183255-96-1

Upstream product

• 26049-94-5 (S)-benzyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate 
• 35909-92-3 N-carbobenzoxy-L-phenylalanine methyl ester 
• 7524-50-7 methyl (2S)-2-amino-3-phenylpropanoate hydrochloride 
• 501-53-1 benzyl chloroformate 
• 143601-45-0 (S)-tert-butyl 4-<(benzyloxycarbonyl)amino>-3-oxo-5-phenylpentanoate 
• 191226-90-1 tert-butyl (4S)-4-N-benzyloxycarbonylamino-2-chloro-3-oxo-5-phenylpentanoate 
• 1161-13-3 N-Cbz-L-Phe 
• 15196-02-8 (S)-3-[(benzyloxycarbonyl)amino]-1-diazo-4-phenyl-2-butanone 

Relevant academic research and scientific papers

Synthetic method of HIV protease inhibitor intermediate compound

The invention is suitable for the technical field of drug synthesis, and provides a synthesis method of an HIV protease inhibitor intermediate compound. The method comprises the following steps: underthe protection of argon, adding a catalyst and hydrogen source mixture into a compound 1a in a reaction solvent, and carrying out asymmetric transfer hydrogenation reaction to obtain the HIV proteaseinhibitor intermediate compound 2a or 2a'. The synthetic route is shown as follows: the group R is one of tert-butyloxycarboryl, carbobenzoxy, p-toluenesulfonyl, acetyl and benzoyl. The asymmetric transfer hydrogenation technology is utilized, compared with existing similar intermediates, the stereoselectivity and yield of the synthesized HIV protease inhibitor intermediate compound can be greatly improved, and the diastereoselectivity ratio of the product reaches 94:6; and in addition, the catalyst is low in dosage and high in catalytic efficiency, reaction activity is improved, raw materialloss is low, the whole process is rapid, simple and convenient, and cost is greatly reduced.

Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: An efficient entry to key intermediates of HIV protease inhibitors

A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(iii) catalyst system, a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99?:?1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(iii) catalyst.

Chiral chlorohydrins from the biocatalyzed reduction of chloroketones: Chiral building blocks for antiretroviral drugs

E. coli cells that contain overexpressed alcohol dehydrogenases (ADHs) were screened as biocatalysts for the stereoselective reduction of chloroketones 5 a-d, the corresponding halohydrins 6 a-d of which are building blocks in the synthesis of antiretroviral drugs. Among them, ADH from Sphingobium yanoikuyae was found to reduce chloroketone 5 c with a high stereoselectivity (90 % de) and conversion (85 %) to furnish threo halohydrin (R,S)-6 c. ADH from Ralstonia sp. (RasADH) was able to reduce 5 a and 5 b with complementary diastereoselectivity to provide access to both threo and erythro halohydrins through "substrate-based" stereocontrol. The RasADH-catalyzed reductions were optimized to provide (R,S)-6 a with 98 % conversion and 84 % diastereomeric excess (de) and (S,S)-6 b with 95 % conversion and 86 % de. Molecular modeling studies showed that 5 b, which features a carboxybenzyl protecting group, is able to bind to the enzyme catalytic site in an "inverted" mode in comparison to tert-butyloxycarbonyl- and methyloxycarbonyl-protected substrates 5 a and 5 c, which sheds light on the observed switching of the stereopreference. RasADH-catalyzed reductions were optimized to provide (R,S)-6 a with 98 % conversion and 84 % de and (S,S)-6 b with 95 % conversion and 86 % de.

Highly diastereoselective catalytic Meerwein-Ponndorf-Verley reductions

Very practical synthesis of ephedrine analogues in high yields and enantiopurity was realized by a highly diastereoselective Meerwein-Ponndorf- Verley (MPV) reduction of protected α-amino aromatic ketones using catalytic aluminum isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminum. In contrast, high syn selectivity was obtained with α-alkoxy ketones and other compounds via Felkin-Ahn control.

New approaches to the industrial synthesis of HIV protease inhibitors

Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.

Asymmetric transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones with chiral Rh complexes

Asymmetric transfer hydrogenation of N-substituted (3S)-3-amino-1-chloro-4- phenyl-2-butanones in the presence of Cp*RhCl[(R,R)-Tsdpen] (S/C = 1000) with a mixture of formic acid/triethylamine gave N-substituted (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with up to 93% de in a quantitative yield, and reduction with the enantiomeric catalyst Cp*RhCl[(S,S)-Tsdpen] gave (2S.3S)-diastereomeric alcohol with up to 96% de.

PROCESS FOR PRODUCING OPTICALLY ACTIVE HALOHYDRIN COMPOUND

A process of preparing an optically active halohydrin compound characterized by comprising asymmetric hydrogen transfer reduction of an α-haloketone compound in the presence of a group 9 transition metal compound having a substituted or unsubstituted cyclopentadienyl group and an optically active diamine compound. The asymmetric hydrogen transfer reduction is preferably conducted in the presence of a base.

Development of a new type of protease inhibitors, efficacious against FIV and HIV variants

Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.

A Practical Synthesis of an HIV Protease Inhibitor Intermediate - Diastreoselective Epoxide Formation from Chiral α-Aminoaldehydes

A practical and efficient synthesis of an HIV protease inhibitor intermediate has been developed based on the diastereoselective epoxide formation from a chiral α-aminoaldehyde and an in situ generated halomethyllithium reagent.

Stereocontrolled synthesis of erythro N-protected α-amino epoxides and peptidyl epoxides

N-protected α-amino epoxides of erythro configuration, derived from α-amino acids, were synthesized in a stereoselective manner. The erythro (2S,3S), configuration was achieved by the synthetic sequence: amino acid -> haloketone -> halohydrin -> epoxide. A mechanistic explanation for the observed stereoselectivity is presented. This stereoselective synthetic approach was applied to the synthesis of a variety of short peptidyl epoxides, bearing a predefined absolute configuration of the chiral epoxide moiety.