Deuterated tetrahydrothieno [3, 4-d] pyrimidinedione compound and pharmaceutical composition containing same
A technology of tetrahydrothiophene and pyrimidinedione, applied in the field of medicine, can solve the problems of slow progress of GnRH inhibitor research and other problems
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[0112] The preparation method of compound VI is shown in the following synthetic route 2:
[0113]
[0114] In an inert solvent (such as dichloromethane), the compound of formula XII and m-chloroperoxybenzoic acid undergo Bayer-Villiger oxidative rearrangement, and then further hydrolyze to obtain compound VI; wherein, R 8 , R 9 , R 10 , R 12 The definition is the same as before.
[0115] The preparation method of compound X is shown in the following synthetic route three:
[0116]
[0117] Active amide ester formula X is formed by acylation of the compound of formula XIII; wherein, R 11 The definition is the same as before.
[0118] Pharmaceutical compositions and methods of administration
[0119] Since the compound of the present invention has excellent inhibitory activity on gonadotropin-releasing hormone, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compou...
Embodiment 1
[0139] Example 1 prepares 3-(5-((2,3-difluoro-6-(methoxy-d 3 )phenyl)methoxy-d 2 )-2-fluoro-4-(methoxy-d 3 )phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 1)
[0140]
[0141] 1. Preparation of 2,3-difluoro-6-(methoxy-d 3 ) methyl benzoate (compound 3)
[0142] At room temperature, compound 2,3-difluoro-6-hydroxybenzoic acid (5.0g) and N,N-dimethylformamide (30ml) were added to the reaction flask, stirred and dissolved, and the reaction solution was clarified; potassium carbonate ( 12.2g), stirred for 30min, slowly added deuteroiodomethane (10.0g) dropwise, after the dropwise addition, the temperature was raised to 40°C, stirred for 15-20h, and detected by thin layer chromatography; after the reaction was completed, water (60ml), ethyl acetate Esters (60ml), stirred for 30min, extracted twice, combined organic phases, washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure to obtain an oily ...
Embodiment 2
[0167] Example 2 Preparation of 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy-d 2 )-2-fluoro-4-(methoxy-d 3 )phenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid (compound 17)
[0168]
[0169] By the method described in Example 1, the difference is: in the steps from formula (II) to formula (III) according to the synthetic route, replace deuteromethyl iodide (CD) with methyl iodide 3 1), thereby obtaining target compound 17. 1 H NMR (400MHz, DMSO-d 6 )δ:14.55(s,1H),12.02(s,1H),7.51-7.44(m,1H),7.40(s,1H),7.26(d,J=7.2Hz,1H),7.13(d,J =11.6Hz, 1H), 6.93-6.90(m, 1H), 3.81(s, 3H). ESI-MS m / z 514[M+H] + .
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