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Novel composition of nucleoside amino phospholipid compound and preparation method thereof

A compound, hydrate technology, applied in the field of pharmaceutical preparations

Pending Publication Date: 2018-06-29
南京汇诚制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] During the preliminary prescription research process, the inventors of the present invention found that the solubility and permeability of the compound of formula (1) need to be improved, and it is easy to gather into agglomerates in water, so it brings a huge challenge to the formulation research of this type of compound

Method used

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  • Novel composition of nucleoside amino phospholipid compound and preparation method thereof
  • Novel composition of nucleoside amino phospholipid compound and preparation method thereof
  • Novel composition of nucleoside amino phospholipid compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: (S)-2-[[[(S)-(1,1'-biphenyl-4-oxyl)]-[((2R,3R,4R,5R)-5-(2 ,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxyl-4-methyltetrahydrofuran-2-yl)methoxy]phosphoryl]amino] Preparation of isopropyl propionate

[0086]

[0087] Synthesis of Step 1 (S)-2-[[(1,1'-biphenyl-4-oxyl)(pentafluorophenoxy)phosphoryl]amino]propionic acid isopropyl ester

[0088]

[0089] In a 50L glass reactor, under the protection of nitrogen, add phosphorus oxychloride (1.53kg, 10mol) and dichloromethane (10L), stir, and cool down to below -30°C. A dichloromethane (5 L) solution of triethylamine (1.01 kg, 10 mol) was added dropwise, and the internal temperature was kept below -30°C during the dropwise addition. After the dropwise addition was completed, a solution of 4-hydroxybiphenyl (1.7kg, 10mol) in tetrahydrofuran (3.4L) was slowly added dropwise, and stirred for 30min after the dropwise completion. Control the internal temperature below -30°C, add L-alanine isopropyl hydro...

Embodiment 2

[0098] Example 2: (S)-2-[[[(S)-(1,1'-biphenyl-4-oxyl)]-[((2R,3R,4R,5R)-5-(2 ,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxyl-4-methyltetrahydrofuran-2-yl)methoxy]phosphoryl]amino] Confirmation of the configuration of isopropyl propionate

[0099] Weigh 15 mg of the compound of formula 1a prepared in Example 1 into a 3 mL vial, add 5 mL of dichloromethane / n-heptane mixed solvent system with a volume ratio of 2:1, shake the obtained clear solution, and cover the vial with a parafilm Prick holes on it and place it at room temperature for 6 days to obtain crystals.

[0100] The single crystal sample obtained by the above method is collected by X-ray single crystal diffraction data and its single crystal structure is analyzed. Table 1 lists the single crystal structure data and structure refinement parameters of the n-heptane solvate of the compound of formula 1a. Single crystal structure analysis has determined the absolute configuration of the chiral center in the c...

Embodiment 3

[0103] Example 3 (S)-2-[[[(S)-(1,1'-biphenyl-4-oxyl)]-[((2R,3R,4R,5R)-5 in solid oral form -(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxyl-4-methyltetrahydrofuran-2-yl)methoxy]phosphoryl ]Amino]propionate Isopropyl Preparation

[0104] Table 2. Prescription

[0105] Compound of formula (1a)

25.64

Crospovidone

38.46

microcrystalline cellulose

15.38

lactose

12.82

Croscarmellose Sodium

7.69

total

100.00

[0106] Unit: % by weight (w / w).

[0107] Preparation steps:

[0108] a. mix the compound of formula (1a) with prescription amount, crospovidone and microcrystalline cellulose in a wet granulator, and add an appropriate amount of ethanol to prepare wet granules;

[0109] b. Dry the wet granules;

[0110] c. mixing the dried granules with lactose and croscarmellose sodium;

[0111] d. Fill the mixed granules into capsules.

[0112] The formulation of this embodiment can disintegrate rapidly an...

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PUM

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Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to an oral preparation. The oral preparation is prepared from: (a) a compound shown as a formula (1) or a pharmaceutically-acceptable salt, isomer, solvent compound, hydrate or crystal thereof; and (b) an adsorbent. The invention further relates to a preparation method of the oral preparation and application of the oralpreparation to a medicament for preventing and / or treating hepatitis C. The oral preparation disclosed by the invention can be completely dissolved, is absorbed well in vivo, and has few impurities and high stability. The formula (1) is shown in the description.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, in particular to (2S)-2-((([1,1'-biphenyl]-4-yloxy)(((2R,3R,4R,5R)-5-( 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxyl-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino ) Oral formulation of isopropyl propionate and its preparation method and application. Background technique [0002] Hepatitis C virus (HCV) infection is a worldwide epidemic disease, the global chronic infection has exceeded 200 million, the chronic infection rate is 15% in Egypt, 4.8% in Pakistan, and 3.2% in China, ranking the top three in the world. The clinical manifestations of hepatitis C virus infection are diverse, ranging from mild inflammation to severe liver cirrhosis and liver cancer. Chronic hepatitis C can also be complicated by certain extrahepatic manifestations, including rheumatoid arthritis, conjunctival keratitis sicca, lichen planus, glomerulonephritis, mixed cryoglobulinemia, B-c...

Claims

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Application Information

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IPC IPC(8): A61K31/7072A61K9/16A61K9/20A61K9/48A61P31/14
CPCA61K9/1611A61K9/1635A61K9/1652A61K9/2054A61K31/7072A61K9/0053A61K9/2095A61K9/2027A61K9/205A61K9/2009A61K9/2059A61K9/2018A61K9/2077A61K9/1682A61K9/1623A61P1/16A61P31/14Y02A50/30
Inventor 赵立文束俭辉丁丽莺陈良慧刘倩赵晶晶张先
Owner 南京汇诚制药有限公司
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