ChemicalBook CAS DataBase List Ripretinib

Ripretinib synthesis

12synthesis methods

Product Name:Ripretinib
CAS Number:1442472-39-0
Molecular formula:C24H21BrFN5O2
Molecular Weight:510.36

The diethyl ester 297 was reacted with triethyl orthoformate and acetic anhydride by heating. Subsequent addition of aqueous ammonia afforded pyridine 298. Pyridine 298 was treated neat with phosphorus oxychloride at reflux to afford dichloride 299 in 90% yield. The 4-chloro group of pyridine 299 was selectively replaced by ethylamine in cooled acetonitrile to afford the product. Oxidation state adjustment using lithium aluminum hydride followed by MnO2 afforded 4-aminopyridine 300. Starting from acid 301, a three-step reaction process involving nitration, esterification, and reduction provided ester 302 directly. Ester 302 reacted with intermediate 300 in DMA (N,N-dimethylacetamide) with the aid of KF on alumina to form naphthyridinone ring system 303 via Knoevenagel cyclization. Methylamine groups were installed on naphthyridinone ring system 303. Reaction with phenylisocyanate to form urea completed the preparation of ripretinib.
Ripretinib synthesis

1,6-Naphthyridin-2(1H)-one, 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-

1442470-53-2
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103-71-9
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1442472-39-0
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Yield:1442472-39-0 64.5%

Reaction Conditions:

with triethylamine in tetrahydrofuran at 20; for 100 h;

Steps:

31 Example 31
A mixture of Example A14 (0.120 g, 0.307 mmol) and TEA (0.043 mL, 0.307 mmol) in THF (3.0 mL) was treated with phenyl isocyanate (0.040 g, 0.337 mmol) and stirred at RT for 4 h.
Over the course of the next 4 days the mixture was treated with additional phenyl isocyanate (0.056 mL) and stirred at RT.
The resulting solid was filtered, rinsed with THF, then triturated with MeOH to afford 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (101 mg, 64.5% yield) as a bright white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.09 (s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.17 (d, 1H), 7.70 (s, 1H), 7.65 (d, 1H), 7.41 (d, 2H), 7.27 (m, 2H), 7.03 (m, 1H), 6.96 (t, 1H), 6.23 (s, 1H), 4.13 (q, 2H), 2.86 (d, 3H), 1.20 (t, 3H); MS (ESI) m/z: 510.1 [M+H]⁺.

References:

Deciphera Pharmaceuticals, LLC;Flynn, Daniel L.;Kaufman, Michael D.;Petillo, Peter A. US8461179, 2013, B1 Location in patent:Page/Page column 85

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959162-97-1
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1442472-39-0
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References

959162-99-3 Synthesis

6-chloro-4-(ethylamino)-3-Pyridinemethanol

959162-99-3
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1442472-39-0
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References

6-chloro-4-(ethylamino)-3-Pyridinecarboxaldehyde

959163-01-0
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1442472-39-0
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References

40296-46-6 Synthesis

40296-46-6
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1442472-39-0
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References

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