阅读说明：本技术 一种去甲基伊托必利亚硝胺的制备方法 (Preparation method of demethyl itopride nitrosamine ) 是由 蔡强 张榕芳 李厚俭 李达胜 覃志俊 谢立 于 2021-08-30 设计创作，主要内容包括：去甲基伊托必利亚硝胺是一种在生产伊托必利的过程中容易出现的杂质,目前关于它的报道很少。去甲基伊托必利亚硝胺是一种基因毒性杂质,需要在药品生产的过程中加以控制。本发明首次报道了一种去甲基伊托必利亚硝胺的合成方法,为伊托必利生产中的杂质控制提供了保障。(Demethylitopride nitrosamine is an impurity that is easily found in the process of itopride production and is currently reported only rarely. Demethylitopride nitrosamines are genotoxic impurities that need to be controlled during the pharmaceutical manufacturing process. The invention reports a method for synthesizing demethylitopride nitrosamine for the first time, and provides guarantee for impurity control in itopride production.)

1. A preparation method of demethylitopridine nitrosamine is characterized by comprising the following steps:

the method comprises the following steps of (1) taking itopride hydrochloride as a starting material, and reacting the starting material with chloroformate under the condition of alkali to obtain N-alkoxycarbonyl demethylitopride;

removing a protecting group of the methyl itopride to obtain the methyl itopride;

under the condition of acid and sodium nitrite, demethyl itopride generates demethyl itopride nitrosamine;

and R is one of phenyl, benzyl and chloroethyl.

2. The method according to claim 1, wherein the base in step (a) is a weak base selected from one of triethylamine, N-diisopropylethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar ratio of the weak base to the raw material itopride hydrochloride is 1:1-5: 1.

3. The method of claim 1, wherein the mole ratio of chloroformate used in step (a) to starting itopride hydrochloride is in the range of 1.05:1 to 2: 1.

4. The method of claim 1, wherein in the deprotection process of step (b), when R is phenyl, the deprotection conditions are 2-3M NaOH or KOH solution, when R is benzyl, the deprotection conditions are Pd/C and hydrogen, and when R is chloroethyl, the deprotection conditions are reflux heating.

5. The method according to claim 1, wherein the solvent used in step (c) is a mixed solvent of dichloromethane and water, and the volume ratio of dichloromethane to water is 1: 1.

6. The method according to claim 1, wherein the acid in step (c) is selected from one of hydrochloric acid or sulfuric acid, the concentration is 1-2M, and the molar ratio of the amount of the sodium nitrite to the initial raw material itopride hydrochloride is 1.2:1-3: 1.

7. The method of claim 1, wherein the purification method of the product in step (c) is recrystallization, the solvent is one or more selected from chloroform, ethyl acetate, dichloromethane and tetrahydrofuran, and the ratio of the volume of the solvent in milliliters to the weight of the crude product is 5:1-20: 1.

Technical Field

The invention relates to the field of synthesis of medical chemicals, in particular to a method for preparing demethylitopride nitrosamine.

Background

Itopride is a gastrointestinal motility promoting drug, first developed by north-land pharmaceutical corporation. Its standard designation is N- [4- [2- (N, N-dimethylamino) ethoxy]Benzyl radical]-3, 4-dimethoxybenzamide (CAS number: 122892-31-3) having the following chemical formula:. In the process of research, the inventor finds an impurity with a brand new structure, namely demethylitopridine nitrosamine. Its standard name is N- [4- [2- (N-nitroso, N-methylamino) ethoxy]Benzyl radical]-3, 4-dimethoxybenzamide, the chemical structure of which is shown below. The impurity is generated because demethylitopride generated in the process reacts with nitrite remained in the system under an acidic condition to generate the impurity with a nitrosamine structure. At present, no relevant report is found on demethylitopridine nitrosamine, and the demethylitopridine nitrosamine is an impurity with a novel structure. It has the structure of N-nitroso group. It is known that nitrosamines are mostly genotoxic, such as N, N-dimethylnitrosamine, N-diethylnitrosamine, etc. The presence of such impurities therefore poses a great risk to the safety of the drug, whose content must be monitored and controlled. However, the literature is irrelevant to the report of the impurity, and the preparation method of demethylitopridine nitrosamine is not available in the published technology.

