879085-55-9

Basic information

• Product Name: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide
• Synonyms: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide;Vismodegib;GDC-0449,Vismodegib;GDC-0449;VisModegib (GDC-0449);BenzaMide, 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(Methylsulfonyl)-;2-Chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)benzamide;VisModegib Base
• CAS NO: 879085-55-9
• Molecular Formula: C19H14Cl2N2O3S
• Molecular Weight: 421.303
• EINECS: 1312995-182-4
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;API;Inhibitor;Inhibitors
• Mol File: 879085-55-9.mol
• Article Data: 27

Chemical Properties

• Boiling Point: 561.6°C at 760 mmHg
• Flash Point: 293.4°C
• Appearance: /
• Density: 1.440
• Vapor Pressure: 1.22E-12mmHg at 25°C
• Refractive Index: 1.64
• Storage Temp.: -20°
• Solubility: Soluble in DMSO (up to 200 mg/ml) or in Ethanol (up to 10 mg/ml with warming)
• PKA: 10.72±0.70(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 3 months.
• CAS DataBase Reference: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide(879085-55-9)
• EPA Substance Registry System: 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide(879085-55-9)

Safety Data

• Hazardous Substances Data: 879085-55-9(Hazardous Substances Data)

Usage

Description

2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide, also known as Vismodegib or Erivedge, is a benzamide compound that has been specifically designed to target and inhibit the Hedgehog (Hh) signaling pathway. This white solid compound has demonstrated potent inhibitory effects on the Hh pathway, making it a valuable pharmaceutical agent for the treatment of various types of human cancers.

Uses

Used in Oncology:
2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide is used as a potent Hedgehog inhibitor for the treatment and prevention of many types of human cancers. By inhibiting the Hh signaling pathway, this compound can effectively reduce the downstream production of proliferation factors, thereby suppressing tumor growth and progression.
Used in the Treatment of Basal Cell Carcinoma:
In January 2012, the US FDA approved vismodegib (Erivedge) for the treatment of adults with metastatic basal cell carcinoma (BCC) or locally advanced BCC that has recurred following surgery or for those who are not candidates for surgery or radiation. As an antagonist of SMO, vismodegib inhibits the activation of Hedgehog target genes, resulting in decreased tumor growth and progression.
Used in Drug Synthesis:
A synthesis of vismodegib starting from 2-chloro-5-nitro aniline and employing a Negishi coupling with 2-pyridyl zinc iodide as a key step has been reported. This synthesis process highlights the potential of 2-Chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide as a key intermediate in the development of novel therapeutic agents targeting the Hedgehog signaling pathway.

Originator

Curis/Genentech (United States)

Clinical Use

Antineoplastic agent: Treatment of basal cell carcinoma which is inappropriate for surgery or radiotherapy

Synthesis

The synthesis began with selective iodination of commercial carboxylic acid 179, affording trisubstituted arene 180 in 73% yield. A Curtius reaction then converted 180 to carbamate 181 in 84% 52 yield, and this was followed by a palladium(0)-catalyzed borylation of 181 which furnished Suzuki coupling partner 182 in 91% yield. Pinacol borane 182 was exposed to commercial 2-bromopyridine under conventional cross-coupling conditions to furnish biaryl 183, which underwent Boc-deprotection in quantitative conversion to generate 184. Amide bond formation with acid chloride 185 (readily available from the corresponding commercial acid) produced vismodegib (XXVIII) in 99% yield.

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: concentration possibly reduced by rifampicin - avoid. Antidepressants: concentration possibly reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin and phenytoin - avoid. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Metabolism

Vismodegib is hepatically metabolised by CYP2C9 and CYP3A4, however more than 98% of total systemic vismodegib is not metabolised. Metabolic pathways of vismodegib include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in faeces are produced in vitro by recombinant CYP2C9 and CYP3A4/5. Vismodegib is slowly eliminated by a combination of metabolism and excretion of parent drug, the majority is recovered in the faeces (82%). Vismodegib and its metabolites are eliminated mainly by the hepatic route.

References

1) Rominger et al. (2009), Evidence for allosteric interactions of antagonist binding to the smoothened receptor; J. Pharmacol. Exp. Therap., 329 995 2) Tian et al. (2012), The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells; Anticancer Res., 32 89 3) Zhang et al. (2009), Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp; Neoplasia, 11 96 4) Cirrone and Harris (2012), Vismodegib anf the hedgehog pathway: a new treatment for basal cell carcinoma; Clin. Ther., 34 2039 5) Wu et al. (2017), Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines; Exp. Ther. Med., 13 2529 6)Singh et al. (2011) Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms; PLoS One 6?e27306 7) Rudin et al. (2009) Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449; N. Engl. J. Med., 361?1173 8) Von Hoff et al. (2009) Inhibition of the hedgehog pathway in advanced basal-cell carcinoma; N. Engl. J. Med., 361?1164

InChI:InChI=1/C19H14Cl2N2O3S/c1-27(25,26)13-6-7-14(17(21)11-13)19(24)23-12-5-8-16(20)15(10-12)18-4-2-3-9-22-18/h2-11H,1H3,(H,23,24)

Upstream product

• 694-80-4 2-bromo-1-chlorobenzene 
• 4381-32-2 2-(2-chlorophenyl)pyridine 
• 2142-68-9 1-(2-chlorophenyl)ethanone 
• 85908-96-9 2-oxopiperidine-1-carboxylic acid tert-butyl ester 
• 675-20-7 piperidin-2-one 
• 100-48-1 pyridine-4-carbonitrile 
• 15889-32-4 3-(2-pyridyl)aniline 
• 1079360-49-8 2-chloro-4-(methylthio)benzoic acid 
• 85953-29-3 methyl 2-chloro-4-fluorobenzoate 
• 2252-51-9 2-choro-4-fluorobenzoic acid 
• 879088-41-2 4-chloro-3-(pyridin-2-yl)benzeneamine 
• 81745-83-7 pyridin-2-ylzinc(ll) bromide 

Downstream Products

• 1616666-78-4 C₂₁H₁₆Cl₂N₂O₅S 
• 1616666-79-5 C₂₁H₁₅Cl₂FN₂O₅S 

Relevant articles and documents

Preparation method of vimodegil

The invention provides a preparation method of vimodegil. 2-chloro-5-nitroacetophenone is used as a raw material; 5-oxo-5-(2-chloro-5-nitrophenyl) n-valeraldehyde is prepared through an addition reaction between 2-chloro-5-nitroacetophenone and acrolein,

Preparation methods of Vismodegib and intermediate of Vismodegib

The invention provides preparation methods of Vismodegib and an intermediate of the Vismodegib, namely, preparation methods of 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide and an intermediate of the 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide. According to the preparation methods, the intermediate, namely 2-chloro-4-methylsulfonyl-N-(3-(2-pyridinyl)phenyl)benzamide is prepared firstly, and then the 2-chloro-N-(4-chloro-3-(2-pyridinyl)phenyl)-4-(methylsulfonyl)benzamide is prepared through a chlorination reaction. The preparation methods have the characteristics that the steps are short, operation is easy, starting materials are cheap and easy to obtain, no palladium reagent is used, the reaction condition has the low requirements for the anhydrous and oxygen-free condition, and the production cost can be effectively lowered.

A [...] synthesis of intermediates method and application

The invention relates to a method for synthesizing intermediate [...] and application, which belongs to the field of organic synthesis, in particular to intermediate 2 - (2 - chloro - 5 - nitrophenyl) pyridine (i.e. compound A) preparation process, compri