Janssen and could receive additional development and commercial milestone payments as well as royalties on future product sales. The collaboration, and the related $30 million up-front payment, is subject to the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act.

About VX-787

VX-787 is an investigational medicine that is designed to directly inhibit replication of influenza A, including recent H1 (pandemic) and H5 (avian) influenza strains, based on in-vitro data. VX-787’s mechanism represents a new class of potential medicines for the treatment of influenza, distinct from neuraminidase inhibitors, the current standard of care for the treatment of influenza. VX-787 is intended to provide a rapid onset of action and an expanded treatment window.

In a Phase 2a influenza challenge study, statistically significant improvements in viral and clinical measurements of influenza infection were observed after treatment with VX-787. The study met its primary endpoint and showed a statistically significant decrease in the amount of virus in nasal secretions (viral shedding) over the seven-day study period. In addition, at the highest dosing regimen evaluated in the study, there was a statistically significant reduction in the severity and duration of influenza-like symptoms. In this study, VX-787 was generally well-tolerated, with no adverse events leading to discontinuation. Those who took part in the study volunteered to be experimentally exposed to an attenuated form of live H3N2 influenza A virus. H3N2 is a common type of influenza virus and was the most common type observed in the 2012/2013 influenza season in the United States.

VX-787 was discovered by Vertex scientists.

About Influenza

Often called “the flu,” seasonal influenza is caused by influenza viruses, which infect the respiratory tract.1 The flu can result in seasonal epidemics2 and can produce severe disease and high mortality in certain populations, such as the elderly.3 Each year, on average 5 to 20 percent of the U.S. population gets the flu4 resulting in more than 200,000 flu-related hospitalizations and 36,000 deaths.5 The overall national economic burden of influenza-attributable illness for adults is $83.3 billion.5 Direct medical costs for influenza in adults totaled $8.7 billion including $4.5 billion for adult hospitalizations resulting from influenza-attributable illness.5 The treatment of the flu consists of antiviral medications that have been shown in clinical studies to shorten the disease and reduce the severity of symptoms if taken within two days of infection.6 There is a significant need for new medicines targeting flu that provide a wider treatment window, greater efficacy and faster onset of action.

About Vertex

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canada and Australia. For four years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences. For additional information and the latest updates from the company, please visit www.vrtx.com.

Vertex’s press releases are available at www.vrtx.com.

WO2002024705A1 13 Sep 2001 28 Mar 2002 Charles Jackson Barnett Stereoselective process for preparing cyclohexyl amine derivatives
WO2003015798A1 13 Aug 2002 27 Feb 2003 Toyama Chemical Co Ltd Novel virus proliferation inhibition/virucidal method and novel pyradine nucleotide/pyradine nucleoside analogue
WO2005095400A1 30 Mar 2005 13 Oct 2005 Vertex Pharma Azaindoles useful as inhibitors of jak and other protein kinases
WO2006069258A1 * 20 Dec 2005 29 Jun 2006 Amgen Inc Substituted heterocyclic compounds and methods of use
WO2007084557A2 17 Jan 2007 26 Jul 2007 Vertex Pharma Azaindoles useful as inhibitors of janus kinases
WO2008079346A1 21 Dec 2007 3 Jul 2008 Vertex Pharma 5-cyan0-4- (pyrrolo [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
WO2009073300A1 31 Oct 2008 11 Jun 2009 Vertex Pharma [1h- pyrazolo [3, 4-b] pyridine-4-yl] -phenyle or -pyridin-2-yle derivatives as protein kinase c-theta
WO2010011756A1 22 Jul 2009 28 Jan 2010 Vertex Pharmaceuticals Incorporated Pyrazolopyridine kinase inhibitors
WO2010011768A1 22 Jul 2009 28 Jan 2010 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
WO2010011772A2 22 Jul 2009 28 Jan 2010 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
WO2010148197A1 * 17 Jun 2010 23 Dec 2010 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
WO2011008915A1 * 15 Jul 2010 20 Jan 2011 Abbott Laboratories Pyrrolopyridine inhibitors of kinases
US20100038988 12 Aug 2008 18 Feb 2010 Gannon Ramy Stator and Method of Making the Same
WO2003015798A1 Aug 13, 2002 Feb 27, 2003 Toyama Chemical Co Ltd Novel virus proliferation inhibition/virucidal method and novel pyradine nucleotide/pyradine nucleoside analogue
WO2005095400A1 Mar 30, 2005 Oct 13, 2005 Vertex Pharma Azaindoles useful as inhibitors of jak and other protein kinases
WO2007084557A2 Jan 17, 2007 Jul 26, 2007 Vertex Pharma Azaindoles useful as inhibitors of janus kinases
WO2009073300A1 Oct 31, 2008 Jun 11, 2009 Vertex Pharma [1h- pyrazolo [3, 4-b] pyridine-4-yl] -phenyle or -pyridin-2-yle derivatives as protein kinase c-theta
WO2010011756A1 Jul 22, 2009 Jan 28, 2010 Vertex Pharmaceuticals Incorporated Pyrazolopyridine kinase inhibitors
WO2010011768A1 Jul 22, 2009 Jan 28, 2010 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
WO2010011772A2 Jul 22, 2009 Jan 28, 2010 Vertex Pharmaceuticals Incorporated Tri-cyclic pyrazolopyridine kinase inhibitors
WO2010148197A1 * Jun 17, 2010 Dec 23, 2010 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
US20100038988 Aug 12, 2008 Feb 18, 2010 Gannon Ramy Stator and Method of Making the Same

……

.

Vertex Pharmaceuticals’ Boston Campus, United States of America

Lynette Hopkinson VP Commercial Regulatory Affairs, Global Regulatory Affairs Vertex Pharmaceuticals Incorporated, United States

swati Patel, a lead analyst, shared a toast with Mir Hussain, a systems engineer, at Vertex Pharmaceuticals during the Friday beer hour, which features beer and chips for employees.

On Fridays around 5 o’clock, after a hard week of work, Frank Holland likes to unwind with a beer. And he doesn’t have to leave work to get one.

Holland is a research scientist at Vertex Pharmaceuticals, which every Friday rings in “beer hour,” offering free adult beverages and munchies to its 1,300 Boston employees.

For Holland, the weekly ritual is a chance to escape the bubble of his chemistry lab and bump into colleagues from other departments — as well as Vertex’s top executives, who regularly attend. For those who prefer grapes to hops, there is also wine.

“Some of the other companies I worked at, you really had to go out of your way to meet people,” said Holland, 32. “At Vertex all you have to do is show up in the cafeteria on a Friday afternoon.”

Sure, free beer is common at hip tech offices; some even have their own bars. But Vertex, best known for its treatment for cystic fibrosis, was doing this way before it was cool. The beer-hour tradition goes back to the company’s founding days, in 1989. Back then, it was just two dozen people in a small office in Cambridge. Someone went to a corner store, bought a case of beer and some chips, and beer hour was born.

Virginia Carden Carnahan
Vice President, New Product Planning and Strategy, Vertex Pharmaceuticals

A scientist works in the lab at Boston-based Vertex Pharmaceuticals.

Vertex Pharmaceuticals Headquarters Lobby

REFERENCES

1: Boyd MJ, Bandarage UK, Bennett H, Byrn RR, Davies I, Gu W, Jacobs M, Ledeboer
MW, Ledford B, Leeman JR, Perola E, Wang T, Bennani Y, Clark MP, Charifson PS.
Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of
charge on antiviral potency and kinase activity of azaindole-based influenza PB2
inhibitors. Bioorg Med Chem Lett. 2015 May 1;25(9):1990-4. doi:
10.1016/j.bmcl.2015.03.013. Epub 2015 Mar 14. PubMed PMID: 25827523.

