402957-28-2 Usage
Uses
Used in Pharmaceutical Industry:
Cyclopenta(c)pyrrole-1-carboxamide, (2S)-2-cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-((cyclopropylamino)oxoacetyl)butyl)octahydro-, (1S,3aR,6aS)is used as an active pharmaceutical ingredient for the treatment of chronic hepatitis C virus genotype 1 infection. It is a potent inhibitor of the HCV NS3-4A protease, blocking the release of nonstructural viral proteins from a polyprotein precursor and exerting its antiviral effect.
Used in Research and Development:
Cyclopenta(c)pyrrole-1-carboxamide, (2S)-2-cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-((cyclopropylamino)oxoacetyl)butyl)octahydro-, (1S,3aR,6aS)is also used in research and development for the synthesis of key fragments in the development of new antiviral drugs. The chemical properties and structure of Cyclopenta(c)pyrrole-1-carboxamide make it a valuable compound for studying and understanding the mechanisms of action against various viral infections.
Used in Quality Control and Analysis:
Cyclopenta(c)pyrrole-1-carboxamide, (2S)-2-cyclohexyl-N-(pyrazinylcarbonyl)glycyl-3-methyl-L-valyl-N-((1S)-1-((cyclopropylamino)oxoacetyl)butyl)octahydro-, (1S,3aR,6aS)can be used as an internal standard for the quantification of related compounds by gas chromatography (GC) or liquid chromatography (LC) mass spectrometry. This application helps ensure the accuracy and reliability of analytical results in the pharmaceutical industry and research settings.
Originator
Eli Lilly (United States)
Clinical Use
Telaprevir is a potent peptide mimetic inhibitor of Hepatitis C
virus (HCV) and works via covalent reversible binding to the
NSV-3A protease enzyme. Telaprevir was discovered and developed
by Vertex pharmaceuticals. The drug is marketed as an oral
treatment for HCV infection in combination with Peg interferon
and ribavarin for patients who are refractory to the initial standard
therapy. The initial SAR studies and the discovery of teleprevir
have been published. In addition, a full review of the discovery
process that led to the development of telaprevir, including
several iterations of the syntheses of teleprevir leading to the process
route, has been reported.
Synthesis
For preparation of bulk API, a convergent synthetic strategy
was utilized as described in the scheme. Retrosynthetically the
penultimate intermediate 212, which was coupled with amine
213 for the final step, was prepared by coupling bicyclic amine
217 with amino acids 216 and 215 and then with pyrazine acid
214.
In the early stages of development, the cyclopropyl amide fragment
213 was made using a MCR coupling sequence by reacting
aldehyde 218 with cyclopropyl isocyanide (219) and triflouroacetic
acid to give amide alcohol 220 in 85% yield. Removal
of the Cbz group was accomplished via hydrogenolysis to provide
key cyclopropyl amide alcohol 213 in 95% yield. While this route
was shorter in terms of steps, it was not amenable to large-scale
preparation due to difficulties associated with the handling of isocyanide
219.Thus, for large-scale synthesis, the route depicted in Scheme 35
was utilized. Commercially available Cbz-protected amino acid
221 was converted to the corresponding Weinreb amide 222 using
CDI as the activating agent. This was followed by LAH reduction to
give aldehyde 218 in 73% yield from 221. Aldehyde 218 was reacted
with sodium cyanide under neutral to mildly basic conditions
allowing for easy workup of the cyanohydrin, which was
immediately hydrolyzed by refluxing in 4 N hydrochloric acid in
dioxane to deliver hydroxy acid HCl salt 223. Since the formation
of the acyloin resulted in removal of the Cbz protecting group, reinstallation
of this protecting group preceded conventional amide
bond formation through the intermediacy of the succinate ester
of 224. This provided the desired amide alcohol 220 in 56% yield
from 223. Hydrogenolysis of Cbz carbamate 220 then furnished
the requisite intermediate amine (213) in 73% yield.The large-scale synthesis of bicyclic pyrrolidine 231 was accomplished
as described in the following scheme. Commercially available 3-azabicyclo[
3.3.0]nonane hydrochloride (225) was first protected as
the corresponding Boc carbamate 226 in 90% yield. Deprotonation
of the bicyclic pyrrolidine carbamate 226 with sec-BuLi and
sequential quench with bubbling carbon dioxide gas followed by
sodium hydrogensulfate resulted in racemic acid 227 in 80% yield.
