阅读说明：本技术 一种***类化合物、其制备方法、分离方法和用途 (Phenylalanine compound, preparation method, separation method and application thereof ) 是由 张福利 高升华 陈松 柯彬 孟丽丽 裘鹏程 夏文婷 张涛 常光宇 林丽娅 于 2018-06-07 设计创作，主要内容包括：本发明公开了一种苯丙胺类化合物、其制备方法、分离方法和用途。本发明公开了如式I所示的苯丙胺类化合物或其盐,其制备方法包括以下步骤：在溶剂中,将式II所示的化合物的盐与过氧化物进行氧化反应,即可。本发明还公开了如式II所示的化合物的盐的氧化产物的分离方法,其包括以下步骤：将如式II所示的化合物的盐的氧化产物在色谱柱中进行洗脱,即可。本发明的苯丙胺类化合物是利右苯丙胺或其盐质量控制的必需品,能够有效鉴定利右苯丙胺或其盐降解过程中产生的杂质并对有关物质进行定量控制。<Image he="140" wi="700" file="DDA0001687915210000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(the invention discloses a phenylpropylamine compound, and a preparation method, a separation method and application thereof. The invention discloses a phenylpropylamine compound shown as a formula I or a salt thereof, and a preparation method of the compound comprises the following steps: and (2) carrying out oxidation reaction on the salt of the compound shown in the formula II and peroxide in a solvent. The invention also discloses a method for separating the oxidation product of the salt of the compound shown in the formula II, which comprises the following steps: eluting the oxidation product of the salt of the compound shown as the formula II in a chromatographic column. The amphetamine compound of the invention is lidextro phenylpropylThe necessities for controlling the quality of the amine or the salt thereof can effectively identify impurities generated in the degradation process of the dextroamphetamine or the salt thereof and quantitatively control related substances.)

1. An amphetamine compound or salt thereof, as shown in formula I:

2. a process for the preparation of amphetamine compounds of formula I as set forth in claim 1, comprising the steps of: in a solvent, carrying out oxidation reaction on the salt of the compound shown in the formula II and peroxide;

3. the preparation method according to claim 2, wherein the salt of the compound represented by the formula II is a salt of the compound represented by the formula II with an acid in a molar ratio of 1: 2;

And/or the peroxide is R-O-OH, wherein R is H or C₁～C₆Linear or branched alkyl of (a);

and/or the molar ratio of the peroxide to the salt of the compound shown in the formula II is (20-120): 1;

And/or the solvent is water or an organic solvent;

and/or the temperature of the oxidation reaction is 40-90 ℃;

and/or the time of the oxidation reaction is 12 to 36 hours.

4. The method according to claim 3, wherein the acid is an organic acid or an inorganic acid;

when the acid is an organic acid, the organic acid is one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid;

When the acid is an inorganic acid, and/or the inorganic acid is one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid;

and/or, the peroxide is hydrogen peroxide or tert-butyl hydroperoxide;

And/or, the solvent is water or methanol;

And/or the volume-mass ratio of the solvent to the salt of the compound shown in the formula II is 0.1mL/mg to 1 mL/mg;

And/or the temperature of the oxidation reaction is 50-70 ℃.

5. The method of claim 2, further comprising the following post-treatment steps after the oxidation reaction is completed: removing the residual peroxide in the reaction system, adding alkali for neutralization, evaporating the solvent, and performing preparative chromatographic separation to obtain the amphetamine compound shown in the formula I.

6. The process according to claim 5, wherein in the preparative chromatographic separation process, the chromatographic column is Welch Ultimate XB-C18 or Xbridge Prep-C18, the mobile phase is a mixed solution of mobile phase A and mobile phase B, the mobile phase A is aqueous trifluoroacetic acid, the mobile phase B is acetonitrile, and the mobile phase can be washed by the following gradient washing procedure: the structural formula of the material is shown in the specification, wherein A is 95:5 → 90:10, A is 90:10 → 52:48, A is 52:48 → 5:95, A is 5:95 → 95:5, and A is 95: 5.

