阅读说明：本技术 Hcv抑制剂的盐及其制备方法 (Salts of HCV inhibitors and process for preparing the same ) 是由 谢洪明 姚加 巫锡伟 方清洪 于 2019-08-05 设计创作，主要内容包括：本发明属于药物领域,涉及HCV抑制剂的盐及其制备方法,具体的涉及N-(6-(3-(叔丁基)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-6-氟-2-甲氧基苯基)萘-2-基)甲磺酰胺的盐及其制备方法；还涉及其组合物和用途。(The invention belongs to the field of medicaments, relates to a salt of an HCV inhibitor and a preparation method thereof, and particularly relates to a salt of N- (6- (3- (tert-butyl) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -6-fluoro-2-methoxyphenyl) naphthalene-2-yl) methanesulfonamide and a preparation method thereof; also relates to compositions and uses thereof.)

A salt of a compound of formula (I):

the salt of claim 1, wherein the salt is a sodium salt, and the sodium salt is a monosodium or disodium salt.

The salt of claim 1 or 2, wherein the salt is a solvate.

The salt of claim 3, wherein the solvate is a hydrate, an ethanol solvate, or a water/ethanol solvate.

The salt of claim 2, wherein the disodium salt is a monohydrate hemiethanolate.

The salt of claim 5, wherein the monohydrate hemiethanolate is form A having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 9.07 ° ± 0.2 °, 13.36 ° ± 0.2 °, 16.15 ° ± 0.2 °, 18.43 ° ± 0.2 ° and 22.18 ° ± 0.2 °; or an X-ray powder diffraction pattern thereof has diffraction peaks at the following 2 theta angles: 5.56 ° ± 0.2 °, 7.18 ° ± 0.2 °, 9.07 ° ± 0.2 °, 13.36 ° ± 0.2 °, 14.76 ° ± 0.2 °, 16.15 ° ± 0.2 °, 17.72 ° ± 0.2 °, 18.43 ° ± 0.2 °, 19.50 ° ± 0.2 ° and 22.18 ° ± 0.2 °; or an X-ray powder diffraction pattern thereof has diffraction peaks at the following 2 theta angles: 5.56 ° ± 0.2 °, 7.18 ° ± 0.2 °, 9.07 ° ± 0.2 °, 13.36 ° ± 0.2 °, 14.76 ° ± 0.2 °, 15.49 ° ± 0.2 °, 16.15 ° ± 0.2 °, 17.72 ° ± 0.2 °, 18.26 ° ± 0.2 °, 18.43 ° ± 0.2 °, 19.50 ° ± 0.2 °, 22.18 ° ± 0.2 °, 23.23 ° ± 0.2 °, 27.57 ° ± 0.2 ° and 28.29 ° ± 0.2 °; or an X-ray powder diffraction pattern substantially as shown in figure 1.

The salt of any of claims 5-6, wherein the monohydrate hemiethanolate is form A having a DSC profile comprising an endothermic peak at 171.65 ℃ ± 3 ℃; or a DSC profile substantially as shown in figure 2.

The salt of any of claims 5-6, wherein the monohydrate hemiethanolate is form A with a TGA weight loss of 7.057 ± 0.7%; or a TGA profile thereof substantially as shown in figure 3.

The salt of claim 2, wherein the disodium salt is amorphous and has an X-ray powder diffraction pattern substantially as shown in figure 6.

A method of preparing a sodium salt comprising: reacting a compound shown as a formula (I) with sodium hydroxide in a first solvent to obtain the sodium salt,

the production method according to claim 10, wherein the first solvent is a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water.

The production method according to claim 11, wherein the first solvent is methanol, ethanol, isopropanol, or acetone; optionally, the volume ratio of water to the hydrophilic organic solvent in the mixed solvent of the hydrophilic organic solvent and water is 1:99 to 50: 50; or the volume ratio of water to the hydrophilic organic solvent in the mixed solvent of the hydrophilic organic solvent and water is 1:99 to 40: 60; or the volume ratio of water to the hydrophilic organic solvent in the mixed solvent of the hydrophilic organic solvent and water is 5:95 to 30: 70; or the volume ratio of water to the hydrophilic organic solvent in the mixed solvent of the hydrophilic organic solvent and water is 10:90 to 30: 70; or the volume ratio of water to the hydrophilic organic solvent in the mixed solvent of the hydrophilic organic solvent and water is 10:90 to 20: 80.

The production method according to claim 10, wherein the molar ratio of the compound represented by the formula (I) to sodium hydroxide is 1:0.5 or more; or the molar ratio of the compound shown in the formula (I) to the sodium hydroxide is more than or equal to 1: 1.5; or the molar ratio of the compound of formula (I) to sodium hydroxide is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8 or 1: 8.5; optionally, the reaction is carried out at 0-100 ℃; or the reaction is carried out at 0-90 ℃; or the reaction is carried out at 10-90 ℃; or the reaction is carried out at 20-80 ℃; or the reaction is carried out at 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃ or 80 ℃.

The production method according to any one of claims 10 to 13, further comprising: slurrying the sodium salt obtained in a second solvent having the same definition as the first solvent.

The production method according to claim 14, wherein the beating is carried out at 0 to 100 ℃; or the beating is carried out at 0-90 ℃; or the pulping is carried out at 10-90 ℃; or the pulping is carried out at 20-80 ℃; or the pulping is carried out at 20 deg.C, 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C or 80 deg.C.

A pharmaceutical composition comprising the sodium salt of any one of claims 1-9 or prepared according to the process of claims 10-15.

The pharmaceutical composition of claim 16, further comprising a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

The pharmaceutical composition of claim 16 or 17, further comprising an additional anti-HCV agent.

Use of the sodium salt of any one of claims 1-9 or the sodium salt prepared by the process of claims 10-15 or the pharmaceutical composition of any one of claims 16-18 in the manufacture of a medicament for inhibiting HCV NS5B protein and/or for preventing, managing, treating or alleviating HCV infection or hepatitis c disease in a patient.