This paper describes a convenient protocol for the regioselective sulfonylation of α-chelatable alcohols. Typically, the reaction of α-heterosubstituted alcohols with 1 equiv of p-TsCl and 1 equiv of ...Et3N in the presence of 2 mol % of Bu2SnO leads to rapid, regioselective, and exclusive monotosylation. The pK a of the amine was correlated to the reaction rate. A plausible mechanism for this reaction has been proposed on the basis of 119Sn NMR studies.
There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing ...researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.
The reaction of substituted glycols with catalytic dibutyltin oxide, stoichiometric p-toluenesulfonyl chloride, and triethylamine in CH2Cl2 resulted in the complete and rapid sulfonylation at the ...primary alcohol. The α-heterosubstituted primary alcohol moiety appeared optimal for best results, supporting the intermediacy of a five-membered chelate. The role of the amine is discussed, in addition to catalyst requirements and solvent effects.
To fuel clinical development of the experimental CNS medicine LY2140023, we developed a scalable route for the multistep synthesis of a pivotal synthetic intermediate. The core of the ...conformationally restricted glutamic acid-based amino acid analogue was built via a Rh-catalyzed cyclopropanation of thiophene. Regioselective functionalization of the remaining double bond was achieved by a hydroboration/oxidation sequence followed by a Bucherer–Bergs reaction to give a hydantoin with the targeted l-glutamic acid configuration. Subsequent resolution, oxidation state, and protecting group manipulations gave the key intermediate in an overall nine-step scalable streamlined route starting from thiophene.
A comprehensive assessment of a Ru-catalyzed direct asymmetric reductive amination (DARA) reaction for producing an intermediate for an active pharmaceutical ingredient (API) was carried out. ...Experiments were conducted to investigate the impact of process parameters (such as reaction temperature, time, concentration, pressure, Ru-catalyst concentration, acid catalyst, and reagent stoichiometry) on chemo- and stereo-selectivity, and yield. An analysis of experimental data led to the development of a mechanistic mathematical model that was mathematically consistent with data from laboratory development and manufacturing campaigns. A combinatory approach outlined herein could be used to provide the optimum conditions for the DARA process. Furthermore, the feasible operating region was mapped out, which highlighted the complexity of the investigated chemistry and aided in developing the control strategy and regulatory submission package pertinent to this reaction. The efforts allowed the process to be successfully validated and scaled using a plug flow reactor (PFR) to manufacture 3200 kg of ( S )-7,9-dimethyl- N -(2-methyl-2 H -tetrazol-5-yl)-2,3,4,5-tetrahydro-1 H -benzo b azepin-5-amine under current Good Manufacturing Practice (cGMP).
Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early ...1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr a pgp (+) MDR tumor: 0%T/C, 3.2 LK; Mam 16/C/Adr a pgp (-) MDR tumor: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 a pgp (+) MDR tumor: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
A synthesis of cryptophycin 52 (2) is reported using a Sharpless asymmetric dihydroxylation (AD) strategy to install the epoxide moiety. The high stereoselectivity of the AD reaction that allows for ...an efficient means of preparing the epoxide is in contrast to the standard direct epoxidation of cryptophycin substrates, which proceeds with poor diastereoselectivity. Methodology for conversion of the diol AD product to the requisite epoxide is disclosed. The transformation has been optimized to proceed in high yield in the presence of base sensitive functionality.
A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in ...high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-α-methylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.
A synthesis of cryptophycin 52 is reported using a Shi epoxidation strategy to install the epoxide moiety in a diastereoselective fashion. Several epoxidation results for cryptophycin substrates are ...disclosed followed by a discussion of the details relating to the preparation of cryptophycin 52 in two synthetic steps from one of the intermediate epoxides.
The asymmetric synthesis and biological activity of (2S,1‘S,2‘R,3‘R)-2-(2‘-carboxy-3‘-hydroxymethylcyclopropyl) glycine ((+)-3) is described. This novel C-3‘ substituted carboxy cyclopropyl glycine ...is a highly potent group 2 and group 3 mGluR agonist that has proven to be orally active in both fear potentiated startle (animal model for anxiety) and PCP-induced motor activation (animal model for psychosis) assays in rats.
