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An efficient route to two functionalized 2-aryl-5H-chromeno[2,3-b]pyridines (azaxanthenes) is reported. The addition of lithiated 2,6-dichloropyridine to salicylaldehyde followed by cyclization was a key process improvement identified for the formation of the azaxanthene core. Further elaboration of 2-chloro-5H-chromeno[2,3-b]pyridin-5-ol at the 5 position was accomplished via Lewis acid-catalyzed coupling with commercially available ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane. A partial classical resolution coupled with a preparative chiral supercritical fluid chromatography (SFC) separation was used to isolate the desired enantiomer of the azaxanthene carboxylic acid that is a common intermediate for both compounds 1 and 2. Suzuki–Miyaura cross-coupling with appropriately substituted boronic acids, followed by condensation with 2-amino-1,3,4-thiadiazole, provided the target compounds with an overall yield of approximately 10%. The use of stable, amorphous materials to support clinical compari...

Preparative chiral supercritical fluid chromatography (SFC) employing an enantioenriched feedstock obtained via partial classical resolution enabled rapid access to kilogram quantities of a key intermediate common to two glucocorticoid (GC) receptor modulator candidates for which neither chemical nor enzymatic resolutions provided the desired chiral purity (>99.0 HPLC area percent). We developed a partial classical resolution of the racemate that afforded 85:15 enantioenriched mixtures with 90% recovery of the desired enantiomer and reduced the SFC processing time by 54%. The SFC method used a 5 cm × 28 cm column packed in-house with 20 μm Chiralpak AD, a total column flow rate of 150 g/min, a cosolvent composition of 12% methanol, and a column back pressure of 75 bar. The feed processing rate was up to 80 mL/h, which translated to 67 g/day of the enantioenriched mixture or 57 g/day of the desired enantiomer. This combined classical resolution/SFC process was employed to obtain a total of 1.0 kg of the de...

The process development and large scale synthesis for the β-hydroxyamino amide 1 is described. The route evolved from a multistep sequence utilizing a classical resolution to a two-step enantioselective process involving an enzyme-catalyzed aldol reaction and a direct amidation of a carboxylic acid. By utilizing a silicon-mediated direct amidation strategy, the route was devoid of protecting and deprotecting steps while retaining the stereochemical integrity of a highly sensitive β-hydroxyamino acid. The two-step strategy employed herein significantly improved the yield, process greenness, cycle time, and estimated cost in the production of 1.

The chiral β-hydroxy-α-amino acid, (2R,3S)-2-amino-3-hydroxy-3-(pyridin-4-yl)-propanoic acid, is a key intermediate in the synthesis of the API (2R,3S)-2-amino-3-hydroxy-3-(pyridin-4-yl)-1-(pyrrolidin-1-yl)propan-1-one, a developmental drug candidate. Two d-threonine aldolase enzymes were identified to catalyze the aldol addition of glycine and pyridine 4-carboxaldehyde for the synthesis of the β-hydroxy-α-amino acid. The two d-threonine aldolase enzymes have similar properties. Efficient recombinant E. coli fermentation processes were developed for producing the enzymes. The stabilities of the enzymes were significantly improved by addition of divalent cations. An unexpected and beneficial finding was that the β-hydroxy-α-amino acid aldol addition product directly crystallized out from the reaction mixture in high purity and high diastereo- and enantioselectivity, contributing also to high yield and allowing easy isolation, processing, and downstream utilization. The temperature, pH, and amounts of react...

The evolution of a process for the preparation of a new heterocyclic dual NK1/serotonin receptor antagonist is described. The final synthesis features a telescoped sequence in which an iron(III)-catalyzed Grignard coupling is followed by a benzylic chlorination utilizing trichlorocyanuric acid to construct an unsymmetrical 2,4,6-trisubstituted pyridine. Etherification of a 4,4′-arylhydroxymethane substituted piperidine fragment completes the synthesis of the active pharmaceutical ingredient in 44% overall yield.

A practical synthesis of the anti-methicillin resistant Staphylococcus aureus cephem (6R-trans)-E-7-[[[[2,5-dichloro-4-[3-[(carboxymethyl)amino]-3-oxo-1-propenyl]phenyl]-thio]-acetyl]amino]-4-[[(2-carboxy-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-en-3-yl)methyl]thio]-2,6-dimethyl-1-[3-(4-methylmorpholino-4-yl)propyl]-1-pyridinium, hydroxide, inner salt (BMS-247243) was developed. A process was developed for the interchange of the iodide counterion in 3a to chloride 3b that was essential for an efficient synthesis of the C-3 side chain 4-mercaptopyridone 6b. Use of catalytic Bu4NCl in the reaction of chlorocinnamide 14 with the Li-salt of methylthioglycolate formed the methyl ester of the C-7 side chain 12b in high yield. Reaction with the dianion of thioglycolic acid gave an increased level of the corresponding Michael addition byproduct that led to lower quality thermodynamic product 12b by the reverse reaction. Cephem nucleus 16 was acylated with the acid chloride of acid 12b in a biphasic system to circum...

Allysine ethylene acetal [(S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (2)] was prepared from the corresponding keto acid by reductive amination using phenylalanine dehydrogenase (PDH) from Thermoactinomyces intermedius ATCC 33205. Glutamate, alanine, and leucine dehydrogenases, and PDH from Sporosarcina species (listed in order of increasing effectiveness) also gave the desired amino acid but were less effective. The reaction requires ammonia and NADH. NAD produced during the reaction was recyled to NADH by the oxidation of formate to CO(2) using formate dehydrogenase (FDH). PDH was produced by growth of T. intermedius ATCC 33205 or by growth of recombinant Escherichia coli or Pichia pastoris expressing the Thermoactinomyces enzyme. Using heat-dried T. intermedius as a source of PDH and heat-dried Candida boidinii SC13822 as a source of FDH,98%, but production of T. intermedius could not be scaled up. Using heat-dried recombinant E. coli as a source of PDH and heat-dried Candida boidinii 98%. In a third generation process, heat-dried methanol-grown P. pastoris expressing endogenous FDH and recombinant Thermoactinomyces98% ee.

The cyclization of acetal amide was carried out with trimethylsilyl trifluoromethanesulfonate, followed by elimination using sodium methoxide to give 2,5-disubstituted oxazole, thus completing a new route to the cardivascular drug ifetroban sodium.

Carbanions generated from 2,4,4-trimethyl-2-oxazoline (1a), 2-benzyl-4,4-dimethyl-2-oxazoline (1b), 2,4-dimethylthiazole (13a), 2-benzyl-4-methylthiazole (13b), N,N-dimethylacetamide (17a), tert-butyl acetate (17b), ethyl phenylacetate (17c), N-methyl-N-phenyl-2-butenamide (22), tert-butyl 3-butenoate (25), and dimethyl methylphosphonate (29a) by means of KNH2 in liquid NH3 all reacted with 2-bromopyridine (2) via photoassisted reactions that exhibited characteristics of the SRN1 mechanism. Similar results were obtained in reactions of these carbanions with other substrates, including 2-chloroquinoline (6), iodobenzene (9), bromobenzene (10), and bromomesitylene (11).

N-acyl-2-bromobenzamides participate in metal-halogen exchange with n -BuLi to form N-acyl-2-lithiobenzamides, which undergo cyclization to afford 3-alkylidenephthalimidines.

Aromatic palladocycles undergo facile reaction with acid halides to reglospecifically provide aryl ketones In high yield.