Substituted isochroman compounds for the treatment of metabolic disorders, cancer and other diseases
A compound, the technology of isochroman, applied in the field of compounds, can solve problems such as weight gain
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[0172] In an alternative method for the preparation of compounds of formula (103) shown in Figure 6, boronic acid (101) can be coupled with an aryl bromide (104) that does not contain a carbonyl group to give biaryl (105), which can then be prepared using methods known in the art Acetylation or formylation by known techniques such as Friedel-Craft acylation or Vilsmeier reaction or Vilsmeier-Half Gram (Vilsmeier-Haack) reaction, Gartmann reaction, Duff (Duff) reaction, Reimer-Tiemann (Reimer-Tiemann) reaction and other reactions. Compound (103) can also be produced in a single step by formylation or acylation of bisaryl (105), for example, by Friedel-Crafts acylation reaction or the like. Alternatively, in a two-step approach, the biaryl (105) is first halogenated to give the biaryl halide (106) (e.g. bromide), followed by a halogen-metal exchange reaction using an alkyllithium, followed by the aryl Reaction of the lithium intermediate with dimethylformamide (or equivalent kn...
Embodiment 11
[0280] Example 11: 5-[2,5-Difluoro-4-methoxy-3-(1,1,4,4,7-pentamethyl-isochroman-6-yl)-phenylmethylene ]-thiazolidine-2,4-dione, which may be referred to as "compound 11".
[0281]
[0282] Using 2,5-difluoro-4-methoxy-3-(1,1,4,4,7-pentamethyl-isochroman-6-yl)-benzaldehyde in a manner similar to Example 1 preparation. The melting point is 142°C. 1 H NMR (300MHz; DMSO): 1.18(s, 6H), 1.49(s, 6H), 2.03(s, 3H), 3.52(s, 2H), 3.77(d, J=2.05Hz, 3H), 7.15( s, 1H), 7.17 (s, 1H), 7.43 (dd, J 1 =6.9Hz,J 2 =12Hz, 1H), 7.70(s, 1H), 12.76(s, 1H).
[0283] The intermediate 2,5-difluoro-4-methoxy-3-(1,1,4,4,7-pentamethyl-isochroman-6-yl)-benzaldehyde was prepared as follows:
[0284] a) 2,5-Difluoro-4-methoxy-3-(1,1,4,4,7-pentamethyl-isochroman-6-yl)benzaldehyde:
[0285] Using 1,1,4,4,7-pentamethyl-isochroman-6-boronic acid and 3-bromo-2,5-difluoromethoxybenzaldehyde (Example 3c) similarly to Example 1a way of preparation. 1 H NMR (300MHz; CDCl 3 )1.25(s, 6H), 1.58(s, 6H), 2.12(...
Embodiment 12
[0308]Example 12: 5-[2,5-difluoro-4-methoxy-3-(1,1,4,4,7-pentamethyl-isochroman-6-yl)-phenylmethylene ]-Tris salt of thiazolidine-2,4-dione, which may be referred to as "compound 12".
[0309]
[0310] Compound 11 (6.87 g, 14.51 mmol) was dissolved in anhydrous THF (50 mL), and tris(hydroxymethyl)aminomethane (“Tris”, 1.76 g, 14.51 mmol) in anhydrous methanol (50 mL) was added dropwise at room temperature ) solution. The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was dissolved in ethanol, evaporated and dried under high vacuum to give 8.6 g of 5-[2,5-difluoro-4-methoxy-3-(1,1,4,4,7-pentamethyl [0010]-isochroman-6-yl)-benzylidene]-thiazolidine-2,4-dione TRIS salt. 1 H-NMR (300MHz; DMSO-d-6): 1.19(s, 6H), 1.50(s, 6H), 2.03(s, 3H), 3.47(s, 6H), 3.52(s, 2H), 3.71( d, J=2.1Hz, 3H), 5.17(s, 3H), 7.14(s, 1H), 7.17(s, 1H), 7.34(s, 1H), 7.42(dd, J 1 =7.5Hz,J 2 = 12.6 Hz, 1H), 7.58 (br s, 2H).
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