2: Byrn RA, Jones SM, Bennett HB, Bral C, Clark MP, Jacobs MD, Kwong AD, Ledeboer
MW, Leeman JR, McNeil CF, Murcko MA, Nezami A, Perola E, Rijnbrand R, Saxena K,
Tsai AW, Zhou Y, Charifson PS. Preclinical activity of VX-787, a first-in-class,
orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.
Antimicrob Agents Chemother. 2015 Mar;59(3):1569-82. doi: 10.1128/AAC.04623-14.
Epub 2014 Dec 29. PubMed PMID: 25547360; PubMed Central PMCID: PMC4325764.

3: Clark MP, Ledeboer MW, Davies I, Byrn RA, Jones SM, Perola E, Tsai A, Jacobs
M, Nti-Addae K, Bandarage UK, Boyd MJ, Bethiel RS, Court JJ, Deng H, Duffy JP,
Dorsch WA, Farmer LJ, Gao H, Gu W, Jackson K, Jacobs DH, Kennedy JM, Ledford B,
Liang J, Maltais F, Murcko M, Wang T, Wannamaker MW, Bennett HB, Leeman JR,
McNeil C, Taylor WP, Memmott C, Jiang M, Rijnbrand R, Bral C, Germann U, Nezami
A, Zhang Y, Salituro FG, Bennani YL, Charifson PS. Discovery of a novel,
first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza
PB2. J Med Chem. 2014 Aug 14;57(15):6668-78. doi: 10.1021/jm5007275. Epub 2014
Jul 24. PubMed PMID: 25019388.

/////////PIMODIVIR , VX-787, JNJ-63623872, JNJ-872, VRT-0928787, 1629869-44-8, VX-787, JNJ-63623872, JNJ-872, VRT-0928787, VX-787, VX 787,  VX787,  JNJ-872, JNJ 872, JNJ872, VRT-0928787, VRT 0928787, VRT0928787, pimodivir, PHASE 2

O=C([C@H]1C(CC2)CCC2[C@@H]1NC3=NC(C4=CNC5=NC=C(F)C=C54)=NC=C3F)O

O.Cl.Cl.OC(=O)[C@H]1C2CCC(CC2)[C@@H]1Nc3nc(ncc3F)c4c[nH]c5ncc(F)cc45.OC(=O)[C@H]6C7CCC(CC7)[C@@H]6Nc8nc(ncc8F)c9c[nH]c%10ncc(F)cc9%10

CEP 33779


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CEP-33779, CEP33779
CAS 1257704-57-6
Chemical Formula: C24H26N6O2S
Molecular Weight: 462.57
Elemental Analysis: C, 62.32; H, 5.67; N, 18.17; O, 6.92; S, 6.93

N-(3-(4-methylpiperazin-1-yl)phenyl)-8-(4-(methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

PRECLINICAL Treatment of Rheumatoid Arthritis, Agents for Colorectal Cancer Therapy Systemic Lupus Erythematosus,

Jak2 Inhibitors

Image result for teva logo

Matthew A. Curry, Bruce D. Dorsey, Benjamin J. Dugan, Diane E. Gingrich, Eugen F. Mesaros, Karen L. Milkiewicz,
Applicant Cephalon, Inc.

Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States

Image result for Cephalon, Inc.

Matt Curry

 Matthew A. Curry

Bruce Dorsey

Bruce Dorsey

Image result for Cephalon, Inc. Benjamin J. Dugan

Benjamin Dugan

Benjamin J. Dugan received a B.S. degree in Chemistry from the University of Delaware in 1993 under the tutelage of the late Dr. Cynthia McClure. He began his career at FMC Corporation in the agricultural products division. In 2006, he moved to Cephalon, Inc., acquired by Teva Pharmaceutical Industries Ltd. in 2011, and engaged in oncology research focused on small molecule, ATP competitive, kinase inhibitors culminating with the discovery of CEP-33779. He is currently a Research Scientist focused on the development of novel, bioactive small molecules for treatment of central nervous system disorders.

Cephalon Inc.
Malvern, United States

Image result for Cephalon, Inc. Diane E. Gingrich

Members of the Cephalon research team that discovered CEP-5214 and CEP-7055 include (from left) Hudkins, Thelma S. Angeles, Bruce A. Ruggeri, and Diane E. Gingrich. CEPHALON PHOTO

Eugen F. Mesaros

Cephalon Inc.
Malvern, United States
Image result for cephalon Karen L. Milkiewicz

Lupus (systemic lupus erythematosus, SLE) is a chronic autoimmune disease characterized by the presence of activated T and B cells, autoantibodies and chronic inflammation that attacks various parts of the body including the joints, skin, kidneys, CNS, cardiac tissue and blood vessels. In severe cases, antibodies are deposited in the cells (glomeruli) of the kidneys, leading to inflammation and possibly kidney failure, a condition known as lupus nephritis.

Although the cause of lupus remains unknown, manifestations of the disease have been linked to genetic polymorphisms, environmental toxins and pathogens (Morel;

Fairhurst, Wandstrat et al. 2006). In addition, gender, hormonal influences and cytokine dysregulation have been tightly linked to the development of lupus (Aringer and Smolen 2004; Smith-Bouvier, Divekar et al. 2008). Lupus affects nine times as many women as men. It may occur at any age, but appears most often in people between the ages of 10 and 50 years. African Americans and Asians are affected more often than people from other races.

There is no cure for lupus. Current treatments for lupus are aimed at controlling symptoms and are limited to toxic and immunosuppressive agents with severe side-effects such as high dose glucocorticoids and/or hydroxchloroquine. Severe disease (e.g., patients that have signs of renal involvement) require more aggressive drugs including

mycophenolate mofetil (MMF), azathioprine (AZA) and/or cyclophosphamide (CTX) (Bertsias and Boumpas 2008). CTX, AZA and MMF are very toxic and

immunosuppressive, and only 50% of treated patients enter complete remission, with relapse rates up to 30% over a 2-year period.

Memory B cells, and more important, long-lived plasma cells (LL-PCs) which differentiate from memory B cells, are key cell types involved in lupus (Neubert, Meister et al. 2008; Sanz and Lee 2010). Long-lived plasma cells synthesize and secrete large quantities of high-affinity isotype switched antibodies (Meister, Schubert et al. 2007;

Muller, Dieker et al. 2008). Circulating antinuclear antibodies (ANAs) increase the chances of antibody depositing onto self tissues, forming immune-complexes and eventually leading to tissue destruction, epitope spreading and involvement of other organ systems. LL-PCs are commonly found to be chemo- and radio-resistant, over expressing various heat shock proteins and drug pumps (Obeng, Carlson et al. 2006; Neubert, Meister et al. 2008). In addition, LL-PCs primarily reside in the bone marrow where they are protected from current lupus therapies such as cyclophosphamide and glucocorticoids.

