Synthesis Of (S)-indoline-2-carboxylic Acid And Its Derivatives With L-phenylalanine As A "Chiral Pool"

(S)-Indoline-2-carboxylic acid and its derivatives are common building block in natural products and it is the characteristic structure fragment of many drugs which are effective for cardiovascular diseases treatment. The synthesis of (S)-indoline-2-carboxylic acid suffers from much difficulty. Multistep, low yield and high cost, which are the main drawback in traditional methods, contribute the ex-tremely high cost of related drugs. The great similarities both in chemical structure and stereochemical configuration between (S)-indo line-2-carboxy lic acid and L-phenylalanine inspire us to carry out a chiral pool route from L-phenylalanine for its facile commercial availability and low price. Thus, this dissertation presents a chiral pool route for the synthesis of (S)-indoline-2-carboxylic acid following the procedure combined with assistant-group introduction and intramolecular ami-no-cycling. It benefits from wide raw material source, concise route, no resolution reagent, low cost, less pollution release and specific configuration.A blocking group is needed in the para position of L-phenylalanine for its subs-titution will firstly occur at that position. A meta guiding group will ensure the second substitution taking place at the ortho place of L-phenylalanine. In this dissertation, nitro group was adopted for its powerful guiding capability and low cost.The nitration of L-phenylalanine with mixed acid could give 4-nitro-L-phenylalanine in low yield with traditional batch reaction. The structure of the by-product was confirmed with 1H-NMR and 13C-NMR. And it is thought to be the con-densation of 2-nitro-L-phenylalanine and 4-nitro-L-phenylanine with sulfuric acid. Based on this, the possible mechanism was proposed and a new tubular reactor was designed. With the tubular reactor,4-nitro-L-phenylalanine can be got in 80.9% yield with optimized conditions as 50℃for 5min in vHNO3:vH2SO4=1:2. The synthesis of 2,4-dinitro-L-phenylalanine following previous way was a failure. The results showed that the main product was 2,4-dinitro benzoic acid instead of 2,4-dinitro-L-phenylalanine. And the reason is that the mixed acid showed high oxid- ative capability and the amino acid moisture was cleaved from the benyl site. Subs-quently, the preparation of 2,4-dinitro-L-phenylalanine follows a stepwise procedure.The nitration of 4-nitro-L-phenylalanine with urea nitrate/H2SO4 affords 2,4-dintro-L-phenylalanine in 87.8% yield at 60℃for 6h. The possible mechanism was discussed. It was thought that the urea greatly decreased the oxidative capability of nitric acid and enhanced the electrophilicity of NO2As sulfuric acid was the only solvent in both nitation, "one-pot" way was tried to synthesize 2,4-dinitro-L-phenylalanine. And the results demonstrated that it could not get the product with nitric acid and urea nitrate as the nitrating reagents for the huge water contained in nitric acid but could give the product with urea nitrate as the sole nitrating reagent. The optimized "one-pot" procedure was 75.7% yield-reaction oper-ated as follows:ice-water bath for 2h with lmole ratio urea nitrate, after that an addi-tional 1.2 mole of urea nitrate was added, the temperature was raised to 60℃, and kept for 4h.The solubilities of 2,4-dinitro-L-phenylalanine in ten different solvents were measured with a synthetic method to find a proper recrystillization solvent to deal with its difficult workup process. And the solubility data was regressed with Apelblat founction. The results demonstrated that 1-propanol was a suitable solvent for its re-crystillization and Apelblat founction fitted the solubility data with a root-mean-square relative deviation (rmsrd) less than 2.5%.The factors affecting intramolecular cyclization of 2,4-dinitro-L-phenylalanine was especially emphasized. Yields varied with the reaction temperature and pressure and 6-nitro-(S)-indoline-2-carboxylic acid could be got in 44.5% yield at 180℃for 6h in water with e.e. higher than 99%. Density founctional theory (DFT) was used to investigate the reaction. Results showed that the intramolecular reaction was the do-minating reaction and the reason why the reaction could proceed was that the intra-molecular cylization released more energy than the side reaction. The nitro amination reaction was researched in detail with expanded substrates and amines. Similar or higer yield could be got under similar conditions with trinitrobenzene and dinitroben-zenes as substrates. The possible mechanism was that the remaining nitro group could enhance the activity of the leaving one and that the nitrobenzene analogues and amines were hard acid and hard base, respectively, which properly matched.Meanwhile, another process was successfully performed starting with 4-nitro-L-phenylalnine through bromination and cyclization for the low yields of its nitro amination. The bromination with tribromoisocyanuric acid (TBCA) in H2SO4 at room temperature could give 72.6% yield of 2-bromo-4-nitro-L-phenylalanine, of which the intramolecular Ullmann reaction catalyzed by CuCl can give 6-nitro-(S)-indoline-2-carboxylic acid in 90.5% yield with water as solvent and K2CO3 as base. No racemizition was observed in the whole process and the enanti-omeric excess (e.e.) of product was higher than 99.5%. The possible mechanism was detailed discussed. Protonated tribromoisocyanuric acid (TBCA) can transfer Br to deactivated aromatics.The subsequently nitro-reduction, diazo-reaction and dediazo-reaction of 6-nitro-(S)-indoline-2-carboxylic acid was carried out with a "one-pot" way to get (S)-indoline-2-carboxylic acid. The yield of the "one-pot" reaction was 85.9% under the optimized conditions.(25,3aS,7aS)-Octahydroindole-2-carboxylic acid could be got with the reduc-tion of (S)-indo line-2-carboxylic acid catalyzed by 5% Pd/C with 75% yield, and it was loaded on Wang resin and subsequently react with N-[1-(S)-ethoxycarbonyl butyl]-(S)-glycine to prepare perindopril in 87.8% yield.All the intermediates and product were confirmed with IR, 1HNMR and 13CNMR. The optical rotations were checked and the enantiomer excess (e.e.) were confirmed with chiral high performance liquid chromatography (HPLC), which showed more than 99% purity.