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A novel and concise synthesis towards DP2 receptor antagonist Fevipiprant (NVS-QAW039) was developed. The initial research route was suffering from lengthy access to the functionalized 7-aza-indole core followed by a low selective N(1)-alkylation with the benzyl side chain. These limitations were overcome by introducing the side chain early via reductive amination between the functionalized aldehyde and 2-amino-3-bromopyridine. Sonogashira coupling with prop-2-yn-1-ol introduces the 3 missing carbon atoms to build the 7-aza-indole core and sets the stage for the innovative Johnson-Claisen key step. Reaction of the advanced propargylic alcohol derivative with trimethyl orthoacetate leads to a reactive allene intermediate that spontaneously and selectively cyclizes to the 7-aza-indole QAW039-methly ester. QAW039 is isolated after ester saponification. Selectivity, yield, and ecological footprint of the new synthesis were significantly improved, and scalability was demonstrated.

An amine transaminase was engineered for the efficient production of a chiral precursor to sacubitril, (2R,4S)-5-([1,1′-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid, a key component in the blockb...

A process using an engineered phenylalanine ammonia lyase (PAL) enzyme was developed as part of an alternative route to a key intermediate of olodanrigan (EMA401). In the first part of this report,...

We present a short overview of the way Novartis chemists interact and collaborate with the academic chemistry community in Switzerland. This article exemplifies a number of collaborations, and illustrates opportunities to foster research synergies between academic and industrial researchers. It also describes established programs available to academic groups, providing them access to Novartis resources and expertise.

LCZ696 is a novel treatment for patients suffering from heart failure that combines the two active pharmaceutical ingredients sacubitril and valsartan in a single chemical compound. While valsartan is an established drug substance, a new manufacturing process suitable for large-scale commercial production had to be developed for sacubitril. The use of chemocatalysis, biocatalysis, and flow chemistry as state-of-the-art technologies allowed to efficiently build up the structure of sacubitril and achieve the defined performance targets.

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.

A one-pot protocol is described which allows direct access to azaindoles from amino-halopyridines and ketones.

Efficient conversion of tetrahydro-2-pyranyl (THP)protected alcohols into the corresponding halides using dichlorophosgeniminium chloride in the presence of tetraalkylammonium halide.

This report, an audit requested by the French government, describes oncological patterns of care, prognostic factors, and survival for patients with newly diagnosed and histologically confirmed glioblastoma multiforme (GBM) in France. The French Brain Tumor DataBase, which is a national multidisciplinary (neurosurgeons, neuropathologists, radiotherapists, neurooncologists, epidemiologists, and biostatisticians) network, prospectively collected initial data for the cases of GBM in 2004, and a specific data card was used to retrospectively collect data on the management and follow-up care of these patients between January 1, 2004, and December 1, 2006. We recorded 952 cases of GBM (male/female ratio 1.6, median age 63.9 years, mean preoperative Karnofsky performance status [KPS] 79). Surgery consisted of resection (RS; n = 541) and biopsy (n = 411); 180 patients did not have subsequent oncological treatment. After surgery, first-line treatment (n = 772) consisted of radiotherapy (RT) and temozolomide (TMZ) concomitant +/- adjuvant in 314 patients, RT alone in 236 patients, chemotherapy (CT) alone in 157 patients, and other treatment modalities in 65 patients. Median overall survival was 286 days (95% CI, 266-314) and was significantly affected by age, KPS, and tumor location. Median survival (days, 95% CI) associated with these main strategies, when analyzed by a surgical group, were as follows: RS + RT-TMZ((n=224)): 476 (441-506), biopsy + RT-TMZ((n=90)): 329 (301-413), RS + RT((n=147)): 363 (331-431), biopsy + RT((n=89)): 178 (153-237), RS + CT((n=61)): 245 (190-361), biopsy + CT((n=96)): 244 (198-280), and biopsy only((n=118)): 55 (46-71). This study illustrates the usefulness of a national brain tumor database. To our knowledge, this work is the largest report of recent GBM management in Europe.

International audience; The diagnosis of high-grade neuroendocrine tumors has strong clinical relevance because it identifies patients at higher risk of an unfavorable Outcome Who Should receive multimodal treatment. However, these tumors call be mistaken for poorly differentiated nonsmall cell carcinoma or carcinoid lung tumors. In fact, no immunohistochemical marker can currently distinguish between histologic lung subtypes. Because the collapsin response mediator protein (CRMP) family is involved in an autoimmune disease associated with small cell lung carcinoma, we explored the relationship between CRMP5 expression and lung tumor behavior. Using World Health Organization morphologic criteria, 123 lung neuroendocrine tumors and 41 randomly selected non-neuroendocrine tumors were classified. CRMP5 protein expression in tumors, metastases, and healthy lung tissue was assessed using immunostaining method. Strong and extensive CRMP5 expression was seen in 98.6% of high-grade neuroendocrine lung tumors, including small cell lung carcinoma and large Cell lung neuroendocrine carcinoma, but not in any of the squamous cell carcinomas or lung adenocarcinomas in our series. In contrast, the majority of low-grade neuroendocrine lung tumors were negative for CRMP5 staining, although weak CRMP5 expression was seen in some, with 2 different staining patterns of either scattered positive cells or small foci of positive cells. Our findings point at CRMP5 as a novel marker for routine pathologic evaluation Of lung tumors surgical samples in distinguishing between highly aggressive neuroendocrine carcinoma and the other lung cancers.

