Process For The Preparation Of 3,7-Dihydroxy-1,5-Diazacyclooctanes

A process for the preparation of a compound of formula I,

• or a salt and/or solvate thereof,
• wherein R1 represents an amino protective group or a structural fragment of formula Ia,
• in which
• R2 represents H, halo, C1-6 alkyl, —OR5, -E-N(R6)R7 or, together with R3, represents ═O;
• R3 represents H, C1-6 alkyl or, together with R2, represents ═O;
• R5 represents H, C1-6 alkyl, -E-aryl, -E-Het1, —C(O)R8a, —C(O)OR8b or —C(O)N(R9a)R9b;
• R6 represents H, C1-6 alkyl, -E-aryl, -E-Het1, —C(O)R8a, —C(O)OR8b, —S(O)2R8c, —[C(O)]pN(R9a)R9b or —C(NH)NH2;
• R7 represents H, C1-6 alkyl, -E-aryl or —C(O)R8d;
• R8a to R8d independently represent, at each occurrence when used herein, C1-6 alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het2), aryl, Het3, or R8a and R8d independently represent H;
• R9a and R9b independently represent, at each occurrence when used herein, H or C1-6 alkyl (optionally substituted by one or more substituents selected from halo, aryl and Het4), aryl, Het5, or together represent C3-6 alkylene, optionally interrupted by an O atom;
• E represents, at each occurrence when used herein, a direct bond or C1-4 alkylene;
• p represents 1 or 2;
• A represents a direct bond, -J-, -J-N(R10a)—, -J-S(O)2N(R10b)—, -J-N(R10c)S(O)2— or -J-O— (in which latter four groups -J is attached to the oxabispidine nitrogen);
• B represents —Z—{[C(O)]aC(H)(R11a)}b—, —Z—[C(O)]cN(R11b)—, —Z—N(R11c)S(O)2—, —Z—S(O)2N(R11d)—, —Z—S(O)n—, —Z—O— (in which latter six groups, Z is attached to the carbon atom bearing R2 and R3), —N(R11e)—Z—, —N(R11f)S(O)2—Z—, —S(O)2N(R11g)—Z— or —N(R11h)C(O)O—Z— (in which latter four groups, Z is attached to the R4 group);
• J represents C1-6 alkylene optionally interrupted by —S(O)2N(R10d)— or —N(R10c)S(O)2— and/or optionally substituted by one or more substituents selected from —OH, halo and amino;
• Z represents a direct bond or C1-4 alkylene, optionally interrupted by —N(R11i)S(O)2— or —S(O)2N(R11j)—;
• a, b and c independently represent 0 or 1;
• n represents 0, 1 or 2;
• R10a to R10e independently represent, at each occurrence when used herein, H or C1-6 alkyl;
• R11a represents H or, together with a single ortho-substituent on the R4 group (ortho-relative to the position at which the B group is attached), R11a represents C2-4 alkylene optionally interrupted or terminated by O, S, N(H) or N(C1-6 alkyl);
• R11b represents H, C1-6 alkyl or, together with a single ortho-substituent on the R4 group (ortho-relative to the position at which the B group is attached), R11b represents C2-4 alkylene;
• R11c to R11j independently represent, at each occurrence when used herein, H or C1-6 alkyl;
• R4 represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from —OH, cyano, halo, nitro, C1-6 alkyl (optionally terminated by —N(H)C(O)OR12a), C1-6 alkoxy, —N(R13a)R13b, —C(O)R13c, —C(O)OR13d, —C(O)N(R13e)R13f, —N(R13g)C(O)R13h, —N(R13i)C(O)N(R13j)R13k, —N(R13m)S(O)2R12b, —S(O)2N(R13n)R13o, —S(O)2R12c, —OS(O)2R12d and/or aryl;
• and an ortho-substituent (ortho-relative to the attachment of B) may
• (i) together with R11a, represent C2-4 alkylene optionally interrupted or terminated by O, S, N(H) or N(C1-6 alkyl), or
• (ii) together with R11b, represent C2-4 alkylene;
• R12a to R12d independently represent C1-6 alkyl;
• R13a and R13b independently represent H, C1-6 alkyl or together represent C3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
• R13c to R13o independently represent H or C1-6 alkyl;
• and
• Het1 to Het5 independently represent, at each occurrence when used herein, five- to twelve-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups are optionally substituted by one or more substituents selected from ═O;
• —OH, cyano, halo, nitro, C1-6 alkyl, C1-6 alkoxy, aryl, aryloxy, —N(R14a)R14b, —C(O)R14c, —C(O)OR14d, —C(O)N(R14e)R14f, —N(R14g)C(O)R14h, —S(O)2N(R14i)(R14j) and/or —N(R14k)S(O)2R14l;
• R14a to R14l independently represent C1-6 alkyl, aryl or R14a to R14k independently represent H;
• provided that:
• (a) when R3 represents H or C1-6 alkyl;
• and
• A represents -J-N(R10a)— or -J-O—, then:
• (i) J does not represent C1 alkylene or 1,1-C2-6 alkylene;
• and
• (ii) B does not represent —N(R11b)—, —N(R11c)S(O)2—, —S(O)n—, —O—, —N(R11e)—Z—, —N(R11f)S(O)2—Z— or —N(R11h)C(O)O—Z—;
• and
• (b) when R2 represents —OR5 or -E-N(R6)R7 in which E represents a direct bond, then:
• (i) A does not represent a direct bond, -J-N(R10a) -J-S(O)2N(R12h)— or -J-O—;
• and
• (ii) B does not represent —N(R11b)—, —N(R11c)S(O)2—, —S(O)n—, —O—, —N(R11e)—Z, —N(R11f)S(O)2—Z— or —N(R11h)C(O)O—Z—;
• and
• (c) when A represents -J-N(R10c)S(O)2, then J does not represent C1 alkylene or 1,1-C2-6 alkylene;
• and
• (d) when R3 represents H or C1-6 alkyl and A represents -J-S(O)2N(R10b), then B does not represent —N(R11b)—, —N(R11c)S(O)2—, —S(O)n—, —O—, —N(R11e)—Z—, —N(R11f)S(O)2—Z— or —N(R11h)C(O)O—Z—;
• and
• wherein each aryl and aryloxy group, unless otherwise specified, is optionally substituted;
• which process comprises reaction in the presence of an aqueous solvent system of:
• one equivalent of a compound of formula II,
• H2N—R1 II
• or a salt and/or solvate thereof, wherein R1 is as hereinbefore defined,
• with at least two equivalents of a compound of formula III,
• wherein L1 represents a leaving group,
• and at least two equivalents of base,
• wherein the reaction is performed by addition of base to an aqueous mixture of the compounds of formulae II and III, the period of base addition comprising:
• (a) a first period, during which the pH of the reaction mixture is raised to between pH 10 and pH 13;
• and then
• (b) a second period, during which the pH of the reaction mixture is controlled such that it is maintained between pH 10 and pH 13,
• wherein the time ratio of the first to second period is 1:5 or less.