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Crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate, and preparation method of corresponding crystals thereof

A technology of benzoate and phenoxybutane, applied in (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybutan-1- The crystal form of alken-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-yl benzoate and the field of preparation of corresponding crystals, which can solve the difficulty in effectively separating 2 and 7 and other problems to achieve the effect of simplifying the purification process

Inactive Publication Date: 2014-05-28
TIEN TIANJIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is also difficult to effectively separate 2 and 7 using column chromatography

Method used

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  • Crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate, and preparation method of corresponding crystals thereof
  • Crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate, and preparation method of corresponding crystals thereof
  • Crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate, and preparation method of corresponding crystals thereof

Examples

Experimental program
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preparation example Construction

[0037] The preparation method one of formula 2 compound:

[0038] (1) Mix the crude product of the compound of formula 2 with solvent a and heat to dissolve to obtain solution a,

[0039] (2) Cool the solution a, and precipitate the crystal of the compound of formula 2.

[0040] The solvent a includes methanol, ethanol, isopropanol, and acetonitrile; the ratio of the compound of formula 2 to the solvent a is 0.1-0.5 (m:V).

[0041] The heating temperature is preferably 30-70°C, more preferably 30°C, 40°C, 50°C, 60°C or 70°C; cooling means cooling to below 10°C.

[0042] The crystallization process can be accelerated by adding seed crystals of the compound of formula 2 before cooling.

[0043] The preparation method two of formula 2 compound:

[0044] (1) heating and dissolving the crude compound of formula 2 with solvent b to obtain solution b;

[0045] (2) Add a solvent c immiscible with the compound of formula 2 into the solution b, cool down, and precipitate the compoun...

Embodiment 1

[0061] Mix 15 grams of the crude product of 2 (HPLC 75%) with 40 ml of ethanol, heat to about 50°C to dissolve, then cool down, the system appears turbid at about 40°C, add a small amount of seed crystals, cool to 10°C, stir for 2 hours, filter, and dry , to obtain 8.0 grams of white powder, HPLC96.3%; recrystallize once with 25 milliliters of ethanol to obtain 6.8 grams of white powder, HPLC99.8%.

Embodiment 2

[0063] Mix 15 g of the crude product of 2 (HPLC 75%) with 60 ml of acetonitrile, heat to about 40°C to dissolve and cool down, the system appears turbid at about 30°C, cool to 10°C, stir for 3 hours, filter, and dry to obtain 8.1 g of white Powder, HPLC96.5%; recrystallized once with 40 ml of acetonitrile to obtain 7.0 g of white powder, HPLC99.7%.

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Abstract

The invention provides a crystal form of (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxylbutyl-1-alkyl-1-yl)-2-oxohexahydro-2H-cyclopentane[b]furan-5-benzoate (a tafluprost intermediate, a difluorination product 2), and a preparation method of corresponding crystals of the crystal form. Crystal form parameters comprise characteristic peak values (2theta) of the XRPD spectrum of the crystals, and DSC and IR characteristic atlas parameters. White crystal powder of the product 2 is obtained through single solvent or mixed solvent recrystallization by adopting a simple crystallization method, the primary crystallization purity is greater than 90% generally, the highest purity after secondary crystallization reaches 99.8%, and the proportion of each of all unimodal impurities is lower than 0.1%, so the purification process of tafluprost synthesized by using the product 2 as a raw material is substantially simplified.

Description

[0001] (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)-2-oxohexahydro-2H-ring A crystal form of pentane [b] furan-5-ylbenzoate and preparation method of corresponding crystal technical field [0002] The invention relates to a new method for crystallization and purification of a tafluprost intermediate and crystal data. Background technique [0003] Tafluprost, a new prostaglandin derivative launched by Merk, is the first preservative-free prostaglandin analogue eye drops for the treatment of open-angle glaucoma. The mescleral route drains, thereby reducing intraocular pressure. [0004] The synthesis of tafluprost generally adopts Corey Lactone as raw material, through oxidation, connecting omega chain, fluorination, DIBAL reduction, Wittig reaction, esterification and corresponding protection and deprotection steps to obtain the final product, such as Tetrahedron Letters45(2004) 1527 -1529), EP0850926. Where (3aR,4R,5R,6aS)-4-((E)-3,3-difluoro-4-phenoxybut-1...

Claims

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Application Information

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IPC IPC(8): C07D307/935
CPCC07D307/935
Inventor 杨波李延华
Owner TIEN TIANJIN PHARMA
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