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Preparation method of high chiral purity efavirenz intermediate

A technology of efavirenz and chiral purity, which is applied in the field of preparation of efavirenz intermediates with high chiral purity, can solve the problems of reduced yield, low refined yield, and no discovery, and achieve low cost and high yield High, easy-to-operate effect

Inactive Publication Date: 2019-05-17
YANCHENG DESANO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Patent CN101786959A discloses a synthetic method of efavirenz intermediate, using 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone as raw material, through asymmetric synthesis reaction , washed with citric acid, the organic layer was concentrated to dryness, dissolved in a polar solvent, crystallized by adding a non-polar solvent or concentrated polar solvent to prepare an efavirenz intermediate with a chiral purity ≥ 99.0% ; This method can prepare the efavirenz intermediate with chiral purity ≥ 99.0%, but the refining yield is low and is not suitable for large-scale production
[0007] Patent WO2012048887A1 discloses a synthesis method of efavirenz intermediate, using 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone as raw material, through asymmetric synthesis reaction , washed with citric acid, after the organic layer was concentrated to dryness, toluene and isopropanol were added, and then methanesulfonic acid was added to prepare the methanesulfonate of the efavirenz intermediate, with a chiral purity ≥ 99%; the method can The efavirenz intermediate with a chiral purity ≥ 99% was prepared, but a new methanesulfonic acid salt-forming process was added, and the subsequent preparation of the efavirenz intermediate with alkali was required. At the same time, methanesulfonic acid can make efavirenz Decomposition of Viren intermediates produces acid-degraded impurities, reducing the purity and yield of the final efavirenz product
[0008] Patent US20120264933 discloses a synthesis method of efavirenz intermediate, using 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone as raw material, through asymmetric synthesis reaction , wash with citric acid, concentrate the organic layer to dryness, add methanol to dissolve, drop water to crystallize to obtain the crude product, and then refine it with toluene to obtain the efavirenz intermediate with chiral purity ≥ 99.7%; the method is first refined with methanol-water To the crude product, then refined with toluene, the twice refined results in a decrease in yield, which is not suitable for industrial production
[0009] In summary, the chiral purity of the efavirenz intermediates prepared in the existing literature is basically ≥99.0%, and the highest is 99.8%, and no efavirenz intermediates with chiral purity ≥99.90% have been prepared. For this reason, our company has developed a method with simple operation, high yield and convenient industrial production to prepare efavirenz intermediates with chiral purity ≥ 99.90%, even as high as 100%

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  • Preparation method of high chiral purity efavirenz intermediate
  • Preparation method of high chiral purity efavirenz intermediate
  • Preparation method of high chiral purity efavirenz intermediate

Examples

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Embodiment 1

[0038] The preparation method of a high chiral purity efavirenz intermediate provided in this example specifically comprises the following steps:

[0039] Step (1): Add 15.71g of crude efavirenz intermediate (97.6% chiral purity) and 9.9g of methyl tert-butyl ether into the reaction flask, heat up to 55°C, stir and dissolve, and wait until the intermediate of Favirenz After the body crude product is completely dissolved, keep it warm for 30 minutes;

[0040] Step (2): Keeping at 50-55°C, slowly add 105.26g of n-heptane dropwise into the solution system of step (1), a large amount of solids will precipitate out during the dropping process;

[0041] Step (3): After the dropwise addition, slowly lower the temperature to 15°C, heat and crystallize for 1h, filter, wash with n-heptane, and dry to obtain 11.32g of efavirenz intermediate, with a chiral purity of 100% and a yield of 72.06% .

Embodiment 2

[0043] The preparation method of a high chiral purity efavirenz intermediate provided in this example specifically includes the following steps:

[0044] Step (1): Add 15.6g of crude efavirenz intermediate (97.6% chiral purity) and 9.83g of methyl tert-butyl ether into the reaction flask, heat up to 55°C, stir and dissolve, and wait until the intermediate of Favirenz After the body crude product is completely dissolved, keep it warm for 30 minutes;

[0045] Step (2): Keeping at 50-55°C, slowly add 104.52g of n-heptane dropwise into the dissolution system of step (1), a large amount of solids will precipitate out during the dropping process;

[0046] Step (3): After the dropwise addition, lower the temperature to 32°C, maintain a negative pressure of -0.01 to -0.09MPa, keep the temperature at 30 to 32°C, and concentrate 31.68g of the mixed organic solvent under reduced pressure;

[0047] Step (4): Slowly lower the temperature to 15° C., heat and crystallize for 1 h, filter, wa...

Embodiment 3

[0049] The preparation method of a high chiral purity efavirenz intermediate provided in this example specifically comprises the following steps:

[0050] Step (1): Add 15.64g of crude efavirenz intermediate (97.6% chiral purity) and 9.85g of methyl tert-butyl ether into the reaction flask, heat up to 55°C, stir and dissolve, and wait until the intermediate of efavirenz After the body crude product is completely dissolved, keep it warm for 30 minutes;

[0051] Step (2): Keeping at 50-55°C, slowly add 104.79g of n-heptane dropwise into the solution system of step (1), a large amount of solids will precipitate out during the dropping process;

[0052] Step (3): After the dropwise addition, lower the temperature to 32°C, maintain a negative pressure of -0.01 to -0.09MPa, keep the temperature at 30 to 32°C, and concentrate 31.72g of the mixed organic solvent under reduced pressure;

[0053] Step (4): crystallize at 30-32°C for 1 hour, filter, wash with n-heptane, and dry to obtai...

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Abstract

The invention discloses a preparation method of a high chiral purity efavirenz intermediate. The preparation method specifically comprises the following steps that step (1) a crude product of efavirenz intermediate is mixed with beneficial organic solvent and heated, and heat preservation is conducted after the crude product of efavirenz intermediate is completely dissolved; step (2) the certain temperature is maintained, and a harmful organic solvent is slowly added into the dissolution system in the step (1); step (3) after adding is completed, the certain temperature is maintained, and thecertain amount of mixed organic solvent is subjected to decompression concentration; and step (4) cooling crystalization, filtration, washing and drying are conducted, and the high chiral purity efavirenz intermediate is obtained. The preparation method is easy to operate, high in yield, and convenient for industrial production, and the chiral purity of the prepared efavirenz intermediate is higher than 99.90% and even as high as 100%.

Description

technical field [0001] The invention relates to a preparation method of an efavirenz intermediate with high chiral purity, belonging to the field of drug synthesis. Background technique [0002] Efavirenz, also known as Efavirenz, is a pure optical isomer, its S-isomer is used in medicine, and its R-isomer has almost no biological activity. It was approved by the US FDA in 1998 for anti-human Immunodeficiency virus infection is the preferred drug for non-nucleoside reverse transcriptase inhibitors recommended by the current international AIDS treatment guidelines. Efavirenz combined with two nucleoside reverse transcriptase inhibitors can be used as the first-line treatment for HIV infection. [0003] Efavirenz intermediate, chemical name (S)-1-(2-amino-5-chlorophenyl)-1-trifluoromethyl-3-cyclopropyl-2-propyn-1-ol, is The S-isomer is a key intermediate for the synthesis of efavirenz, and the chiral purity of this intermediate directly affects the chiral purity of efavirenz...

Claims

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Application Information

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IPC IPC(8): C07C215/70C07C213/10C07C213/00
Inventor 汪守军杨续生张超吴德全
Owner YANCHENG DESANO PHARMA CO LTD