阅读说明：本技术 一种伊万卡塞中间体ii及其合成方法 (Yiwan kasai intermediate II and synthetic method thereof ) 是由 王智军 李贺峰 王帅军 刘攀 王云鹏 于 2021-08-27 设计创作，主要内容包括：本发明涉及药物化学合成领域,具体涉及一种伊万卡塞中间体II及其合成方法。所述合成方法包括：以4-氨基苯乙酸和醇类化合物为起始原料,滴加酯化剂,减压浓缩制得中间体I,然后将中间体I滴入L-苹果酸溶液中混合加热,减压浓缩再重结晶得到一种伊万卡塞中间体II,所述醇类化合物为甲醇、乙醇、丙醇和异丙醇中的任一种,中间体II的结构简式如下。本发明的合成方法条件安全,原料价廉易得,得到的伊万卡塞中间体II质量好、收率高,适合工业化生产。(The invention relates to the field of pharmaceutical chemistry synthesis, and in particular relates to an Yiwan kasai intermediate II and a synthesis method thereof. The synthesis method comprises the following steps: 4-aminophenylacetic acid and an alcohol compound are taken as initial raw materials, an esterifying agent is dripped into the initial raw materials, an intermediate I is prepared by decompression and concentration, then the intermediate I is dripped into an L-malic acid solution to be mixed and heated, and the intermediate I is subjected to decompression, concentration and recrystallization to obtain an Yiwanka intermediate II, wherein the alcohol compound is any one of methanol, ethanol, propanol and isopropanol, and the intermediate II has the following structural formula. The synthesis method provided by the invention has the advantages of safe conditions, cheap and easily available raw materials, good quality of the obtained avancin kasai intermediate II, high yield and suitability for industrial production.)

1. The Yiwan kasai intermediate II is characterized in that the structure simple formula is as follows:

R＝CH₃，CH₃CH₂，CH₃CH₃CH，CH₃CH₂CH₂。

2. a synthetic method of an avancin kasai intermediate II is characterized by comprising the following steps:

mixing L-malic acid and an organic solvent A, heating to 70-200 ℃, adding an intermediate I and the organic solvent A, refluxing at 100-130 ℃ for 5-15h, concentrating, evaporating to dryness, adding an organic solvent B for dissolving and concentrating, adding the organic solvent B, heating for dissolving, stirring for crystallization, performing suction filtration, and finally adding the organic solvent B for recrystallization to obtain an intermediate II;

the structure of the intermediate I is shown as the simple formula

Wherein R is-CH₃、-CH₂CH₃、-CH(CH₃)₂and-CH₂CH₂CH₃Any one of the above.

3. The method for synthesizing the ivacaic kazakh intermediate II according to claim 2, wherein the molar ratio of the intermediate I to the L-malic acid is 1: (1.0-1.2).

4. The method for synthesizing the ivacaide intermediate II according to claim 2, wherein the organic solvent A is any one of toluene, xylene, tetrahydrofuran and acetonitrile;

the organic solvent B is any one of methanol, absolute ethyl alcohol and acetonitrile.

5. The method for synthesizing the itavanckazabete intermediate II according to claim 2, wherein the specific preparation steps of the intermediate I are as follows:

stirring 4-aminophenylacetic acid and an alcohol compound in an ice-water bath until the temperature is 0-8 ℃, then dropwise adding an esterifying agent, refluxing for 3-8h at 65-98 ℃ after the dropwise adding is finished, concentrating, adding n-hexane, performing suction filtration, sequentially adding triethylamine and water into the obtained gray solid and ethyl acetate under mixing and stirring, then performing liquid separation and water washing, and finally concentrating to obtain the intermediate I;

the alcohol compound is any one of methanol, ethanol, propanol and isopropanol.

