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This article explores the catalytic C–H functionalization of trimethylamine, an important intermediate in the chemical industry. Trimethylamine is often obtained as an undesired by-product, and separating it from other methylamines is challenging and expensive. The authors discuss the development of new chemical reactions that use trimethylamine as a starting material for the synthesis of valuable products, particularly those with a dimethylaminomethyl substructure commonly found in pharmaceuticals. The article reports successful reactions of trimethylamine with various compounds, offering flexible and direct methods for its functionalization. The authors highlight the efficient activation of the α-C–H bond of trimethylamine using titanium catalysts, which allows for the synthesis of various dimethylaminomethyl-substituted products. The article also mentions the successful synthesis of the antidepressant butriptyline as an example of the potential of these new reactions. The assistance of Jessica Reimer and the supply of ampoules by Kirstin Glaser, Karin Grittner, and Frank Fleischer are acknowledged. [Extracted from the article]

(E)- N -(2-Cyclohexyl-1-phenyl-3-(trimethylsilyl)allyl)aniline (19) General procedure A was used to react I N i -benzylaniline (183 mg, 1.0 mmol) with (cyclohexylethynyl)trimethylsilane (180 mg, 1.0 mmol) in the presence of catalyst B II-Bu b (111 mg, 0.1 mmol) for 24 h at 140 °C. Keywords: alkynes; allylamines; C-H activation; hydroaminoalkyl-ation; titanium; catalysis EN alkynes allylamines C-H activation hydroaminoalkyl-ation titanium catalysis 3759 3776 18 11/01/23 20231116 NES 231116 Graph The catalytic hydroaminoalkylation of alkenes [1][8] (Scheme 1), which takes place by a 100% atom-economical addition of the -C-H bond of a primary, [8] secondary, [8][8][8][8] or tertiary [8][8] amine across the alkene double bond, has received considerable attention over the past 15 years. N -(3,3-Dimethyl-2-methylenebutyl)aniline (1) 4d General procedure A was used to react I N i -methylaniline (107 mg, 1.0 mmol) with I tert i -butylacetylene (99 mg, 1.2 mmol) in the presence of catalyst B II-DIPP b (194 mg, 0.1 mmol) for 24 h at 140 °C. 3-Chloro- N -(3,3-dimethyl-2-methylenebutyl)aniline (5) General procedure A was used to react 3-chloro- I N i -methylaniline (142 mg, 1.0 mmol) with I tert i -butylacetylene (99 mg, 1.2 mmol) in the presence of catalyst B II-DIPP b (194 mg, 0.1 mmol) for 24 h at 140 °C. N -(3,3-Dimethyl-2-methylenebutyl)-4-(trifluoromethoxy)aniline (7) General procedure A was used to react I N i -methyl-4-(trifluoromethoxy)aniline (191 mg, 1.0 mmol) with I tert i -butylacetylene (99 mg, 1.2 mmol) in the presence of catalyst B II-DIPP b (194 mg, 0.1 mmol) for 24 h at 140 °C. [Extracted from the article]

Intermolecular hydroaminoalkylation reactions of 1,1‐ and 1,3‐disubstituted allenes as well as methylenecyclopropanes with secondary amines can be achieved in the presence of a 2,6‐bis(phenylamino)pyridinato titanium catalyst at 140 °C within 2–8 h. Corresponding reactions of allenes with N‐benzylanilines deliver branched allylamine products in very good yields (up to 83 %) and with branched‐linear‐ratios between 75 : 25 and 95 : 5. In contrast, bicyclic methylenecyclopropanes undergo hydroaminoalkylation with N‐benzylanilines or N‐alkylbenzylamines to give linear products in good to excellent yields (up to 98 %) with perfect regio‐ and diastereoselectivity. The corresponding 1,2,3‐trisubstituted (2‐aminoethyl)cyclopropane products exhibit a structurally interesting cis‐orientation of all three cyclopropane hydrogen atoms. [ABSTRACT FROM AUTHOR]

Traditionally, dose-finding process for oncology compound is carried out in phase I dose escalation study and is driven by safety in order to find maximum tolerated dose (MTD). However, with the recent paradigm shift from cytotoxic drugs to new generation of targeted therapies and immuno-oncology therapies, it may be difficult or unnecessary to identify the MTD because of the possible non-monotonic dose–response curves, and efficacy data should be incorporated into the dose-finding process. In this article, we have proposed efficacy-driven dose-finding designs with a safety-driven warm-up phase. Both local investigation and adaptive randomization using the framework of double-sided isotonic regression are investigated. Simulation studies are used to compare the proposed design to the original double-sided isotonic design. The results show that a safety-driven warm-up phase at the beginning can significantly improve the performance of double-sided isotonic regression, and both local investigation and adaptive randomization have good operating characteristics for finding the best dose/dose range under different tested scenarios. [ABSTRACT FROM AUTHOR]

Multiple comparison procedures and modeling (MCPMod) has established itself as a method for dose‐finding under model uncertainty. A downside of MCPMod is that due to its frequentist nature in particular with respect to the multiple comparison part it is tough to incorporate historical information in a systematic fashion. A typical situation where such historical information is available is existing data for the placebo group from previous trials. There are multiple Bayesian concepts for integrating historical data in a systematic and even dynamic fashion like the meta‐analytic prior approach. In this article, we define Bayesian MCPMod (BMCPMod) that is build upon these two aspects. BMCPMod is able to mimic the results of the classical MCPMod for non‐informative priors. At the same time, it allows for the inclusion of historical data in a systematic fashion. After the definition of BMCPMod related characteristics for a Bayesian approach similar to the MCP‐testing part are derived. The BMCPMod is compared to classical MCPMod/non‐informative priors via simulations. Aspects of mixture priors, optimal contrast vectors, and impact of allocation ratios are discussed and an example for designing a BMPCMod trial is given. [ABSTRACT FROM AUTHOR]

