Synthesis of the piperazine subunit of Indinavir

Aiming an alternative short synthesis of the piperazine fragment of Indinavir we developed the following strategy: i) regioselective C-3 ring opening of ( S )-tert-butyl- N - p -tosylaziridine-carboxamide by 3-picolylamine; ii) N , N ´-bisalkylation with diphenyl vinyl sulfonium triflate ; iii) N-detosylation. By this sequence, after only three steps, the ( S )- N -tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide was obtained, in 20% overall yield.


Introduction
Indinavir (1, Figure 1), also known as Crixivan ® (as the sulfate salt; L-735,524, MK-639), is an HIV protease inhibitor, acting in the last stage of replication of HIV.The Indinavir molecule presents the piperazine substructure A (red square, in Figure 1), and the synthesis of such fragment aroused our interest.Most methods focusing the synthesis of Indinavir usually start from piperazines 2 (Scheme 1).For example, Bruce et al. 1 obtained compound 2a (38%; R=Boc; R 1 =H; route i, Scheme 1) by the catalyzed kinetic resolution of the racemic piperazine-2-carboxamide 3, using L-leucine-amino-peptidase; Rossen et al., 2 via hydrogenation of pyrazine-2-tert-butylamine 4, in the presence of catalyst [(R)-BINAP(COD)Rh]TfO, obtained 2b (96%; R=Boc; R 1 = t Bu; route ii, in Scheme 1).In 1999, Rossen 3 also established a new route to the same piperazine, by reacting the N-Boc-1,2-diaminoethane and dichloroacetaldeyde (58%; route iii, in Scheme 1); Fuchs, 4 in 1997, patented the synthesis of 2c (67-88%; R=H; R 1 = t Bu) by asymmetric hydrogenation of compound 4, using an optically active rhodium complex as catalyst (route iv, in Scheme 1).[3][4] In addition to the above described methods, and considering the usefulness of aziridines in organic synthesis, [5][6][7] we believe that a more concise synthesis of the piperazine fragment A can be developed by an aziridine ring opening process.

Results and Discussion
In this work, we designed the synthesis of piperazine 2d by our recently developed sequence comprising the aziridine C-3 ring opening by a primary amine, followed by alkylative cyclization of both nitrogen atoms of the resulting diamine with 1,2-dibromoethane. 8After N-detosylation, the complete construction of subunit A can be completed in only three steps (Scheme 2).The starting N-tosylaziridine 5, is prepared 9 from L-serine by the simple and inexpensive method previously described by us, as follows: N-tosylation of L-serine with TsCl/NaOH/H2O; amidation using t BuNH2/DCC/HOBt/THF; cyclization employing K2CO3/TsCl/18-Crown-6/CH2Cl2.Scheme 2. Synthesis of piperazine 2d, starting from N-tosylaziridine 5.
In order to prepare aziridine 5, the p-tosylated L-serine 10 was submitted to the amidation reaction employing N,N'-dicyclohexylcarbodiimide and N-hydroxisuccinimide tert-butylammonium salt, 11 in lieu of HOBt.By this modification of the previously described method, 9 the crude (S)-N-tert-butyl-3-hydroxy-2-(4methylphenylsulfonamido)propanamide was obtained in almost pure state, without need of purification.Next, aziridination was carried out by PTC, 9 yielding pure 5, in 84% yield.Ring opening of 5 by a stoichiometric amount of 3-picolylamine, in THF, in the presence of triethylamine, afforded 6, in 55% yield.Initial attempts to prepare piperazine 7, by N,N´-bisalkylation of 6 with 1,2-dibromoethane/K2CO3, under PTC conditions, 8 were unsuccessful.However, cyclization using diphenyl vinyl sulfonium triflate 12,13 yielded piperazine 7 in 98% yield.For this compound, the axial position of the carboxamide group can be advanced based on the close similarity of the piperazine ring protons chemical shifts and those of the N-benzylated compound (Table 1), prepared in 96% ee, by the analogous synthetic sequence. 8Next, detosylation of 7 was successfully achieved using HBr 30% in acetic acid, in the presence of phenol. 14After basification of the aqueous solution salt 8 with sodium bicarbonate, and extraction with dichloromethane, 2d was isolated, in 45% yield 15 (Scheme 3).Scheme 3. Detosylation of piperazine 7, and isolation of 2d.

Conclusions
In summary, the chiral piperazine 2d was successfully prepared from the readily available L-serine, in few synthetic steps.This new simple and greener synthetic route can be advantageously incorporated to the total synthesis of the HIV protease inhibitor Indinavir.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on a Varian Inova 300 MHz or on a Bruker AIII 500 MHz spectrometers in CDCl3 or D2O as solvents.A digital polarimeter JASCO model DIP-370 was used for the optic activity determination.Sigma-Aldrich silica gel 60 (2-25 µ) was used for dry-flash column chromatography, and TLC analyses were conducted using Merck F254 aluminum chromate sheets coated with silica gel 60.All the precursor chemicals were purchased from Merck, Sigma-Aldrich without any further purification.The solvents were acquired from Synth, purified and distilled according to the standard procedures prior to use.