CN102866222A

CN102866222A - Method for separating and determining duloxetine midbody and optical isomer thereof by utilizing liquid chromatography

Info

Publication number: CN102866222A
Application number: CN 201210338518
Authority: CN
Inventors: 陈东; 李倩; 郭夏
Original assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Current assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Priority date: 2012-09-14
Filing date: 2012-09-14
Publication date: 2013-01-09

Abstract

The invention belongs to the analysis chemical field, and particularly discloses a method for separating and determining a duloxetine midbody [(S)-(+)-N, N-dimethyl-3-(1-naphthalene oxygen base)-3-(2-thiophene base)-c amine] and an optical isomer thereof by utilizing the liquid chromatography. The method is characterized in that cellulose (p-methylphenyl) is used as chiral liquid chromatography, mixed solvent of n-hexane-low alcohol solution with a given is used as a flow phase, and the content of the optical isomer of the duloxetine midbody can be quantitatively measured, so that the quality of a final product duloxetine raw material medicine can be effectively controlled through the orientation synthesis. The method is strong in specificity, high in accuracy and simple and convenient to operate.

Description

A kind of method with liquid chromatography for separating and determining duloxetine. intermediate and optical isomer thereof

Technical field

The invention belongs to the analytical chemistry field, be specifically related to a kind of method with liquid chromatography for separating and determining duloxetine. intermediate and optical isomer thereof.

Background technology

Duloxetine is that a kind of serotonin and norepinephrine extract double inhibitor again, is used for the treatment of various depression and anxiety disorder, and the medicine of alleviating central pain such as diabetes peripheral nerve characteristic of disease pain and women's fibromyalgia etc.(S)-(+)-and N, N-dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-propylamine, molecular formula is C ₁₉H ₂₁NOS is the important intermediate in the Duloxetine synthetic route, its structure See Figure.Because itself and finished product Duloxetine contain same chiral center, therefore, as synthetic essential chiral intermediate, in directed synthetic route, its optical purity has material impact to the quality of finished product.

For the optical isomer impurity of duloxetine. intermediate, in the process of the synthetic target finished product Duloxetine of orientation, need to carry out quality control to the content of its optical isomer, to guarantee the quality of finished product.The separation that contains the enantiomorph of asymmetric carbon atom is the difficult point of the synthetic middle quality control of chiral drug always, realizes the separation to duloxetine. intermediate and optical isomer thereof, has realistic meaning aspect the quality control of Duloxetine.

Summary of the invention

The object of the present invention is to provide a kind of separation determination duloxetine. intermediate [(S)-(+)-N, N-dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-propylamine] and the high efficiency liquid phase method of optical isomer, thereby realize separating and measuring of duloxetine. intermediate and its optical isomer, qualified intermediate enters directed synthetic, to guarantee the quality control of finished product Duloxetine bulk drug.

Method with liquid chromatography analysis duloxetine. intermediate and optical isomer thereof of the present invention, it is the chiral chromatographic column that adopts take cellulose iii (p-methylphenyl formic ether) as filler, take normal hexane-low-alcohol solution as mobile phase, wherein comprise organic base in the low-alcohol solution.

Above-mentioned said chiral chromatographic column is selected from the chromatographic column that the trade mark is CHIRALCEL OJ and CHIRALCEL OJ-H take cellulose iii (p-methylphenyl formic ether) as filler.

Above-mentioned said lower alcohol is selected from a kind of in the following solution: methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol are preferably ethanol or isopropyl alcohol.

Above-mentioned said method, its mobile phase normal hexane-low-alcohol solution volume ratio is 99.5:0.5～95:5, and preferred volume ratio is 99:1, and more preferably the volume ratio of normal hexane-ethanol or isopropyl alcohol is 99:1.

In the above-mentioned said method, the organic base that comprises in the low-alcohol solution is selected from a kind of organic base in ethylenediamine, diethylamine and the triethylamine, is preferably diethylamine.

Wherein comprise organic base in the low-alcohol solution, its concentration (V/V) that contains organic base is 0.05～0.5%, and preferred concentration is 0.1%, and is optimum for containing 0.1% diethylamine.

Method of separating and assaying of the present invention, can realize in accordance with the following methods:

(1) gets the duloxetine. intermediate sample an amount of, with methyl alcohol, ethanol or mobile phase dissolution sample, be mixed with the sample solution that contains duloxetine. intermediate 0.1～1.5mg.

(2) flow rate of mobile phase being set is 0.4～1.0mL/min, and flow rate of mobile phase is preferably 0.5mL/min, and the detection wavelength is 210～250nm, and the optimum detection wavelength is 225nm, and chromatographic column post case temperature is 20～40 ℃, and post box column temperature the best is 20 ℃.

(3) get sample solution 10～50 μ L of (1), the injection liquid chromatography is finished the separation determination of duloxetine. intermediate and optical isomer.Wherein:

The model of high performance liquid chromatograph has no special requirements, and the chromatograph that the present invention adopts is Shimadzu Shimadzu: LC-10ATvp, SPD-M10Avp

(CHIRALCEL 250 * 4.6mm) for chromatographic column: OJ-H

Mobile phase: normal hexane-isopropyl alcohol (containing 0.1% diethylamine)=99:1

Flow velocity: 0.5 mL/min

Detect wavelength: 225nm

Column temperature: 20 ℃

Sampling volume: 20 μ L

The present invention adopts OJ-H, and (CHIRALCEL 250 * 4.6mm), can effectively separate duloxetine. intermediate.The invention solves the separation determination problem of duloxetine. intermediate and optical isomer thereof, can carry out content detection to duloxetine. intermediate with this, thereby guaranteed the quality controllable of finished product Duloxetine bulk drug.