A need exists for new treatments for lupus, including lupus nephritis. A need particularly exists for lupus treatments that can target and reduce LL-PCs.

str0

CEP-33779 is a highly selective, orally active, small-molecule inhibitor of JAK2. CEP-33779 induced regression of established colorectal tumors, reduced angiogenesis, and reduced proliferation of tumor cells. Tumor regression correlated with inhibition of STAT3 and NF-κB (RelA/p65) activation in a CEP-33779 dose-dependent manner. The ability of CEP-33779 to suppress growth of colorectal tumors by inhibiting the IL-6/JAK2/STAT3 signaling suggests a potential therapeutic utility of JAK2 inhibitors in multiple tumors types, particularly those with a strong inflammatory component.

str0

{[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine} (1)

LC/MS: (M+H+)+ = 463.2;
1H NMR (DMSO, 400 MHz) δ 9.61 (s, 1H), 8.85 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 6.8 Hz, 2H), 8.06 (d, J = 6.8 Hz, 2H), 7.96 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.17 (t, J = 6.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 8.6 Hz 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.30 (s, 3H), 3.13 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H).
CEP-33779 Diglycolate Salt
1H NMR (DMSO, 400 MHz) δ 9.61 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.43 (d, J = 6.7 Hz, 2H), 8.06 (d, J = 6.7 Hz, 2H), 7.97 (d, J = 7.5 Hz, 1H), 7.59 (s, 1H), 7.18 (d, J = 6.7 Hz, 1H), 7.11 (m, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.89 (s, 4H), 3.30 (s, 3H), 3.13 (m, 4H), 2.48 (m, 4H), 2.24 (s, 3H).
DSC: Endotherm onset at 153.0 °C; Peak at 155.8 °C.

PATENT

WO 2010141796

https://www.google.com/patents/WO2010141796A3?cl=en

Example 35 [8-(4-Methanesulfonyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-

1 -yl)-phenyl]-amine

Figure imgf000156_0001

35 a) l-(3-Bromo-phenyl)-4-methyl-piperazine was prepared from l-(3-bromo-phenyl)- piperazine (1.33 g, 5.52 mmol) in a manner analogous to Step 32a. The reaction product was isolated as a pale yellow oil (1.4 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, IH), 7.04 (dd, J=2.1, 2.1 Hz, IH), 6.95 (ddd, J=I. S, 1.7, 0.7 Hz, IH), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, IH), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS = 255, 257 (MH)+. 35b) [8-(4-Methanesulfonyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl]-[3-(4-methyl- piperazin-l-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)- [l,2,4]triazolo[l,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and l-(3-bromo-phenyl)-4- methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d and was isolated as a yellow solid (0.072 g, 60%).

MP = 232-234 0C.

1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=I 2 Hz, IH), 8.25 (d, J=I .5 Hz, 2H), 8.08 (d, J=I .9 Hz, 2H), 7.65 (d, J=I .1 Hz, IH), 7.38 (s, IH), 7.27-7.20 (m, IH), 7.04-6.95 (m, 2H), 6.84 (s, IH), 6.60 (d, J=8.0 Hz, IH), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H).

MS = 463 (MH)+.

PATENT

WO 2012078504

PATENT

WO 2012078574

https://google.com/patents/WO2012078574A2?cl=da

COMPOUND A is a JAK2 inhibitor with the chemical name [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine. COMPOUND A has the following structure:

COMPOUND A

COMPOUND A was prepared in a manner analogous to the five-step method described below (see Example 35 of International Application No. PCT/US10/37363):

Step 1 : To a solution of 1-(3-bromo-phenyl)-piperazine (about 1 g) and acetic acid (about 0.4 mL) in methanol (about 25 mL) is added 37% formaldehyde in water/methanol (about 56.7:37:6.3, water:formaldehyde:methanol; about 5 mL). The mixture is stirred at room temperature for about 18 hours. The suspension is cooled to about 5°C in an ice/water bath and sodium cyanoborohydride (about 5 g) is added in small portions. The mixture is stirred and warmed to room temperature for about 18 hours. The mixture is slowly poured into saturated aqueous ammonium chloride (about 200 mL) and stirred for about 1 hour. The mixture is extracted with dichloromethane (3 x about 75 mL). The combined organic layers are dried over magnesium sulfate, filtered and evaporated. The material is placed under high vacuum for about 18 hours to yield 1-(3-bromo-phenyl)-4-methyl-piperazine as a pale yellow oil (about 1 g). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.10 (dd, J=8.2, 8.2 Hz, 1H), 7.04 (dd, J=2.1, 2.1 Hz, 1H), 6.95 (ddd, J=7.8, 1.7, 0.7 Hz, 1H), 6.83 (ddd, J=8.3, 2.4, 0.6 Hz, 1H), 3.23-3.18 (m, 4H), 2.58-2.54 (m, 4H), 2.35 (s, 3H). MS = 255, 257 (MH)+.

Step 2: To a solution of 3-bromo-pyridin-2-ylamine (about 10 g) in 1,4-dioxane (about 100 mL) is added dropwise ethoxycarbonyl isothiocyanate (about 7 mL). The mixture is stirred under an atmosphere of nitrogen for about 18 hours. The volatiles are evaporated to yield a waxy solid. The recovered material is triturated with hexane (about 250 mL). N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea is isolated and used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 11.46 (s, 1H), 11.43 (s, 1H), 8.49 (dd, J=4.6, 1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.5 Hz, 1H), 7.33 (dd, J=8.0, 4.7 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). MS = 215 (MH)+.

Step 3: To a stirred suspension of hydroxylamine hydrochloride (about 17 g) and Ν,Ν-diisopropylethylamine (about 26 mL) in a mixture of methanol (about 70 mL) and

ethanol (about 70 mL) is added N-(3-bromo-2-pyridinyl)-N’-carboethoxy-thiourea. The mixture is stirred for about 2 hours at room temperature then heated to about 60°C for about 18 hours. The suspension is cooled to room temperature, filtered and rinsed with methanol, water then methanol. 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as an off-white solid (about 8 g). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.58 (d, J=6.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.80 (t, J=7.0 Hz, 1H), 6.25 (s, 2H). MS = 213, 215 (MH)+.

Step 4: An oven dried tube is charged with palladium acetate (about 0.2 g) and triphenylphosphine (about 0.6 g). The tube is evacuated under high vacuum and backflushed under a stream of nitrogen for about 5 minutes. A suitable solvent such as

1,4-dioxane (about 10 mL) is added and the mixture is stirred under nitrogen for a suitable time (e.g., for about 10 minutes). 8-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 0.75 g), (4-methylsulfonylphenyl)boronic acid (about 1 g), a suitable solvent, such as N,N-dimethylformamide (about 10 mL) and a suitable base, such as about 1.5 M of sodium carbonate in water (about 10 mL) are added. The mixture is stirred for about 2 minutes at room temperature under nitrogen then the tube is sealed and heated at about 80°C for about 18 hours. The mixture is transferred to a round bottom flask and the volatiles are evaporated under reduced pressure. The product is isolated in a suitable manner. For example, water (about 100 mL) may be added and the mixture stirred. The solid may then be collected by filtration, and optionally rinsed with water, air dried, triturated with ether/dichloromethane (about 4: 1; about 10 mL), filtered and rinsed with ether. 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine is isolated as a tan solid (about 0.6 g). MP = 236-239 °C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.63 (d, J=6.3 Hz, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.03 (d, J=7.9 Hz, 2H), 7.84 (d, J= 7.3 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.21 (br s, 2H), 3.28 (s, 3H). MS = 289 (MH)+.

Step 5: To an oven dried tube is added palladium acetate (about 10 mg) and 2,2′-bis-dicyclohexylphosphanyl-biphenyl (about 30 mg), 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (about 75 mg), 1-(3-bromo-phenyl)-4-methyl-piperazine (about 80 mg), a suitable base, such as cesium carbonate (about 270 mg) and a suitable solvent, such as 1,4-dioxane (about 5 mL). The tube is evacuated and backflushed with nitrogen three times. The tube is sealed and heated at about 80°C for about 72 hours. The mixture is cooled to room temperature and the product isolated in a suitable manner.

