CRYSTALLINE FORMS OF DIAZABICYCLOOCTANE DERIVATIVE AND METHOD FOR PRODUCTION THEREOF Russian patent published in 2019 - IPC C07D471/08 A61K31/43 A61K31/439 A61K31/545 A61P31/04 A61P43/00 C07B61/00 

FIELD: chemistry.

SUBSTANCE: invention relates to versions of an improved method of producing a diazabicyclooctane derivative of formula (VII), including a compound (VII-1). Invention also relates to a method of producing intermediate products IV and VI. Compound (VII) is an inhibitor of β-lactamase and can be used as an antimicrobial agent.

[Chemical formula 80],

VII,

for example, compounds

[Chemical formula 101]

.

Method of producing a compound of formula (VII) involves reacting a compound of formula (III)

[Chemical formula 76]

[Chemical formula 77]

,

where R¹ is 2,5-dioxopyrrolidin-1-yl, 1,3-dioxo-3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-yl, 1,3-dioxohexahydro-1H-isoindole-2(3H)-yl or 3,5-dioxo-4-azatricyclo[5.2.1.0^2.6]dec-8-en-4-yl; and OBn is benzyloxy; with a compound: R³ONH₂, to obtain a compound of formula (IV), where R³ is C_1-6alkyl or heterocyclyl, R³ can be modified 0–5 R⁴; R⁴ can be successively substituted, wherein R⁴ is C_1-6alkyl, heterocyclyl, R⁵(R⁶)N- or protective group; R⁵ and R⁶, each independently represents hydrogen or C_1-6alkyl or together form heterocyclyl; in addition, when R³ is C_1-6alkyl, and R⁴, which modifies R³, namely R⁵ or R⁶, contained in R⁵(R⁶)N-, are C_1-6alkyl, R³ and R⁵ or R⁶ can together form 3–7-member saturated ring; and OBn is benzyloxy; treating compound IV with a palladium-carbon catalyst in a hydrogen atmosphere, with simultaneous or sequential sulphation reaction using a sulphur trioxide-trimethylamine complex in the presence of a catalytic amount of a base in an aqueous solvent based on alcohol and treatment with tetrabutylammonium hydrogen sulphate to obtain a compound of formula (VI),

[Chemical formula 78]

[Chemical formula 79]

where R³ is C_1-6alkyl or heterocyclyl, R³ can be modified 0–5 R⁴; R⁴ can be successively substituted, wherein R⁴ is C_1-6alkyl, heterocyclyl, R⁵(R⁶)N- or protective group; R⁵ and R⁶, each independently represents hydrogen or C_1-6alkyl or together form heterocyclyl; in addition, when R³ is C_1-6alkyl, and R⁴, which modifies R³, namely R⁵ or R⁶, contained in R⁵(R⁶)N-, are C_1-6alkyl, R³ and R⁵ or R⁶ can together form 3–7-member saturated ring; with subsequent, in case when side chain R³ONHC(=O)- has a protective group, removing the protective acid group, and depositing the crude product by adding a weak solvent to the reaction solution to obtain a crude compound of formula (VII-CR), where R³ is C_1-6alkyl or heterocyclyl, R³ can be modified 0–5 R⁴; R⁴ can be successively substituted, wherein R⁴ is C_1-6alkyl, heterocyclyl or R⁵(R⁶)N-; R⁵ and R⁶, each independently represents hydrogen or C_1-6alkyl or together form heterocyclyl; in addition, when R³ is C_1-6alkyl, and R⁴, which modifies R³, namely R⁵ or R⁶, contained in R⁵(R⁶)N-, are C_1-6alkyl, R³ and R⁵ or R⁶ can together form 3–7-member saturated ring; followed by alternate addition of crude compound of formulas (VII-CR), and ice-cooled buffer to obtain a solution having pH from 4 to 5.5, by concentration after demineralisation with a synthetic adsorbent, if necessary, controlling temperature, adding the starch, if necessary, and crystallisation by adding a weak solvent to obtain a compound represented by the following formula (VII), where R³ is C_1-6alkyl or heterocyclyl, R³ can be modified 0–5 R⁴; R⁴ can be successively substituted, wherein R⁴ is C_1-6alkyl, heterocyclyl or R⁵(R⁶)N-; R⁵ and R⁶, each independently represents hydrogen or C_1-6alkyl or together form heterocyclyl; in addition, when R³ is C_1-6alkyl, and R⁴, which modifies R³, namely R⁵ or R⁶, contained in R⁵(R⁶)N-, are C_1-6alkyl, R³ and R⁵ or R⁶ can together form 3–7-member saturated ring; (in each of said formulas heterocyclyl means 3–7-member monocyclic heterocyclic saturated ring or non-aromatic ring, having total of 1–3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, as ring components).

EFFECT: disclosed method increases stability of maintaining high quality (according to HPLC) and output of intermediate and target products during storage and increase in reaction time, which enables use of the method in large-scale production.

11 cl, 4 dwg, 12 tbl, 13 ex