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Preparation method of Tafluprost crude drug

A technology of tafluprost and raw materials, applied in the field of pharmacy, can solve the problems of many times of refining, low yield, high price, etc., and achieve the effect of high product purity, strong operability and strong repeatability

Active Publication Date: 2018-12-21
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After repeating this patent for the purification of trans isomers, it was found that the crystals were viscous, and it was difficult to enlarge the crystallization. After the amplification, the purification efficiency of trans isomers decreased, the number of refining times increased, and the yield decreased.
The Chinese patent application with the application number CN201310166937.1 adopts the preparative HPLC separation and purification method to prepare tafluprost with a purity of 98.64%, a trans isomer purity of 0.08%, and a total impurity of 1.28%. Individual impurity content requirements
And because the price of tafluprost raw material drug is extremely expensive, about 1kg / 10 million yuan, the method reported in WO2013118058A1 has more refining times and lower yield, which greatly increases the cost of raw material drug synthesis
The tafluprost obtained by the preparation method of patent CN201310166937.1 has low purity, high total impurity content, and unknown single impurity purity, which cannot meet the quality standard requirements of pharmaceutical raw materials

Method used

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  • Preparation method of Tafluprost crude drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1, Example 2 (directly proceed to Example 3) and Example 3 without using the subsequent L-arginine salt-forming and refining process, but are not limited to this method.

[0045] In the following examples, unless otherwise specified, all are common commercially available products.

[0046] Example 1

[0047] Preparation and separation of high-efficiency preparative liquid phases

[0048] Preparation of diluent: Add 20ml of isopropanol into 80ml of n-hexane at room temperature, stir to make it evenly mixed.

[0049] Sample preparation: take 25 g of crude tafluprost with a purity of 90% (trans isomer content 0.81%), add 100 ml of diluent, dissolve the sample at room temperature, and filter with a 0.22 μM filter membrane.

[0050] Prepare the mobile phase: add 15 L of isopropanol to 85 L of n-hexane, stir evenly, and filter with a 0.22 μM filter membrane.

[0051] Preparation method: The total running time of each needle sample is 13min, the detection wavelength...

Embodiment 2

[0055] Preparation and separation of high-efficiency preparative liquid phases

[0056] Preparation of diluent: Add 15ml of isopropanol into 85ml of n-hexane at room temperature, stir to make it evenly mixed.

[0057] Sample preparation: take 10 g of crude tafluprost with a purity of 90% (trans isomer content 1.37%), add 70 ml of diluent, dissolve the sample at room temperature, and filter with a 0.22 μM filter membrane.

[0058] Prepare the mobile phase: add 6L of isopropanol to 34L of n-hexane, stir evenly, and filter with a 0.22 μM filter membrane.

[0059] Preparation method: The total running time of each needle sample is 13min, the detection wavelength is 254nm, and the temperature is 25±5°C. The chromatographic column is a Unichiral OZ-5H normal phase preparative column, 50×250 mm, 5 μM. Each injection volume is 6mL, and the main peak height of the automatic collection is greater than 100mAU. The collected product solutions are combined, concentrated at 40±5°C, and th...

Embodiment 3

[0063] Preparation and separation of high-efficiency preparative liquid phases

[0064] Preparation of diluent: Add 20ml of isopropanol into 80ml of n-hexane at room temperature, stir to make it evenly mixed.

[0065] Sample preparation: take 14.5 g of crude tafluprost with a purity of 90% (0.45% trans-isomer content), add 58 ml of diluent, dissolve the sample at room temperature, and filter with a 0.22 μM filter membrane.

[0066] Prepare the mobile phase: add 9 L of isopropanol to 53 L of n-hexane, stir well, and filter with a 0.22 μM filter membrane.

[0067] Preparation method: The total running time of each needle sample is 13min, the detection wavelength is 254nm, and the temperature is 25±5°C. The chromatographic column is a Unichiral OZ-5H normal phase preparative column, 50×250 mm, 5 μM. Each injection volume is 4.5mL, the main peak height is automatically collected and the peak height is greater than 100mAU, the collected product solutions are combined, concentrate...

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Abstract

The invention discloses a preparation method of a tafluprost crude drug. The preparation method comprises the following steps: preparing and separating by adopting a high-performance preparation liquid phase, and pulping C6 to C8 alkane. The preparation method of the invention is stable in process, and high in operability. The total purity of the prepared Tafluprost is greater than 99.5 percent, the content of trans isomer impurities is less than 0.1 percent, and the content of other monomer impurities is less than 0.1 percent.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a method for preparing tafluprost by efficiently preparing a liquid phase. Background technique [0002] Tafluprost (Tafluprost) is a new type of prostaglandin analog developed and produced by Japan Santen Co., Ltd. It is mainly used for the treatment of open-angle glaucoma or ocular hypertension in patients with elevated intraocular pressure. The main mechanism of lowering intraocular pressure is to promote the outflow of aqueous humor through the uveal sclera to reduce intraocular pressure. The 15th hydroxyl group in the traditional prostaglandin analog structure is an essential functional group for prostaglandin receptor agonists to exert physiological activity. Tafluprost replaces this functional group with 2 F atoms. As an isopropyl ester, it can be Corneal esterase rapidly hydrolyzes to the free acid form, the active form of the drug. The affinity of tafluprost for the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/736C07C67/56C07C67/48
CPCC07B2200/09C07C67/48C07C67/56C07C2601/08C07C69/736
Inventor 周崴海徐镜人蔡伟李鹏飞周华新范兴宝黄淑萍郝秀斌刘景龙
Owner YANGTZE RIVER PHARM GRP CO LTD
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