For example, the cooled mixture may be diluted with dichloromethane (about 10 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material may then be purified, e.g., via chromatography, e.g., utilizing an ISCO automated purification apparatus (e.g., amine modified silica gel column 5%→100% ethyl acetate in hexanes). [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (i.e., COMPOUND A) is isolated as a yellow solid (about 0.07 g). MP = 232-234 °C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=7.2 Hz, 1H), 8.25 (d, J=7.5 Hz, 2H), 8.08 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.7 Hz, 1H), 7.38 (s, 1H), 7.27-7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J=8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS = 463 (MH)+.

PATENT

WO 2015089153

https://www.google.com/patents/WO2015089153A1?cl=un

This disclosure relates to a l,2,4 riazolo[l,5a]pyridine derivative, [8-(4 methanesulfonyl-phenyl)-[ 1 ,2,4]triazoio[1 ,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin- 1 -yl phenyl] -amine, re g structure:

or a pharmaceutical salt thereof, and its use in the treatment of multiple sclerosis.

Compound A is a potent, orally active, small molecule inhibitor of JA 2. See, e.g..International Application No. PCT/USlO/37363, U.S. Patent Nos. 8,501,936 and ,633,173, and U.S. Published Patent Application Nos. 2013/0267535 and 2014/0024655, each of which is incorporated by reference herein. Compound A can be prepared, for example, using methods analogous to Example 35 of International Application No.PCT/US 10/37363.

PAPER

A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-a]pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of CEP-33779

Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States
J. Med. Chem., 2012, 55 (11), pp 5243–5254
DOI: 10.1021/jm300248q
Publication Date (Web): May 10, 2012
Copyright © 2012 American Chemical Society
*Phone: 610-738-6733. Fax: 610-738-6643. E-Mail: bdugan@cephalon.com.

Abstract

Abstract Image

Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure–activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.

[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine (29)

 1H NMR (CDCl3) δ 8.49 (dd, J = 6.6, 1.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.66 (dd, J = 7.5, 0.9 Hz, 1H), 7.39–7.36 (m, 1H), 7.23 (t, J = 8.2 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H), 6.97 (dd, J = 7.8, 1.4 Hz, 1H), 6.88 (s, 1H), 6.60 (dd, J = 8.3, 1.8 Hz, 1H), 3.30–3.25 (m, 4H), 3.10 (s, 3H), 2.63–2.58 (m, 4H), 2.38 (s, 3H).
13C NMR (CDCl3) δ 162.65, 152.28, 148.87, 141.00, 140.91, 140.05, 129.64, 129.29, 128.18, 127.85, 127.76, 124.77, 112.03, 109.40, 108.59, 104.80, 55.19, 49.02, 46.19, 44.59;
mp 208–211 °C.
High resolution mass spectrum (ESI+) m/z 463.1925 [(M + H)+calcd for C24H26N6O2S: 463.1916]. HPLC: 95 A%.

PAPER

An Improved Synthesis of the Free Base and Diglycolate Salt of CEP-33779; A Janus Kinase 2 Inhibitor

Chemical Process Research and Development, Teva Branded Pharmaceutical Products R&D Inc., 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00311
Publication Date (Web): November 30, 2016
Copyright © 2016 American Chemical Society

Abstract

Abstract Image

CEP-33779 is a triazole that has been reported to show highly selective inhibition of Janus kinase 2 (JAK2). An efficient process to form CEP-33779 will be presented that uses multiple palladium couplings to provide the drug substance in a convergent manner. The existing medicinal chemistry route was modified to avoid chromatographic purification, improve safety, and utilize palladium ligands which are available in quantities amenable to scale-up. Challenges faced during the development of the new process included optimization of conditions for Buchwald–Hartwig and Suzuki couplings, control of homocoupled impurities and removal of residual palladium. In addition, a screen of conditions to form a diglycolate salt of the parent compound are also presented.

REFERENCES

1: Dugan BJ, Gingrich DE, Mesaros EF, Milkiewicz KL, Curry MA, Zulli AL, Dobrzanski P, Serdikoff C, Jan M, Angeles TS, Albom MS, Mason JL, Aimone LD, Meyer SL, Huang Z, Wells-Knecht KJ, Ator MA, Ruggeri BA, Dorsey BD. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779. J Med Chem. 2012 Jun 14;55(11):5243-54. doi: 10.1021/jm300248q. Epub 2012 May 18. PubMed PMID: 22594690.

2: Tagoe C, Putterman C. JAK2 inhibition in murine systemic lupus erythematosus. Immunotherapy. 2012 Apr;4(4):369-72. doi: 10.2217/imt.12.20. PubMed PMID: 22512630.

3: Seavey MM, Lu LD, Stump KL, Wallace NH, Hockeimer W, O’Kane TM, Ruggeri BA, Dobrzanski P. Therapeutic efficacy of CEP-33779, a novel selective JAK2 inhibitor, in a mouse model of colitis-induced colorectal cancer. Mol Cancer Ther. 2012 Apr;11(4):984-93. doi: 10.1158/1535-7163.MCT-11-0951. Epub 2012 Feb 14. PubMed PMID: 22334590.

4: Lu LD, Stump KL, Wallace NH, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Mason JL, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. Depletion of autoreactive plasma cells and treatment of lupus nephritis in mice using CEP-33779, a novel, orally active, selective inhibitor of JAK2. J Immunol. 2011 Oct 1;187(7):3840-53. doi: 10.4049/jimmunol.1101228. Epub 2011 Aug 31. PubMed PMID: 21880982.

5: Stump KL, Lu LD, Dobrzanski P, Serdikoff C, Gingrich DE, Dugan BJ, Angeles TS, Albom MS, Ator MA, Dorsey BD, Ruggeri BA, Seavey MM. A highly selective, orally active inhibitor of Janus kinase 2, CEP-33779, ablates disease in two mouse models of rheumatoid arthritis. Arthritis Res Ther. 2011 Apr 21;13(2):R68. doi: 10.1186/ar3329. PubMed PMID: 21510883; PubMed Central PMCID: PMC3132063.

/////////////CEP-33779, CEP33779, CEP 33779, 1257704-57-6, PRECLINICAL, TEVA,  Rheumatoid Arthritis, Colorectal Cancer Therapy, Systemic Lupus Erythematosus,

Jak2 Inhibitors

O=S(C1=CC=C(C2=CC=CN3C2=NC(NC4=CC=CC(N5CCN(C)CC5)=C4)=N3)C=C1)(C)=O

str1 str2

str0

Lumefantrine


Image result for lumefantrine synthesis

lumefantrine

2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]-9H-fluoren-4-yl]ethan-1-ol

(±)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-α-((dibutylamino)methyl)fluorene-4-methanol
2-Dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanol
2-Dibutylamino-1-{2,7-dichloro-9-[1-(4-chloro-phenyl)-meth-(Z)-ylidene]-9H-fluoren-4-yl}-ethanol
Benflumetol
dl-Benflumelol

UNII F38R0JR742
CAS number 82186-77-4
Weight Average: 528.94
Monoisotopic: 527.154947772
Chemical Formula C30H32Cl3NO

Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term “co-artemether” is sometimes used to describe this combination.[1] Lumefantrine has a much longer half-life compared to artemether and so is therefore thought to clear any residual parasites that remain after combination treatment.[2]

Lumefantrine, along with pyronaridine and naphtoquine, were synthesized in course of the Project 523 antimalaria drug research initiated in 1967; these compounds are all used in combination antimalaria therapies.[3][4][5]

Image result for lumefantrine synthesis

Lumefantrine is an antimalarial drug chemically known as 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4- chlorobenzylidene)-9H-floren-4-yl] ethanol, which is used in the prevention and treatment of Malaria in worm blooded animals. Lumefantrine is using the combination of β-Artemether in the treatment of Malaria

http://derpharmachemica.com/vol8-iss3/DPC-2016-8-3-91-100.pdf

REFERENCES

[1] Ulrich Beutler, C Peter.; Fuenfschilling.; and Andreas, Steinkemper.; Novartis Pharma AG; Chemical and Analytical Development: CH-4002 Basel, Switzerland, Organic Process Research & Development 2007, 11, 341- 345.