7. The method of claim 6, wherein in the preparative chromatographic separation process, the chromatographic column is Welch Ultimate XB-C18;

And/or the volume fraction of the trifluoroacetic acid aqueous solution is 0.1%;

And/or, the mobile phase is washed by the following gradient: 0min → 0.5min, A: B95: 5 → 90:10, 0.5min → 14min, A: B90: 10 → 52:48, 14min → 14.5min, 52:48 → 5:95, 14.5min → 16.5min, A: B5: 95, 16.5min → 17min, A: B5: 95 → 95:5, 17min → 20min, A: B95: 5;

And/or the flow rate of the method for preparing chromatographic separation is 8 mL/min-20 mL/min;

And/or, the column temperature of the preparative chromatographic separation method is room temperature;

and/or the ultraviolet absorption wavelength in the detection of the method for preparing chromatographic separation is 210 nm-220 nm.

8. A process for the separation of the oxidation product of a salt of a compound of formula II, comprising the steps of: eluting the oxidation product of the salt of the compound shown in the formula II in a chromatographic column;

the chromatographic column is Welch Ultimate XB-C18 or Xbridge Prep-C18, the mobile phase is a mixed solution of a mobile phase A and a mobile phase B, the mobile phase A is trifluoroacetic acid aqueous solution, the mobile phase B is acetonitrile, and the mobile phase is washed according to the following parameters: the structural formula of the material is shown in the specification, wherein A is 95:5 → 90:10, A is 90:10 → 52:48, A is 52:48 → 5:95, A is 5:95 → 95:5, and A is 95: 5.

9. The separation process of claim 8, wherein the oxidation product of the salt of the compound of formula II comprises a phenylalamine compound of formula I,

And/or, the chromatographic column is Welch Ultimate XB-C18;

And/or the volume fraction of the trifluoroacetic acid aqueous solution is 0.1%;

And/or, the mobile phase is washed by the following gradient: 0min → 0.5min, A: B95: 5 → 90:10, 0.5min → 14min, A: B90: 10 → 52:48, 14min → 14.5min, 52:48 → 5:95, 14.5min → 16.5min, A: B5: 95, 16.5min → 17min, A: B5: 95 → 95:5, 17min → 20min, A: B95: 5;

and/or, in the separation method, the sample is injected in the form of methanol solution of the oxidation product of the salt of the compound shown in the formula II;

and/or the concentration of the methanol solution of the oxidation product of the salt of the compound shown in the formula II is 10-100 mg/mL;

and/or the sample amount of the methanol solution of the oxidation product of the salt of the compound shown in the formula II is 200-300 mu L;

And/or the flow rate of the separation method is 8mL/min to 20 mL/min;

and/or, the column temperature of the separation method is room temperature;

And/or the ultraviolet absorption wavelength in the detection of the separation method is 210 nm-220 nm.

10. Use of the amphetamine-type compound of formula I or the salt thereof according to claim 1 as a reference substance in the quality control of dextroamphetamine or the salt thereof.

Technical Field

the invention relates to a phenylpropylamine compound, and a preparation method, a separation method and application thereof.

background

Didymine mesylate, chemical name (2S) -2, 6-amino-N- [ (1S) -1-methyl-2-phenylethyl]ammonium adipate dimesylate of formula C₁₇H₃₃N₃O₇S₂Molecular weight 455.58982, CAS registry No. 608137-33-3, is an amphetamine derivative developed by Hilei (fire) biopharmaceutical, UK in cooperation with New River Pharma. The composition is first marketed in US 2.2007 for treating Attention Deficit and Hyperactivity Disorder (ADHD) in children, and is currently prepared from dimethyl sulfonic aciddexamphetamine is the only stimulant approved for maintenance therapy in all ADHD patients older than 6 years of age. The FDA approved the drug again as the first and only one treatment for moderate to severe bulimia in adults 1 month 2015. The structure is as follows:

the synthesis method of the didymine mesylate reported in the patent US20050054561 is optimized to be as follows: s-phenylethylamine and 1-phenyl-2-acetone are used as raw materials, asymmetric reductive amination is carried out under the action of sodium triacetoxyborohydride to prepare a compound shown as a formula 2, then a compound shown as a formula 3 is prepared by debenzylation of ammonium formate, and meanwhile L-lysine monohydrochloride is subjected to di-tert-butyl dicarbonate (Boc)₂O) protection to obtain a compound shown as a formula 4, then carrying out amide condensation on the compound shown as the formula 3 and the compound shown as the formula 4 to obtain a compound shown as a formula 5, and finally carrying out methanesulfonic acid deprotection to form salt to obtain the methanesulfonic acid lidocaine hydrochloride, wherein the specific synthetic route is as follows:

