1353550-13-6

Basic information

• Product Name: Olmutinib
• Synonyms: HM-71224;Olmutinib;Olmutinib, HM71224;N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide dihydrochloride monohydrate;N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;N-[3-[[2-[[4-(4-Methyl-1-piperazinyl)phenyl]amino]thieno[3,2-d]pyrimidin-4-yl]oxy]phenyl]-2-propenamide;HM71224, Olmutinib;Olmutinib (HM61713, BI 1482694)
• CAS NO: 1353550-13-6
• Molecular Formula: C₂₆H₂₆N₆O₂S
• Molecular Weight: 486.58864
• EINECS: -0
• Mol File: 1353550-13-6.mol

Chemical Properties

• Appearance: /
• Density: 1.336±0.06 g/cm3(Predicted)
• Solubility: insoluble in H2O; ≥9.11 mg/mL in EtOH with ultrasonic; ≥96.6 mg/mL in DMSO
• PKA: 12.87±0.70(Predicted)
• CAS DataBase Reference: Olmutinib(CAS DataBase Reference)
• NIST Chemistry Reference: Olmutinib(1353550-13-6)
• EPA Substance Registry System: Olmutinib(1353550-13-6)

Safety Data

• Hazardous Substances Data: 1353550-13-6(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Olmutinib is used as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC). It is particularly effective against EGFR T790M mutation-positive NSCLC, as it inhibits both EGFR activating and T790M resistance mutations while sparing wild-type EGFR. This third-generation EGFR TKI has shown promise in overcoming resistance developed to earlier generations of EGFR tyrosine kinase inhibitor therapy, providing a new treatment option for patients with NSCLC who have developed resistance to first and second-generation EGFR TKIs.

Synthesis

Synthetically, olmutinib can be accessed in two steps beginning with 2,4-dichloro-thieno[3,2-d]pyrimidine (147), which is commercially available and can be prepared in two steps from urea and 3-aminothiophene 2- carboxylate. Nucleophilic addition of N-(3-hydroxyphenyl)-2- propenamide (148) to 147 proceeded with complete regioselectivity via treatment with K2CO3 in warm DMSO, smoothly providing the desired diaryl ether 149 in 87% yield after crystallization from isopropanol and water. From 149, substitution with commercially available piperazinyl aniline 150 under acidic heating conditions (DMA, IPA, TFA, 90 °C) provided olmutinib in 82% yield. After recrystallization, olmutinib (XVI) was obtained in 60% overall yield and 99.1% purity.

in vitro

olmutinib has been identified as an irreversible kinase inhibitor and could covalently bind to a cysteine residue near the kinase domain of mutant egfr. olmutinib had a half-life of over 24h for egfr inhibition. olmutinib was able to cause potent inhibition in cell lines h1975 (l858r and t790m) and hcc827 (exon 19 deletion). olmutinib showed a low potency for nsclc cell line h358 with wild-type egfr [1].

in vivo

the previous in vivo studies of xenograft models with grafts of h1975 and hcc827 showed that olmutinib was active against the tumors without dasplaying any side effects [1].

references

[1] wang s, cang s, liu d. third-generation inhibitors targeting egfr t790m mutation in advanced non-small cell lung cancer. j hematol oncol. 2016 apr 12;9:34.

Upstream product

• 13040-21-6 N-(3-hydroxyphenyl)prop-2-enamide 
• 16234-14-3 2,4-dichlorothieno[3,2-d]pyrimidine 
• 1245811-20-4 2-chloro-3H,4H-thieno[3,2-d]pyrimidin-4-one 
• 31895-77-9 2-thioxo-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one 
• 176530-46-4 2-(methylthio)thieno[3,2-d]pyrimidin-4(3H)-one 
• 19962-06-2 tert-butyl 3-hydroxyphenylcarbamate 
• 591-27-5 m-Hydroxyaniline 
• 814-68-6 acryloyl chloride 
• 16153-81-4 4-(4-Methyl-piperazino)-anilin 

Downstream Products

• 1353551-84-4 N-(3-(2-(4-(4-methyl-4-oxy-piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidine-4-yloxy)-phenyl)-acrylamide 

Relevant articles and documents

NOVEL METHOD FOR PREPARING THIENOPYRIMIDINE COMPOUND AND INTERMEDIATE

Provided are a novel method of preparing a thienopyrimidine compound having activity of selectively inhibiting tyrosine kinase, particularly, mutant epidermal growth factor receptor tyrosine kinase, and a novel intermediate used for the novel method. According to the method of the present disclosure, a compound of Formula 1 useful as a therapeutic agent for non-small cell lung cancer induced by mutant epidermal growth factor receptor tyrosine kinase can be industrially mass-produced more easily and efficiently than the prior art.

NOVEL PROCESS FOR PREPARING THIENOPYRIMIDINE COMPOUND AND INTERMEDIATES USED THEREIN

The present invention relates to a novel method for preparing thienopyrimidine compound having an activity of selectively inhibiting tyrosine kinase, specifically the mutant epidermal growth factor receptor tyrosine kinase; and a novel intermediate used therein. According to the method of the present invention, the industrial mass-production of the compound of Formula 1, which is useful as a therapeutic agent for non-small cell lung cancer induced by the mutant epidermal growth factor receptor tyrosine kinase, can be implemented more conveniently and efficiently than the conventional technology.

NOVEL METHOD FOR PREPARING THIENOPYRIMIDINE COMPOUND AND INTERMEDIATES USED THEREIN

The present invention provides a novel method for preparing a thienopyrimidine compound of Formula 1, which is a selective inhibitor of tyrosine kinase activity, in particular, of mutant epidermal growth factor receptor tyrosine kinase, and novel intermediates used in the method.[ 1 ]