6. The method for synthesizing itavancomycin intermediate II according to claim 5, wherein the molar ratio of the 4-aminophenylacetic acid, the alcohol compound and the esterifying agent is 1:

(5-20)：(1-3)。

7. the method for synthesizing the ivacaide intermediate II according to claim 5, wherein the esterifying agent is any one of thionyl chloride, sulfuric acid and hydrochloric acid.

Technical Field

The invention belongs to the technical field of synthesis of medicines and medicine intermediates, and particularly relates to an ivacaine kasai intermediate II and a synthesis method thereof.

Background

Avancil, a novel CaR agonist of arylalkyl amine compounds, having the chemical name (4- { (3S) -3- [ (1R) -1- (naphthalen-1-yl) ethylamino ] pyrrolidin-1-yl } phenyl) acetic acid [ 4- { (3S) -3- [ (1R) -1- (naphtalen-1-yl) ethyl lamino ] pyrrolidin-1-yl } phenyl acetic acid ], and having the chemical structure as follows.

Avancin plugs are used to treat secondary hyperparathyroidism in maintenance dialysis patients. It acts on Ca receptor on the surface of parathyroid cell, inhibits secretion of PTH, lowers the concentration of PTH in blood, and further relieves symptoms, and furthermore, avancin also regulates the biosynthesis of PTH and proliferation of parathyroid cell, controlling the production of PTH. Compared with the early calcium mimetic cinacalcet hydrochloride, avancin significantly reduced digestive tract disease.

Currently, there are few methods available to synthesize avanci jams. One of the synthetic routes is as follows:

for example, Hiroshi Miyazaki et al (Bioorganic & Medicinal Chemistry Letters 28 (2018)) 2055-.

The advantages and disadvantages of this route: the route can be used for industrial production, but 3-pyrrolidinol is used in the process and is expensive.

Therefore, the synthesis method of the intermediate of the avancin kazakh, which is low in cost, safe, environment-friendly, convenient to operate, high in yield, good in quality and suitable for industrial production, is provided by adopting the alcohol compound, the L-malic acid and the 4-aminophenylacetic acid as raw materials.

Disclosure of Invention

In view of the above, the invention aims to provide a synthesis method of the intermediate II of avancin kasai, which has the advantages of low cost, safety, environmental protection, convenient operation, good quality, high yield and suitability for industrial production. The method comprises the steps of taking 4-aminophenylacetic acid and any one of methanol, ethanol, propanol and isopropanol as starting raw materials, dropwise adding an esterifying agent, carrying out reduced pressure concentration to obtain an intermediate I, then adding the intermediate I into an L-malic acid solution, carrying out reduced pressure concentration and recrystallization to obtain an intermediate II. The synthesis method of the preparation method of the intermediate II of the avancin kazakh has mild conditions, cheap and easily available raw materials, high yield of the obtained product and suitability for mass production.

In order to achieve the purpose, the invention adopts the following technical scheme:

the Yiwan kasai intermediate II is characterized in that the structure simple formula is as follows:

a synthetic method of an avancin kasai intermediate II specifically comprises the following steps:

mixing L-malic acid and an organic solvent A, heating to 70-200 ℃, adding an intermediate I and the organic solvent A, refluxing for 5-15h at the temperature of 100 ℃ and 130 ℃, concentrating, evaporating to dryness, adding an organic solvent B for dissolving, concentrating until no liquid is evaporated to obtain brown viscous liquid, adding the organic solvent B, heating for dissolving, magnetically stirring for crystallization, performing suction filtration to obtain a light yellow solid, and finally adding the organic solvent B for recrystallization to obtain a pure white crystal intermediate II (S) -2- (4- (3-hydroxy-2, 5-dioxapyrrolidine-1-yl) phenyl) acetate compound;

the structure of the intermediate I is shown as the simple formula

Wherein R is-CH₃、-CH₂CH₃、-CH(CH₃)₂and-CH₂CH₂CH₃Any one of the above.

Preferably, the molar ratio of the intermediate I to the L-malic acid is 1: (1.0-1.2).

