阅读说明：本技术 一种加巴喷丁的杂质及其制备方法 (Gabapentin impurity and preparation method thereof ) 是由 朱晓仁 朱元勋 颜峰峰 于 2021-06-07 设计创作，主要内容包括：本发明提供了一种加巴喷丁新的未知杂质化合物(VII)及其制备方法,化学名称为2-[1-[(1,3-双氧杂-2-氮杂螺环[4.5]癸-2-基)甲基]环己基]-乙酸。该杂质由(1-羧甲基)环己基羧酸(VI)与加巴喷丁(I)反应制备得到,合成路线如下所示。由此制得的该杂质可用于支持该杂质的质量研究,并用于支持关于该杂质控制的加巴喷丁的工艺改进。(The invention provides a new unknown impurity compound (VII) of gabapentin and a preparation method thereof, wherein the chemical name is 2- [1- [ (1, 3-dioxygen-2-nitrogen)Heterospiro [4.5] rings]Decan-2-yl) methyl]Cyclohexyl radical]-acetic acid. The impurity is prepared by reacting (1-carboxymethyl) cyclohexyl carboxylic acid (VI) with gabapentin (I), and the synthetic route is shown as follows. The impurities thus produced can be used to support quality studies of the impurities and to support process improvements of gabapentin with respect to the control of the impurities.)

1. A compound, named 2- [1- [ (1, 3-dioxido-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid, has the structural formula shown in formula VII:

2. a process for the preparation of a compound according to claim 1, wherein: prepared by the reaction of (1-carboxymethyl) cyclohexyl carboxylic acid (VI) and gabapentin (I), and the synthetic route is as follows:

3. the method of claim 2, wherein: the reaction is carried out in any one or a mixed solvent of two or more of lower alcohol, lower ketone and water; preferably in any one or a mixed solvent of two or more of methanol, ethanol, isopropanol, acetone or water; more preferably in water.

4. The method of claim 2, wherein: the reaction temperature of the reaction is 30-100 ℃.

5. The method of claim 2, wherein: the reaction time is 3-10 hours.

6. The method of claim 2, wherein: the (1-carboxymethyl) cyclohexylcarboxylic acid (VI) in the reaction was prepared by the following method:

(1) reacting cyclohexanone (II) and methyl cyanoacetate (III) in the presence of an organic solvent and a catalyst to obtain a compound (IV);

(2) dissolving the compound (IV) obtained in the step (1) by using an organic solvent, and then adding a cyanide metal salt aqueous solution to react to obtain a compound (V);

(3) reacting the compound (V) obtained in the step (2) with concentrated hydrochloric acid to obtain (1-carboxymethyl) cyclohexyl carboxylic acid (VI);

the synthetic route is as follows:

7. the method according to claim 6, wherein: the organic solvent in the step (1) is selected from: toluene, xylene, acetone, preferably toluene; the catalyst in the step (1) is selected from: acetic acid, ammonium acetate, citric acid, sodium acetate.

8. The method according to claim 6, wherein: the organic solvent in the step (2) is selected from methanol, ethanol and isopropanol, preferably ethanol; the metal cyanide salt in the step (2) is selected from: sodium cyanide, potassium cyanide.

9. The method according to claim 6, wherein: the temperature required by the reaction in the step (1) is 70-110 ℃; the temperature required by the reaction in the step (2) is reflux temperature, and the time required by the reaction is 2-10 hours; the temperature required by the reaction in the step (3) is reflux temperature, and the time required by the reaction is 5-20 hours.

10. Use of a compound according to claim 1 as a reference substance in the study of gabapentin quality and in the production of gabapentin.

Technical Field

The invention relates to a new impurity compound (VII) of gabapentin, preparation and application thereof, belonging to the field of pharmaceutical chemicals.

Background

Gabapentin (also known as Neurontin) was the first antiepileptic drug developed by Warner-Lanbert, USA, and it is a gamma-aminobutyric acid (GABA) analogue with chemical name of 1- (aminomethyl) -1-cyclohexane acetic acid and molecular formula of C₉H₁₇NO₂Molecular weight is 171.24, and the structure is shown in formula I:

patents CN 201510304138 and WO 2013190357a1 report that gabapentin can be obtained by condensation, hydrolysis and hydrogenation of cyclohexanone represented by formula II and cyanoacetate represented by formula III as raw materials, and the synthetic route is shown as follows:

adverse reactions generated by the medicine in clinical use are not only related to the pharmacological activity of the medicine, but also are sometimes greatly related to impurities existing in the medicine. Therefore, the research on impurities is carried out in a standardized way, and the quality and the safety of the medicines on the market are directly related. In the course of studying the above gabapentin production process, the inventors have found a new compound (VII) which is an impurity not reported and which can be carried over from the intermediate to the final product, affecting the quality of the final product. So far, no report about the impurity compound (VII) is found.