[2] Boehm, M. Fuenfschilling.; Krieger, P. C.; Kuesters, E. M.; Struber, F.; Org. Process Res. DeV. 2007, 11, 336- 340.

[3] (a) Rao, D. R.; Kankan, R. N.; Phull, M. S.; Patent Application CN 1009-3724 20060424, 2005. (b) Deng, R.; Zhong, J.; Zhao, D.; Wang, J.; Yaoxue, X. 2000, 35 (1), 22. (c) Allmendinger, Th.; Wernsdorfer, W. H. PCT WO 99/67197.

[4] Perrumattam, J.; Shao, Ch.; Confer, W. L. Synthesis 1994, 1181.

[5] Fuenfschilling, P. C.; Hoehn P.; Mutz J.-P. Organic Process Res. Dev. 2007, 11, 13.

[6] Di Nunno, L.; Scilimati, A. Tetrahedron 1988, 44, 3639.

[7] Pharmacopeial Forum, Vol. 36(2) [Mar.-Apr. 2010]

Preparation of 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4-chlorobenzylidene)-9H-floren-4-yl] ethanol (Lumefantrine) 1.

To a stirred solution of NaOH (1.97 g 0.0492 mol) in methanol (100 ml) there was added 1-(2, 7- dichloro-9 H-fluren-4-yl)-2-(dibutyl amino) ethanol (10 g, 0.0246 mol) and para chloro benzaldehyde (5.24 g 0.0372). The suspension obtained was stirred at reflux temperature till the absence of starting material by TLC. After confirming the product formation reaction mixture was cooled to room temperature and further stirred at same temperature for overnight. The precipitated solids were filtered and washed with methanol and dried under vacuum at 50°C to get desired compound.  (Purity by HPLC: 99%).

IR (cm-1): 3408, 3092, 2953, 2928, 2870, 2840, 1634, 1589, 1487, 1465, 1443, 1400, 1365, 1308, 1268, 1241, 1207, 1173, 1156, 1085, 1071, 1014, 980, 933, 874, 839, 815, 806, 770;

1H NMR (CDCl3, δ ppm): 7.75 (d, 1H, CH, J 1.5 Hz), 7.68 (d, 1H, CH, J 1.5 Hz), 7.60-7.63 (m, 1H, CH), 7.32-7.35 (dd, 1H, CH, J 1.7,8.3 Hz), 7.45-7.50 (m, 1H, CH), 5.35-5.39 (dd, 1H, CH, J 3.0,9.9 Hz), 2.41-2.74 (m, 1H, CH2Ha), 2.86-2.92 (m, 1H, CH2Hb), 2.41-2.74 (m, 4H, CH2), 1.25-1.56 (m, 8H, CH2), 0.97 (t, 1H, CH, J 7.2 Hz), 7.60-7.63 (m, 1H, CH), 7.45-7.50 (m, 4H, CH), 4.54 (broad, 1H, OH),

13C NMR (CDCl3, δ ppm): 138.2, 141.5, 120.6, 133.2, 126.3, 135.0, 135.0, 136.4, 123.9, 128.3, 132.8, 123.0, 139.8, 65.5, 60.0, 53.5, 29.1, 20.6, 14.0, 127.6, 134.7, 130.5, 129.1, 133.2;

MS: m/z: 528 [M+H]+ ; Analysis calcd. for C30H32Cl3NO: C, 68.12; H, 6.10; N, 2.65% Found: C, 68.38; H, 6.14; N, 2.63 %.

 

CLIP

str0

One-dimensional 1H NMR spectrum of B) a lumefantrine standard,

A CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532012000100010&lng=en&nrm=iso

Image result for lumefantrine synthesis

CLIP

A simple and precise method for quantitative analysis of lumefantrine …

https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)
by P Hamrapurkar – ‎2010 – ‎Cited by 2 – ‎Related articles

[2–4] Thus, today lumefantrine is a drug of choice in antimalarial treatment against P. …. The NMRspectra observed triplet at 0.943-0.989 (methyl protons of alkyl …

str0
The spectroscopic techniques were used to confirm the identity of lumefantrine. The IR spectra, showed strong absorption band at 3404.67 cm-1 (OH), 2953.28 cm-1 (aliphatic and aromatic CH), 1757.31 cm-1 (-C=C-), 933 cm-1 (alkanes) and 696.37-373.22 cm-1 (Cl). Thus, IR spectra confirmed the presence of these functional groups in the structure of lumefantrine.
The mass spectrum showed a sharp molecular ion peak at 528.0 m/z in Q1 MS (m/z, parent ion) parameter at negative polarity confirming the molecular weight of lumefantrine.
The NMR spectra observed triplet at 0.943-0.989 (methyl protons of alkyl chain); a multiplet at 1.372-1.498 (methylene protons of alkyl chains); a multiplet at 2.449-2.909 (methylene protons of alkyl chain); broad singlet at 4.573 (OH proton); and multiplet at 7.314-7.733 (aromatic proton), thus confirming identity of lumefantrine.
 IH NMR PREDICT
 str0
str1
13C NMR PREDICT
str0
str1

Image result for lumefantrine synthesis

Image result for lumefantrine synthesis

 

References

  1. Jump up^ Toovey S, Jamieson A, Nettleton G (2003). “Successful co-artemether (artemether-lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique”. Travel medicine and infectious disease. 1 (3): 177–9. doi:10.1016/j.tmaid.2003.09.002. PMID 17291911.
  2. Jump up^ White, Nicholas J.; van Vugt, Michele; Ezzet, Farkad (1999). “Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine”. Clinical Pharmacokinetics. 37 (2): 105–125. doi:10.2165/00003088-199937020-00002. ISSN 0312-5963.
  3. Jump up^ Cui, Liwang; Su, Xin-zhuan (2009). “Discovery, mechanisms of action and combination therapy of artemisinin”. Expert Review of Anti-infective Therapy. 7 (8): 999–1013. doi:10.1586/eri.09.68. PMC 2778258Freely accessible. PMID 19803708.
  4. Jump up^ http://aac.asm.org/content/56/5/2465.full
  5. Jump up^ Laman, M; Moore, BR; Benjamin, JM; Yadi, G; Bona, C; Warrel, J; Kattenberg, JH; Koleala, T; Manning, L; Kasian, B; Robinson, LJ; Sambale, N; Lorry, L; Karl, S; Davis, WA; Rosanas-Urgell, A; Mueller, I; Siba, PM; Betuela, I; Davis, TM (2014). “Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial”. PLoS Med. 11: e1001773. doi:10.1371/journal.pmed.1001773. PMC 4280121Freely accessible. PMID 25549086.
Lumefantrine
Lumefantrine.svg
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a609024
Routes of
administration
Oral
ATC code P01BF01 (WHO) (combination with artemether)
Legal status
Legal status
  • US: C
Identifiers
CAS Number 82186-77-4 
PubChem (CID) 6437380
DrugBank DB06708 Yes
ChemSpider 4941944 Yes
UNII F38R0JR742 Yes
KEGG D03821 Yes
ChEBI CHEBI:156095 Yes
ChEMBL CHEMBL38827 Yes
Chemical and physical data
Formula C30H32Cl3NO
Molar mass 528.939 g/mol
3D model (Jmol) Interactive image
Title: Lumefantrine
CAS Registry Number: 82186-77-4
CAS Name: (9Z)-2,7-Dichloro-9-[(4-chlorophenyl)methylene]-a-[(dibutylamino)methyl]-9H-fluorene-4-methanol
Additional Names: 2-dibutylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)-9,11-fluoren-4-yl]ethanol; dl-benflumelol; benflumetol; BFL
Manufacturers’ Codes: CPG-56695
Molecular Formula: C30H32Cl3NO
Molecular Weight: 528.94
Percent Composition: C 68.12%, H 6.10%, Cl 20.11%, N 2.65%, O 3.02%
Literature References: Racemic aryl alcohol originally synthesized in the 1970’s by the Academy of Military Medical Sciences in Beijing, China. Inhibits hemozoin formation. Prepn: R. Deng et al., CN 1042535 (1990 to Acad. Military Med. Sci., Microbiol. & Epidemic Dis. Instit.); C.A. 114, 6046 (1991). LC determn in plasma: A. Annerberg et al., J. Chromatogr. B 822, 330 (2005). In vitro activity against Plasmodium falciparum: B. Pradines et al., Antimicrob. Agents Chemother. 43, 418 (1999).
Properties: Odorless, yellow powder. Poorly sol in water, oil, and most organic solvents. Sol in unsaturated fatty acids.
Derivative Type: Co-artemether
CAS Registry Number: 141204-94-6
Manufacturers’ Codes: CPG-56697
Trademarks: Coartem (Novartis); Riamet (Novartis)
Literature References: Fixed 6:1 mixture with artemether, q.v. Clinical pharmacokinetics and bioavailability: F. Ezzet et al., Br. J. Clin. Pharmacol. 46, 553 (1998). Clinical trial in children against P. falciparum malaria: C. Hatz et al., Trop. Med. Int. Health 3, 498 (1998); in adults: S. Looareesuwan et al., Am. J. Trop. Med. Hyg. 60, 238 (1999). Review of comparative clinical trials in malaria: A. A. Omari et al., Trop. Med. Int. Health 9, 192-199 (2004).
Therap-Cat: Antimalarial.
Keywords: Antimalarial.

