PROCESSES FOR PREPARING DIHYDROPYRIMIDINE DERIVATIVES AND INTERMEDIATE COMPOUNDS THEREOF Russian patent published in 2019 - IPC C07D417/04 C07D417/14 C07D413/04 C07D413/14 C07D405/04 C07D405/14 C07D401/14 

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to versions of a novel method of producing a dihydropyrimidine derivative of formula (I-2) or a tautomer thereof of formula (Ia-2) and to a novel intermediate product for producing formula (Va-2). Compounds of formula (I-2) and formula (Ia-2) can be used for treating or relieving viral infection, particularly HBV infection, or diseases caused by HBV infection. Process of preparing a dihydropyrimidine compound of formula (I-2) or a tautomer thereof of formula (Ia-2)

where each R¹ is F or Cl; and R² is Cl or Br; R³ is C_1-4 alkyl; Z is -S-; Y is -O-, -S-, -S(=O)_t-, -(CH₂)_q- or -N(R⁵)-; each t and q independently has value of 0, 1 or 2; R⁵ is H or C_1-4 alkyl; each R⁶ independently represents H, halo, C_1-4 alkyl, C_1-4 haloalkyl, amine, C_1-4 alkylamine, C_1-4 alkoxy, nitro, triazolyl, tetrazole, -(CR⁷R^7a)_m-OH, -S(=O)_qOR^8a, -(CR⁷R^7a)_m-S(=O)_qN(R^8a)₂, -(CR⁷R^7a)_t-N(R^8a)₂, -(CR⁷R^7a)_m-C(=O)O-R⁸, -(CR⁷R^7a)_m-C(=O)O-(CR⁷R^7a)_m-OC(=O)O-R⁸, -(CR⁷R^7a)_m-C(=O)O-(CR⁷R^7a)_m-OC(=O)-R⁸, -(CR⁷R^7a)_m-C(=O)O-(CR⁷R^7a)_m-C(=O)OR⁸, -(CR⁷R^7a)_m-OC(=O)-R⁸ or -(CR⁷R^7a)_m-C(=O)-N(R⁸R^8a); each R^7a and R⁷ independently represents H, C_1-4 alkyl, C_1-4 haloalkyl, -(CH₂)_m-OH or -(CH₂)_m-C(=O)OR⁸; each R⁸ and R^8a independently represents H, C_1-4 alkyl, amine-C_1-4-alkyl, C_1-4 alkoxy, C_1-6 alkyl-S(=O)_q-, C_6-10 aryl, C_1-9 heteroaryl, C_3-6 cycloalkyl, C_2-9 heterocyclyl, C_6-10 aryl-C_1-6-alkyl, C_1-9 heteroaryl-C_1-6-alkyl, C_3-6 cycloalkyl-C_1-4-alkyl, C_2-9 heterocyclyl-C_1-6-alkyl, C_2-9 heterocyclyl-S(=O)_q-, C_1-9 heteroaryl-S(=O)_q-, C_3-6 cycloalkyl-S(=O)_q-, C_6-10 aryl-S(=O)_q-, -(CH₂)_m-OH, -(CH₂)_m-C(=O)O-(CH₂)_m-H or -(CH₂)_m-OC(=O)-(CH₂)_m-H; n takes values of 0, 1, 2, 3, 4 or 5; each m independently assumes values of 0, 1, 2, 3 or 4; consists in that step (A) is carried out: reacting an amidine compound with formula (II-1) or a salt thereof and an aldehyde compound of formula (III-2) and a compound of formula (IVa)

to obtain a compound of formula (Va-2)

where R^3b is ethoxy; and R^3a is H; R¹, R² and Z have the above values; wherein reaction at step (A) is carried out at temperature of 25 °C to 154 °C, and step (A) further includes cooling the compound of formula (Va-2) obtained at step (A) to obtain a solid compound of formula (Va-2) at cooling temperature in the range of -40 °C to 40 °C. Step (B) is then carried out: halogenation of the compound of formula (Va-2) to form a halide and then reacting halide and a compound of formula (VI) or a salt thereof to obtain a compound of formula (VIIa-2)

and step (C): formation of a compound of formula (I-2) or formula (Ia-2) from a compound of formula (VIIa-2) by re-esterification, wherein the re-esterification step is carried out in the presence of a base. Either the compound of formula (I-2) or its tautomer of formula (Ia-2) is obtained using a method comprising step 1): reacting an amidine (II-1) compound or a salt thereof and an aldehyde compound of formula (III-2) and a compound of formula (IVa)

to obtain a compound of formula (Va-2)

where R^3b is ethoxy; and R^3a is H; wherein reaction at step (1) is carried out at temperature of 25 °C to 154 °C, wherein step (1) further includes cooling the compound of formula (Va-2) obtained at step (1) to obtain a solid compound of formula (Va-2) at a cooling temperature in the range of -40 °C to 40 °C. Step (2) is then carried out: to form a compound of formula (X-2) from a compound of formula (Va-2) through reesterification, where the re-esterification step is carried out in the presence of a base,

,

and step (3): halogenation of compound with formula (X-2) to form halide; and then reacting halide and a compound of formula (VI) or a salt thereof to obtain a compound of formula (I-2) or formula (Ia-2).

EFFECT: method enables to obtain products with high output and high optical purity of up to 98 %, and also provides simple release of the end product, which enables use thereof for industrial production.

20 cl, 32 tbl, 17 ex