CN110437076B

CN110437076B - Synthesis method of high-purity cinacalcet hydrochloride

Info

Publication number: CN110437076B
Application number: CN201910781383.3A
Authority: CN
Inventors: 黄乐群; 施敏峰; 王天天; 李玉凤
Original assignee: Jiangsu Jiayi Medicine Co ltd
Current assignee: Jiangsu Jiayi Medicine Co ltd
Priority date: 2019-08-22
Filing date: 2019-08-22
Publication date: 2021-03-30
Anticipated expiration: 2039-08-22
Also published as: CN110437076A

Abstract

The invention relates to a high-purity saltThe synthesis method of the cinacalcet hydrochloride is characterized in that the cinacalcet hydrochloride is obtained by carrying out reduction reaction on amide shown in a formula IV in a reducing agent, a catalyst and a solvent, hydrolyzing and then carrying out hydrochloric acid salt formation, wherein the solubility of the reducing agent in the used solvent at a reaction temperature is not more than 2.0 g per 100 ml, and the synthesis equation is as follows:

the invention has the advantages that: the method for synthesizing the high-purity cinacalcet hydrochloride has the advantages that reasonable combination of the reducing agent and the solvent is selected, the solubility of the selected reducing agent in the used solvent is controlled to be not more than 2.0 g per 100 ml, the high-purity cinacalcet hydrochloride is obtained after reaction, and the content of impurities shown in the formulas II and III in the product can be greatly reduced or even cannot be detected.

Description

Synthesis method of high-purity cinacalcet hydrochloride

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a synthesis method of high-purity cinacalcet hydrochloride.

Background

Cinacalcet hydrochloride, which has a structural formula shown in formula I, is a calcimimetic and is approved by the FDA in the United states in 2004 to be marketed in the United states, and is marketed in 2016 in China, and is used for treating hypercalcemia caused by secondary hyperparathyroidism and thyroid cancer of patients suffering from kidney disease attack.

There are various methods for synthesizing cinacalcet hydrochloride, which will be described below.

1.1 synthetic route one

Reference is made to the following documents: organic Process Research & Development, 2011,15,455-

The synthetic route has the advantages of good yield in each step and little solvent. But the main disadvantages are:

1) the raw material 3- (m-trifluoromethylphenyl) bromopropane is not easy to obtain, and is genotoxic impurity, and the content of the product needs to be strictly controlled.

2) The benzaldehyde by-product as a protecting group is difficult to remove in the post-treatment process.

1.2 synthetic route II

Reference is made to the following documents: organic Process Research & Development, 2012,16,1566-

The main disadvantage of this route is its yield

1) The reagent in the current format in the industry has a relatively large danger

2) The final step of hydrogenation with palladium-carbon is prone to bring a large palladium content in the final product, and extra recrystallization or palladium removal steps are required to ensure that the content of metal palladium does not exceed the standard.

3) In the first step of the reaction with 1, 3-dichloropropene, there is the possibility that two alkylation reactions may be carried out to produce the dialkylated compound, which is difficult to remove.

1.3 synthetic route III

In the reference CN 103450027 a, the desired cinacalcet free base can be obtained in one step by condensation reaction using naphthylethylamine and 3- (trifluoromethylphenyl) propanol mesylate, and then salified in MTBE solvent.

The main drawbacks of this route are:

1)3- (trifluoromethylphenyl) propanol mesylate is not readily available, and the starting material is a genotoxic impurity that needs to be tightly controlled in the product.

2) The alkylation of amine is difficult to control in the primary substitution stage, and a secondary substitution product of naphthylethylamine is easily formed, which brings difficulty to product separation.

1.4 synthetic route IV

Reference documents: tetrahedron Letters, 2008,49,13-15

The biggest problem of this route is that a large amount of formula II is generated during the synthesis

And formula III

The impurities shown, are difficult to remove in the product.

1.5 synthetic route five

Reference documents: EP2327684

All raw materials in the route are easy to obtain, but the consumption of sodium triacetoxyborohydride is too large, and the raw material 3- (3-trifluoromethylphenyl) propionaldehyde is expensive and has poor economy.

