A kind of refining method of teprenone and its intermediate

A refining method and technology of teprenone, applied in the field of teprenone refining method and its intermediates, can solve the problems of farnesyl acetone separation and removal difficulties, column chromatography is not suitable for large-scale industrial production, etc.

Active Publication Date: 2022-03-11
CHENGDU GUOHONG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The applicant of the present invention purified the crude product of teprenone according to the vacuum distillation method disclosed in the document, and found that the purity could not be increased to 98%, and when studying the structure and impurity content of individual impurities, it was found that one of the ketone impurities Farnesylacetone is difficult to separate, and its content is always higher than the 0.2% limit of the drug standard
[0006] The further refining method of the reaction product in Chinese patent CN102050714 is to use a molecular distillation device for rectification and purification, but another patent CN103058839 reports that the rectification and purification method of the above-mentioned patent is due to the existence of impurities such as by-products, and impurities and target products The structure is similar, the boiling point is similar, the high-temperature heating process also has a certain influence on the product, and the purity after rectification is difficult to reach more than 98.5%, which is not suitable for large-scale production, and the applicant of this patent further purifies teprenone according to the method disclosed in CN102050714 , found that the highest purity of teprenone can only reach 97%, and the content of ketone impurity farnesyl acetone is higher than the limit of 0.2%. Molecular rectification or more than 2 tower rectifications, or a combination of molecular rectification and tower rectification can be achieved, so repeated 2 rectifications lead to a significant reduction in the yield of the product, and the yield of the refining step is only 50%-60% %, and even if the purity can be increased to 98.5%, the ketone impurity farnesyl acetone can not be reduced to less than 0.2%. The applicant speculates that the structure of farnesyl acetone and the product teprenone may be very similar, except that they are all ketones Except for the substance, the only difference in its molecular structure is that the length of the carbon chain is slightly shorter, the physical and chemical properties are close, and it is difficult to remove it during vacuum distillation or distillation
[0007] Patent CN103058839 reports that the crude product of teprenone is further purified by column chromatography, but it is well known in the art that column chromatography is not suitable for large-scale industrial production, and the method is very inefficient, consumes a large amount of solvent, and has high industrial production costs
Patent CN102627539 discloses the method of further refining teprenone by low-temperature solidification, but this method requires special equipment, and the obtained product is all-trans, and the teprenone required for marketing has not been prepared

Method used

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  • A kind of refining method of teprenone and its intermediate
  • A kind of refining method of teprenone and its intermediate
  • A kind of refining method of teprenone and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Mix 1 mol of crude teprenone {the ratio of monocis-isomer (5Z, 9E, 13E) to all-trans-isomer (5E, 9E, 13E) is 0.61-0.68}, 1w / w methanol (density 0.8 g) and 5w / w water (20% methanol) were added into the flask and stirred evenly, 2mol potassium bisulfite was added, and the reaction was completed under reflux with stirring. The reaction solution was centrifuged to discard the filtrate, and the granular solid in the centrifuge bag was taken out to obtain the intermediate 2-hydroxy-6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene- Potassium 2-sulfonate.

[0074] Add 3w / w water and 2mol potassium hydroxide to the flask, stir until dissolved, then add 3w / w n-heptane, add the intermediate 2-hydroxy-6,10,14,18-tetramethyl obtained in the previous step while stirring base-5,9,13,17-nonadecatetraene-2-sulfonate potassium, and then reacted with stirring at 25~35°C. Stand to separate the layers, discard the water phase, and wash the organic phase with 3×3 w / w water, and let stand ...

Embodiment 2

[0076] 1 mol of crude teprenone {the ratio of monocis-isomer (5Z, 9E, 13E) to all-trans-isomer (5E, 9E, 13E) is 0.61-0.68}, 8.5w / w / tetrahydrofuran ( Density is calculated as 0.9) and 0.5w / w water (95% tetrahydrofuran) are added into the flask and stirred evenly, 2mol sodium bisulfite is added, and the reaction is completed by stirring at -20°C. Centrifuge the reaction solution to discard the filtrate, and take out the granular solid in the centrifuge bag to obtain the intermediate 2-hydroxy-6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2 - sodium sulfonate.

[0077] Add 3w / w water and 2mol hydrochloric acid to the flask, stir until dissolved, then add 3w / w n-heptane, and add the intermediate 2-hydroxy-6,10,14,18-tetramethyl- 5,9,13,17-Nadecatetraene-2-sodium sulfonate, then stirred and reacted at 25~35℃. Stand to separate the layers, discard the water phase, and wash the organic phase with 3×3 w / w water, and let stand overnight. The next day, it was concentrated under r...

Embodiment 3

[0079] 1mol teprenone crude product {the ratio of monocis isomer (5Z, 9E, 13E) to all trans isomer (5E, 9E, 13E) is 0.61-0.68}, 9w / w / DMF (density 0.95) and 0.5w / w water (95% DMF) were added into the flask and stirred evenly, 1mol of potassium metabisulfite was added, and the reaction was completed with stirring at -20°C. The reaction solution was centrifuged to discard the filtrate, and the granular solid in the centrifuge bag was taken out to obtain the intermediate 2-hydroxy-6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene- Potassium 2-sulfonate.

[0080] Add 3w / w water and 1mol barium hydroxide to the flask, stir until dissolved, then add 3w / w n-heptane, add the intermediate 2-hydroxy-6,10,14,18-tetramethyl obtained in the previous step while stirring base-5,9,13,17-nonadecatetraene-2-sulfonate potassium, and then reacted with stirring at 25~35°C. Stand to separate the layers, discard the water phase, and wash the organic phase with 3×3 w / w water, and let stand overnight...

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Abstract

The present invention relates to a refining method of teprenone and an intermediate used in the refining process, specifically to purify teprenone by addition reaction of bisulfite or pyrosulfite with crude teprenone. The purification method provided by the invention has a high purification yield, and the prepared teprenone refined product has high purity, has low requirements on experimental equipment, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for refining teprenone and an intermediate thereof. Background technique [0002] The chemical name of teprenone (teprenone, A) is 6,10,14,18-tetramethyl-5.9.13.17-nonadecatetraen-2-one, which is (5E,9E,13E)-type and ( 5Z, 9E, 13E)-type geometric isomer mixture (3:2), is an anti-peptic ulcer drug launched by Eisai Co., Ltd. in Japan in 1984. [0003] [0004] The listing drug standard of teprenone requires that the purity of teprenone is greater than 98.5%, and the maximum single impurity content cannot exceed 0.2%. The ratio between 13E)-types is between 0.61-0.68. Since this substance is a polyketene compound, it is in a liquid state and is easily oxidized in the air, especially under heating conditions. The purified high-quality standard tip Ritone is technically difficult, and there is no domestic manufacturer of this product on the market. [000...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C45/85C07C49/203C07C303/20C07C309/20
CPCC07C45/85C07C303/20C07C49/203C07C309/20
Inventor 张健郭礼新郭晖
Owner CHENGDU GUOHONG PHARMA
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