Disclosure of Invention

In order to solve the problems, the scheme provides a preparation method of demethylitopride nitrosamine, which specifically comprises the following steps: a preparation method of demethylitopride nitrosamine comprises the following steps:

(1) the method comprises the following steps of (1) taking itopride hydrochloride as a starting material, and reacting the starting material with chloroformate under the condition of alkali to obtain N-alkoxycarbonyl demethylitopride;

(2) removing a protecting group of the methyl itopride to obtain the methyl itopride;

(3) under the condition of acid and sodium nitrite, demethyl itopride generates demethyl itopride nitrosamine;

r is one of phenyl, benzyl and chloroethyl.

Further, the base in the step 1 is a weak base selected from one of triethylamine, N-diisopropylethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar ratio of the consumption of the weak base to the raw material itopride hydrochloride is 1:1-5: 1.

Further, the mole ratio of the chloroformate used in step 1 to the raw material itopride hydrochloride is 1.05:1-2: 1.

Further, in the deprotection process of step 2, when R is phenyl, the deprotection condition is 2-3M concentration NaOH or KOH solution, when R is benzyl, the deprotection condition is Pd/C and hydrogen, and when R is 2-chloroethyl, the deprotection condition is reflux heating.

Further, the solvent used in the step 3 is a mixed solvent of dichloromethane and water, and the volume ratio of dichloromethane to water is 1: 1.

Further, in the step 3, the acid is selected from one of hydrochloric acid or sulfuric acid, the concentration is 1-2M, and the molar ratio of the amount of the sodium nitrite to the initial raw material itopride hydrochloride is 1.2:1-3: 1.

Further, the refining method of the product in the step 3 is recrystallization, the used solvent is one or more selected from chloroform, ethyl acetate, dichloromethane and tetrahydrofuran, and the ratio of the volume milliliter number of the solvent to the gram number of the crude product is 5:1-20: 1.

has the advantages that: the method for preparing demethylitopride nitrosamine provided by the invention has the advantages of easily available raw materials, simplicity, convenience and high efficiency, provides an efficient standard preparation method for the first report of a substance synthesis route and the detection of demethylitopride nitrosamine impurities.

Drawings

FIG. 1 shows the preparation of demethylitopridine nitrosamine¹H NMR；

FIG. 2 shows the preparation of demethylitopridine nitrosamine¹³C NMR；

FIG. 3 is ESI-MS of demethylitopridine nitrosamine.

Detailed Description

Example 1

100ml of dichloromethane, 10g of itopride hydrochloride and 6.1g of triethylamine are added into a 250ml flask, the temperature of a reaction system is reduced to 10 ℃ after the materials are fully dissolved, 4.7g of phenyl chloroformate is slowly added, then the temperature is increased to 40 ℃ for reflux reaction for 2 hours, a proper amount of water and hydrochloric acid are added after the reaction is finished, and the pH is adjusted to be = 3. After extraction and stratification, the organic layer is taken and evaporated to dryness, and about 12g of crude N-phenoxycarbonyldemethylitopride is obtained.

Dissolving the obtained crude product N-phenoxycarbonyl demethylitopride in a mixed solvent of 50ml DMSO and 50ml water, adding 10g of potassium hydroxide, heating to 90 ℃, refluxing for 2h, cooling to room temperature, adding 100ml of water, extracting with dichloromethane, washing the obtained dichloromethane layer by using 100ml of 1M hydrochloric acid aqueous solution, combining water phases, adding 4g of sodium nitrite, reacting for 2h at room temperature, extracting with dichloromethane after the reaction is finished, obtaining 2.9g of crude product demethylitopride nitrosamine, adding 20ml of ethyl acetate, and recrystallizing to obtain 1.4g of refined demethylitopride nitrosamine.