Disclosure of Invention

The object of the present invention is to provide a new unknown impurity compound (VII) of gabapentin, chemical name 2- [1- [ (1, 3-dioxa-2-azaspiro [4.5] dec-2-yl) methyl ] cyclohexyl ] -acetic acid, for supporting the quality studies of this impurity and for supporting the process improvement of gabapentin with respect to the control of this impurity.

The invention further characterizes the structure of the 2- [1- [ (1, 3-dioxyhetero-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) by high resolution mass spectrometry liquid chromatography-mass spectrometry (LC-HRMS) and nuclear magnetic resonance.

MS(MS-ESI)：

[M+H]+	322.2
		Molecular formula	C18H27NO4
Theoretical exact molecular weight	321.2

The nuclear magnetic resonance spectrum is shown in the table 1, and the nuclear magnetic resonance structure number of the impurity compound (VII) is shown as follows:

TABLE 1 NMR analysis of impurity Compound (VII)

Proton type	Chemical shift (ppm)	Home H number	Number of protons
				C-H	3.59	H-13	2
C-H	2.58	H-7	2
				C-H	2.35	H-20	2
C-H	1.75～1.80	H-1/5	4
				C-H	1.45～1.55	H-2/3/4/16/17/18/15/19	10
C-H	1.20～1.27	H-2/3/4/16/17/18	6

The present invention also provides a process for preparing impurity compound (VII): prepared by the reaction of (1-carboxymethyl) cyclohexyl carboxylic acid (VI) and gabapentin (I), and the synthetic route is as follows:

further, the reaction is carried out in any one or a mixed solvent of two or more of lower alcohol, lower ketone and water.

Further, the reaction is carried out in any one or a mixture of two or more of methanol, ethanol, isopropanol, acetone or water.

Further the reaction is carried out in water.

Further the reaction temperature of the reaction is: 30-100 ℃; the reaction time is as follows: 3-10 hours.

Further the (1-carboxymethyl) cyclohexylcarboxylic acid (VI) in the reaction was prepared by the following method:

(1) reacting cyclohexanone (II) and methyl cyanoacetate (III) in the presence of an organic solvent and a catalyst to obtain a compound (IV);

(2) dissolving the compound (IV) obtained in the step (1) by using an organic solvent, and then adding a cyanide metal salt aqueous solution to react to obtain a compound (V);

(3) reacting the compound (V) obtained in the step (2) with concentrated hydrochloric acid to obtain (1-carboxymethyl) cyclohexyl carboxylic acid (VI);

the synthetic route is as follows:

further the organic solvent in step (1) is selected from: toluene, xylene, acetone, preferably toluene.

Further in step (1) the catalyst is selected from: acetic acid, ammonium acetate, citric acid, sodium acetate.

Furthermore, the temperature required by the reaction in the step (1) is 70-110 ℃.

Further, the organic solvent in step (2) is selected from methanol, ethanol, isopropanol, preferably ethanol.

Further in step (2), the metal cyanide salt is selected from: sodium cyanide, potassium cyanide.

Further, the temperature required for the reaction in the step (2) is reflux temperature.

Furthermore, the time required by the reaction in the step (2) is 2-10 hours.

Further, the temperature required for the reaction in the step (3) is reflux temperature.

Furthermore, the time required by the reaction in the step (3) is 5 to 20 hours.

The 2- [1- [ (1, 3-dioxy-2-aza spiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) is difficult to remove in the finished gabapentin product, and in the storage process of gabapentin, the existence of the impurity can influence the stability of the product, promote the content of the impurity in the product to be gradually increased, and influence the quality of the finished product. And the content of the impurities in the gabapentin finished product is controlled, so that the increase of the content of the impurities can be effectively inhibited in the storage process of the finished product, and the stability of the gabapentin finished product is ensured to meet the quality standard. Therefore, the research on the production way of the impurity, the directional synthesis of the impurity and the control of the generation of the impurity from the source have important significance on the quality control of the gabapentin bulk drug. On the other hand, the 2- [1- [ (1, 3-dioxygen-2-aza spiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) prepared by the invention has high purity, can be used as a standard substance or a reference substance for the accurate positioning of gabapentin and the quantitative research of an external standard method on the impurity in the process production, and has strong practical application value.

Drawings

FIG. 1 LC-MS spectrum of impurity compound (VII)

FIG. 2 of impurity Compound (VII)¹H-NMR spectrum

FIG. 3 is HPLC detection spectrum of gabapentin finished product

Detailed Description

The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention only, but not to limit the scope of the invention. Based on the embodiments of the present invention, those skilled in the art can change or modify the present invention without creative efforts to cover the protection scope of the present invention.

