US 12,319,686 B2
Process for the preparation of tetrahydropyridopyrimidines
Junli Chen, Shanghai (CN); Weichun Chen, Shanghai (CN); and Lin Wang, Shanghai (CN)
Assigned to Hoffmann-La Roche Inc., Little Falls, NJ (US)
Appl. No. 17/423,069
Filed by Hoffmann-La Roche Inc., Little Falls, NJ (US)
PCT Filed Jan. 16, 2020, PCT No. PCT/EP2020/050951
§ 371(c)(1), (2) Date Jul. 14, 2021,
PCT Pub. No. WO2020/148352, PCT Pub. Date Jul. 23, 2020.
Claims priority of application No. PCT/CN2019/072102 (WO), filed on Jan. 17, 2019.
Prior Publication US 2022/0098189 A1, Mar. 31, 2022
Int. Cl. C07D 471/04 (2006.01)
CPC C07D 471/04 (2013.01) 28 Claims
 
1. A process for preparing a compound of formula (I),

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wherein:
R1 is C1-6alkyl;
R2 is C1-6alkyl or halogen; and
R3 is C1-6alkyl or C1-6alkoxy;
or a pharmaceutically acceptable salt thereof;
the process comprising one or more of the following steps:
a) formation of dihydropyridine (III);

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b) formation of dihydropyridine (IV) via the alkylation reaction of the dihydropyridine (III) and ethyl diethoxyphosphorylformate;

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c) formation of piperidine (V) via the reduction reaction of the compound of formula (IV);

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d) formation of the compound of formula (VI) via the cyclization reaction of piperidine (V) and pyrimidine-2-carboxamidine;

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e) formation of the compound of formula (VII) via chlorination of the compound of formula (VI);

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f) formation of the compound of formula (VIII) via selective hydrogenation of the compound of formula (VII);

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g) formation of the compound of formula (X) by N-alkylation of the compound of formula (VIII) with the compound of formula (IX);

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h) SFC separation of the compound of formula (X) to afford the compound of formula (I).