PROCESSES FOR PREPARING DIHYDROPYRIMIDINE DERIVATIVES AND INTERMEDIATE PRODUCTS THEREOF Russian patent published in 2019 - IPC C07D417/04 C07D401/14 C07D413/14 C07D417/14 C07D405/14 C07D413/04 C07D407/04 C07D405/04 

FIELD: chemistry.

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). Invention also relates to a novel intermediate product for synthesis thereof of formula (V-2) for getting compound of formula (I-2) or its tautomer of formula (Ia-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)

(I-2) or (Ia-2), where each R¹ is F; 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)O-R⁸, -(CR⁷R^7a)_m-OC(=O)-R⁸ or -(CR⁷R^7a)_m-C(=O)-N(R⁸R^8a); each R^7a and R⁷ independently represents H, halo, 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, amino-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 of following steps: step (A): reacting an amidine compound with formula (II-1)

,

or a salt thereof, and an aldehyde compound of formula (III-2)

and compounds with formula (IV)

,

to obtain a compound of formula (V-2)

where R¹ independently represents F; R² is Cl or Br; R^3b is isopropoxy; R^3a is H; Z is -S-; wherein reaction at step (A) is carried out at temperature from 25 to 154 °C, wherein step (A) further comprises cooling the compound of formula (V-2) obtained at step (A) to obtain a solid compound of formula (V-2) to a cooling temperature in the range of from -40 to 40 °C, step (B) comprises halogenating a compound of formula (V-2) to form a halide; and then reacting a halide and a compound of formula (VI)

or a salt thereof, to obtain a compound of formula (VII-2)

and step (C) consists in obtaining a compound of formula (I-2) or formula (Ia-2) from compound of formula (VII-2) by re-esterification, where re-esterification step is carried out in presence of base. Either a compound of formula (I-2) or a tautomer thereof of formula (Ia-2) is obtained by a method involving step (1) involving reaction of compound

and

and

to obtain compound

where R^3b is isopropoxy; and R^3a is H, R¹ is F; R² is Cl or Br; Z is -S-; wherein reaction at step (1) is carried out under conditions as described above for step A, then, step (2) is carried out: forming a compound of formula (X-2) from a compound of formula (V-2) by re-esterification, wherein the re-esterification step is carried out in the presence of 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). Values of radicals R¹, R², R³, R⁶, Y, Z are given above.

EFFECT: disclosed process is simple by mechanism of action, reduces total time of process, provides high output of end product (up to 78 %) and convenient separation of finished product, which is suitable for industrial production.

20 cl, 22 tbl, 12 ex