///////////lumefantrine

CCCCN(CCCC)CC(O)C1=C2C(=CC(Cl)=C1)\C(=C/C1=CC=C(Cl)C=C1)C1=C2C=CC(Cl)=C1

Designing Polymers for Amorphous Solid Dispersions — AAPS Blog


By: Laura I. Mosquera-Giraldo and Lynne S. Taylor Imagine spending billions of dollars in the discovery of a new drug, and then realizing that it is impractical to administer it orally because it cannot reach the systemic circulation and achieve a therapeutic effect. This is the case for many emerging drugs that are insoluble in water, […]

via Designing Polymers for Amorphous Solid Dispersions — AAPS Blog

Ranolazine Intermediate, An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers


Abstract Image

An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.

http://pubs.acs.org/doi/suppl/10.1021/op300056k

str0

Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypropane 4.

To a stirring solution of 2-methoxy phenol 2 (10 kg, 80.55 mol) and water (40 L) at about 30 °C was added sodium hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was added and stirred for 10−12 h at 25−35 °C. Layers were separated, and water (40 L) was added to the organic layer (bottom layer) containing product. Sodium hydroxide solution (3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and stirred for 5−6 h at 27 °C.

The bottom product layer was separated and washed with sodium hydroxide solution (3.0 kg 75 mol) and water (30 L). Excess epichlorohydrin (3) was recovered by distillation of the product layer at below 90 °C under vacuum (650−700 mmHg) to give 13.65 kg (94%) of title compound with 98.3% purity by HPLC, 0.2% of 2- methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy 13.

1 H NMR (400 MHz, CDCl3, δ) 6.8−7.0 (m, 4H), 4.3 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s, 3H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7 (dd, J = 5.6 Hz, 5.3 Hz, 1H);


IR (KBr, cm−1 ) 2935 (C−H, aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231 (C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);


MS (m/z) 181 (M+ + H).



Compound Details

Properties
MWt 180.2
MF C10H12O3


CAS 2210-74-4

Glycidyl 2-methoxyphenyl ether
Guaiacol glycidyl ether

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

logo

CREDIT……….http://www.molbase.com/en/synthesis_2210-74-4-moldata-95563.html

str0

RakeshwarBandichhor

DR REDDYS LABORATORIES

An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

 Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur – 500073, Andhra Pradesh, India

 Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India

Org. Process Res. Dev.201216 (10), pp 1660–1664

DOI: 10.1021/op300056k

Publication Date (Web): September 14, 2012

Copyright © 2012 American Chemical Society

*Telephone: +91 4044346000. Fax: +91 4044346285. E-mail: rakeshwarb@drreddys.com.

////////////////1-(2-Methoxyphenoxy)-2,3-epoxypropane,  β-Adrenoblockers, ranolazine


COc2ccccc2OCC1CO1



OTHER COMPD

Glycidyl 2-methylphenyl ether technical grade, 90%


ADRAFINIL


Adrafinil.svg

ADRAFINIL

2-((diphenylmethyl)sulfinyl)-acetohydroxamicaci;2-((diphenylmethyl)sulfinyl)-n-hydroxy-acetamid;2-((diphenylmethyl)sulfinyl)-n-hydroxyacetamide;2-(benzhydrylsulfinyl)acetohydroxamicacid;ADRAFINIL;2-[(DIPHENYLMETHYL)SULFINYL]ACETOHYDROXAMIC ACID;CRL 40028;OLMIFON

  • CAS 63547-13-7
  • MF:C15H15NO3S
  • MW:289.35
  • EINECS:264-303-1

WATCH THIS POST AS DETAILS LIKE SYNTHESIS ARE UPDATED………….

Adrafinil is touted mainly for its stimulant properties and ability to provide alertness and wakefulness.

  • Stay up late/stay awake during normal sleeping hours: Adrafinil may be helpful for night workers who need a kick-start adapting their body’s natural circadian rhythm of wakefulness in the daytime and sleepiness in the evening to their job needs. This can also make it helpful for periodic late-night study sessions. Adrafinil is best taken in the afternoon or evening for nighttime wakefulness.
  • Boost energy, alertness, and focus during the day time: Adrafinil can also be used as an energy-boost during waking hours.
  • CONTACT SKYPE CATHERINESSPC WICKR

Adrafinil (INN) (brand name Olmifon)[2] is a discontinued wakefulness-promoting agent (or eugeroic) that was formerly used inFrance to promote vigilance (alertness), attention, wakefulness, mood, and other parameters, particularly in the elderly.[3][4] It was also used off-label by individuals who wished to avoid fatigue, such as night workers or others who needed to stay awake and alert for long periods of time. Additionally, “adrafinil is known to a larger nonscientific audience, where it is considered to be a nootropic agent.”[3] Adrafinil is a prodrug; it is primarily metabolized in vivo to modafinil, resulting in very similar pharmacological effects.[3] Unlike modafinil, however, it takes time for the metabolite to accumulate to active levels in the bloodstream. Effects usually are apparent within 45–60 minutes when taken orally on an empty stomach. Adrafinil was marketed in France under the trade name Olmifon[2] until September 2011 when it was voluntarily discontinued.[4]

Pharmacology

Pharmacodynamics

Because α1-adrenergic receptor antagonists were found to block effects of adrafinil and modafinil in animals, “most investigators assume[d] that adrafinil and modafinil both serve as α1-adrenergic receptor agonists.”[3] However, adrafinil and modafinil have not been found to bind to the α1-adrenergic receptor and they lack peripheral sympathomimetic side effects associated with activation of this receptor;[5] hence, the evidence in support of this hypothesis is weak, and other mechanisms are probable.[3] Modafinil was subsequently screened at a variety of targets in 2009 and was found to act as a weak, atypical blocker of the dopamine transporter(and hence as a dopamine reuptake inhibitor), and this action may explain some or all of its pharmacological effects.[6][7][8] Relative to adrafinil, modafinil possesses greater specificity in its action, lacking or having a reduced incidence of many of the common side effects of the former (including stomach pain, skin irritation, anxiety, and elevated liver enzymes with prolonged use).[9][10][11] There is a case report of two patients that adrafinil may increase interest in sex.[3] A case report of adrafinil-induced orofacial dyskinesia exists.[12][13] Reports of this side effect also exist for modafinil.[12]

Pharmacokinetics

In addition to modafinil, adrafinil also produces modafinil acid (CRL-40467) and modafinil sulfone (CRL-41056) as metabolites, which form from metabolic modification of modafinil.

