Timothy Norris

Determination of End-points for Polymorph Conversions of Crystalline Organic Compounds Using On-line Near-infrared Spectroscopy

Trovafloxacin mesylate exists in two anhydrous polymorphic forms, I and II. The fundamental band vibration spectra information does not readily differentiate between the two forms, although the crystal lattice of each form has a distinct X-ray powder diffraction pattern. Subtle spectral differences between the two polymorphs can be detected in the NIR spectral region and the interconversion of the two forms can be monitored in hot solvent crystal slurries using NIR spectroscopy and an on-line fibre optic probe. A generally applicable method has been developed to monitor the conversion of form I into form II as a crystal slurry. The free energy profile in principal component space has been modelled as the process proceeds to give a computer graphic of the change which readily shows when the conversion is complete.

New hydroxy-pyrazoline intermediates, subtle regio-selectivity and relative reaction rate variations observed during acid catalyzed and neutral pyrazole cyclization.

Arylhydrazines 4 and 1,3-dicarbonyl compounds 5 react to form pyrazoles by loss of water via hydrazone isomer pairs 6 and 7 which give rise to two possible regio-isomers. Occasionally, 3-hydroxy-3,4-dihydropyrazoles or hydroxy-pyrazolines 9 and 9 are observed as stable isolatable intermediates that can be fully characterized prior to loss of the second molecule of water that gives rise to pyrazoles 10 and 11. Fully characterized examples of intermediates of type 8 and 9 are relatively rare. We studied the reaction series where R = CH3, CHF2 and CF3 and Ar = Ph and 5-methanesulfonylpyridin-2-yl, (Scheme 2), and observed differences in properties between kinetic behavior and regio-isomerism depending on the degree of electron-withdrawing capability of the R and Ar substituents. The reaction conditions that caused cyclization to pyrazoles varied from direct condensation of the hydrazine and 1,3-dicarbonyl compounds, to reactions requiring catalytic quantities of sulfuric acid to sulfuric acid in excess. Unexpected regio-selectivity was observed in the case of R = CF3 that depended upon the reaction conditions.

On-Line Determination of Reaction Completion in a Closed-Loop Hydrogenator Using NIR Spectroscopy

An on-line near-infrared (NIR) spectroscopic method has been developed to determine in situ the endpoint of a bulk pharmaceutical hydrogenation reaction in a loop hydrogenator. This hydrogenation employs a 5% palladium-on-carbon catalyst with tetrahydrofuran (THF) as the reaction solvent. The traditional test for monitoring the endpoint of the hydrogenation is a gas chromatographic procedure that requires an estimated 60 min from the time a sample is taken to the point where the analysis results become available. The use of NIR spectroscopy in an on-line mode of operation allows spectra to be collected every 2 min and thereby significantly improves response time and result availability. The need for obtaining results in “real time” stems from the creation of undesired side products if the reaction is allowed to continue past the optimal endpoint. If the reaction is not stopped before these side products reach a level of approximately 0.8% (wt/wt), the batch requires additional purification at considerable time and cost. A partial least-squares model was constructed, validated, and successfully used to determine the endpoint of subsequent batches.

Discovery of a new stable polymorph of 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazolinium methanesulfonate using near-infrared spectroscopy to monitor form change kinetics

Polymorphism is an important property of crystalline organic molecules, particularly when used to develop medicines. Discovery of all the polymorphs in a series is often difficult. This paper highlights the use of near-infrared spectroscopy to monitor the kinetics of form changes of polymorphs and solvates (hydrates). In the case of mesylate salt 5, this led to the discovery of a new preferred form. Identification and confirmation of unique polymorph crystal states are determined using X-ray powder diffraction patterns. This complements and confirms the kinetic change observed in the near-infrared. The technique is generally applicable to the study of two-phase solid–liquid crystal slurries under isothermal conditions.

End-point determination on-line and reaction co-ordinate modelling of homogeneous and heterogeneous reactions in principal component space using periodic near-infrared monitoring

Advancement of organic homogeneous and heterogeneous reactions to their steady state end-points has been determined directly using near-infrared spectroscopy and fibre optic probes. The reaction times can be obtained without specifically measuring decay of individual starting materials or formation of products. The technique is passive and can be generally applied to most organic reactions in the laboratory or chemical plant. This report uses the formation of zopolrestat ethyl ester and its saponification to zopolrestat sodium salt, as typical examples of a heterogeneous and a homogeneous reaction matrix, respectively. Data has been collected directly from full size chemical reactors. The steady state is detected when the change in the spectra does not change significantly with time. The end-point can be confirmed computationally shortly after the data has been collected using open ended models. These can be constructed directly from the spectral data using commercially available software. The end-point can be confirmed with multivariate calibration methods using dendrograms derived from hierarchical cluster analysis or scores plots obtained from principal component analysis. The reaction co-ordinate can be modelled in principal component space using the locus of the spectral scores plot.