HPLC analytical method:

example 1: synthesis of (1-carboxymethyl) cyclohexyl carboxylic acid

70g of cyclohexanone, 71g of methyl cyanoacetate, 210ml of toluene, 5.6g of sodium acetate and 1.5g of citric acid are added into a four-mouth bottle, the mixture is heated to 70 ℃ for reflux, water is divided for 10 hours under reflux, the reaction is stopped after the water division is finished, the toluene is concentrated, and 1000ml of ethanol is added into the materials to be stirred and dissolved clearly.

Adding sodium cyanide aqueous solution (water: 140g, sodium cyanide 32g) into ethanol solution, heating and refluxing for 2 hours, refluxing, concentrating ethanol under reduced pressure, concentrating, extracting water layer with 3 × 500ml ethyl acetate for 3 times, washing ethyl acetate layer with 2 × 300ml drinking water for 2 times, drying ethyl acetate layer with 50g anhydrous magnesium sulfate, filtering, concentrating organic phase under reduced pressure to obtain solid.

Adding 200ml of concentrated hydrochloric acid into the solid material, heating and refluxing for 5 hours, cooling and crystallizing after refluxing is finished, filtering, and drying a wet product to obtain 158.3g of (1-carboxymethyl) cyclohexyl carboxylic acid.

Example 2: synthesis of (1-carboxymethyl) cyclohexyl carboxylic acid

70g of cyclohexanone, 71g of methyl cyanoacetate, 210ml of toluene, 5.6g of ammonium acetate and 1.5g of citric acid are added into a four-mouth bottle, the mixture is heated to 110 ℃ for reflux, reflux and water diversion are carried out for 6 hours, the reaction is stopped after the water diversion is finished, the toluene is concentrated, and 1000ml of ethanol is added into the materials to be stirred and dissolved clearly.

Adding potassium cyanide aqueous solution (water: 140g, sodium cyanide 42.5g) into ethanol solution, heating and refluxing for 10 hours, refluxing, concentrating the ethanol under reduced pressure, concentrating, extracting the water layer with 3 × 500ml ethyl acetate for 3 times, washing the ethyl acetate layer with 2 × 300ml water for 2 times, drying the ethyl acetate layer with 50g anhydrous magnesium sulfate, filtering, concentrating the organic phase under reduced pressure to obtain solid.

Adding 200ml concentrated hydrochloric acid into the solid material, heating and refluxing for 20 hours, cooling and crystallizing, filtering, and drying the wet product to obtain 171.5g of (1-carboxymethyl) cyclohexyl carboxylic acid.

Example 3: synthesis of 2- [1- [ (1, 3-dioxyhetero-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII)

Adding 18.6g of (1-carboxymethyl) cyclohexyl carboxylic acid, 100ml of water and 17g of gabapentin into a four-necked flask, heating to 100 ℃, keeping the temperature and stirring for 3 hours, cooling to 25 ℃, crystallizing, filtering, and drying wet products to obtain 29.2g of impurity 2- [1- [ (1, 3-dioxyhetero-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid, wherein the yield is as follows: 90.8%, purity: 98.5 percent.

Example 4: synthesis of 2- [1- [ (1, 3-dioxyhetero-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII)

Adding 18.6g of (1-carboxymethyl) cyclohexyl carboxylic acid, 100ml of water and 17g of gabapentin into a four-necked flask, heating to 30 ℃, keeping the temperature and stirring for 10 hours, cooling to 25 ℃, crystallizing, filtering, and drying wet products to obtain 27.6g of impurity 2- [1- [ (1, 3-dioxyhetero-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid, wherein the yield is as follows: 95.8%, purity: 96.0 percent.

Example 5: application of 2- [1- [ (1, 3-dioxygen hetero-2-aza spiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) as reference substance in determination of impurity content of gabapentin finished product

The results of 6 batches of gabapentin finished products of different batches were detected by the area normalization method and the external standard method respectively using the above chromatographic conditions are shown in table 2.

TABLE 2 detection results of gabapentin product purity

The impurity compound 2- [1- [ (1, 3-dioxido-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) has an RRT of 0.84. As can be seen from Table 2, when the impurity is calculated by the area normalization method, the impurity compound (VII) has stronger response than the main component of gabapentin, which results in lower main purity of the product than the actual result. By preparing the impurity standard substance and using the impurity standard substance to calibrate the impurity content in the sample during sample detection, the product quality can be reflected more truly, and safe medication is realized.

Example 6: experiment on influence of 2- [1- [ (1, 3-dioxyhetero-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) on stability of gabapentin

Gabapentin stability test method:

the results of the experiment are shown in table 3.

TABLE 32- [1- [ (1, 3-Bioxa-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) stability Effect on gabapentin product

The RRT of 2- [1- [ (1, 3-dioxy-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII) is 0.84, and the stability test results in Table 3 show that when the finished gabapentin contains 2- [1- [ (1, 3-dioxy-2-azaspiro [4.5] decan-2-yl) methyl ] cyclohexyl ] -acetic acid (VII), the impurities increase significantly with the increase of the stability time, thereby affecting the final product quality.