Process for synthesizing and purifying teprenone

Abstract

The invention discloses a process for synthesizing and purifying teprenone, comprising the following steps: A: taking (6E, 10E) geranyl linalool, organic aluminum catalyst and lower alcohol liquor; heating to 30-80 DEG C; continuously stirring during the heating process; adding alkyl acetoacetate so as to carry out the Carroll rearrangement reaction, wherein the reaction time is controlled within 8-20 hours; and then obtaining the teprenone crude product; and B: concentrating the teprenone crude product prepared in step A to remove the low-boiling point organic impurities; centrifuging to obtain supernatant liquid; carrying out chromatography via a silica column, and then adopting organic reagent as flow phase to elute; collecting the cingula of the teprenone; and combining the positive eluant tested in thin-layer chromatography qualitative detection, later reducing the pressure of the eluant, and then concentrating the eluant to obtain the teprenone product. The synthetic route of the teprenone in the invention is only one step, so that the reaction conversion rate is high, and the control is easy. The synthetic reaction conversion rate of the teprenone crude product is larger than 95%, and the purity of the highly finished teprenone product is larger than 99.0%.

Description

technical field [0001] The embodiment of the present invention relates to a synthesis and purification process of a drug, in particular to a synthesis and purification process of teprenone. Background technique [0002] Teprenone is a terpene compound with the molecular formula C 23 h 38 O, molecular weight 330.55, the chemical name of the compound is 6,10,14,18-tetramethyl-5,9,13,17-nonadecanetraen-2-one, composed of (5E, 9E, 13E) and ( 5Z, 9E, 13E) are a mixture of two geometric isomers in a molar ratio of 3:2. [0003] Teprenone has a broad-spectrum anti-ulcer effect and has a repairing effect on the tissue; Teprenone improves the gastric mucosa by promoting the biosynthesis of high-molecular glycoproteins, phospholipids and prostaglandins in the gastric mucosa, and stimulating the secretion of gastric mucus. Defensive and protective functions, it has strong anti-ulcer effect and improvement effect on gastric mucosa for various experimental ulcers and gastric mucosal l...

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Problems solved by technology

[0005] The reported teprenone mainly has two kinds of ways to synthesize, and one is to prepare by Carroll reaction through geranyllinalool and alkyl acetoacetate; The relevant content of teprenone synthesis is not specifically listed, and it is difficult to industrialize; the patent CN101343219 is prepared by Zeng Qingle of Chengdu University of Technology using (2E, 6E)-farnesol as the starting material, and Shanghai Sanwei Pharmaceutical Co., Ltd. Chen Hairong et al. used farnesyl acetone as the starting material to prepare (improvement of the synthesis process of teprenone, Chinese Journal of Pharmaceutical Industry, 2004, 35 (8), 449-450). Phyllyl linalool, and then prepare teprenone through Carroll reaction, and synthesize teprenone through five-step and four-step reactions. These two methods have more synthesis steps, and the increase of by-products brings great difficulties to purification , and the yield is low; patent KR20080111777 is that Rhee Hak June of Korea HANSEO Chemical Co., Ltd. uses geranyl linalool and diketene as starting materials, and Carroll reaction occurs to prepare teprenone, and patent CN102050714 uses geranyl linalool Alcohol and alkyl acetoacetate are raw materials, and the organoaluminum that the alkyl acetoacetate is pretreated is a catalyst, prepares teprenone by Carroll reaction, but these two kinds of methods have all used acid in the process of preparing teprenone or alkali aqueous solution to remove the catalyst, although the catalyst can be effectively removed, the emulsification is severe and the process operation is troublesome. Patent KR20080111777 does not report the final purification of the reaction product. The subsequent treatment of the reaction product in the patent CN102050714 is carried out by rectification and purification with a molecular distillation device. However, due to the existence of impurities such as by-products, which are similar in structure to the target substance and have a close boiling point, the high-temperature heating process also has a certain impact on the product. It is difficult to achieve a purity of more than 99% after rectification, which is not suitable for large-scale production.

[0006] Another method is to prepare teprenone by substituting halotetramethylhexadetraene and alkyl acetoacetate, and then decarboxylate to prepare teprenone. Patent US4814353 uses 1-halo-3,7,11, Substitution reaction of 15-tetramethyl-hexadeca-2,6,10,14-tetraene with the sodium salt of hydrocarbyl acetoacetate, followed by saponification and decarboxylation to obtain teprenone, which requires halotetramethyldeca The raw material of hexacarbonatetraene must be a mixture of two isomers (molar ratio is 3:2), which increases the difficulty of synthesis and is not suitable for production. There are few follow-up studies

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