Synthesis of 1'-arylcarbamoylthiocarbonyl-3'-methyl- 3-oxoandrost-4-eno[16 α ,17 α -d]pyrazolines

A convenient four-step synthesis of progesterone fused to N-arylcarbamoylthiocarbonyl-pyrazoline at position 16,17 starting from 3 β -acetoxypregna-5,16-dien-20-one was developed.


Introduction
Steroids with a heterocyclic moiety have high biological activity and are of interest as potential drugs. 1 Therefore, we turned our attention to the synthesis of pyrazoline-containing compounds in order to study their structure-biological activity relationship.2][3][4][5] 16,17-Heterocyclic steroids, prepared by cyclization of recently synthesized substituted steroid hydrazones derived from Naryl-2-hydrazinyl-2-thioxoacetamide, 4,5 may be of particular interest.The chemical properties of oxamic acid thiohydrazides are determined by the difference in the reactivity of the oxamide and thiohydrazide groups.Due to the high polarizability of the π bond, the thiocarbonyl group reacts much more readily with nucleophiles than the carbonyl group.Combination of these groups with chiral steroid skeletons offers considerable scope for the systematic synthesis of heterocyclic steroids having valuable biological properties, which, in turn, can lead to the design of drugs.

Results and Discussion
Earlier, we have carried out the reaction of 3β-acetoxypregna-5,16-dien-20-one (1) with monothiohydrazides of oxamides [H 2 NNHC(=S)-C(=O)NHR] affording the corresponding 16,17-pyrazoline derivatives in low yields; in some cases attempts to perform the cyclization failed. 4,5In the present study, we developed a convenient route in four steps to progesterone analogs containing the N-arylcarbamoylthiocarbonylpyrazoline moiety fused to positions 16,17.

Scheme 1
The structures of the reaction products were confirmed by elemental analyses, MS, 1 Н and 13 С NMR.A series of 2D NMR experiments (COSY, TOCSY, ROESY, HSQS, HMBC) was used for the assignment of 1 H and 13 C NMR spectra as well as for the determination of the stereochemistry of the ring D/pyrazoline fusion.
The 1 H NMR spectra exhibit signals of one amide proton at δ 8.27, four aromatic protons in the range of δ 7.55-7.26,and four methine protons at δ 5.32, 5.08, 3.53 and 3.21.All other aliphatic protons signals are between δ 2.5 and 0.8; three methyl groups resonate at δ 2.10, 1.01 and 0.97.Isolated spin systems for rings A and all protons of rings B, C, and D of the steroid were found in the TOCSY spectrum; the COSY spectrum enabled the proton assignment of each spin system.The 13 C spectrum of 5a contains 27 different signals, which were assigned using the APT method.Three methyl, seven methylene, six methine, three protic sp 2 -carbon atoms, two quaternary sp 3 -and six aprotic sp 2 carbon atoms were identified.All correlations between carbons and protons through one bond were found in the HSQC spectrum.The HMBC spectrum permits the assignment of all quaternary atoms and interconnections between the steroid and the N-(4-chlorophenyl)carbamoylthiocarbonylpyrazoline moiety.The stereochemistry was explored with 1D-and 2D-ROESY experiments.The ROESY spectrum revealed the correlations between H-16 and H-15, H-15', H-17, H-18 as well as between H-17 and H-18.These correlations are possible only in the case of the 16α,17αconfiguration of ring D (Figure 1).No correlations between H-14 and H-16 or H-17 were found.The observed correlations between H-3 and H-1', H-2 and both H-4 and H-4' are possible only with the 3-OH group in β-position.

Figure 1 .
Figure 1.The most important ROESY correlations between protons of the steroidal ring D.

Table 1 .
Yields, melting points, and elemental analysis data for products 2-5