Racemate 227 was resolved using (S)-tetrahydronapthalamine
(228) in ethyl acetate and isopropanol at 70–75°C. This mixture
was allowed to cool down slowly to effect the crystallization of
the optically enriched chiral salt 229 in 83% yield with greater than
99.5% ee. This enatioenriched salt was free based with sodium
hydrogen sulfate and converted to t-butyl ester 230 using Boc
anhydride and DMAP. The secondary amine of 230 was liberated
using methane sulfonic acid at room temperature followed by salt formation with oxalic acid in isopropyl acetate to give oxalic acid
salt 231 in 81% yield over 3 steps.With the synthesis of the key intermediates complete, sequential
coupling events were then executed to complete the synthesis
of teleprevir (following scheme). Fragment 217 was coupled with the
Cbz-protected valine (216) using EDCI and HOBt to give intermediate
232 in 87% yield. Similarly, after removal of the Cbz group of
232 via catalytic hydrogenolysis, the resulting amine was coupled
with cyclohexyl amino acid 215 to give dipeptide intermediate 233
in 89% yield over 2 steps. Sequential cleavage of the Cbz group in
233 followed by CDI-mediated coupling with commercially available
pyrazine acid 214 gave rise to the expected pyrazine amide
intermediate. Subsequent hydrolysis of the t-butyl ester through
the use of concentrated acid in DCM provided the key intermediate
tripeptidic acid (212) in 68% over 3 steps. The tripeptide 212 was
then coupled with cyclopropyl amide amine 213 using EDCI, HOBt
and N-methyl morpholine (NMM) to provide penultimate intermediate
alcohol 234 in 95% yield. Subjection of 234 to Dess–Martin
periodinane (DMP) oxidation in t-butanol and DCM furnished telaprevir
(XXI) in 85% yield.
Drug interactions
Potentially hazardous interactions with other drugs
Alpha-blockers: avoid with alfuzosin.
Analgesics: risk of ventricular arrhythmias with
methadone.
Anti-arrhythmics: risk of ventricular arrhythmias
with amiodarone and disopyramide - avoid; risk
of ventricular arrhythmias with flecainide andpropafenone - use with caution; use IV lidocaine
with caution.
Antibacterials: concentration of both drugs increased
with clarithromycin, erythromycin and telithromycin,
increased risk of ventricular arrhythmias; avoid with
rifabutin and rifampicin (concentration significantly
reduced by rifampicin).
Anticoagulants: concentration of warfarin possibly
affected; avoid with apixaban; possibly increased
dabigatran concentration.
Antidepressants: possibly increased trazodone
concentration; avoid with St John’s wort.
Antiepileptics: avoid with carbamazepine,
fosphenytoin, phenobarbital, phenytoin and
primidone.
Antifungals: concentration of both drugs possibly
increased with ketoconazole, increased risk
of ventricular arrhythmias; possibly increased
itraconazole concentration; possibly increased
posaconazole concentration - increased risk of
ventricular arrhythmias; possibly altered voriconazole
concentration - increased risk of ventricular
arrhythmias.
Antipsychotics: avoid with pimozide; possibly
increases lurasidone and quetiapine concentration -
avoid.
Antivirals: concentration possibly reduced by
atazanavir; concentration of atazanavir possibly
increased; avoid with darunavir, fosamprenavir and
lopinavir; concentration of daclatasvir and possibly
olaparib increased - reduce daclatasvir and olaparib
dose; concentration reduced by efavirenz - increase
telaprevir dose; concentration possibly reduced
by ritonavir; concentration of tenofovir possibly
increased.
