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Simeprevir

Product Name
Simeprevir
CAS No.
923604-59-5
Chemical Name
Simeprevir
Synonyms
TMC435;CS-954;SiMeprevir;TMC 435350;siMeprevir/TMC435;Simeprevir-13C-d3;PubChem ID: 24873435;Simeprevir(TMC 435350);TMC435350 (Simeprevir);Simeprevir (sodium salt)
CBNumber
CB82510099
Molecular Formula
C38H47N5O7S2
Formula Weight
749.94
MOL File
923604-59-5.mol
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Simeprevir Property

Density 
1.38
storage temp. 
Store at -20°C
solubility 
insoluble in H2O; insoluble in EtOH; ≥18.75 mg/mL in DMSO
form 
solid
pka
4.47±0.40(Predicted)
color 
White to off-white
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Safety

Hazardous Substances Data
923604-59-5(Hazardous Substances Data)
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Hazard and Precautionary Statements (GHS)

Symbol(GHS)
Signal word
Warning
Hazard statements

H302Harmful if swallowed

Precautionary statements

P280Wear protective gloves/protective clothing/eye protection/face protection.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

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N-Bromosuccinimide Price

Cayman Chemical
Product number
22144
Product name
Simeprevir
Purity
≥98%
Packaging
1mg
Price
$35
Updated
2021/12/16
Cayman Chemical
Product number
22144
Product name
Simeprevir
Purity
≥98%
Packaging
5mg
Price
$123
Updated
2021/12/16
Cayman Chemical
Product number
22144
Product name
Simeprevir
Purity
≥98%
Packaging
10mg
Price
$228
Updated
2021/12/16
Cayman Chemical
Product number
22144
Product name
Simeprevir
Purity
≥98%
Packaging
25mg
Price
$525
Updated
2021/12/16
Usbiological
Product number
466122
Product name
Simeprevir
Packaging
5mg
Price
$425
Updated
2021/12/16
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Simeprevir Chemical Properties,Usage,Production

Description

In September 2013, simeprevir (also known as TMC435) was approved in Japan (trade name Sovriad?) for the treatment of genotype 1 hepatitis C virus (HCV) infection in combination with pegylated interferon and ribavirin (PR). Simeprevir was approved for the same indication in November 2013 in the United States (trade name Olysio?) and Canada (trade name Galexos?). Simeprevir is the third HCV PI to receive approval and was discovered from an effort to optimize a novel series of cyclopentane-core macrocyclic HCV PIs. Unlike the earlier PIs, simeprevir does not rely on formation of a covalent intermediate to inhibit the enzyme, but instead gains binding affinity through a large P2 quinoline substituent that occupies an extended S2 subsite of HCV protease by induced fit. This pocket is not occupied by inhibitors such as telaprevir and boceprevir. Other key features of simeprevir are truncation of the P3 capping group (the N-methyl amide), use of an acylsulfonamide as an acid isostere, and incorporation of an isopropylthiazole group to give improved permeability. Simeprevir is a potent NS3/4A PI (Ki=0.36 nM), with antiviral activity in the HCV replicon assay (genotype 1b EC50=7.8 nM; genotype 1a EC50=28.4 nM). It is 25-fold less potent against HCV genotype 2, >1000 less potent for HCV genotype 3, but has 3-fold better potency for HCV genotype 4.

Originator

Tibotec and Medivir (Ireland and Sweden)

Uses

Simeprevir-d3 is labelled Simeprevir (S466500) which is a hepatitis C virus (NS3/4A) protease inhibitor. Simeprevir (S466500) is used for the cure and treatment of hepatitis C.

Definition

ChEBI: Simeprevir is an azamacrocycle and a lactam.

brand name

Sovriad

Clinical Use

HCV NS3/4A serine protease inhibitor:
Treatment of hepatitis C in combination with other treatment

Synthesis

Commercial 2-methyl-3-methoxybenzoic acid (153) was treated with diphenylphosphorylazide (DPPA) and triethylamine to affect a Curtius rearrangement and the resulting isocyanate was trapped with t-butanol to produce the Boc-protected aniline 154 in quantitative yield. Upon removal of the Boc protecting group with TFA, the resulting aniline was reacted with boron trichloride followed by the addition of acetonitrile and aluminum trichloride to affect Friedel¨CCrafts acylation to give aminoacetophenone 155 in 40% yield. Acylation of the amino group with 4-isopropylthiazole- 2-carbonyl chloride (156) gave ketoamide 157 in 90% yield, which was treated with potassium tert-butoxide in t-butanol at 100 ?? to furnish quinolinol 158 in 88% yield.
Use of a ring closing metathesis approach, enabling the synthesis of the macrocyclic portion of the drug and ultimately simeprevir, is described. Hydrogenation of commercial trans-cyclopentanone-3,4-dicarboxylic acid (159) over Raney Ni in the presence of triethylamine followed by cyclization to the lactone using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM), and subsequent cinchonidine salt formation gave lactone acid 160 in 26% yield over the 3 steps in 97% ee. Next, amide coupling with N-methylhexenylamine using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), Fischer esterification, and subsequent introduction of the quinolinol fragment 158 under Mitsunobu conditions using triphenylphosphine (PPh3) and diisopropyl azodicarboxylate (DIAD) provided methyl ester 161 in 65% overall yield for the three steps. Saponification of the ester with lithium hydroxide followed by EEDQ-promoted coupling to (1R,2S)-1-amino-2-vinyl-cyclopropane ethyl ester (162) and Boc protection of the resulting amide gave the RCM substrate, diene 163 in 95% yield for the two steps. Macrocyclization of 163 using the second generation M2 catalyst under dilute concentration in refluxing toluene followed by acidic removal of the amide protecting group gave cycloalkene ester 164 in high yield. Saponification of the ester, activation of the resulting acid with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), and coupling with cyclopropylsulfonamide led to simeprevir (XXI) in high overall yield.