Intermolecular hydroaminoalkylation reactions of symmetrical and unsymmetrical alkynes with tertiary amines take place in the presence of catalytic amounts of TiBn4, Ph3C[B(C6F5)4], and a sterically demanding aminopyridinato ligand precursor. The resulting products, synthetically and pharmaceutically useful tertiary β,γ‐disubstituted allylic amines, are formed in convincing yields and with excellent stereoselectivity. Particularly promising for future applications is the fact that even the industrial side product trimethylamine can be used as a substrate. [ABSTRACT FROM AUTHOR]

Intermolecular hydroaminoalkylation reactions of propadiene with selected secondary amines take place in the presence of a 2,6‐bis(phenylamino)pyridinato titanium catalyst. The corresponding products, synthetically useful allylamines, are formed in convincing yields and with high selectivities. In addition, propadiene easily inserts into the titanium‐carbon bond of a titanaaziridine. [ABSTRACT FROM AUTHOR]

The scientific interest in catalytic hydroaminoalkylation reactions of alkenes has vastly increased over the past decade, but these reactions have struggled to become a viable option for general laboratory or industrial use because of reaction times of several days. The titanium‐based catalytic system introduced in this work not only reduces the reaction time by several orders of magnitude, into the range of minutes, but the catalyst is also demonstrated to be easily available from common starting materials, at a cost of approximately 1 € per millimole of catalyst. We were also able to formally perform C−H activation of methylamine and achieve coupling to a broad variety of alkenes, through silyl protection of the amine and simple deprotection by water. [ABSTRACT FROM AUTHOR]

After exploratory drug development, companies face the decision whether to initiate confirmatory trials based on limited efficacy information. This proof-of-concept decision is typically performed after a Phase II trial studying a novel treatment versus either placebo or an active comparator. The article aims to optimize the design of such a proof-of-concept trial with respect to decision making. We incorporate historical information and develop pre-specified decision criteria accounting for the uncertainty of the observed treatment effect. We optimize these criteria based on sensitivity and specificity, given the historical information. Specifically, time-to-event data are considered in a randomized 2-arm trial with additional prior information on the control treatment. The proof-of-concept criterion uses treatment effect size, rather than significance. Criteria are defined on the posterior distribution of the hazard ratio given the Phase II data and the historical control information. Event times are exponentially modeled within groups, allowing for group-specific conjugate prior-to-posterior calculation. While a non-informative prior is placed on the investigational treatment, the control prior is constructed via the meta-analytic-predictive approach. The design parameters including sample size and allocation ratio are then optimized, maximizing the probability of taking the right decision. The approach is illustrated with an example in lung cancer. [ABSTRACT FROM AUTHOR]

This paper reviews the production, synthesis, crystallography, particle morphology and spectroscopy of the insensitive high explosive nitroguanidine, (NGu, CH4N4O2), CAS‐No: [556‐88‐7] and its isotopologues [2D4]‐NGu and [15N4]‐NGu]. When compared with standard insensitive high explosives such as 1,3,5‐triamino‐2,4,6‐trinitrobenzene (TATB), 1,1‐diamino‐2,2‐dinitroethylene (FOX‐7) and N‐guanylurea dinitramide (FOX‐12), Nitroguanidine proves to be the least sensitive. The review gives 170 references to the public domain. For Part II see ref. [1]. [ABSTRACT FROM AUTHOR]

Purpose: A drug is defined as highly variable if its intra-individual coefficient of variation (CV) is greater than or equal to 30%. In such a case, bioequivalence may be assessed by means of methods that take the (high) variability into account. The Scaled Average Bioequivalence (SABE) approach is such a procedure and represents the recommendations of FDA. The aim of this investigation is to compare the performance characteristics of classical group sequential designs (GSD) and fixed design settings for three-period crossover bioequivalence studies with highly variable drugs, where the SABE procedure is utilized.Methods: Monte Carlo simulations were performed to assess type I error rate, power, and average sample size for GSDs with Pocock’s and O’Brien-Fleming’s stopping rules and various timings of the interim analysis and for fixed design settings.Results: Based on our investigated scenarios, the GSDs show comparable properties with regard to power and type I error rate as compared to the corresponding fixed designs. However, due to an advantage in average sample size, the most appealing design is Pocock’s approach with interim analysis after 50% information fraction.Conclusions: Due to their favorable performance characteristics, two-stage GSDs are an appealing alternative to fixed sample designs when assessing bioequivalence in highly variable drugs. [ABSTRACT FROM AUTHOR]

In the linear model for cross-over trials, with fixed subject effects and normal i.i.d. random errors, the residual variability corresponds to the intraindividual variability. While population variances are in general unknown, an estimate can be derived that follows a gamma distribution, where the scale parameter is based on the true unknown variability. This gamma distribution is often used for the sample size calculation for trial planning with the precision approach, where the aim is to achieve in the next trial a predefined precision with a given probability. But then the imprecision in the estimated residual variability or, from a Bayesian perspective, the uncertainty of the unknown variability is not taken into account. Here, we present the predictive distribution for the residual variability, and we investigate a link to the F distribution. The consequence is that in the precision approach more subjects will be necessary than with the conventional calculation. For values of the intraindividual variability that are typical of human pharmacokinetics, that is a gCV of 17-36%, we would need approximately a sixth more subjects. [ABSTRACT FROM AUTHOR]