A rapid and convenient method for the synthesis of a wide range of 2-substituted 7-azaindole derivatives from methyl ketones and 2-amino-3-halopyridines is given.

Whole-cell enzymatic hydrolysis was shown to be the choice in the preparation of (S)-3-(thiophen-2-ylthio)butanoic acid. While all chemical methods of hydrolysis failed, 12 bacterial strains expressing nitrile hydratase and amidase activities have been identified to hydrolyze (S)-3-(thiophen-2-ylthio)butanenitrile 1 directly into the corresponding acid. The substrate was also shown to be an efficient inducer of the enzymatic activity. However, it inhibited microbial growth. Acid 3 was prepared on a gram scale with the recombinant Rhodococcus erythropolis, formerly Brevibacterium sp. pYG811b as shown by sequencing of its 16S rRNA.

Palladium-catalyzed Suzuki cross-coupling reaction (between phenylboronic acid and 4-bromobenzonitrile) in presence of catalytic quaternary ammonium salts is described. With Aliquat 336 (tricaprilylmethylammonium chloride), the rates of the reaction were increased in DME and toluene allowing to work with lower stirring and at lower temperatures in some cases.

Formal α-chlorovinylation of aldehydes using CH 3 CCl 3 CrCl 2 affords 2-chloropropenyl alcohols from which terminal propargyl alcohols are obtained via base induced elimination.

In the presence of poorly reactive olefins such as dichloroolefins, meta-chloroperbenzoic acid reacts with dichloromethane, probably via a radical mechanism, to produce a powerful chlorinating species which behaves like other chlorinating agents.

L-Lemonose, the glycosidic part of (–)-lemonomycin, has been synthesized in ten steps with 18% overall yield from Dthreonine. The key steps are a double, highly diastereoselective Grignard addition to a Weinreb amide and a chemoselective oxidation of a primary alcohol in the presence of a secondary alcohol, a tertiary alcohol and a tertiary amine, leading directly to the lactol.

Dimethylphosgeniminium chloride was used as dehydrating agent for the preparation of carbodiimides from ureas.

Efficient conversion of tetrahydro-2-pyranyl (THP)protected alcohols into the corresponding halides using dichlorophosgeniminium chloride in the presence of tetraalkylammonium halide.

The total synthesis of the polyhalogenated antitumour agent halomon (1) was accomplished with two novel transformations as key steps: a Johnson-Claisen rearrangement of a dichlorinated alkene for the preparation of the tertiary chlorinated C3 and a new rearrangement of bromohydrins for the regiospecific introduction of the bromine and chlorine atoms on C6 and C7, respectively.

Formal α-chlorovinylation of aldehydes using CH 3 CCl 3 CrCl 2 affords 2-chloropropenyl alcohols from which terminal propargyl alcohols are obtained via base induced elimination.

A new effective Suzuki-Miyaura coupling reaction between alkynylboronic esters (generated in situ from acetylenic derivatives) and arylbromides or vinylbromides is reported.

International audience; Asymmetric synthesis of lemonomycinone amide (2) was accomplished from readily accessible starting materials. Enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester (11) by 5-tert-butyldimethylsilyloxy-2,4-dimethoxy-3-methylbenzyl bromide (10) in the presence of Corey-Lygo's phase transfer catalyst [O-(9)-ally-N-(9'-anthracenylmethyl) cinchonidium bromide, 0.1 equiv] afforded, after chemoselective hydrolysis of the imine function (THF/H(2)O/AcOH), the substituted l-tert-butyl phenylalanate 13 in 85% yield. A Pictet-Spengler reaction of 14 with benzyloxyacetaldehyde (15) provided the 1,3-cis-disubstituted tetrahydroisoquinoline 16 in 85% yield as a single diastereomer. Coupling of hindered secondary amine 16 with amino acid 9 was accomplished under carefully controlled conditions to furnish the amide 22, which was in turn converted to hemiaminal 24. A hafnium triflate catalyzed conversion of hemiaminal to alpha-amino thioether followed by a silver tetrafluoroborate promoted intramolecular Mannich reaction of 26 afforded the tetracycle 27 in excellent overall yields. Debenzylation of 27 [Pd(OH)(2), H(2), MeOH, 0 degrees C], removal of N-Boc function (aqueous 3 N HCl, MeOH/H(2)O), and oxidation of hydroquinone to quinone [(NH(4))(2)Ce(NO(3))(6), H(2)O, rt] afforded the lemonomycinone amide 2 in 76% yield over three steps.