Preparation method of P2Y2 receptor stimulant diquafosol tetrasodium

The technology of a receptor agonist and tetrasodium fossodium is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc. It can solve the problems of high price, low economic benefit, and scale-up, and achieve easy industrial production, Simple process and high yield

Pending Publication Date: 2020-07-28
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material UTP price that this method uses is comparatively high and the instability of UTP has limited the enlargement of the industrial scale of this method
South Korea Co., Ltd. Zhong Gentang patent (CN109096346A) synthetic route uses UDP as the starting material for the reaction, adopts the method of one-pot cooking, and under the action of the activated condensing agent and metal chloride, the two molecules of UDP undergo condensation reaction to obtain the target product diquafosol Sodium, this method uses the most expensive UDP as the starting material for the reaction, the economic benefit is low, and the price of the anion resin used in the separation and purification is relatively high, which is not conducive to large-scale industrial production

Method used

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  • Preparation method of P2Y2 receptor stimulant diquafosol tetrasodium
  • Preparation method of P2Y2 receptor stimulant diquafosol tetrasodium
  • Preparation method of P2Y2 receptor stimulant diquafosol tetrasodium

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Embodiment 1

[0018] Embodiment 1: Preparation of uridine monophosphate diisobutylbutylamine salt

[0019]

[0020] Uridine monophosphate disodium salt (1000g, 2.72mol) was dissolved in deionized water (10L). Butylamine (1007.6g, 5.44mol) was salified, and after stirring at room temperature for 12 hours, the above-mentioned solution that had been concentrated into a salt in vacuo became an oil, and its water content was controlled below 1%. The oily substance of uridine monophosphate diisobutylbutylamine salt was obtained, and 3 L of DMF was added to dissolve the oily substance to obtain a DMF solution of uridine monophosphate diisobutylbutylamine salt, which was stored for future use.

Embodiment 2

[0021] Embodiment 2: Preparation of diisobutylbutylamine pyrophosphate

[0022]

[0023] Tetrasodium pyrophosphate (361.6g, 1.36mol) was dissolved in deionized water (10L), the aqueous solution was passed through a strong acid type cation exchange resin (Amberlite 732 proton type), the effluent containing pyrophosphate was combined, and diisobutyl Butylamine (503.8g, 2.72mol) was salted, and after stirring at room temperature for 12 hours, the above solution that had been concentrated into a salt in vacuo became an oil, and its water content was controlled below 1%. The oily substance of diisobutylbutylamine pyrophosphate was obtained, and 3 L of DMF was added to dissolve the oily substance to obtain a DMF solution of diisobutylbutylamine pyrophosphate, which was stored for future use.

Embodiment 3

[0024] Embodiment 3: Preparation of imidazole diisobutylbutylamine pyrophosphate

[0025]

[0026] In the DMF solution of diisobutylbutylamine pyrophosphate, add 1,1-carbonyldiimidazole (441.1 g, 2.72 mol) as an activator, stir at room temperature for 6 hours, add excess methanol to quench the unreacted CDI, Stir at room temperature for 1 hour, then concentrate in vacuo to remove excess methanol, and obtain a DMF solution of imidazole diisobutylbutylamine pyrophosphate and store it for future use.

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Abstract

The invention discloses a preparation method of a P2Y2 receptor stimulant, namely diquafosol tetrasodium. The preparation method comprises the following steps: salifying a pyrophosphoric acid compoundas shown in a formula II and long-chain organic amine to obtain a compound as shown in a formula III; activating the compound as shown in the formula III with carbonyl diimidazole to obtain a pyrophosphoric acid active compound as shown in a formula IV; salifying an uridine monophosphate compound as shown in a formula V and long-chain organic amine to obtain a compound as shown in a formula VI; and finally, reacting the compound as shown in the formula IV and the compound as shown in the formula VI in a hydrophilic solvent under the catalysis of Lewis acid to obtain the target product diquafosol tetrasodium as shown in a formula I. According to the method, cation exchange resin is used for treating reaction raw materials which are low in price and easy to obtain and store, organic alkaliand the reaction raw materials are used for salifying to improve thermal stability, and finally, a target product is obtained through anion exchange chromatography purification. The method is efficient, and the produced P2Y2 receptor stimulant is easy to separate and high in yield.

Description

technical field [0001] The invention relates to the technical field of organic chemistry, in particular to a preparation method of a P2Y2 receptor agonist diquafosol tetrasodium. Background technique [0002] Diquafosol Tetrasodium (Diquafosol Tetrasodium; compound I; chemical name: P1, P4-Di (Uridine-5'-Tetraphosphate) is a potent P2Y2 receptor agonist, and its structural formula is as follows: [0003] [0004] Dry eye is the most common eye disorder that can cause eye discomfort and visual impairment. In recent years, due to the increasing use of mobile phones and computers, etc., the incidence of dry eye disease has generally increased. Therefore, many research groups are committed to exploring P2Y family receptor agonists to obtain new methods for the treatment of dry eye disease. Diquafosol tetrasodium (I) discovered by Inspire Pharmaceuticals is a potent P2Y2 receptor agonist. Due to its great potential in the treatment of dry eye syndrome, it was licensed to Sa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00A61P27/02
CPCC07H19/10C07H1/00A61P27/02
Inventor 李志裕王海卞金磊徐鹏飞屠永锐范新华孙永强彭鹏
Owner CHINA PHARM UNIV
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