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The need for effective solid-form screening approaches, especially designed for the early discovery phases, is well recognized within the pharmaceutical industry. Here we report on the early polymorphism and solvatomorphism evaluation of a new drug candidate for selective α2C-adrenoceptor antagonists ORM10921·HCl. The approach we use is based on the systematic batch-to-batch characterization of the solids generated during the salt synthesis optimization. Within this study three crystalline forms, two anhydrous and one hemihydrate, were discovered and identified by X-ray powder diffraction (XRPD), differential scanning calorimery (DSC), and thermal gravimetry (TGA). Moreover, coupling the gravimetric vapor sorption analysis with a conventional XRPD enabled the relative stability of these solid-state forms at ambient conditions to be established and the most stable form, the hemihydrate, to be selected for further development. Hence, the utilized approach has proven to be an effective and fast tool for init...

For the first time, it has been shown that 2,6-dicyanopiperidines are formed in the Fry reaction via 1,4-dihydropyridine intermediates. A new synthetic approach for building 2,6-dicyanopiperidine derivatives by an extension of the sodium dithionite reduction of pyridinium salts is described. The stereochemistry of 2,6-dicyanopiperidine derivatives formed is discussed.

The total syntheses of 11-methoxydeethyleburnamonines (4) and (13) were carried out with use of 6-methoxytryptophyl bromide (5) as starting material. Compound 5 was converted in three steps to trans-ester 8. Acid-catalysed epimerization of 8, lithium aluminum hydride reduction of the ester group, tosylation and substitution with cyanide gave the cis-nitrile 12. Acid-induced cyclization of 12 yielded mainly (±)-trans-11-methoxydeethyleburnamonine (13), whereas base-induced cyclization gave (±)-cis-11-methoxydeethyleburnamonine (4).

The ring system of the novel indole alkaloid tangutorine (1) has been synthesized via the Fry reaction. The final key steps were an oxidation/reduction procedure or alternatively, an epimerization sequence. Conformational and stereochemical aspects of the skeleton are discussed.

19S-Hydroxytacamine (3) and 19R-hydroxytacamine (4) were prepared from cis hydroxyesters 7 and 8 via corresponding O-TMS esters 9 and 22. Comparison of the spectral data of isomers 3 and 4 with those of 19-hydroxytacamine from Tabernaemontana eglandulosa confirms that isomer 3 represents the naturally occurring 19-hydroxytacamine.

The role of the nitrogen lone pairs in the mechanism of the acid-catalysed epimerization of indolo[2,3- a ]quinolizidines is investigated using lactams as model compounds. Deethyleburnamonine ( 3 ) did not epimerize with trifluoroacetic acid (TFA), whereas deethyldihydroeburnamenine ( 7 ) underwent epimerization smoothly. Under treatment with TFA, lactams 12 and 13 both epimerized with ease to a mixture of lactams 12 and 13 . An analogous equilibrium was achieved when the experiment was repeated with lactams 18 and 19 . Intermediate 20 was trapped (Zn reduction) in the acid-catalysed epimerization of lactam 12 , allowing conclusions about the mechanism.

Intramolecular aldol condensation of ketoaldehyde 8 affords three new compounds: enone 9 , hydroxyketone 10 , and enone 11 . Enone 9 possesses the ring system of (−)-voaketone ( 1 ), which is a skeletal rearrangement product of the indole alkaloid (−)-voacangine.

Base-catalysed epimerization of the easily accessible trans ester 3 at C-1 gives rise in good yield to the seemingly less stable cis ester 2, which can be converted into the indole alkaloid tacamonine (1) in three steps.

Total syntheses are described for seven tacamine-type indole alkaloids (1–7) found in Tabernaemontana eglandulosa. (±)-Tacamine (1), (±)-16-epitacamine (2), and (±)-apotacamine (3) were prepared from pentacyclic intermediates 18. Apotacamine (3) was also obtained from aldehyde 12 via epimerization of 20-epiapotacamine (19) by the Polonovski-Potier reaction. Homologation of ester 13 led to 20-epitacamonine (23), which was similarly converted to (±)-tacamonine (4). Reduction of 4 gave (±)-descarbomethoxytacamines 5 and 6. Aldehyde 11 was reacted with trimethylsilyl cyanide (TMSCN) to yield the two (±)-17-hydroxytacamonines (7), of which the isomer with an axial hydroxy group (17β-OH) was found to be identical with the natural compound. Finally, an attempt to prepare (±)-19S-hydroxytacamine (8) is described. As an intermediated for this, a new synthesis of the pyridine alkaloid methyl 5-(1′-hydroxyethyl)nicotinate (34) was achieved.

Methyl 3α-1,2,3,4,6,7,12,12bβ-cotahydroindolo[2,3- a ]quinolizine-1α-carboxylate ( 6 ), a key intermediate for the synthesis of tacamine-type indole alkaloids, was prepared in six simple steps from methyl 5-(1′-hydroxyethyl)nicotinate ( 7 ). The last step was the catalytic hydrogenation of the two ethylidene isomers 14 and 15 , both of which gave the target ester stereoselectively.

A simple and efficient method is described for the preparation of tacamonine (1) from the easily accessible ester 3. The method is based on the stereoselective synthesis of 20-epitacamonine (7), which is transformed to 1 using the Polonovski-Potier reaction.