Anxiolytics and hypnotics: possibly increased
midazolam concentration - risk of prolonged
sedation, avoid concomitant use with oral
midazolam.
Beta-blockers: risk of ventricular arrhythmias with
sotalol - avoid.
Ciclosporin: concentration of both drugs increased,
reduce ciclosporin dose.
Cilostazol: possibly increases cilostazol
concentration.
Colchicine: possibly increased risk of colchicine
toxicity - suspend or reduce colchicine dose, avoid in
hepatic or renal impairment.
Cytotoxics: possibly increases bosutinib
concentration - avoid or consider reducing dose of
bosutinib; reduce dose of ruxolitinib. Domperidone: possibly increased risk of ventricular
arrhythmias - avoid.
Ergot alkaloids: avoid concomitant use.
Guanfacine: possibly increases guanfacine dose -
halve dose of guanfacine.
Lipid-regulating drugs: avoid with lomitapide,
simvastatin and atorvastatin.
Oestrogens: possibly reduced ethinylestradiol
concentration and contraceptive effect.
Sildenafil: avoid concomitant use.
Sirolimus: concentration of both drugs increased,
reduce sirolimus dose.
Beta2
sympathomimetics: avoid with salmeterol - risk
of ventricular arrhythmias.
Tacrolimus: concentration of both drugs increased,
reduce tacrolimus dose.
Tadalafil: avoid with high dose tadalafil.
Vardenafil: avoid concomitant use.
Metabolism
Extensively metabolised in the liver, involving hydrolysis,
oxidation, and reduction.
Multiple metabolites were detected in faeces, plasma and
urine.
Check Digit Verification of cas no
The CAS Registry Mumber 402957-28-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 4,0,2,9,5 and 7 respectively; the second part has 2 digits, 2 and 8 respectively.
Calculate Digit Verification of CAS Registry Number 402957-28:
(8*4)+(7*0)+(6*2)+(5*9)+(4*5)+(3*7)+(2*2)+(1*8)=142
142 % 10 = 2
So 402957-28-2 is a valid CAS Registry Number.
InChI:InChI=1/C36H53N7O6/c1-5-10-25(29(44)34(48)39-23-15-16-23)40-33(47)28-24-14-9-13-22(24)20-43(28)35(49)30(36(2,3)4)42-32(46)27(21-11-7-6-8-12-21)41-31(45)26-19-37-17-18-38-26/h17-19,21-25,27-28,30H,5-16,20H2,1-4H3,(H,39,48)(H,40,47)(H,41,45)(H,42,46)/t22-,24-,25?,27-,28-,30+/m0/s1
402957-28-2Relevant articles and documents
Stereoselective synthesis of β-amino acids by aldol-type addition
Benito-Garagorri, David,Felzmann, Wolfgang,Nerdinger, Sven,Hoferl-Prantz, Kathrin
, p. 299 - 311 (2020/01/31)
A synthesis of α-oxygenated β-amino acid derivatives using an aldol-type addition is described. Depending on the enol equivalent different oxidation states of the oxygen substituent are accessible, while choosing a chiral imine allows to generate the aldol product in a stereoselective manner. This methodology has been applied to the synthesis of the biologically active compound Telaprevir, used in the traetment of hepatitis C.
Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: Application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir
Moni, Lisa,Banfi, Luca,Basso, Andrea,Carcone, Luca,Rasparini, Marcello,Riva, Renata
, p. 3411 - 3428 (2015/04/22)
Lipase mediated desymmetrization of a meso-diol (1,2-cyclopentanedimethanol) allows the synthesis of both enantiomers of some chiral aldehydes, whose behavior in Passerini and Ugi reactions has been explored. Exploiting these two complementary multicomponent reactions and coupling them with a subsequent cyclization process, we observed that 6 out of all 8 possible stereoisomers of peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been proved by the development of a new efficient synthesis of antiviral drug telaprevir.
