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8.3 Gutknecht Pyrazine Synthesis.
As an aside the synthesis of 2-pyridones (i.e. 1.42) can be achieved via a number of methods. For example the classical Guareschi–Thorpe condensation in which cyanoacetamide reacts with a 1,3-diketone delivers highly substituted 2-pyridones () [–]. This protocol is closely related to the Hantzsch pyridine synthesis and offers access to a wide range of products with well-defined regioselectivity. The simple undecorated parent 2-pyridone (1.42) can be somewhat harder to access but is obtained in a linear sequence via the corresponding 2-pyrone (e.g. ), which is converted to the 2-pyridone through an exchange with ammonia or an equivalent nitrogen source (NH4X; X = Cl, Br, I, OAc, OH).
Since phenylalanine and the pyrazine carboxylic acid are commercially available the main synthetic challenge in the preparation of bortezomib (4.27) lies in the asymmetric synthesis of the boronic acid residue. Using the Ellman chemistry, N-tert-butanesulfinylaldimes (4.28) are readily transformed into amino boronates using a copper mediated borylation . Application of this method gave the desired leucine analogue 4.31 in high yield and excellent diastereoselectivity (). Removal of the N-sulfinyl group under standard acidic conditions subsequently yields the α-amino acid 4.31 as the ammonium salt. This was subjected to standard peptide coupling protocols to furnish bortezomib in four additional steps.
8.3 Gutknecht Pyrazine Synthesis
The synthesis of cilazapril starts with a double condensation between piperazic acid derivative 5.13 and acid chloride 5.14 () . Upon hydrogenative cleavage of both benzyl groups and activation of the liberated carboxylic acid the bicyclic core structure 5.16 was obtained in good overall yield. A borane mediated reduction of the more accessible amide carbonyl in 5.16 followed by hydrazine induced removal of the phthalimide protecting group furnishes the primary amine 5.17. Subsequent treatment with trilflate 5.18 yields the corresponding substitution product which through saponification of the ethyl ester and hydrolysis of the tert-butyl ester furnishes cilazapril (5.12).
The reported synthesis of carmegliptin enlists a Bischler-Napieralski reaction utilising the primary amine 2.76 and methyl formate to yield the initial dihydroquinoline 2.77 as its HCl salt () . This compound was next treated with 3-oxoglutaric acid mono ethyl ester (2.78) in the presence of sodium acetate. Decarboxylation then yields the resulting aminoester 2.79 which was progressed through an intramolecular Mannich-type transformation using aqueous formaldehyde to allow isolation of enaminoester 2.80 after treatment of the intermediate with ammonium acetate in methanol. The next step involves a very efficient crystallisation-induced dynamic resolution of the racemic material using the non-natural (S,S)-dibenzoyl-D-tartaric acid ((+)-DBTA). It is described that the desired (S)-enantiomer of compound 2.81 can be isolated in greater than 99% ee and 93% overall yield. This approach is certainly superior to the original separation of the two enantiomers (at the stage of the final product) by preparative chiral HPLC that was used in the discovery route (albeit it should be noted that both enantiomers were required for physiological profiling at the discovery stage). Next, a 1,2-syn diastereoselective reduction of enaminoester 2.81 occurs with high diastereocontrol imposed by the convexed presentation of the substrate for the formal conjugate addition and subsequent protonation steps. This is followed by Boc-protection and interconversion of the ethyl ester to its amide derivative 2.82 in 80% overall yield for this telescoped process. The primary amide in 2.82 was then oxidised via a modern variant of the classical Hoffmann rearrangement using phenyliodine diacetate (PIDA). Following extensive investigation it was found that slowly adding this reagent in a mixture of acetonitrile/water to a suspension of amide 2.82 and KOH gave clean conversion to the amine product in high yield. This new procedure was also readily scalable offering a cleaner, safer and more reliable transformation when compared to other related rearrangement reactions. During a further telescoped procedure amine 2.83 was treated with lactone 2.84 to regenerate the corresponding lactam after mesylate formation. Finally, removal of the Boc-group with aqueous hydrochloric acid furnished carmegliptin as its HCl salt.
is the Gutknecht Pyrazine Synthesis ..
In order to generate vardenafil on a production scale the Bayer group also reported the use of a amidrazone 6.100 as a cyclisation precursor (). First the amide oxime 6.101 was formed from the corresponding nitrile 6.102 which upon palladium-mediated N–O bond cleavage yielded an amidine derivative on route to the desired amidrazone 6.100 through exchange with hydrazine. This material was then subjected to a condensation reaction with keto-ester 6.103 in refluxing methanol followed by a phosphorous oxychloride mediated ring closure yielding imidazotriazinone 6.95. The synthesis of vardenafil was completed by a stepwise sulfamoylation protocol.
The synthesis of nifedipine can be readily achieved using the classical Hantzsch reaction condensing 2-nitrobenzaldehyde (2.4) with methyl acetoacetate (2.5) in the presence of an ammonia source. However, gaseous ammonia as well as ammonia solutions are considered difficult reagents due to handling issues, often giving problems due to corrosion as well as the obvious associated stench. One interesting protocol circumventing the problem describes the use of bench stable magnesium nitride, a solid material which upon hydrolysis liberates the required ammonia in situ () . However, there have been several reports on explosions caused by runaway reactions so extreme care must be administrated when using this reagent .
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Gutknecht pyrazine synthesis; H ..
Other syntheses of pioglitazone use related pyridine building blocks and aim to generate late stage intermediates that deliver the target compound upon de novo synthesis of the thiazolidinedione ring system. For instance phenyl ether 1.73 can be obtained via Williamson ether synthesis between mesylate 1.74 and phenol 1.75 (). Removal of the acetyl protecting group under acidic conditions renders aniline 1.76 which is subsequently subjected to a Meerwein arylation reaction which occurs via diazotisation and subsequent treatment with acrylonitrile in the presence of cuprous oxide [–].
8.3 Gutknecht Pyrazine Synthesis ..
An alternative process is based on the availability of 3-picoline (1.15) which is generated as a major side product in the synthesis of pyridine prepared from formaldehyde, acetaldehyde and ammonia in a gas phase reaction () . The 3-picoline can be readily oxidised via another gas-phase protocol using a fixed-bed reactor charged with vanadium pentoxide on high surface titanium dioxide (5–50 wt % vanadium). A modification of the sequence utilises a dehydrative amminolysis (ammoxidation) to furnish the corresponding 3-cyanopyridine, which can then be subsequently hydrolysed to nicotinic acid. The catalyst systems most commonly used in this high temperature ammoxidation are based on vanadium, molybdenum or antimony oxides supported on silica or alumina.
A variation is the Gutknecht pyrazine synthesis ..
Transformations that lead to six-membered heterocycles show high dependence on condensation reactions between carbonyl compounds and nitrogen-containing building blocks as the primary synthesis route. As such ammonia, amidines/guanidines or amidrazones become classical reaction partners with ketoesters and diketones. Due to the electron-deficient nature of many of these heterocycles nucleophilic aromatic substitutions are widely used to subsequently functionalise these ring systems. For fully reduced heterocycles more linear synthesis sequences are used in their construction often with an eye to developing asymmetric processes. Newer chemistries using metathesis or various organometallic protocols are beginning to have a more important impact. Owing to the multi-step nature which is necessary to generate novel heterocycles we should anticipate that further advances will be necessary, especially sequences that lead to ready telescoping of the routes. Without doubt the pressure currently imposed on pharmaceutical companies in order to deliver novel species more rapidly and at lower cost will drive innovation and discovery to enable many new methods.
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