Pradefovir crystal

A technology of crystal and volume ratio, which is applied in the fields of pill delivery, digestive system, metabolic diseases, etc. It can solve the problems of unpublished compound crystallography, difficulty in obtaining single crystals, complex crystal distribution, etc., and achieve long-term storage, good temperature and moderate stability, high purity effect

Active Publication Date: 2012-12-19
XIAN XINTONG PHARM RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prior art does not disclose or suggest a crystallographic study of the compound
[0005] Moreover, the compound is crystallized, and the crystal distribution is very complicated, and polycrystals form polycrystals, and it is not easy to obtain single crystals

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (+)-cis-9-{2-[4-[(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorin-2-methylene] Preparation and identification of type I crystal form of -1-ethyl}adenine mesylate

[0027] 1. Compound Synthesis

[0028] (+)-cis-9-{2-[4-[(S)-(3-chlorophenyl)-2-oxo-1,3,2- Dioxaphosphorane-2-methylene]-1-ethyl}adenine mesylate.

[0029] Specific steps are as follows:

[0030] step 1:

[0031]

[0032] Regent

[0033] Adefovir (1.25g, 4.58mmol) and N,N-methylformamide (0.5g, 4.95mmol) were added to 35ml of dichloromethane, and oxalyl chloride (1.4ml) was slowly added dropwise. The solvent was concentrated under reduced pressure to obtain a crude product, which was dissolved in 25 ml of dichloromethane, and the temperature was controlled at 0°C, and pyridine (0.75 mL, 9.16 mmol) was slowly added. Then the temperature was lowered to -78°C, and another part of dichloromethane (15mL) solution containing compound 5 (0.85g, 4.58mmol) and triethylamine (3.7mL, 29.06mmol) was added...

Embodiment 2

[0041] (+)-cis-9-{2-[4-[(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorin-2-methylene] Preparation and identification of the II crystal form of -1-ethyl}adenine mesylate

[0042] Add 1.2 g of the powder obtained in the above Example 1 "Synthesis of Compounds" into 60 ml of methanol containing 55% (V / V) water, stir while heating to 55 ° C until completely dissolved, then cool to 25 ° C, and find that The crystals were precipitated, filtered with suction to retain the crystals, and then directly dried in an oven at 55°C. The obtained crystal powder was tested with a PHI-5400 X-ray photoelectron analyzer (purchased from PE Company in the United States), and the test parameters were: voltage: 46kv, current: 40mA, copper kα radiation, λ: Test results such as figure 2 As shown in Table 2, it shows that stable type II single crystal can be obtained by this method.

[0043] Table 2 Peak List of Type II Crystals

[0044] Peak No.

[0045] 15

Embodiment 3

[0047] Stability Comparison of Crystals of the Invention and Compounds of the Prior Art

[0048] This example describes the crystals of the present invention (Type I crystals prepared in Example 1 and Type II crystals prepared in Example 2, respectively numbered as sample 1 and sample 2) and according to the prior art (Chinese patent application 200510098771.X, The number is sample 3) The stability comparison experiment of the compound prepared.

[0049] The high-temperature stability test was carried out at 65° C., and the results are shown in the table below, which shows that the crystal of the present invention has more high-temperature stability than the prior art.

[0050]

[0051] The stability test was carried out at 40°C for 6 months, and the results are shown in the table below, which shows that the crystals of the present invention are more stable under long-term storage than those of the prior art.

[0052]

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Abstract

The invention discloses a crystal of (+)-cis-9-(2-(4-((S)-(3-chlorphenyl)-2-oxygen-1, 3, 2-dioxo phosphorus heterocyclic hexa-ring-2-methylene)-1-ethyl) adenine mesylate (Pradefovir), a drug of the crystal, a preparation method of the crystal and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to (+)-cis-9-{2-[4-[(S)-(3-chlorophenyl)-2-oxo-1,3,2 - Crystals of dioxaphosphacycline-2-methylene]-1-ethyl}adenine mesylate (Pdefovir) and its medicines and preparation methods. Background technique [0002] (+)-cis-9-{2-[4-[(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorin-2-methylene] The structure of -1-ethyl}adenine methanesulfonate (Pradfovir) is shown in formula (I): [0003] [0004] The compound is a prodrug compound of adefovir among the prodrug compounds disclosed in Chinese Patent No. 200510098771.X, and can be used for treating or preventing liver diseases or metabolic diseases, including hepatitis B and the like. However, the prior art does not disclose or suggest crystallographic studies of this compound. [0005] Moreover, when the compound is crystallized, the crystal distribution is very complicated, and polycrystals form polycrystals,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6574C07C309/04C07C303/44A61K31/675A61K9/20A61P1/16A61P3/00A61P31/20
Inventor 张登科李旭
Owner XIAN XINTONG PHARM RES CO LTD
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