PROCESS FOR THE PREPARATION OF TELAPREVIR AND ITS INTERMEDIATES
-
Page/Page column 15, (2015/01/07)
The present invention provides a process for the preparation of telaprevir and its intermediates.
PROCESS FOR THE PREPARATION OF TELAPREVIR AND INTERMEDIATES THEREOF
-
Page/Page column 20, (2015/01/07)
The present invention provides a process for the preparation of telaprevir and intermediates thereof.
Asymmetric synthesis of 3,4-disubstituted proline derivatives: Application in synthesis of hepatitis C virus protease inhibitor telaprevir
Zhang, Fan,Wen, Xiaoan,Xu, Qing-Long,Sun, Hongbin
, p. 8101 - 8109 (2015/02/02)
A practical asymmetric synthesis of 3,4-disubstituted proline derivatives has been realized with high stereoselectivity and moderate yield. The key steps involved are desymmetric ring-opening reaction of commercially available anhydrides, intramolecular Strecker reaction and thermodynamically controlled cyanide hydrolysis. Based on this methodology, the synthesis of HCV protease inhibitor Telaprevir was achieved.
SYNTHESIS OF A VIRAL PROTEASE INHIBITOR
-
Page/Page column 10; 11, (2014/01/08)
Disclosed is a process for the preparation of telaprevir of formula (I) or a salt thereof, comprising the oxidation reaction of a compound of formula (II) or a salt thereof, (II) wherein said oxidation is conducted in a solvent in the presence of a supported oxidising agent.
PROCESS FOR THE SYNTHESIS OF TELAPREVIR, OR PHARMACEUTICALLY ACCEPTABLE SALTS OR SOLVATES AS WELL AS INTERMEDIATE PRODUCTS THEREOF
-
Page/Page column 27-28, (2013/09/26)
The invention relates to a process for the preparation of telaprevir, or a pharmaceutically acceptable salt or solvate thereof, wherein the process requires a smaller number of process steps and/or does not require the use of toxic and instable compounds compared to the known processes. Another embodiment refers to telaprevir, or a pharmaceutically acceptable salt or solvate thereof as well as to intermediate products for preparation of the same, wherein the afore-mentioned products are obtained by the process described herein.
SYNTHESIS OF TELAPREVIR AND BOCEPREVIR, OR PHARMACEUTICALLY ACCEPTABLE SALTS OR SOLVATES AS WELL AS INTERMEDIATE PRODUCTS THEREOF INCLUDING ?-AMINO ACIDS PREPARED VIA MUKAIYAMA ALDOL ADDITION
-
, (2014/01/09)
The invention relates to synthetic routes for preparing telaprevir and boceprevir, and its intermediates as well as peptides other than telaprevir. The synthetic routes are based on a Mukaiyama aldol addition reaction of a silyl enol ether or an enolate with an imine. The invention also refers to novel intermediates for preparing telaprevir/boceprevir or other peptides.
A PROCESS FOR THE PREPARATION OF SUBSTITUTED PROLYL PEPTIDES AND SIMILAR PEPTIDOMIMETICS
-
Page/Page column 50; 51, (2011/09/21)
The present invention relates to a process for the stereoselective preparation of a compound having the general formula (I) or its respective diastereomers: comprising reacting a compound having the general formula (II) or its diastereomers: with a compound of the general formula III: R3-COOH and a compound of the general formula IV: R4-NC wherein R1 represents each independently, or jointly a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R2 represents a hydrogen atom, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure, and R3 represents a substituted or unsubstituted alkyl, alkenyl, or alkynyl, or an aromatic or non-aromatic aromatic or non-aromatic, mono-, di- or tricyclic, or heterocyclic structure.
A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions
Znabet, Anass,Polak, Marloes M.,Janssen, Elwin,De Kanter, Frans J. J.,Turner, Nicholas J.,Orru, Romano V. A.,Ruijter, Eelco
supporting information; experimental part, p. 7918 - 7920 (2010/12/19)
A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective groups.