At present, no report of related substances of the didymidine dimesylate is found at home and abroad. Therefore, the identification of the praduisexyl dimesylate related substances is needed to degrade the praduisyl dimesylate to prepare the related substances for degradation.

Disclosure of Invention

The invention aims to solve the technical problem that the oxidation impurities generated by the existing dexamphetamine dimesylate cannot be effectively identified and the quality of the oxidation impurities can not be effectively controlled, and provides a amphetamine compound, a preparation method, a separation method and application thereof. The amphetamine compound is an important reference substance for controlling the quality of the dexamphetamine dimesylate, and can effectively identify impurities generated in the stability experiment or the storage process of the dexamphetamine dimesylate, so that the quality of the drug of the dexamphetamine dimesylate is controlled.

The invention provides an amphetamine compound or salt thereof shown as a formula I,

in the invention, the salt of the amphetamine compound is formed by the amphetamine compound shown in the formula I and acid in a molar ratio of 1: 1-2. The acid may be an organic or inorganic acid capable of forming a salt as is conventional in the art. The organic acid can be one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, such as methanesulfonic acid; the inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.

in the invention, the salt of the amphetamine compound can be prepared according to the conventional method and conditions of salt forming reaction in the field.

The invention also provides a preparation method of the amphetamine compound shown in the formula I, which comprises the following steps: in a solvent, carrying out oxidation reaction on the salt of the compound shown in the formula II and peroxide;

In the oxidation reaction, the salt of the compound shown in the formula II is formed by the compound shown in the formula II and acid in a molar ratio of 1: 2. The acid may be an organic or inorganic acid capable of forming a salt as is conventional in the art. The organic acid may be one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, for example, methanesulfonic acid. The inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.

In the invention, the salt of the compound shown in the formula II can be prepared according to the conventional method and conditions for salt forming reaction in the field.

In the present invention, the solvent may be a solvent conventional in such reactions in the art, subject to no participation or interference in the reaction; for example, the solvent is water or an organic solvent, and for example, the solvent is water or methanol. The organic solvent may be one or more of an ether solvent (e.g., diethyl ether, isopropyl ether, methyl tert-ether), an ester solvent (e.g., ethyl acetate, isopropyl acetate), an alcohol solvent (e.g., methanol, ethanol), and a ketone solvent (e.g., acetone, methyl isobutyl ketone).

in the invention, the dosage of the solvent can be the conventional dosage of the reaction in the field so as to ensure the smooth reaction; for example, the volume-to-mass ratio of the solvent to the salt of the compound represented by the formula II is 0.1mL/mg to 1 mL/mg.

In the present invention, the peroxide may be a peroxide conventional in such reactions in the art; for example, the peroxide is R-O-OH, wherein R is H or C₁～C₆Straight or branched alkyl (e.g. C)₁～C₄straight or branched alkyl groups of (a), further for example tert-butyl); as another example, the peroxide is hydrogen peroxide or t-butyl hydroperoxide.

In the invention, the amount of the peroxide can be the amount conventionally used in such reactions in the field, for example, the molar ratio of the peroxide to the salt of the compound represented by the formula II is (20-120): 1.

In the present invention, the temperature of the oxidation reaction may be a temperature conventional in the art for such reactions; the temperature of the oxidation reaction is, for example, 40 to 90 ℃ and, for example, 50 to 70 ℃.

in the present invention, the progress of the oxidation reaction can be monitored by a conventional test method in the art (such as TLC or HPLC), and the time of the oxidation reaction is preferably 12 hours to 36 hours, which is generally used as a reaction endpoint when the salt of the compound represented by formula II is no longer reacted.