¹H NMR (400MHz, DMSO-d6)δ 8.85 (t, J = 5.9 Hz, 1H ), 7.52 (dd, J = 8.4 Hz, J = 2.1 Hz 1H ), 7.48 (d, J = 2.1 Hz, 1H ), 7.24(m, 2H ), 7.01 (d, J = 8.4 Hz, 1H ), 6.90 (m, 2H ), 4.50 (m, 2H ), 4.40 (d, J = 5.9 Hz, 2H ), 4.29 (m, 2H), 3.80 (d, J = 1.7, 6H), 3.05 (s, 2H)。

¹³C NMR(100MHz, DMSO-d6) δ165.6, 156.84, 156.78, 151.2, 148.2, 132.48, 132.47, 128.7, 126.6, 120.5, 114.5, 114.3, 110.9, 110.6, 65.0, 63.5, 55.6, 55.5, 52.3, 44.0, 42.0, 40.1, 40.0, 39.8, 39.7, 39.5, 39.3, 39.1, 39.0, 31.7。

ESI-MS : C19H23N3O5 Cacl.(M+H)⁺:374.1716 found 374.1715。

Example 2

100ml of dichloromethane, 10g of itopride hydrochloride and 6.1g of triethylamine are added into a 250ml flask, the temperature of a reaction system is reduced to 10 ℃ after the materials are fully dissolved, 4.7g of phenyl chloroformate is slowly added, then the temperature is increased to 40 ℃ for reflux reaction for 2 hours, a proper amount of water and hydrochloric acid are added after the reaction is finished, and the pH is adjusted to be = 3. After extraction and stratification, the organic layer is taken and evaporated to dryness, and about 12g of crude N-phenoxycarbonyldemethylitopride is obtained.

Dissolving the obtained crude product N-phenoxycarbonyl demethylitopride in a mixed solvent of 50ml DMSO and 50ml water, adding 10g of potassium hydroxide, heating to 90 ℃, refluxing for 2h, cooling to room temperature, adding 100ml of water, extracting with dichloromethane, washing the obtained dichloromethane layer by using 100ml of 1M hydrochloric acid aqueous solution, combining water phases, adding 4g of sodium nitrite, reacting for 2h at room temperature, extracting with dichloromethane after the reaction is finished, obtaining 2.9g of crude product demethylitopride nitrosamine, adding 35ml of tetrahydrofuran, and recrystallizing to obtain 1.6g of refined demethylitopride nitrosamine.

Example 3

50ml of water and 50ml of dioxane, 10g of itopride hydrochloride and 5.1g of sodium bicarbonate are added into a 250ml flask, the temperature of a reaction system is reduced to 10 ℃ after the materials are fully dissolved, 5.2g of Cbz-Cl is slowly added, then the temperature is increased to 90 ℃ for reflux reaction for 2 hours, a proper amount of water is added after the reaction is finished, and the pH is adjusted to be = 3. Chloroform extraction and layering are carried out, then the organic layer is taken and evaporated to dryness, and about 10g of N-benzyloxycarbonyl demethylitopride crude product is obtained.

Dissolving the obtained crude product N-benzyloxycarbonyl demethylitopride in 100ml of methanol, adding 0.2g of 5% Pd/C catalyst, performing hydrogen replacement, reacting at room temperature for 24 hours, filtering after the reaction is finished, evaporating the filtrate to dryness, dissolving the obtained oily substance in 100ml of 1M hydrochloric acid solution, adding 4g of sodium nitrite, reacting at room temperature for 2 hours, extracting with dichloromethane after the reaction is finished to obtain 2.4g of crude product demethylitopride nitrosamine, adding 20ml of ethyl acetate, and recrystallizing to obtain 1.3g of refined demethylitopride nitrosamine.

Example 4

100ml of dichloromethane, 10g of itopride hydrochloride and 6.1g of triethylamine are added into a 250ml flask, the temperature of a reaction system is reduced to 0 ℃ after the materials are fully dissolved, 4.4g of chloroethyl chloroformate is slowly added, then the temperature is kept for reaction for 6 hours, a proper amount of water and hydrochloric acid are added after the reaction is finished, and the pH is adjusted to be = 3. After extraction and stratification, the organic layer is taken and evaporated to dryness, and about 11g of N-chloroethoxy carbonyl demethyl itopride crude product is obtained.

Dissolving the obtained crude product N-chloroethoxycarbonyl demethyl itopride in 100ml of methanol, heating to reflux for 12h, evaporating the solution to dryness after cooling to room temperature to obtain oily matter, dissolving the oily matter in 100ml of 1M hydrochloric acid solution, adding 4g of sodium nitrite, reacting for 2h at room temperature, extracting with dichloromethane after the reaction is finished to obtain 2.2g of crude product demethyl itopride nitrosamine, adding 20ml of ethyl acetate, and recrystallizing to obtain 1.2g of refined demethyl itopride nitrosamine.