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High-purity Latanoprost, preparation method therefor and use of Latanoprost

A latanoprost and high-purity technology, which is applied in the field of high-purity latanoprost and its preparation, can solve the problems that the separation method is not efficient enough, perfect, complicated and difficult to achieve, and is beneficial to industrial production and preparation And the purification process is simple, the effect of removing impurities

Inactive Publication Date: 2017-03-01
SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Yet impurity and product carry out esterification at the same time, its polarity is still very close, so purification is still very difficult, it is difficult to reach and formula II impurity content is controlled below 0.1%
[0015] So far, the separation methods of latanoprost and its related substances are still not efficient and perfect. Looking at the existing technologies, most of the separation methods are complicated and difficult to achieve the desired effect and realize industrial production

Method used

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  • High-purity Latanoprost, preparation method therefor and use of Latanoprost
  • High-purity Latanoprost, preparation method therefor and use of Latanoprost
  • High-purity Latanoprost, preparation method therefor and use of Latanoprost

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Formula IV compound (intermediate 1, R 1 = H, R 2 =H) Preparation of a composition containing latanoprost

[0092]

[0093] In a four-necked bottle, N 2 For protection, put in 4-carboxybutyltriphenylphosphine bromide (247.6g) and THF (270ml), stir, cool to -5°C, add 1mol / L tetrahydrofuran solution (1039ml) of t-BuOK dropwise. The temperature is controlled at -5~0°C, after 1 hour of dripping, stir at this temperature for 40min after dripping, then raise the temperature to 10~15°C and stir for 60min, cool to -30~-20°C, add dropwise 1-1 (41.1g ) THF (410ml) solution, after 1.5h dropwise, maintain the temperature and stir overnight after dropwise. The next day, add saturated ammonium chloride solution (about 350g / L, 400ml) and ethyl acetate (1600ml), stir for 15min after the temperature rises to 10-20°C, separate the layers, and extract the aqueous layer with EA (400ml, 200ml). All organic layers were combined, washed successively with 700ml of saturated ammonium chl...

Embodiment 2

[0097] Formula IV compound (intermediate 1, R 1 = tert-butyldimethylsilyl, R 2 =H) Preparation of a composition containing latanoprost

[0098]

[0099] In a four-necked bottle, N 2 For protection, put in TPBA (247.6g) and THF (270ml), stir, cool to 0-5°C, add 1mol / L tetrahydrofuran solution (1040ml) of t-BuOK dropwise, and control the temperature at -5-0°C during the dropwise addition. After 1 hour of dropping, stir at this temperature for 10 minutes, then raise the temperature to 8-12°C and stir for 45 minutes, cool to -30--20°C, add intermediate 1-2 (47.0g) in THF (370ml) dropwise, After 1.5 hours of dripping, the temperature was maintained and stirred overnight. The next day, add saturated ammonium chloride solution (about 350g / L, 400ml) and EA (1600ml), rise to 10-20°C, stir for 15min, separate the layers, extract the aqueous layer with EA (400ml, 300ml), and combine all organic layer, washed successively with half-saturated ammonium chloride (about 180g / L), satura...

Embodiment 3

[0104] Formula IV compound (intermediate 1, R 1 = R 2 =tetrahydropyranyl) for the preparation of compositions containing latanoprost

[0105]

[0106] In a four-necked bottle, N 2 For protection, put in TPBA (247.6g) and THF (270ml), stir, cool to 0-5°C, add 1mol / L tetrahydrofuran solution (1040ml) of t-BuOK dropwise, and control the temperature at -5-0°C during the dropwise addition. After 1 hour of dropping, stir at this temperature for 10 minutes, then raise the temperature to 8-12°C and stir for 45 minutes, cool to -30--20°C, add intermediate 1-3 (51.0g) in THF (390ml) dropwise, After 1.5 hours of dripping, the temperature was maintained and stirred overnight. The next day, add half-saturated ammonium chloride solution (about 180g / L, 400ml) and EA (1600ml), rise to 10-20°C, stir for 15min, separate the layers, extract the aqueous layer with EA (400ml, 300ml), and combine all The organic layer was washed successively with half-saturated ammonium chloride (about 180g / ...

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Abstract

The invention discloses high-purity Latanoprost, a preparation method therefor and use of the Latanoprost. According to the high-purity Latanoprost disclosed by the invention, the content of an impurity with a structure represented by a formula II shown in the description in the high-purity Latanoprost is not higher than 0.1%. The preparation method comprises the steps: (1) subjecting a compound represented by a formula IV shown in the description (an intermediate 1 of the Latanoprost) to a wittig reaction, so as to obtain a compound represented by a formula V shown in the description (an intermediate 2 of the Latanoprost); (2) subjecting the compound V to washing and purifying by a ammonium chloride solution, then, carrying out dehydroxylation protection or not, and carrying out a reaction with iodo-isopropane, so as to obtain a crude raw pharmaceutical material of the Latanoprost; and (3) loading a sample of the raw pharmaceutical material of the Latanoprost to a silica-gel column, carrying out eluting with an eluate, and carrying out chromatographic purification, thereby obtaining the high-purity Latanoprost.

Description

technical field [0001] The invention relates to the field of medicine purification, in particular to a high-purity latanoprost and its preparation method and application. Background technique [0002] Latanoprost (Latanoprost), structure as shown in formula I: [0003] [0004] is a novel phenyl substituted propyl ester prostaglandin F 2 a, for selective prostaglandin F 2 α-receptor agonists are used in the treatment of glaucoma and ocular hypertension, as well as various diseases of increased intraocular pressure. They are widely used in clinic because of their remarkable curative effect. It is an inactive but rapidly penetrating substance into the cornea where it is hydrolyzed to active free acids in the cornea and plasma. It can increase the outflow of aqueous humor through the corneum layer, and the dosage is small, but it can promote the filling of aqueous humor in a large amount, and the medicinal solution can penetrate into the upper layer of the upper ciliary c...

Claims

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Application Information

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IPC IPC(8): C07C69/732C07C67/48C07C67/10A61K31/5575A61P27/06
CPCC07C51/00C07C51/367C07C51/48C07C67/10C07C67/56C07C69/732C07D307/06C07F7/1892C07C59/54
Inventor 唐志军何兵明杨君季晓铭
Owner SHANGHAI TECHWELL BIOPHARMACEUTICALS CO LTD
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