History

Adrafinil was discovered in 1974 by two chemists working for the French pharmaceutical company Laboratoires Lafon who were screening compounds in search of analgesics.[14] Pharmacological studies of adrafinil instead revealed psychostimulant-like effects such as hyperactivity and wakefulness in animals.[14] The substance was first tested in humans, specifically for the treatment of narcolepsy, in 1977–1978.[14] Introduced by Lafon (now Cephalon), it reached the market in France in 1984,[4] and for the treatment of narcolepsy in 1985.[14][15] In 1976, two years after the discovery of adrafinil, modafinil, its active metabolite, was discovered.[14] Modafinil appeared to be more potent than adrafinil in animal studies, and was selected for further clinical development, with both adrafinil and modafinil eventually reaching the market.[14] Modafinil was first approved in France in 1994, and then in the United States in 1998.[15] Lafon was acquired by Cephalon in 2001.[16] As of September 2011, Cephalon has discontinued Olmifon, its adrafinil product, while modafinil continues to be marketed.[4]

Society and culture

Regulation

Athletic doping

Adrafinil and its active metabolite modafinil were added to the list of substances prohibited for athletic competition according to World Anti-Doping Agency in 2004.[17]

New Zealand

In 2005 a Medical Classification Committee in New Zealand recommended to MEDSAFE NZ that adrafinil be classified as a prescription medicine due to risks of it being used as a party drug. At that time adrafinil was not scheduled in New Zealand.[18]

Research

In a clinical trial with clomipramine and placebo as active comparators, adrafinil showed efficacy in the treatment of depression.[3] In contrast to clomipramine however, adrafinil was well-tolerated, and showed greater improvement in psychomotor retardation in comparison.[3] As such, “further investigations of the antidepressive effects of adrafinil are warranted.”[3]

/////////////

SYNTHESIS

Adrafinil (CAS NO.63547-13-7) was discovered in the late 1970s by scientists working with the French pharmaceutical company Group Lafon. First offered in France in 1986 as an experimental treatment for narcolepsy, Lafon later developed modafinil, the primary metabolite of adrafinil. Modafinil possesses greater selective alpha-1 adrenergic activity than adrafinil without the side effects of stomach pain, skin irritations, feelings of tension, and increases in liver enzyme levels.
It is important to monitor the liver of an individual using adrafinil. It can cause liver damage in some instances.

The Adrafinil with CAS registry number of 63547-13-7 is also known as 2-[(Diphenylmethyl)sulfinyl]-N-hydroxyacetamide. The IUPAC name is 2-Benzhydrylsulfinyl-N-hydroxyacetamide. It belongs to product categories of Aromatics Compounds; Aromatics; Intermediates & Fine Chemicals; Pharmaceuticals; Sulfur & Selenium Compounds. This chemical is a light pink solid and its EINECS registry number is 264-303-1. In addition, the formula is C15H15NO3S and the molecular weight is 289.35. This chemical is harmful if swallowed.

Physical properties about Adrafinil are: (1)ACD/LogP: 1.596; (2)ACD/LogD (pH 5.5): 1.60; (3)ACD/LogD (pH 7.4): 1.53; (4)ACD/BCF (pH 5.5): 9.60; (5)ACD/BCF (pH 7.4): 8.34; (6)ACD/KOC (pH 5.5): 175.52; (7)ACD/KOC (pH 7.4): 152.63; (8)#H bond acceptors: 4; (9)#H bond donors: 2; (10)#Freely Rotating Bonds: 6; (11)Index of Refraction: 1.653; (12)Molar Refractivity: 78.858 cm3; (13)Molar Volume: 215.542 cm3; (14)Polarizability: 31.262 10-24cm3; (15)Surface Tension: 67.25 dyne/cm; (16)Density: 1.342 g/cm3

Preparation of Adrafinil: it is prepared by reaction of diphenyl methyl bromide with thiourea. This reaction needs reagent NaOH. After reacting with chloroacetic acid, hydrochloric acid amine and hydrogen peroxide, the product is obtained. The yield is about 73%.

Adrafinil is prepared by reaction of diphenyl methyl bromide with thiourea.

Uses of Adrafinil: it is used as non-amphetamine-type psychostimulant and can wake up and raise awareness. For the elderly arousal disorder and depressive symptoms in symptomatic treatment.

Image result for ADRAFINIL

Image result for ADRAFINIL SYNTHESIS

Benzhydrylsulphinyl-acetohydroxamic Acid (Adrafinil)1

US Pat 4,066,686

Diphenylmethanethiol

15.2 g (0.2 mol) of thiourea and 150 ml of demineralized water are introduced into a 500 ml three-neck flask equipped with a central mechanical stirrer, and with a dropping funnel and a condenser on the (respective) side-necks.The temperature of the reaction mixture is brought to 50°and 49.4g (0.2 mol) of bromodiphenyl- methane are added all at once whilst continuing the heating. After refluxing for about 5 minutes, the solution, which has become limpid, is cooled to 20°C and 200 ml of 2.5 N NaOH are then added dropwise whilst maintaining the said temperature. The temperature is then again kept at the reflex for 30 minutes after which, when the mixture has returned to ordinary temperature (15-25°C), the aqueous solution is acidified with 45 ml of concentrated hydrochloric acid. The supernatant oil is extracted with 250 ml of diethyl ether and the organic phase is washed with 4×80 ml of water and then dried over magnesium sulphate. 39 g of crude diphenylmethane-thiol are thus obtained. Yield 97.5%.

Benzhydryl-thioacetic acid

10 g (0.05 mol) of diphenylmethane-thiol and 2g (0.05 mol) of NaOH dissolved in 60 ml of demineralised water are introduced successively into a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. The reactants are left in contact for 10 minutes whilst stirring, and a solution consisting of 7g (0.075 mol) of chloroacetic acid, 3g (0.075 mol) of NaOH pellets and 60 ml of demineralized water is then added all at once. The aqueous solution is gently warmed to about 50°C for 15 minutes, washed with 50 ml of ether, decanted and acidified with concentrated hydrochloric acid. after filtration, 10.2g of benzhydryl-thioacetic acid are thus obtained. Melting point 129-130°C. Yield 79%.

Ethyl benzhydryl-thioacetate

The following reaction mixture is heated under reflux for 7 hours: 10.2 g (0.0395 mol) of benzhydryl-thioacetic acid, 100 ml of anhydrous ethanol and 2 ml of sulphuric acid. When heating has been completed, the ethanol isevaporated in vacuo; the oily residue is taken up in 100 ml of ethyl ether and the organic solution is then washed with water, with an aqueous sodium carbonate solution and then with water until the wash waters have a neutral pH. After drying over sodium sulphate, the solvent is evaporated. 10.5g of ethyl benzhydryl- thioacetate are thus obtained. Yield 93%.