Preferably, the organic solvent a is any one of toluene, xylene, tetrahydrofuran and acetonitrile; the organic solvent B is any one of methanol, absolute ethyl alcohol and acetonitrile.

Preferably, the preparation steps of the intermediate I are as follows: magnetically stirring 4-aminophenylacetic acid and an alcohol compound in an ice water bath until the temperature is 0-8 ℃, then slowly dropwise adding an esterifying agent, refluxing for 3-8h at 65-98 ℃ after dropwise adding, concentrating under reduced pressure until no liquid is evaporated out to obtain a light yellow oily substance, adding n-hexane, generating a solid, performing suction filtration to obtain a gray solid, adding ethyl acetate into the gray solid, sequentially dropwise adding triethylamine and water under magnetic stirring, performing liquid separation, washing with water, and finally concentrating under reduced pressure to obtain a brown liquid intermediate I;

the alcohol compound is any one of methanol, ethanol, propanol and isopropanol.

Preferably, the molar ratio of the 4-aminophenylacetic acid, the alcohol compound and the esterifying agent is 1: (5-20): (1-3).

Preferably, the esterifying agent is any one of thionyl chloride, sulfuric acid and hydrochloric acid.

The overall reaction flow for preparing the intermediate II and the Yiwan kasai is as follows:

wherein R is-CH₃、-CH₂CH₃、-CH(CH₃)₂and-CH₂CH₂CH₃Any one of the above.

Through the technical scheme, compared with the prior art, the invention discloses a synthetic method of an avancin kasai intermediate. The method has the following technical effects:

1. the raw materials are cheap and easy to obtain, and the preparation method is safe and environment-friendly.

2. The yield of the finally prepared avancin kasai intermediate is high, the quality is good, and the method is suitable for large-scale production.

Drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.

FIG. 1 shows a hydrogen spectrum of intermediate II in the example of the present invention.

FIG. 2 is a carbon spectrum of intermediate II in the example of the present invention.

FIG. 3 is an enlarged view of the carbon spectrum of intermediate II in the example of the present invention.

FIG. 4 is a mass spectrum of intermediate II in the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Examples

(1) Preparation of intermediate I

5.05g of 4-aminophenylacetic acid and 25mL of methanol are added into a 500mL three-necked flask, the mixture is stirred by magnetic force in an ice water bath, and 2.5mL of thionyl chloride starts to be slowly dropped at 5 ℃. After the dripping is finished, refluxing is carried out for 6h at 65 ℃, and decompression concentration is carried out at 45 ℃ until no liquid is evaporated out, thus obtaining light yellow oily matter. Adding 50mL of n-hexane to generate solid, performing suction filtration to obtain 6.75g of gray solid, transferring the gray solid into a 250mL three-necked bottle, adding 50mL of ethyl acetate, dropwise adding 5mL of triethylamine under magnetic stirring, adding 30mL of water, separating, washing with 30mL of water for three times each time, and concentrating under reduced pressure to obtain 5.12g of brown liquid, namely the intermediate I4-methyl aminophenylacetate with the yield of 92.57%.

(2) Preparation of intermediate II

Adding 3.10g of L-malic acid and 40mL of dimethylbenzene into a 250mL three-necked bottle, heating to 80 ℃, adding 3.46g of intermediate I and 10mL of dimethylbenzene, refluxing for 12h, concentrating under reduced pressure, evaporating to dryness, adding 60mL of acetonitrile, concentrating under reduced pressure after complete dissolution until no liquid is evaporated to obtain brown viscous liquid, adding 20mL of organic solvent B, heating to completely dissolve the intermediate, magnetically stirring for crystallization, performing suction filtration to obtain light yellow solid, and recrystallizing with acetonitrile to obtain 2.63g of white solid, namely intermediate II (methyl (S) -2- (4- (3-hydroxy-2, 5-dioxapyrrolidine-1-yl) phenyl) acetate, wherein the yield is 50.01%.

The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.