Highly active drug combination for treatment of hepatitis c virus
A pharmaceutical dosage form and pharmacy technology, applied in drug delivery, antiviral agents, organic active ingredients, etc., can solve problems such as increased drug resistance
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Embodiment 3
[0153] The crystallization studies of Example 3 also yielded two other solid crystalline salt forms of Compound 2, the dinitrate salt (Compound 2-B) and the dihydrobromide salt (Compound 2-C). These crystalline forms are very solvent specific. Although studied in four other solvents, compound 2-B is only in CH 3 CN was a crystalline solid when tested, and CH 3 CN is not suitable for pharmaceutical use. Compound 2-C is a crystalline solid only in i-PrOH, while in H 2 Not in O. The XRPD pattern of the isolated crystalline form of the dinitrate salt of compound 2 is provided at figure 2 Among them, the XRPD pattern of the isolated crystalline form of the dihydrobromide salt of compound 2 is provided in image 3 middle.
[0154] In another embodiment, Compound 2 is administered as the pharmaceutically acceptable bisnitrate salt Compound 2-B.
[0155]
[0156] The present invention also describes the crystalline form of the bisnitrate salt of Compound 2 (Compound 2-B). ...
Embodiment 1
[0290] Embodiment 1. Synthesis of compound 1
[0291]
[0292] Step 1: (2R,3R,4R,5R)-5-(2-Amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4 -Synthesis of Methyltetrahydrofuran-3-ol (1-2)
[0293] Add methanol (30L) to the 50L flask and stir at 10±5°C. NH at 10±5°C 2 CH 3 (3.95Kg) was slowly passed into the reactor. Compound 1-1 (3.77 kg) was added in portions at 20±5°C and stirred for 1 hour to obtain a clear solution. The reaction was stirred for an additional 6-8 hours at which point HPLC indicated that the intermediate was less than 0.1% of the solution. Solid NaOH (254 g) was added to the reactor, stirred for 30 minutes and concentrated at 50±5°C (vacuum: -0.095). To the resulting residue was added EtOH (40 L) and reslurried at 60 °C for 1 h. The mixture was then filtered through celite, and the filter cake was reslurried with EtOH (15 L) at 60 °C for 1 h. The filtrate was filtered again, combined with the previously filtered filtrate, and then c...
Embodiment 2
[0298] Embodiment 2. Synthesis of compound 1-A
[0299]
[0300] To a 250 mL flask was added MeOH (151 mL) and the solution was cooled to 0-5 °C. Concentrated H was added dropwise over 10 min 2 SO 4 solution. Compound 1 (151 g) and acetone (910 mL) were added to another flask, and H was added dropwise at 25-30 °C over 2.5 h 2 SO 4 / MeOH solution. A large amount of solid precipitated out. After stirring the solution at 25-30°C for 12-15 hours, the mixture was filtered, washed with MeOH / acetone (25mL / 150mL), and dried in vacuo at 55-60°C to give compound 1-A (121 g, 74% ). 1 HNMR: (400MHz, DMSO-d 6 ): δ8.41(br,1H),7.97(s,1H),7.36(t,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.17(t,J=8.0Hz ,1H),6.73(s,2H),6.07(d,J=8.0Hz,1H),6.00(dd,J=12.0,8.0Hz,1H),5.81(br,1H),4.84-4.73(m, 1H), 4.44-4.28(m, 3H), 4.10(t, J=8.0Hz, 2H), 3.85-3.74(m, 1H), 2.95(s, 3H), 1.21(s, J=4.0Hz, 3H ),1.15-1.10(m,9H).
[0301] Example 3. Salt Research of Compound 2
[0302] As shown in Table 1, 16 acids (4 i...
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