Drug manufacturing in a fridge-sized box Commodity chemicals tend to be manufactured continuous fashion. However, the preparation of pharmaceuticals still proceeds batch by batch, partly on account complexity their molecular structures. Adamo et al. now present an apparatus roughly size household refrigerator that can synthesize and purify under continuous-flow conditions (see Perspective Martin). The integrated set modules produce hundreds thousands accumulated doses day, delivered aqueous...

Abstract In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield above 90 % for each step. A scale‐up this five‐stage process (3 bond‐forming steps, one work‐up, and in‐line liquid–liquid separation) provided at rate 8.09 g h −1 (equivalent to 70.8 kg y ) using system overall footprint half the size standard laboratory fume hood. Aside high throughput, several other aspects synthesis expand capabilities continuous‐flow...

A continuous end-to-end synthesis and purification of diphenhydramine hydrochloride featuring atom economy waste minimization is described. Combining a 1 : molar ratio the two starting material streams (chlorodiphenylmethane N,N-dimethylaminoethanol) in absence additional solvent at high temperature gives target compound directly as molten salt (ionic liquid above 168 °C) yield. This represents first example active pharmaceutical ingredient (API) production this manner. Six twelve principles...

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination cytidine.

Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for the treatment of COVID-19. Herein, we describe supply-centered and chromatography-free synthesis molnupiravir from cytidine, consisting two steps: selective enzymatic acylation followed by transamination to yield final product. Both steps have been successfully performed on decagram scale: first step at 200 g second 80 g. Overall, has obtained in 41% overall isolated compared maximum 17% patented route....

A two-step synthesis of molnupiravir (1) is presented. This work focuses on the development practical reaction and purification conditions toward a manufacturing route. The sequence commences from highly available cytidine (2), formed through direct hydroxamination cytosine ring esterification sugar's primary alcohol without use protecting or activating groups. crystalline hydrate N-hydroxycytidine (3) resulted in an easily purified intermediate, practical, off-the-shelf enzyme was selected...

N-heterocyclic carbenes (NHCs) serve as highly proficient ligands in many transition metal catalyzed reactions. As such, significant efforts have been devoted to the extension of NHCs into field asymmetric catalysis. Development was slow at first but is now rapidly accelerating, evidenced by increase number transformations displaying excellent enantioselectivities. Chronicled here are attempts catalysis with NHC ligands, and results categorized effecting well type reaction. Ruthenium,...

Abstract In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield above 90 % for each step. A scale‐up this five‐stage process (3 bond‐forming steps, one work‐up, and in‐line liquid–liquid separation) provided at rate 8.09 g h −1 (equivalent to 70.8 kg y ) using system overall footprint half the size standard laboratory fume hood. Aside high throughput, several other aspects synthesis expand capabilities continuous‐flow...

Pyrrolotriazine

A simple reordering of the reaction sequence allowed improved synthesis EIDD-2801, an antiviral drug with promising activity against SARS-CoV-2 virus, starting from uridine. Compared to original route, yield was enhanced 17 % 61 %, and fewer isolation/purification steps were needed. In addition, a continuous flow procedure for final acetonide deprotection developed, which proved be favorable toward selectivity reproducibility.

A commercial route to adagrasib (1) was developed support clinical and needs. Yield improved 32% over six chemical steps. doubly regioselective SNAr reduced consumption of a chiral intermediate, reaction optimization led parts per million palladium catalysis, new method deprotect Cbz-groups were mitigate risk associated with benzyl iodide.

2-Alkylpyrrolidines were used as building blocks for acyclic diaminocarbenes (ADCs). First, ureas made from the corresponding amines, and then converted to chloroamidiniums. The chloroamidiniums served direct precursors ADCs, palladium complexes utilizing oxidative addition, whereas lithium−halogen exchange was performed generate rhodium complexes. carbene ligands characterized through use of NMR, mass spectrometry, X-ray analysis, structures, steric parameters calculated % VBur values....

Abstract A new route to MK-4482 was developed. The replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for chemical transformations, yield is improved from 17% 44%. step removed longest linear sequence, these advancements expected expand access should it become a viable drug substance.

A high-yielding protocol for atropisomeric resolution was developed by rectifying incompatibilities between crystallization and epimerization via continuous processing. Application toward synthesis of MRTX1719, a densely functionalized active pharmaceutical ingredient (API), improved yield from 37% to 87%. This provides complementary means access rotamers which challenge current asymmetric methodologies, greatly improves sustainability decreasing the consumption solvent advanced synthetic...

An efficient gram-scale synthesis of the antituberculosis agent pretomanid using straightforward chemistry, mild reaction conditions, and readily available starting materials is reported. Four different protecting groups on glycidol moiety were investigated for their technical feasibility ability to suppress side reactions. Starting from protected (R)-glycidols 2-bromo-4-nitro-1H-imidazole, could be prepared in a linear three-step up 40% isolated yield. In contrast most syntheses reported so...

A lithium−halogen exchange route has been developed to generate acyclic diaminocarbenes (ADC) from chloroamidinium salts. Convenient access various ADC complexes (B, Rh, Ir, Pd) stems a one-pot transmetalation protocol. Formation of carbenoid species is suggested by 1D and 2D NMR studies with 13C-labeled precursor also X-ray structures transition metal−carbene complexes. Rh-ADC complex 4 an effective catalyst for the 1,2-addition aryl boronic acids aldehydes.

A novel acyclic diaminocarbene–copper complex appears to be generated from a chloroamidinium salt and Cu(I)-thiophenecarboxylate in the presence of Grignard reagent based on 13C NMR studies is highly efficient catalyst for SN2′-allylic alkylation.

A series of sterically demanding acyclic aminooxycarbenes (AAOCs) were prepared in good yields from chloroiminium salts and alkoxysilanes via the TMS-Cl elimination pathway. The steric profiles bulky AAOCs determined by X-ray crystallographic studies Au(I) complexes. percent buried volume values (%VBur) AAOC ligands range 35.8% to 47.9%. Acyclic maintain coplanarity around carbene center, sharp contrast similarly diaminocarbenes that show significant distortion coplanarity. complexes...

We report the development of a one-pot synthesis 2-fluoroadenine from an inexpensive 2,6-diaminopurine starting material using diazonium chemistry in continuous fashion. Given sensitivity this transformation to temperature, we conducted critical experiments study exothermicity reaction and heat removal, which were for process. Our goal was improve yield purity pharmaceutical intermediate (2-fluoroadenine) develop more robust

An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served dual purpose activating carbohydrate's anomeric center for N-glycosylation transferring stereochemical information substrate simultaneously. Both enantiomers are available, either β-enantiomer in challenging class 2′-deoxynucleoside active pharmaceutical...

Herein, we report further improvements to the synthesis of tenofovir 1, precursor disoproxil fumarate (TDF) and alafenamide (TAF). Starting from acyclic diaminomalononitrile 12, a four-step protocol 1 will allow for vertical integration more manufacturers. The key transformation is convergent one-step procedure 6 as compared current commercial process, with an improved yield 59% (two steps) 70%. Further include eliminating need problematic magnesium tert-butoxide (MTB) significant solvent...

MRTX1719 was identified as a potent inhibitor of the PRMT5/MTA complex, designed to selectively target MTAP-deleted cancers. A scalable synthesis this atropisomeric compound and an efficient isolation desired isomer were required support Phase 1 clinical trials, established through further development racemic medicinal chemistry route. In key step, (M)-atropisomer amplified from API by combining crystallization (20 °C) racemization (160 °C, 4 min). Concurrent execution these, ostensibly...