Therefore, it is desirable to provide a method for obtaining cinacalcet hydrochloride with high purity in an economical manner.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for synthesizing high-purity cinacalcet hydrochloride, which is good in economy and can obtain a high-purity product.

Tetrahedron Letters, 2008,49,13-15 provide a method for synthesizing cinacalcet hydrochloride, and the cinacalcet hydrochloride synthesized by the method has high yield and less impurities. However, the synthesis method reported in this document has a significant drawback in that impurities represented by formula II and formula III are generated during the synthesis process, and the content of impurities in the reaction solution after the reaction is high, and the content of impurities cannot be controlled well even if recrystallization is performed by the method reported in the document. For pharmaceutical substances, the impurities contained in the final product need to be strictly controlled, and the impurities are preferably controlled to be less than 0.15%, and more preferably to be less than 0.10%.

We have repeated the synthesis conditions of this document and found that the impurities of formulae II and III are indeed produced in large amounts, the total amount of both impurities being more than 0.15% in the precipitated cinacalcet hydrochloride crystals. By conventional reaction optimization methods, such as shortening the reaction time or lowering the reaction temperature, there is no satisfactory effect on reducing the content of the impurities represented by the formulae II and III in cinacalcet hydrochloride.

Surprisingly, however, the level of impurities of the formulae III and III can be greatly reduced, even undetectable in the product, by choosing a reasonable combination of reducing agent and solvent during the reduction of the amide (formula IV). The key to this is that the reducing agent selected has a solubility in the solvent used of less than 2.0 g per 100 ml, more preferably less than 0.20 g per 100 ml.

In order to solve the technical problems, the technical scheme of the invention is as follows: the synthesis method of the high-purity cinacalcet hydrochloride is characterized in that the cinacalcet hydrochloride is obtained by carrying out reduction reaction on amide shown in a formula IV in a reducing agent, a catalyst and a solvent, hydrolyzing and then salifying with hydrochloric acid, and the innovation points are that: the solubility of the reducing agent in the solvent used is not more than 2.0 g per 100 ml at the reaction temperature, and the synthesis equation is as follows:

further, the reducing agent has a solubility in the solvent used of not more than 0.2 g per 100 ml at the reaction temperature.

Further, the reducing agent is one or a mixture of several of sodium borohydride, potassium borohydride, lithium borohydride or lithium aluminum hydride, the catalyst is one or a mixture of several of Lewis acid or protonic acid, and the solvent is one or a mixture of several of tetrahydrofuran, dioxane and dipropyl ether.

Further, the Lewis acid is boron trifluoride diethyl etherate or boron trifluoride tetrahydrofuran, and the protonic acid is hydrochloric acid or sulfuric acid.

Further, the reducing agent is sodium borohydride, the catalyst is boron trifluoride tetrahydrofuran, and the solvent is tetrahydrofuran.

The invention has the advantages that: according to the synthesis method of the high-purity cinacalcet hydrochloride, reasonable combination of the reducing agent and the solvent is selected, and the solubility of the selected reducing agent in the used solvent is controlled to be not more than 2.0 g per 100 ml, so that the content of impurities shown in the formula II and the formula III can be greatly reduced, and even the impurities cannot be detected in the product; the cinacalcet hydrochloride with the purity of more than 99.5 percent can be synthesized by the invention, wherein the content of the impurities shown in the formulas II and III is less than 0.15 percent, and the purity of 99.8 percent is more preferably obtained, wherein the content of the impurities shown in the formulas II and III is less than 0.10 percent.

Drawings

The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.

Fig. 1 is a chromatogram of cinacalcet hydrochloride synthesized in example 1.

Fig. 2 is a chromatogram of cinacalcet hydrochloride synthesized in example 2.

Detailed Description

The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the scope of the embodiments described herein.

Example 1: control description (Synthesis according to the method reported by Tetrahedron Letters, 2008,49, 13-15)

A1000 ml reaction vessel was charged with 47.7 g of an amide represented by the formula IV, 143 g of a mixed solvent of tetrahydrofuran and diglyme (1:1), and 12.4 g of sodium borohydride, and mechanically stirred, 68 g of boron trifluoride complex was added dropwise at 40 to 60 ℃ and, after completion of the addition, reacted at 40 to 60 ℃ for 3 hours. Adding 270 g of water for quenching reaction, adding 290 g of toluene for extraction, reserving an organic phase, washing by using 270 g of water, adding 17.3 g of concentrated hydrochloric acid for salt formation, crystallizing by using 190 g of n-heptane at 70 ℃, cooling to normal temperature, filtering, and drying to obtain 42 g of cinacalcet hydrochloride crystals with the purity of 99.4 percent, wherein the sum of the impurities shown in the formula II and the formula III is 0.284 percent.

