Spiroindoline derivatives as gonadotropin-releasing hormone receptor antagonists
A technology of compound and alkyl, which is applied in the field of disease treatment, can solve the problem that the activity of GnRH receptor antagonist is not described, etc.
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Embodiment 1
[0602] N-[(3-chloropyridin-2-yl)methyl]-1-[(4-fluorophenyl)sulfonyl]-2-methyl-1,2,2',3',5',6 ′-Hexahydrospiro[indole-3,4′-pyran]-5-carboxamide
[0603]
[0604] According to GP 9.1, 250 mg (0.62 mmol) of intermediate F.3 and 105 mg (0.74 mmol, 1.2 eq) of 1-(3-chloro Pyridin-2-yl)methanamine (CAS No. [500305-98-6]) was reacted with 280 mg (0.74 mmol, 1.2 equiv) of HATU in 10 mL DMF to yield 300 mg (84%) of the desired amide. 1 H-NMR (300MHz, DMSO-d6): chemical shift [ppm]=-0.02(d, 1H), 0.97-1.08(m, 1H), 1.25(d, 3H), 1.67(d, 1H), 1.96- 2.08(m, 1H), 3.32-3.50(m, 3H), 3.79-3.87(m, 1H), 4.50(q, 1H), 4.63(d, 2H), 7.33(dd, 1H), 7.35-7.41( m, 2H), 7.54 (d, 1H), 7.76 (d, 1H), 7.81 (dd, 1H), 7.87-7.92 (m, 3H), 8.44 (dd, 1H), 8.80 (t, 1H). UPLC-MS(ESI+): [M+H] + =530 / 532 (chlorine isotope pattern).
[0605] The enantiomers of the racemic material of Example 1 were analyzed by chiral preparative HPLC (System: Dionex: Pump P 580, Gilson: Liquid Handler 215) , Nuoer Company (Knauer...
Embodiment 11
[0606] Example 1.1: R t =17.81min;
Embodiment 12
[0607] Example 1.2: R t =23.01min;
[0608] Table 1 Applying the indicated general procedures, the following examples (3 to 11) were prepared in analogy to example 1 starting from intermediate F.3 and commercially available amines. Example 2 was prepared from intermediate C.5 according to the given procedure.
[0609]
[0610]
[0611]
[0612] Example 12
[0613] N-(2-chlorobenzyl)-2-cyclopropyl-1-[(4-fluorophenyl)sulfonyl]-1,2,2',3',5',6'-hexahydrospiro[ Indole-3,4′-thiopyran]-5-carboxamide
[0614]
[0615] With GP 10: Dissolve 2.70 g (5.60 mmol) of intermediate C.1 in 40 mL 1,4-dioxane (containing 0.1 mL water) and add 2.38 g (3 equiv.) of 2-chlorobenzyl Amine (CAS No. [89-97-4]), 1.48 g (1 equivalent) of molybdenum hexacarbonyl, 1.78 g (3 equivalents) of sodium carbonate, 162 mg (0.1 equivalent) of tri-tert-butylphosphonium tetrafluoroborate and 126 mg (0.1 equivalent) palladium(II) acetate. The mixture was heated to reflux for 18h (bath temperature wa...
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