Igermetostat

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Igermetostat Structure

Igermetostat

C32H46N4O4. 550.73

2409538-60-7

2KES6YSH8D

INN 12655

BENZAMIDE, N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-3-(ETHYL(TETRAHYDRO-2H-PYRAN-4-YL)AMINO)-2-METHYL-5-((TRANS-3-(1-PIPERIDINYL)CYCLOBUTYL)OXY)-
IGERMETOSTAT
IGERMETOSTAT [INN]
N-((1,2-DIHYDRO-4,6-DIMETHYL-2-OXO-3-PYRIDINYL)METHYL)-3-(ETHYL(TETRAHYDRO-2H-PYRAN-4-YL)AMINO)-2-METHYL-5-((TRANS-3-(1-PIPERIDINYL)CYCLOBUTYL)OXY)BENZAMIDE
N-((4,6-DIMETHYL-2-OXO-1,2-DIHYDROPYRIDIN-3-YL)METHYL)-3-(ETHYL(OXAN-4-YL)AMINO)-2-METHYL-5-(((1R,3R)-3-(PIPERIDIN-1-YL)CYCLOBUTYL)OXY)BENZAMIDE

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020020374&_cid=P22-LR1SQG-34075-1

PATENT

US20230382898

https://patentscope.wipo.int/search/en/detail.jsf?docId=US415363922&_cid=P22-LR1S46-25135-1

The compound has been disclosed in patent WO2020020374A1. It is an enhancer of Zeste homolog 2 (EZH2) inhibitor, and can be used for preventing or treating EZH2-mediated diseases, including brain cancer, thyroid cancer, cardiac sarcoma, lung cancer, oral cancer, stomach cancer and various other cancers.

PATENT

US20210308141

https://patentscope.wipo.int/search/en/detail.jsf?docId=US338556625&_cid=P22-LR1S8P-27079-1

Example 4: Preparation of the Compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(trans-3-morpholinylcyclobutoxy)benzamide (4)

(MOL) (CDX)

The title compound was prepared by referring to Example 1 with cyclobutanol replaced by cis-3-morpholinylcyclobutyl-1-ol. The cis-3-morpholinylcyclobutyl-1-ol was prepared as follows:

3-benzyloxy-cyclobutyl-1-one (3 g, 17 mmol, 1 eq) and morpholine (2.97 g, 34 mmol, 2 eq) were dissolved in DCE (30 mL). After stirring at room temperature for 0.5 h, the solution was added with NaBH(OAc)₃ (7.23 g, 34 mmol, 2 eq) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, adjusted to basicity with aqueous NaHCO₃ solution, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by a phase preparative column to give 4-(3-(benzyloxy)cyclobutyl)morpholine (2.9 g). M/z (ES+), [M+H] ⁺=248.

4-(3-(benzyloxy)cyclobutyl)morpholine (2.9 g, 117.4 mmol) and methane sulfonic acid (20 mL) was added to dichloromethane (40 mL). The mixture was stirred overnight at room temperature and concentrated under reduced pressure to remove the solvent to give a crude product, which was purified by a preparative column to give cis-3-morpholinylcyclobutyl-1-ol; m/z (ES+), [M+H] ⁺=158. The trans-3-morpholinylcyclobutyl-1-ol can also be separated and obtained by this method.

m/z (ES ⁺), [M+H] ⁺=553; HPLC t _R=1.296 min. 1H NMR (400 MHz, DMSO-d ₆) δ 11.53-11.42 (s, 1H), 8.08-8.00 (s, 1H), 6.63-6.58 (d, J=2.4 Hz, 1H), 6.44-6.38 (d, J=2.5 Hz, 1H), 5.89-5.84 (s, 1H), 4.28-4.22 (d, J=4.7 Hz, 2H), 3.63-3.57 (d, J=4.0 Hz, 4H), 3.29-3.17 (t, J=10.5 Hz, OH), 3.02-2.87 (m, OH), 2.39-2.25 (d, J=19.9 Hz, 6H), 2.22-2.17 (s, 3H), 2.15-2.03 (d, J=2.9 Hz, 8H), 1.67-1.57 (d, J=10.7 Hz, 2H), 1.53-1.42 (d, J=8.4 Hz, 2H), 0.82-0.76 (t, J=6.9 Hz, 3H). No isomerization was found in chiral HPLC.

[1]. Peng, et al. Polysubstituted benzene compound and preparation method and use thereof.

World Intellectual Property Organization, WO2020020374 A1. 2020-01-30.

//////////Igermetostat

CCN(C1CCOCC1)c2cc(O[C@H]3C[C@@H](C3)N4CCCCC4)cc(C(=O)NCc5c(C)cc(C)[nH]c5=O)c2C

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Igermetostat

Igermetostat

Example 4: Preparation of the Compound N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(trans-3-morpholinylcyclobutoxy)benzamide (4)

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