Benzhydryl-thioacetohydroxamic acid

The following three solutions are prepared:

  1. Ethyl Benzhydryl-thioacetate 10.8 g (0.0378 mol) in 40 ml methanol
  2. Hydroxylamine hydrochloride 5.25 g (0.0756 mol) in 40 ml methanol
  3. Potassium Hydroxide pellets 7.3 g (0.0134 mol) in 40 ml methanol

The solutions are heated, if necessary, until they become limpid, and when the temperatures have again fallen to below 40°C, the solution of potassium hydroxide in methanol is poured into the solution of hydroxylamine hydrochloride in alcohol. Finally, at a temperature of about 5° to 10°C, the solution of ethyl benzhydryl- thioacetate is added in its turn. After leaving the reactants in contact for 10 minutes, the sodium chloride is filtered off the limpid solution obtained is kept for about 15 hours at ordinary temperature. The methanol is then evaporated under reduced pressure, the residual oil is taken up in 100 ml of water and the aqueous solution is acidified with 3 N hydrochloric acid. The hydroxamic acid which has crystallized is filtered off, washed with water and then dried. 9.1 g of product are obtained. Yield = 87.5%. Melting point 118-120°C.

Adrafinil (CRL 40,028)

10.4g (0.038 mol) of benzhydryl-thioacetohydroxamic acid are oxidized at 40°C, over the course of 2 hours, by means of 3.8 ml (0.038 mol) of hydrogen peroxide of 110 volumes strength (33%), in 100 ml of acetic acid.

When the oxidation has ended, the acetic acid is evaporated under reduced pressure and the residual oil is taken up in 60 ml of ethyl acetate. The product which has crystallized is filtered off and then purified by recrystallisation from a 3:2 (by volume) mixture of ethyl acetate and isopropyl alcohol.

8g (73%) of Adrafinil, mp 159-160°C, are thus obtained. H2O Solubility

CLIP

Image result for adrafinil nmr

Figure 2: GC/MS extracted ion chromatogram (a) and mass spectrum (b) of derivatized adrafinil in the electron ionization mode (monitoring the m/z 167, 165 and 152 ions; all the four peaks are derivatised adrafinil products).

Figure 4: LC/ESI-MS full scan chromatogram of adrafinil and its metabolites (a) (modafinil acid RT 3.8 min, adrafinil RT 4.0 min, modafinil RT 4.1 min), and LC/ESI-MS full scan mass spectra of modafinil acid (b), adrafinil (c), and (d) modafinil. (b, c and d showing the similar ions at m/z 167, 165, 152 together with the appropriate sodium and potassium adducts).

Image result for adrafinil nmr

NMR

1H NMR PREDICT

13C NMR PREDICT

Patent

https://www.google.com/patents/US6180678 below

FIG. 1 shows the structure of adrafinil and its metabolites.

FIG. 2 shows the chemical synthesis of adrafinil.

Image result for adrafinil nmr

//////////////

References

  1. Jump up^ Robertson P, Hellriegel ET (2003). “Clinical pharmacokinetic profile of modafinil”. Clin Pharmacokinet. 42 (2): 123–37. doi:10.2165/00003088-200342020-00002.PMID 12537513.
  2. ^ Jump up to:a b Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 20–. ISBN 978-3-88763-075-1.
  3. ^ Jump up to:a b c d e f g h i Milgram, Norton (1999). “Adrafinil: A Novel Vigilance Promoting Agent”.CNS Drug Reviews. 5 (3): 193–212. doi:10.1111/j.1527-3458.1999.tb00100.x. Retrieved2 October 2014.
  4. ^ Jump up to:a b c d AFSSAPS (2011). “Point d’information sur les dossiers discutés en commission d’AMM Séance du jeudi 1er décembre 2011 – Communiqué”.
  5. Jump up^ Simon P, Chermat R, Puech AJ (1983). “Pharmacological evidence of the stimulation of central alpha-adrenergic receptors”. Prog. Neuropsychopharmacol. Biol. Psychiatry. 7 (2-3): 183–6. doi:10.1016/0278-5846(83)90105-7. PMID 6310690.
  6. Jump up^ Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE, Baumann MH (May 2009). “Evidence for the involvement of dopamine transporters in behavioral stimulant effects of modafinil”. The Journal of Pharmacology and Experimental Therapeutics. 329 (2): 738–46. doi:10.1124/jpet.108.146142.PMC 2672878Freely accessible. PMID 19197004.
  7. Jump up^ Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (Feb 2015). “Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter”. Drug and Alcohol Dependence. 147: 1–19. doi:10.1016/j.drugalcdep.2014.12.005. PMC 4297708Freely accessible. PMID 25548026.
  8. Jump up^ Quisenberry AJ, Baker LE (Dec 2015). “Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats”. Psychopharmacology. 232 (24): 4411–9.doi:10.1007/s00213-015-4065-0. PMID 26374456.
  9. Jump up^ Ballas, Christos A; Deborah Kim; Claudia F Baldassano; Nicholas Hoeh (July 2002). “Modafinil: past, present and future”. Expert Review of Neurotherapeutics. 2 (4): 449–57.doi:10.1586/14737175.2.4.449. PMID 19810941.
  10. Jump up^ Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 850–. ISBN 978-1-58562-309-9.
  11. Jump up^ Ballas, Christos A; Kim, Deborah; Baldassano, Claudia F; Hoeh, Nicholas (2002). “Modafinil: past, present and future”. Expert Review of Neurotherapeutics. 2 (4): 449–457.doi:10.1586/14737175.2.4.449. ISSN 1473-7175. PMID 19810941.
  12. ^ Jump up to:a b Jeffrey K Aronson (31 December 2012). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Newnes. pp. 6–. ISBN 978-0-444-59503-4.
  13. Jump up^ Thobois S, Xie J, Mollion H, Benatru I, Broussolle E (2004). “Adrafinil-induced orofacial dyskinesia”. Mov. Disord. 19 (8): 965–6. doi:10.1002/mds.20154. PMID 15300665.
  14. ^ Jump up to:a b c d e f Antonio Guglietta (28 November 2014). Drug Treatment of Sleep Disorders. Springer. pp. 212–. ISBN 978-3-319-11514-6.
  15. ^ Jump up to:a b Jie Jack Li; Douglas S. Johnson (27 March 2013). Modern Drug Synthesis. John Wiley & Sons. pp. 2–. ISBN 978-1-118-70124-9.
  16. Jump up^ url=http://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=1366624
  17. Jump up^ World Anti-Doping Agency – 2007 Prohibited List
  18. Jump up^ MCC Minutes Out of Session Meeting. Medsafe.govt.nz (2013-05-23). Retrieved on 2013-12-18.

External links

Adrafinil
Adrafinil.svg
Adrafinil.png
Clinical data
Trade names Olmifon
AHFS/Drugs.com International Drug Names
Routes of administration Oral
ATC code N06BX17 (WHO)
Legal status
Legal status
  • US: Unscheduled
Pharmacokinetic data
Bioavailability 80%
Metabolism 75% (Liver)
Metabolites Modafinil
Biological half-life 1 hour (T1/2 is 12–15 hours for modafinil)[1]
Excretion Kidney
Identifiers
Systematic (IUPAC) name: (±)-2-Benzhydrylsulfinylethanehydroxamic acid
Synonyms CRL-40028
CAS Number 63547-13-7 
PubChem (CID) 3033226
DrugBank DB08925 
ChemSpider 2297976 Yes
UNII BI81Z4542G Yes
KEGG D07348 Yes
ChEMBL CHEMBL93077 Yes
Chemical and physical data
Formula C15H15NO3S
Molar mass 289.351 g/mol
3D model (Jmol) Interactive image

////////////ADRAFINIL

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

+91 9323115463
GLENMARK SCIENTIST ,  INDIA
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Dr. Anthony Melvin Crasto
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