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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...

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.

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 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 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 .

(±)-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.

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.

The chemical shifts and most of the main coupling constants of seven sarpagine alkaloids 1- 7 have been determined in a 400 MHz (1)H-NMR study.

The formation of lactonic amines 3 and 4 from alpha-methylene-gamma-butyrolactone (tulipalin A) 1 is described.