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: possible increased risk of bradycardia with amiodarone.
Antibacterials: concentration possibly increased by clarithromycin - avoid; concentration of both drugs increased with erythromycin - avoid; concentration reduced by rifampicin and possibly rifabutin - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole - avoid.
Antivirals: concentration of both drugs increased with darunavir - avoid; concentration reduced by efavirenz; avoid with etravirine; concentration possibly reduced by nevirapine - avoid; concentration increased by ritonavir - avoid.
Ciclosporin: avoid concomitant use, increased simeprevir concentration.
Cobicistat: concentration possibly increased by cobicistat - avoid.

Metabolism

Hepatically metabolised. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A4 system.
Elimination of simeprevir occurs via biliary excretion. Following a single oral administration of 200 mg [14C]-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in faeces. Unchanged simeprevir in faeces accounted for on average 31% of the administered dose. Renal clearance plays an insignificant role in its elimination.

Simeprevir Preparation Products And Raw materials

Raw materials

Preparation Products

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Simeprevir Suppliers

Sinfachem Limited.
Tel
025-84683399 13952017251
Email
sinfachem@foxmail.com
Country
China
ProdList
268
Advantage
58
Shanghai Boyle Chemical Co., Ltd.
Tel
Fax
86-21-57758967
Email
sales@boylechem.com
Country
China
ProdList
2922
Advantage
55
J & K SCIENTIFIC LTD.
Tel
010-82848833 400-666-7788
Fax
86-10-82849933
Email
jkinfo@jkchemical.com
Country
China
ProdList
94657
Advantage
76
Chembest Research Laboratories Limited
Tel
+86-21-20908456
Fax
021-58180499
Email
sales@BioChemBest.com
Country
China
ProdList
6005
Advantage
61
Chemsky(shanghai)International Co.,Ltd.
Tel
021-50135380
Email
shchemsky@sina.com
Country
China
ProdList
32321
Advantage
50
Dalian Meilun Biotech Co., Ltd.
Tel
0411-62910999 13889544652
Email
meilunui@163.com
Country
China
ProdList
4727
Advantage
58
ShangHai YuanYe Biotechnology Co., Ltd.
Tel
021-61312847 13636370518
Fax
021-55068248
Email
shyysw007@163.com
Country
China
ProdList
4940
Advantage
60
Haoyuan Chemexpress Co., Ltd.
Tel
021-58950125
Fax
(86) 21-58955996
Email
info@chemexpress.com
Country
China
ProdList
7552
Advantage
61
Shanghai Aladdin Bio-Chem Technology Co.,LTD
Tel
400-400-6206333 18521732826
Fax
021-50323701
Email
market@aladdin-e.com
Country
China
ProdList
25003
Advantage
65
Shanghai Witofly Chemical Co.,Ltd
Tel
Email
sales@witofly.com
Country
China
ProdList
2864
Advantage
52
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View Lastest Price from Simeprevir manufacturers

Zhuozhou Wenxi import and Export Co., Ltd
Product
Simeprevir 923604-59-5
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-10
Zhuozhou Wenxi import and Export Co., Ltd
Product
Simeprevir 923604-59-5
Price
US $15.00-10.00/KG
Min. Order
1KG
Purity
99%+ HPLC
Supply Ability
Monthly supply of 1 ton
Release date
2021-07-09
Career Henan Chemical Co
Product
Simeprevir 923604-59-5
Price
US $0.00/KG
Min. Order
1KG
Purity
99%
Supply Ability
kg/T
Release date
2019-12-18

923604-59-5, SimeprevirRelated Search:


  • (2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide
  • TMC 435350
  • SiMeprevir
  • TMC435,TMC435350,TMC-435350
  • (2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13, 14,14a-tetradecahydro-2-[[7-
  • siMeprevir/TMC435
  • (2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-Methoxy-8-Methyl-2-[4-(1-Methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-Methyl-4,14-dioxocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1
  • Simeprevir(TMC 435350)
  • TMC435
  • (2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-7-methoxy-8-methyl-2-4-(1-methylethyl)-2-thiazolyl-4-quinolinyloxy-5-methyl-4,14-dioxocyclopentaccyclopropag1,6diazacyclotetradecine-12a(1H)-carboxami
  • (2R,3aR,10Z,11aS,12aR,14aR)-N-(Cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxocyclopenta[c]cyclopropa[g][1,6]diazacyclotetrad
  • JTZZSQYMACOLNN-JMSVMWJJSA-N
  • (2R,3aR,11aS,12aR,14aR,Z)-N-(cyclopropylsulfonyl)-2-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)-5-methyl-4,14-dioxo-1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-hexadecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a-carb
  • CS-954
  • TMC435350 (Simeprevir)
  • PubChem ID: 24873435
  • Simeprevir-13C-d3
  • Simeprevir (sodium salt)
  • (2R,3aR,11aS,12aR,14aR,Z)-N-(cyclopropylsulfonyl)-2-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)-5-methyl-4,14-dioxo-1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a-hexadecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a-carboxamide
  • Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide, N-(cyclopropylsulfonyl)-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, (2R,3aR,10Z,11aS,12aR,14aR)-
  • Simeprevir (1.0mg/ml in DMSO)
  • (1R,4R,6S,15R,17R)-N-(cyclopropanesulfonyl)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0,4,6]octadec-7-ene-4-carboxamide
  • (2R,3aR,11aS,12aR,14aR,Z)-N-(Cyclopropylsulfonyl)-2-((2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yl)oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamide
  • 923604-59-5
  • C38H47N5O7S2
  • API