171866-36-7Relevant articles and documents
Process for preparing 2-piperazinecarboxylic acid derivatives
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, (2008/06/13)
A process for preparing 2-piperazinecarboxamides in the form of their enantiomers or their enantiomer mixtures of the general formula: STR1 wherein R1 is (a) unsubstituted or substituted alkyl or (b) --OR4, wherein R4 is unsubstituted or substituted alkyl, alkenyl or aryl, or (c) --NR5 R6, wherein R5 is hydrogen or alkyl and R6 is alkyl, and R2 and R3 are identical or different and are hydrogen, unsubstituted or substituted alkyl, alkenyl or aryl, or the radical of an amino acid or an amino acid ester. A 2-piperazinecarboxylic acid of the formula: STR2 or a salt thereof, is first converted into an N-acyl derivative of the general formula: STR3 where R1 and R4 are as defined above. This compound is then cyclized in a second stage in the presence of a halogenating agent to form a piperazinecarboxylic anhydride of the general formula: STR4 where R1 is as defined above, which is finally reacted with an amine of the general formula: STR5 where R2 and R3 are as defined above, to give the end product of the general formula I. Certain piperazinecarboxylic anhydrides are also novel.
An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan piperazine intermediate
Rossen,Pye,DiMichele,Volante,Reider
, p. 6823 - 6826 (2007/10/03)
The Crixivan HIV protease inhibitor piperazine intermediate 2 was prepared by a four step sequence using a chiral hydrogenation of the tetrahydropyrazine 9 to establish the absolute stereochemistry.
Process for preparing optically active piperazine derivatives and Intermediates for preparation
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, (2008/06/13)
Process for preparing optically active 2-piperazine-carboxylic acid derivatives, particularly S-enantiomer thereof, in high yield and high optical purity on industrial scale. As the optical resolving agents, easily accessible sulfonamides derived from selected optically active amino acids, such as N-tosyl-L-phenylalanine, N-tosyl-D-phenylglycine, N-tosyl-L-alanine or N-tosyl-L-valine, give excellent results. These resolving agents are stable and easily recovered from the reaction mixture and reused. Resolved 2-piperazinecarboxylic acid derivatives are preferably isolated as 4-t-butoxycarbonyl (Boc) derivatives. Diastereomeric salts (an example being shown below) formed as the intermediates of resolution are novel. STR1 ?In the formula "Ar" stands for a phenyl or naphthyl group which may be substituted with one to three C1-C6 alkyl groups, halogen atoms, nitro or alkoxy groups; and n=0 or 1.!
Asymmetric hydrogenation of tetrahydropyrazines: Synthesis of (S)-piperazine-2-tert-butylcarboxamide, an intermediate in the preparation of the HIV protease inhibitor indinavir
Rossen,Weissman, Steven A.,Sager,Reamer,Askin,Volante,Reider
, p. 6419 - 6422 (2007/10/02)
Hydrogenation of tetrahydropyrazine 4g with [(R)-BINAP(COD)Rh]TfO gave piperazine 6g in 96% yield and 99% ee. Simple hydrogenolytic deprotection and crystallization afforded the key chiral (S)-N-Boc-piperazine MK-639 intermediate I in high yield and enant
L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor
Dorsey,Levin,McDaniel,Vacca,Guare,Darke,Zugay,Emini,Schleif,Quintero,Lin,Chen -,Holloway,Fitzgerald,Axel,Ostovic,Anderson,Huff
, p. 3443 - 3451 (2007/10/02)
A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with K(i) values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1(IIIb)-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.
Highly Diastereoselective Reaction of a Chiral, Non-Racemic Amide Enolate with (S)-Glycidyl Tosylate. Synthesis of the Orally Active HIV-1 Protease Inhibitor L-735,524
Askin, David,Eng, Kan K.,Rossen, Kai,Purick, Robert M.,Wells, Kenneth M.,et al.
, p. 673 - 676 (2007/10/02)
Reaction of chiral amide enolate Li-1 with (S)-glycidyl tosylate 11 affords the epoxide 3 in 72percent yield with high diastereoselectivity.Epoxide 3 is converted to the orally-active HIV-1 protease inhibitor L-735,524 in 71percent isolated yield.
Amino acid derivatives
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, (2008/06/13)
Compounds of the formula STR1 wherein R1 is alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, aralkanoyl, aroyl, heterocyclylcarbonyl, alkylsulphonyl, arylsulphonyl, monoaralkylcarbamoyl, cinnamoyl or α-aralkoxycarbonylaminoalkanoyl and R2 is hydrogen or R1 and R2 together with the nitrogen atom to which they are attached represent a cyclic imide group of the formula STR2 in which P and Q together represent an aromatic system; R3 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, cyanoalkyl, alkyl- sulphinylalkyl, carbamoylalkyl or alkoxycarbonylalkyl or, when n stands for zero, R3 can also represent alkylthioalkyl or, when n stands for 1, R3 can also represent alkylsulphonylalkyl; R4 is alkyl, cycloalkyl, cycloalkylalkyl, aryl or aralkyl; R5 is hydrogen and R6 is hydroxy or R5 and R6 together represent oxo; R7 and R8 together represent a trimethylene or tetramethylene group which is optionally substituted by hydroxy, alkoxycarbonylamino or acylamino or in which one --CH2 -- group is replaced by --NH--, --N(alkoxycar- bonyl)--, --N(alkyl)-- or --S-- or which carries a fused cycloalkane, aromatic or heteroaromatic ring; and R9 is alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula STR3 in which R10 and R11 each represent alkyl; and their pharmaceutically acceptable acid addition salts inhibit proteases of viral origin and can be used as medicaments for the treatment or prophylaxis of viral infections. They can be manufactured according to generally known procedures.