The detection method comprises the following steps: a chromatographic column: octylsilane bonded silica gel (Inertsil C8, 4.6 mm. times.150 mm, 5 μm or equivalent performance column). Mobile phase: phase A: sodium dodecyl sulfate solution (sodium dodecyl sulfate 5.05g, dissolved by adding water 900ml, added with phosphoric acid 0.35ml, diluted to 1000ml with water), phase B: acetonitrile; elution was performed according to the following gradient 1:

TABLE 1

Detection wavelength: 210 nm.

Flow rate: 1.2ml/min

Column temperature: at 50 ℃.

Sample introduction amount: 10 μ l.

The impurities represented by formula II and formula III cannot be separated from each other, and the degree of separation of the main peak from it is not less than 1.5, calculated as the total amount. The detection spectrum is shown in figure 1, and the test data of each peak number on figure 1 are shown in the following table 2.

TABLE 2 detection peak table of cinacalcet hydrochloride

Detector A210 nm

From FIG. 1 and Table 2, it can be seen that the total amount of impurities represented by the formulae II and III is 0.284%.

Example 2

In a 1000ml reaction flask, 47.7 g of amide shown in formula IV, 143 g of tetrahydrofuran and 12.4 g of sodium borohydride are added, mechanically stirred, 68 g of boron trifluoride complex is dropwise added at 40-60 ℃, and after dropwise addition, the mixture is reacted for 3 hours at 40-60 ℃. Adding 270 g of water for quenching reaction, adding 290 g of toluene for extraction, reserving an organic phase, washing by using 270 g of water, adding 17.3 g of concentrated hydrochloric acid for salt formation, crystallizing by using 190 g of n-heptane at 70 ℃, cooling to normal temperature, filtering, and drying to obtain 45 g of cinacalcet hydrochloride crystals with the purity of 99.8 percent, wherein the impurities shown in the formula II and the formula III are not detected (the content corresponding to the detection limit is less than 0.01 percent).

The detection method comprises the following steps: a chromatographic column: octylsilane bonded silica gel (Inertsil C8, 4.6 mm. times.150 mm, 5 μm or equivalent performance column). Mobile phase: phase A: sodium dodecyl sulfate solution (sodium dodecyl sulfate 5.05g, dissolved by adding water 900ml, added with phosphoric acid 0.35ml, diluted to 1000ml with water), phase B: acetonitrile; elution was performed according to the following gradient 3:

TABLE 3

Detection wavelength: 210 nm.

Flow rate: 1.2ml/min

Column temperature: at 50 ℃.

Sample introduction amount: 10 μ l.

The impurities represented by formula II and formula III cannot be separated from each other, and the degree of separation of the main peak from it is not less than 1.5, calculated as the total amount. The detection spectrum is shown in figure 2, and the test data of each peak number on figure 2 are shown in the following table 4.

TABLE 4 detection peak table of cinacalcet hydrochloride

Detector A210 nm

From FIG. 2 and Table 4, it can be seen that the total amount of impurities represented by the formulae II and III was not detected.

The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims

1. A method for synthesizing high-purity cinacalcet hydrochloride, which is obtained by carrying out reduction reaction on amide shown in a formula IV in a reducing agent, a catalyst and a solvent, hydrolyzing and then salifying hydrochloric acid, and is characterized in that: the solubility of the reducing agent in the solvent used is not more than 2.0 g per 100 ml at the reaction temperature, and the synthesis equation is as follows:

the reducing agent is sodium borohydride, the catalyst is boron trifluoride tetrahydrofuran, and the solvent is tetrahydrofuran.

2. The method of synthesizing high purity cinacalcet hydrochloride according to claim 1, characterized in that: the reducing agent has a solubility in the solvent used of not more than 0.2 g per 100 ml at the reaction temperature.