Dinucleotide crystals

A technology for crystallization and uridine, applied in the field of P1-P4-tetraphosphate or a pharmaceutically acceptable salt thereof, to prepare the crystallization, can solve the problems that it cannot be used as a practical method and the synthesis yield is low

Inactive Publication Date: 2002-07-17
MERCK & CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the conventional method provides very low synthetic yields; i.e. as low as about 9% by weight (see Example 20 of WO 98 / 24942), and may never be a practical method

Method used

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Embodiment 1

[0044] The present invention will be described in more detail through examples below, but the examples do not limit the present invention. Example 1 Preparation of dCP4U·4Na crystals (1) Method using DCC

[0045] dCP4U was prepared by the application of UTP, dCMP and DCC by conventional methods as described in WO 98 / 34942. Reactions were performed on a 20 mmol scale.

[0046] The dCP4U solution thus obtained was diluted with water to adjust to a total volume of 1000 ml, and the diluted solution was loaded on a column of a moderately basic anion exchange resin (AMBERLITE IRA-67, product of Rohm & Hass Co.). Fractions containing dCP4U were collected by sequentially eluting with water, 0.18M aqueous hydrochloric acid solution, and 0.005M aqueous hydrochloric acid solution containing 0.5M sodium chloride.

[0047] The thus obtained dCP4U fraction (4000 ml) was applied to a column with chromatography-grade activated carbon (Taiko Granular Activated Charcoal SGP, product of Futamu...

Embodiment 2

[0096] (13) 39.3 Example 2: Synthesis of dCP4U initiated by UMP

[0097] Formamide (2.5 ml) and pyridine (7.6 ml) were added to triethylamine salt (10 mmol) of anhydrous pyrophosphoric acid (TEA-PPi), followed by stirring the resulting mixture. To tributylamine salt of anhydrouridine 5'-monophosphate (UMP-TBA) (10 mmol) in another vessel was added DMAC (3.6 ml), dioxane (3.2 ml), and tributyl Amine (3.3ml) was stirred and DPC (2.3ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hour, whereby UMP-DPP was formed, which was added to the previously prepared dehydrated TEA-PPi solution described above. The reaction mixture was stirred at room temperature for 1 hour, resulting in UTP. To the tributylamine salt of 2'-deoxycytidine 5'-monophosphate (TBA-dCMP) (4.9 g, 10 mmol) in another vessel was added DMAC (7.2 ml), thereby forming a suspension, And DPC (2.2ml, 1.1 equiv) was added to the suspension. The resulting mixture was stirred for 40 minut...

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Abstract

The present invention is directed to crystals of P<1>-(2'-deoxycytidine 5'-)P<4>-(uridine 5'-)tetraphosphate (dCP4U) or a salt thereof and to a process for producing the crystals. The present invention also provides a process for producing dCP4U involving reacting uridine 5'-monophosphate (UMP), 2'-deoxycytidine 5'-monophosphate (dCMP), diphenyl phosphochloridate (DPC), and pyrophosphate (PPi). The crystals of dCP4U obtained through the process according to the present invention have high purity and high stability and no hygroscopicity as compared with a freeze-dried product, and thereby serve as a useful raw material for preparing a pharmaceutical. The process for producing dCP4U according to the present invention permits use of inexpensive UMP as a raw material and realizes high yield. Thus, the process is suitable for large-scale synthesis of dCP4U.

Description

field of invention [0001] The present invention relates to P 1 -(2'-deoxycytidine 5'-)P 4 -(Uridine 5'-)tetraphosphate (dCP4U) or a pharmaceutically acceptable salt thereof (hereinafter may simply be referred to as "dCP4U"), which is suitable as a therapeutic agent for chronic bronchitis, sinusitis, etc.; the present invention relates to the preparation A method of said crystallization; and relates to a method of efficiently preparing dCP4U. Background technique [0002] dCP4U represented by the following formula (I): or a salt thereof is a selective agonist for P2Y2 purinoceptor and / or P2Y4 purinoceptor, and is a compound expected to be developed as a therapeutic agent for chronic bronchitis, sinusitis, etc. (see WO 98 / 34942). [0003] To date, dCP4U has not been obtained in crystalline form, and dCP4U can only be obtained in the form of a white powder (white solid) by freeze-drying. The conventionally obtained powdery product of dCP4U has a low purity of 82% (determin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/06C07H21/00
CPCC07H21/00C07H1/06C07H19/10
Inventor 盛健也宫下孝德前田秀明佐藤浩史野田丰
Owner MERCK & CO INC
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