In the invention, the preparation method of the amphetamine compound shown in the formula I preferably further comprises the following post-treatment steps after the oxidation reaction is finished: removing the residual peroxide in the reaction system, adding alkali for neutralization, evaporating the solvent, and performing preparative chromatographic separation to obtain the amphetamine compound shown in the formula I.

In the present invention, the peroxide can be removed by a method conventional in the art, preferably, by adding a reducing agent, which can be a reducing agent conventional in such reactions in the art (e.g., sodium sulfite or sodium bisulfite). The addition amount of the reducing agent can be determined by a conventional method in the field, so that peroxide is completely removed.

in the present invention, the alkali in the alkali neutralization may be an alkali conventional in the art, for example, one or more of sodium bicarbonate, sodium carbonate and sodium hydroxide.

In the method for preparative chromatographic separation, the chromatographic column can be Welch Ultimate XB-C18 or Xbridge Prep-C18, the mobile phase is a mixed solution of mobile phase A and mobile phase B, the mobile phase A can be trifluoroacetic acid aqueous solution, the mobile phase B can be acetonitrile, and the mobile phase can be washed by the following gradient washing procedures: the structural formula of the material is shown in the specification, wherein A is 95:5 → 90:10, A is 90:10 → 52:48, A is 52:48 → 5:95, A is 5:95 → 95:5, and A is 95: 5.

In the preparative chromatographic separation method, preferably, the chromatographic column is Welch Ultimate XB-C18.

in the method for preparative chromatographic separation, the volume fraction of the aqueous trifluoroacetic acid solution may be 0.1%.

In the method for preparative chromatographic separation, preferably, the mobile phase is washed by the following gradient procedure:

Time (min)	Mobile phase A (%, v/v)	Mobile phase B (%,v/v)
			0	95	5
0.5	90	10
			14.0	52	48
14.5	5	95
			16.5	5	95
17.0	95	5
			20.0	95	5

in the preparative chromatographic separation method, the mixture obtained after evaporation of the solvent can be introduced by a method conventional in the art, for example, in the form of a methanol solution of the mixture.

the concentration of the methanol solution of the mixture may be a concentration conventional in the art, for example, 10 to 100mg/mL, and further for example, 10 mg/mL.

The methanol solution of the mixture may be introduced in an amount conventional in the art, for example, 200. mu.L to 300. mu.L, and further, for example, 200. mu.L.

In the present invention, the flow rate of the method for preparative chromatographic separation may be a flow rate conventional in the art; for example, 8 to 20mL/min, or 10.0 mL/min.

In the present invention, the column temperature of the preparative chromatographic separation method may be a column temperature conventional in the art, for example, room temperature (20 ℃ C. to 30 ℃ C.).

in the present invention, the ultraviolet absorption wavelength detected by the preparative chromatographic separation method can be an ultraviolet absorption wavelength conventional in the art, such as 210nm to 220nm, and further such as 215 nm.

The invention also provides a method for separating the oxidation product of the salt of the compound shown as the formula II, which comprises the following steps: eluting the oxidation product of the salt of the compound shown in the formula II in a chromatographic column;

The chromatographic column is Welch Ultimate XB-C18 or Xbridge Prep-C18, the mobile phase is a mixed solution of a mobile phase A and a mobile phase B, the mobile phase A is trifluoroacetic acid aqueous solution, the mobile phase B is acetonitrile, and the mobile phase is washed according to the following parameters: the structural formula of the material is shown in the specification, wherein A is 95:5 → 90:10, A is 90:10 → 52:48, A is 52:48 → 5:95, A is 5:95 → 95:5, and A is 95: 5.

In the separation method, the oxidation product of the salt of the compound shown in the formula II is a substance obtained by oxidizing the salt of the compound shown in the formula II (for example, oxidation by using the peroxide or oxidation generated during storage); preferably, the oxidation product of the salt of the compound shown in the formula II comprises a phenylpropylamine compound shown in the formula I; more preferably, the oxidation product of the salt of the compound shown in the formula II is prepared by the oxidation reaction.

