Antidepressant minaprine or deriv. prepn. - from 3-methoxy-6-chloro-pyridazine via new 3-methoxy-6-(hetero)aryl-pyridazine deriv.

摘要

3-Methoxy-6-(hetero)aryl-pyrazine derivs. of formula (I) are new: R1 = H or a gp. E selected from halogen (pref. Br or I), 1-8C (pref. 1-4C) alkyl, SO3H, SO2H, SH, SRa, CH2OH, CHRaOH, CraRb-OH (or their ethers), COOH, COORa, CORa, CHO, CO (sic), CONH2, N3, NH2, NHRa, NRaRb, B(ORa)2, B(OH)2, SnRa, SiRa (sic) or As(Ra)2; Ra, Rb = 1-8C (pref. 1-4C) alkyl; R2 = opt. substd. aromatic or heteroaromatic gp. Prepn. of minaprine and its derivs. of formula (VI) comprises: (i) reacting 3-methoxy-6-chloropyridazine of formula (II) with a (hetero)aryl boronic acid deriv. of formula R2-B(OH)2 (III) to give (I; R1=H); (ii) opt. converting (I; R1=H) into (I; R=E) by reacting with a metallising agent followed by an electrophile and opt. further converting the substit. introduced (e.g. by hydrolysis or redn.; (iii) reacting (I) with halogenated acid to give a pyridazinone of formula (V); (iv) reacting (V) with a chlorinating agent to give a 3-chloropyridazine deriv. of formula (VII); and (v) reacting (VII) with 4-(2-aminoethyl)-morpholine (VIII): Also claimed are the prepn. of (I) by step (i) and opt. step (ii); and the use of (I) for prepn. of (V). R2 = 6-10C aromatic gp. (e.g. phenyl or naphthyl), 5- or 6- membered N-contg. heterocycle (e.g. imidazole, pyridine, pyrimidine or pyridazine), O-contg. heterocycle (e.g. oxazole), O- and N-contg. heterocycle (e.g. oxadiazole) or S-contg. heterocycle (e.g. thiazole); R2 gps. are all opt. substd. by one or more of halogen, OH, ORa, alkyl, alkenyl or alkynyl (pref. with 1-8C, esp. 1-4C), COOH, COORa, CORa, CH2OH, CHRaOH, CRaRbOH (or their ethers), CHO, CONH2, NH2, NHRa, NRaRb, S, SH, SRa, NO2 or functional gps. such as amine, ketone, sulphydryl or amide. In step (ii) for the prepn. of (I), metallation reaction may be followed by transmetallation to replace the metal introduced by an orgaometallic gp. USE/ADVANTAGE - Minaprine, i.e. (VI; R1 = Me; R2 = Ph), is an antidepressant. Minaprine can be prepd. easily and rapidly from a starting material readily obtainable from maleic anhydride. A wide range of substd. minaprine derivs. can be prepd. Overall yield is ca. 35% starting from dichloropyridazine (sic). In an example, a degassed mixt. of 20 ml toluene, 1 ml 2 M aq. Na2CO3 and 0.55 ml EtOH was treated successively at room temp. with 0.145g (II), 0.187g phenylboronic acid and 0.042g Pd(PPh3)4 (catalyst), heated at reflux until reaction was complete by TLC (ca. 12 hrs.) and evapd. The prod. was worked up and purified by silica gel chromatography to give 0.14g (75%) of 3-methoxy-6-phenylpyridazine, m.pt. 116 deg.C. The prod. was converted successively into 3-methoxy-4-phenyl-pyridazine (by reaction with -Buli in THF then with MeI; 81% yield), 4-methyl-6-phenyl-3(2H)-pyridazinone (by reaction with aq. HI; 96% yield) and minaprine (by reaction with POCl3 then (VIII); no detail given).