Route Optimization and Manufacture of Multihundred Grams of a Ghrelin Receptor Agonist

Karlsson, Staffan; Gardelli, Cristina; Lindhagen, Marika; Nikitidis, Grigorios; Svensson, Tor

doi:10.1021/acs.oprd.8b00179

Cited by 9 publications

(3 citation statements)

References 30 publications

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“…Therefore, it was apparent that room-temperature Suzuki–Miyaura coupling conditions needed to be developed, preferably employing a mild base to further reduce the risk of protodeboronation. In addition, it was known that the free carboxylic acid of 1 is highly unstable and instantaneously decarboxylates, further highlighting the necessity to use a mild base in the Suzuki–Miyaura coupling to avoid the saponification of the ethyl ester.…”

Section: Initial Experimentsmentioning

confidence: 99%

Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki–Miyaura Coupling

Schäfer

Fleischer

Ahmetovic

et al. 2020

Org. Process Res. Dev.

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To avoid the use and handling of Lawesson's reagent or other thiation agents in the in-house kilolab, a new scalable route to ethyl 5-(2,4-difluorophenyl)-1,3,4-thiadiazole-2-carboxylate (1) was developed. The key to success was the use of a commercially available amino-thiadiazole building block, which was converted into the desired product via a sequence of Sandmeyer bromination and Suzuki−Miyaura coupling. The different parameters of the Pd-catalyzed coupling have been studied in detail and allowed the reaction to be performed under mild conditions at room temperature and with low catalyst loading. The inconsistencies of the initial scale-up runs with regard to the sluggish conversion of the Suzuki−Miyaura coupling due to Cu contamination were addressed, and the findings were directly implemented in the subsequent batches, which finally led to an improved overall understanding and robustness of the process.

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Section: Initial Experimentsmentioning

confidence: 99%

Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki–Miyaura Coupling

Schäfer

Fleischer

Ahmetovic

et al. 2020

Org. Process Res. Dev.

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“…We rationalized that such a process would be possible due to the greater electrophilicity of ester 33 . Indeed, the use of K 2 CO 3 in conjunction with 3-nitrophenol cleanly promoted the desired aminolysis at 65 °C in 48 h. Presumably, this union proceeded via the intermediacy of the more reactive aryl ester generated in situ by transesterification of 33 with the phenoxide . Importantly, 1 H NMR analysis indicated a complete consumption of (+)- 11 .…”

Section: Resultsmentioning

confidence: 99%

Development of an Effective Scalable Enantioselective Synthesis of the HIV-1 Entry Inhibitor BNM-III-170 as the Bis-trifluoroacetate Salt

Chen

Park

Kirk

et al. 2019

Org. Process Res. Dev.

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We report here the development and optimization of a process synthesis for the human immunodeficiency virus-1 entry inhibitor BNM-III-170 bis-trifluoroacetate salt (1). The synthesis features a dynamic-kinetic resolution to establish the initial stereogenicity. By taking advantage of significant sequence modifications of our first-generation synthesis, in conjunction with the low solubility of late-stage intermediates, the overall efficiency of the synthesis has been significantly improved, now to proceed in an overall yield of 9.64% for the 16 steps, requiring only a single chromatographic separation.

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“…Classical enzymatic kinetic resolution (EKR) relies on a simple and well-known phenomenon that due to the chirality of the active site of the enzyme, one enantiomer fits better into the active site than its counterpart and is therefore converted at a higher rate . The EKR methodology has become one of the most prevalent approaches used nowadays in the synthesis of optically active compounds (especially chiral sec -alcohols/esters, − carboxylic acids/esters, − and primary amines/amides − ) mostly because of the possibility of obtaining both enantiomeric forms of the respective racemic substrates in a single run at relatively mild temperatures. However, the applicability of the EKR process on an industrial scale is strongly limited as this method is not attractive from the practical point of view due to several drawbacks mainly associated with low reaction yields (in the best-case scenario, only one substrate enantiomer reacts for a theoretical maximum yield of 50%) and high cost of isolation and purification operations of the desired products.…”

Section: Introductionmentioning

confidence: 99%

From Waste to Value—Direct Utilization of α-Angelica Lactone as a Nonconventional Irreversible Acylating Agent in a Chromatography-Free Lipase-Catalyzed KR Approach toward sec-Alcohols

Poterała

Borowiecki

2021

ACS Sustainable Chem. Eng.

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Although the classical enzymatic kinetic resolutions (EKRs) are among the most important reactions in biocatalysis, the requirement of application of chromatographic purification technique, which is responsible for the generation of large amounts of waste organic solvents, is its major drawback. To minimize the environmental impact of such attempts and to address the current sustainability challenges, we decided to develop a novel EKR methodology, which relies on the usage of cheap, fully renewable, nontoxic, and irreversible acyl group donor reagent, namely, α-angelica lactone. The employed activated enol lactone-based acyl donor proved to be a versatile reagent enabling efficient and highly enantioselective (up to E ≫ 500) lipase-catalyzed resolution of a set of racemic sec-alcohols with up to >99% ee and near to quantitative isolation yields according to conversions achieved during the respective EKR procedure. Moreover, α-angelica lactone provided, in this case, an ability of fast and straightforward separation of the enzymatic reactions’ products via chromatography-free reactive liquid–liquid extraction (LLE) workup using either saturated aqueous sodium bisulfate in dimethylformamide (DMF) or Girard’s P reagent in a mixture of EtOH/AcOH (90:10, v/v), respectively. The NaHSO3/DMF LLE workup and the subsequent reisolation of the respective levulinate from the aqueous layer turned out to be less efficient than a separation with Girard’s P reagent. The selective LLE of optically active levulinate-Girard P-hydrazones from the respective alcohols and further hydrolysis of the respective hydrazides with diluted HClaq. could be performed with high levels of recovery of both EKR products isolated usually without loss of enantiomeric purity.

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Route Optimization and Manufacture of Multihundred Grams of a Ghrelin Receptor Agonist

Cited by 9 publications

References 30 publications

Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki–Miyaura Coupling

Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki–Miyaura Coupling

Development of an Effective Scalable Enantioselective Synthesis of the HIV-1 Entry Inhibitor BNM-III-170 as the Bis-trifluoroacetate Salt

From Waste to Value—Direct Utilization of α-Angelica Lactone as a Nonconventional Irreversible Acylating Agent in a Chromatography-Free Lipase-Catalyzed KR Approach toward sec-Alcohols

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