In the separation method, preferably, the chromatographic column is Welch Ultimate XB-C18.

In the separation method, the volume fraction of the aqueous trifluoroacetic acid solution may be 0.1%.

In the separation method, preferably, the mobile phase is washed by the following gradient:

in the separation method, the oxidation product of the salt of the compound represented by the formula II can be fed by a method conventional in the art, for example, in the form of a methanol solution of the oxidation product of the salt of the compound represented by the formula II.

the concentration of the methanol solution of the oxidation product of the salt of the compound shown in the formula II can be the concentration which is conventional in the field, for example, 10-100 mg/mL, and for example, 10 mg/mL.

The methanol solution of the oxidation product of the salt of the compound represented by the formula II can be used in an amount which is conventional in the art, for example, 200. mu.L-300. mu.L, and 200. mu.L.

in the present invention, the flow rate of the separation method may be a flow rate conventional in the art; for example, 8 to 20mL/min, or 10.0 mL/min.

In the present invention, the column temperature of the separation method may be a column temperature conventional in the art, for example, a normal temperature (20 ℃ C. to 30 ℃ C.).

In the present invention, the ultraviolet absorption wavelength detected by the preparative chromatographic separation method can be an ultraviolet absorption wavelength conventional in the art, such as 210nm to 220nm, and further such as 215 nm.

The invention also provides application of the amphetamine compound shown as the formula I or salt thereof as a related substance reference substance in quality control of the lisdexamphetamine or salt thereof.

The salt of the limonadate is formed by the limonadate and acid in a molar ratio of 1: 1-2. The acid may be an organic or inorganic acid capable of forming a salt as is conventional in the art. The organic acid may be one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, for example, methanesulfonic acid. The inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.

The dextroamphetamine is the compound shown as the formula II.

in the present invention, the related substances refer to starting materials, intermediates, polymers, side reaction products and degradation impurities which may be present during the preparation and storage of the drug. The degradation impurity refers to a substance obtained by degrading dextroamphetamine or salts thereof or naturally degrading the dextroamphetamine or salts thereof; the degradation reaction may be a degradation reaction conventional in the art, such as an oxidative degradation reaction.

In the invention, when the amphetamine compound or salt thereof is used as a related substance reference substance in the quality control of the limonadyl or salt thereof, the mass content of the amphetamine compound or salt thereof is less than 0.05%, and the mass content refers to the percentage content of the amphetamine compound or salt thereof in the total mass of the amphetamine compound or salt thereof and the limonadyl or salt thereof.

preferably, the amphetamine compound shown in the formula I or the salt thereof is used as an impurity degradation control substance in the quality control of the lidocaine or the salt thereof.

On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

the amphetamine compound is a necessity for controlling the quality of the dextroamphetamine or the salt thereof, and can effectively identify impurities generated in the degradation process of the dextroamphetamine or the salt thereof and quantitatively control related substances.

Drawings

FIG. 1 is an HPLC chromatogram of recrystallized limonadyl dimesylate;

FIG. 2 is an HPLC chromatogram of the amphetamine-type compound of formula I prepared in example 1.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, it is preferred that,¹H NMR spectra were obtained using a Bruker-600 NMR spectrometer with tetramethylsilane as internal standard and chemical shifts in delta (ppm). The mass spectrum was measured using an Agilent 6210 liquid chromatography-time of flight mass spectrometer. The preparative chromatography instrument used waters prep system. The HPLC instrument used a thermo scientific 3000.

The structural formula of the didymidine mesylate is as follows:

The lisdexamphetamine dimesylate used in the following examples is obtained by recrystallizing and purifying a lisdexamphetamine dimesylate product (lot number 20160918) provided by the national ruit pharmaceutical industry ltd, pharmaceutical group, and the recrystallization conditions are specifically as follows: the method comprises the steps of taking isopropanol as a solvent, heating the isopropanol and the dextroamphetamine dimesylate product to 80 ℃ until the isopropanol and the dextroamphetamine dimesylate product are completely dissolved, and slowly cooling and crystallizing to obtain the dextroamphetamine dimesylate.