Description of drawings

The high-efficient liquid phase chromatogram of Fig. 1 blank solvent

The high-efficient liquid phase chromatogram of Fig. 2 duloxetine. intermediate raceme

The high-efficient liquid phase chromatogram of Fig. 3 duloxetine. intermediate

Embodiment:

Following examples are used for further understanding the present invention, but are not limited to the scope of this enforcement.

Embodiment 1

Instrument and condition

High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp;

(CHIRALCEL 250 * 4.6mm) for chromatographic column: OJ-H;

Mobile phase: normal hexane-isopropyl alcohol (containing 0.1% diethylamine)=99:1;

Flow velocity: 0.5 mL/min;

Detect wavelength: 225nm;

Column temperature: 20 ℃;

Sampling volume: 20 μ L.

Experimental procedure

The raceme of getting duloxetine. intermediate is 25mg approximately, puts in the 50mL measuring bottle, adds the ethanol dissolving and is diluted to scale, shakes up, as need testing solution.

Get respectively blank reagent solution and need testing solution, carry out efficient liquid phase chromatographic analysis by above-mentioned condition, the record chromatogram the results are shown in Figure 1, Fig. 2.

Retention time is that the chromatographic peak of 23.163min is the chromatographic peak of duloxetine. intermediate enantiomter among Fig. 2,28.007min chromatographic peak be the chromatographic peak of duloxetine. intermediate, as seen from the figure, duloxetine. intermediate and its enantiomorph can reach baseline separation, meet the requirement of Chinese Pharmacopoeia.

Embodiment 2

Instrument and condition

High performance liquid chromatograph: Shimadzu: LC-10ATvp, SPD-M10Avp;

(CHIRALCEL 250 * 4.6mm) for chromatographic column: OJ-H;

Flow velocity: 0.5 mL/min;

Detect wavelength: 230nm;

Column temperature: 20 ℃;

Sampling volume: 20 μ L.

Experimental procedure

Get approximately 25mg of duloxetine. intermediate, put in the 50mL measuring bottle, add the ethanol dissolving and be diluted to scale, shake up, as need testing solution.

Get need testing solution, carry out efficient liquid phase chromatographic analysis by above-mentioned condition, the record chromatogram the results are shown in Figure 3.

Retention time is that the chromatographic peak of 22.015min is the chromatographic peak of duloxetine. intermediate among Fig. 3, can be proved by figure, the optical purity of duloxetine. intermediate meets the requirements, and can be used for the synthetic reaction of follow-up Duloxetine, and this law can be used for the quality monitoring of duloxetine. intermediate.

Show from Fig. 1-Fig. 3: method of the present invention, can clearly duloxetine. intermediate be separated with its optical isomer, and can accurately detect quantitatively, to calculate the content of optical isomer, start with from the quality control of synthetic intermediate, thereby effectively control the product quality of finished product Duloxetine.

Claims

A liquid chromatography for separating and determining duloxetine. intermediate or/and the method for its optical isomer it is characterized in that: adopt the chiral chromatographic column take cellulose iii (p-methylphenyl formic ether) as filler, take normal hexane-low-alcohol solution as mobile phase; Comprise a kind of organic base that is selected from ethylenediamine, diethylamine or the triethylamine in the wherein said low-alcohol solution, the concentration (V/V) of organic base in low-alcohol solution is 0.05～0.5%, and normal hexane-low-alcohol solution volume ratio is 99.5:0.5～95:5.
2. method of separating and assaying according to claim 1, chiral chromatographic column is selected from the chromatographic column of CHIRALCEL OJ and CHIRALCEL OJ-H.
3. described method of separating and assaying according to claim 1, said lower alcohol are selected from a kind of in the following solution: methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol.
4. described method of separating and assaying according to claim 3, said lower alcohol is ethanol or isopropyl alcohol.
5. described method of separating and assaying according to claim 1, the volume ratio of said normal hexane-low-alcohol solution is 99:1.
6. method of separating and assaying according to claim 1, the organic base that comprises in the said low-alcohol solution is diethylamine.
7. according to claim 6 in the method, the concentration of contained organic base diethylamine is 0.1% in the said low-alcohol solution.
8. described method of separating and assaying according to claim 1 is characterized in that, this method of separating and assaying comprises following step:

1) gets the duloxetine. intermediate sample an amount of, use respectively a kind of dissolution with solvents sample in ethanol, methyl alcohol or the mobile phase, be mixed with the sample solution that every 1mL contains duloxetine. intermediate 0.1～1.5mg;

2) flow rate of mobile phase being set is 0.4～1.0mL/min, and the detection wavelength is 210～250nm, and chromatographic column post case temperature is 20～40 ℃;

3) get 1) sample solution 10～50 μ L, the injection liquid chromatography is finished the separation determination of duloxetine. intermediate and its optical isomer.
9. Analyze ﹠ separate method according to claim 8, step 2) said flow rate of mobile phase is preferably 0.5 mL/min.
10. Analyze ﹠ separate method according to claim 8, step 2) said detection wavelength is 225 nm.