The mixture of pentacyclic intermediates ( 4 ) was successfully converted into the pharmacologically interesting indole alkaloid (±)-tacamine ( 1 ). In a similar manner, the two unnatural isomers of 1 , (±)-14-epitacamine ( 9 ) and (±)-14-epi-16-epitacamine ( 10 ), were obtained from intermediate 7 . The key reaction, an acid-catalyzed displacement of the dimethylamino group with the hydroxyl group, is believed to take place via an iminium intermediate.

The synthesis of aldehyde intermediates suitable for the preparation of indole alkaloids of the tacamine (1) type is described. The four possible aldehydes 4–7 were prepared from methyl 5-ethylnicotinate (8) in a few simple steps using a base-catalyzed epimerization as the final step (Schemes 1 and 2). The key aldehyde 4, which is an analogue of the important vincamine intermediate 3 (‘Oppolzer's aldehyde’), was finally converted into the indole alkaloid (±)-apotacamine (21).

The HPLC enantiomeric separation of racemic indole alkaloids tacamonine, 17α-hydroxytacamonine, deethyleburnamonine, and vindeburnol was accomplished using Chiralpak AD and Chiralcel OD as chiral stationary phases. Small structural differences affect the enantioselectivity ability of these phases. Single enantiomers of tacamonine and vindeburnol were isolated by semipreparative HPLC and their CD spectra and optical rotations were measured. Chirality 13:691–693, 2001. © 2001 Wiley-Liss, Inc.

The synthesis of aldehyde intermediates suitable for the preparation of indole alkaloids of the tacamine (1) type is described. The four possible aldehydes 4–7 were prepared from methyl 5-ethylnicotinate (8) in a few simple steps using a base-catalyzed epimerization as the final step (Schemes 1 and 2). The key aldehyde 4, which is an analogue of the important vincamine intermediate 3 (‘Oppolzer's aldehyde’), was finally converted into the indole alkaloid (±)-apotacamine (21).

Both (±)-17α-hydroxytacamonine ( 3 ) and its 17β-isomer ( 4 ) were synthesized in two steps (one-pot) from aldehyde mixture 5/6 via the cyanohydrin reaction. NMR spectral characterization of isomer 3 revealed it to be unidentical with natural 17-hydroxytacamonine, whereas spectral data of isomer 4 were in agreement with those published for the natural isomer. The configuration at C-17 was confirmed by NOE difference spectroscopy.

A simple and efficient method is described for the preparation of tacamonine (1) from the easily accessible ester 3. The method is based on the stereoselective synthesis of 20-epitacamonine (7), which is transformed to 1 using the Polonovski-Potier reaction.

Base-catalysed epimerization of the easily accessible trans ester 3 at C-1 gives rise in good yield to the seemingly less stable cis ester 2, which can be converted into the indole alkaloid tacamonine (1) in three steps.

Intramolecular aldol condensation of ketoaldehyde 8 affords three new compounds: enone 9 , hydroxyketone 10 , and enone 11 . Enone 9 possesses the ring system of (−)-voaketone ( 1 ), which is a skeletal rearrangement product of the indole alkaloid (−)-voacangine.

The first total synthesis of the novel indole alkaloid, tangutorine 1 was performed in seven steps from 7,8-dihydroquinoline-5(6H)-one 2 .

Synthese de la vincamine, alcaloide a noyau indole et de certains analogues desethyles. La synthese a haut rendement est basee sur l'utilisation d'aldehydes tetracycliques. L'intermediaire cle de la synthese est obtenu a partir d'un aldehyde d'Oppolzer par reaction avec le LDA enolate de l'ester methyle de la N,N-dimethylglycine

The first total synthesis of racemic tangutorine, a novel indole alkaloid, was performed in 7 steps. The key reactions, dithionite reduction and acidic cyclization provided easy access with good yields to the tangutorine skeleton. Comprehensive NMR spectroscopic data of new compounds are given. Chiral HPLC separation of enantiomers is reported.

(±)-20-Epiapotacamine (8) was synthesized in two steps from aldehyde 6 and was converted into the indole alkaloid (±)-apotacamine (2) by the Polonovski-Potier reaction.

The first total synthesis of the novel indole alkaloid, tangutorine 1 was performed in seven steps from 7,8-dihydroquinoline-5(6H)-one 2 .

Both (±)-17α-hydroxytacamonine ( 3 ) and its 17β-isomer ( 4 ) were synthesized in two steps (one-pot) from aldehyde mixture 5/6 via the cyanohydrin reaction. NMR spectral characterization of isomer 3 revealed it to be unidentical with natural 17-hydroxytacamonine, whereas spectral data of isomer 4 were in agreement with those published for the natural isomer. The configuration at C-17 was confirmed by NOE difference spectroscopy.

Six different lactams of the desethyleburnamonine-homoeburnamonine series were synthesized. Complete 13 C NMR data are presented for these compounds, as well as for their precursors. Special attention is paid to their C(20)–C(21) stereochemistry.

The synthesis of 1-formyl-3,4,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine 4 and its use as an intermediate for desethyl eburnamine-vincamine alkaloids are described.