Cycloaddition reactions of dehydrodithizone. X-Ray crystal structures of 5-diethylamino-4-methyl-1-phenyl-3-phenylazopyrazole, 4a,5,6,7,8,8a-hexahydro-6-methyl-8a-morpholino-1-phenyl-3-phenylazo-1H-pyrido[4,3-e][1,3,4]thiadiazine, and 3′-phenyl-5′-phenylazo-2-pyrrolidinospiro-[1H-indene-1,2′(3′H)-[1,3,4]thiadiazole]

The title compounds [(3a), (11), and (15a)] were obtained from dehydrodithizone and, respectively, 1-diethylaminopropyne, the morpholine enamine of 1-methyl-4-piperidone, and 2-pyrrolidinoindene, and their structures were determined by single-crystal X-ray structure analysis. Likewise, reaction of dehydrodithizone with 1-dimethylamino-2-phenylacetylene gave the phenylazopyrazole (3c), with β-piperidinostyrene the phenylazo-1,3,4-thiadiazine (12), and with 2-piperidino- and 2-morpholino-indene the phenylazospiro[indene-[1,3,4]thiadiazoles](15b and c). In contrast, dimethyl acetylenedicarboxylate and tetraphenylcyclopentadienone formed 1,3-dipolar cycloadducts, which are formulated as the thiazolo[3,2-d]tetrazoles (4) and (5)[or (6)], respectively. The different modes of behaviour of dehydrodithizone towards electron-rich and electron-poor components are rationalized by means of frontier-orbital theory.

Synthesis of trovafloxacin using various (1α,5α,6α)-3-azabicyclo[3.1.0]hexane derivatives

Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6α-nitro-3-azabicyclo[3.1.0]hexane intermediate 10. The synthesis of 6α-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected exo 6-amino derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected trovafloxacin compounds 20–22 in good yield. The ethyl ester of trovafloxacin 21 can also be accessed from the product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of protecting groups from 20–22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin zwitterion 1 can be liberated with base treatment. Zwitterion 1 can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26.

Reaction of dehydrodithizone with tetraphenylcyclopentadienone. X-Ray crystal structures of a stable 1,5-dipole, azobenzene N-(cis-3a,6a-dihydro-4-oxo-3a,5,6,6a-tetraphenyl-4H-cyclopentathiazol-2-yl)-imide, and of cis-3a,6a-dihydro-3a,5,6,6a-tetraphenyl-2-phenylazo-4H-cyclopentathiazol-4-one

The title compounds (5) and (8) were obtained from the reaction of dehydrodithizone with tetraphenylcyclopentadienone and their structures were determined by single-crystal X-ray analysis by direct methods. Crystals of both compounds are triclinic, with Z= 8 in unit cells of dimensions: (5)a= 19.933(6), b= 9.755 (3), c= 36.515-(12)A; α= 87.429(8), β= 102.659(6), γ= 99.675(4)°; (8)a= 14.855(2), b= 19.816(3), c= 19.335(3), α= 94.260(6), β= 90.815(6), γ= 93.041(8)°. The structures were refined to R 0.046 [(5) 2 808 observed reflections] and 0.040 [(8) 2 380 observed reflections].

Reactions of dehydrodithizone with dimethyl acetylenedicarboxylate and with benzyne. X-Ray crystal structure of azobenzene N-(4,5-bis-methoxycarbonylthiazol-2-yl)imide, a stable dipole

Dehydrodithizone adds dimethyl acetylenedicarboxylate to yield the title compound (7), whose structure was determined by single-crystal X-ray analysis. 2-Phenylazobenzothiazole and azobenzene were obtained from dehydrodithizone and benzyne. These products are thought to be formed by the decomposition of initial 1,3-cycloadducts.

An unusual carbon–carbon bond scission reaction with molecular oxygen under mild conditions; formation of piperidines from 1-azabicyclo[2.2.2]octanes

Molecular oxygen reacts with 2-(1-phenylethyl)- and 2-benzhydryl-3-alkylimino-1-azabicyclo[2.2.2]octanes 1–7 in neutral solution at room temperature to form 1-acylpiperidine-4-carboxylic acid N-alkylamides 8–14. During the transformation two new carbonyl bonds are formed and a carbon–carbon bond is cleaved. The transformation is quite general provided the 2-substituent of the imine is of sufficient steric bulk, such as the 2-(1-phenylethyl) or 2-benzhydryl groups. No reaction is observed in the absence of a 2-substituent, as in the case of imine 15.