CN113929657A - Duloxetine hydrochloride impurity, its preparation and analysis method - Google Patents

Abstract

The invention provides duloxetine hydrochloride impurities, and a preparation and analysis method thereof, which can better control the quality of duloxetine hydrochloride. The structural formulas of the two impurities are as follows:

Description

Duloxetine hydrochloride impurity, its preparation and analysis method

Technical Field

The invention relates to the field of synthesis of drug intermediates, in particular to duloxetine hydrochloride impurities, and a preparation method and an analysis method thereof.

Background

Duloxetine hydrochloride is a selective 5-hydroxytryptamine and norepinephrine reuptake inhibitor developed by Eli Lilly. Duloxetine hydrochloride, chemical name: (S) - (+) -N, N-dimethyl-3- (1-naphthoxy) -3- (2-thiophene) -propylamine hydrochloride, compound structural formula as follows:

both 5-hydroxytryptamine and norepinephrine are central neurotransmitters and play an important role in regulating emotion and sensitivity to pain. Duloxetine inhibits the reuptake of neurons of 5-hydroxytryptamine and norepinephrine, thereby increasing the concentration of these two central neurotransmitters in the brain and spinal cord, and is useful for treating mood disorders such as depression and anxiety, and relieving central pain such as diabetic peripheral neuropathic pain and fibromyalgia in women. Duloxetine also acts on 5-hydroxytryptamine and norepinephrine receptors in the urinary tract to increase the nervous tone and contractile capacity of the urinary sphincter muscle, and is therefore also effective in treating stress urinary incontinence in women. Duloxetine is an oral enteric capsule formulation, which is now marketed in over 70 countries after first approval in the united states in 2004 for 8 months. The global sales of duloxetine in 2006 exceeds $ 13 billion, and the sales in 2007 and 2008 are greatly increased to $ 2 billion and $ 27 billion respectively, which is one of the fastest-increasing medicines in the world in recent years.

EP0650965B1 discloses a method for synthesizing duloxetine hydrochloride, which comprises the steps of taking a compound VIII as a starting material, reducing the compound VIII by sodium borohydride to obtain a racemate of a compound IX, resolving the racemate by a resolving agent (such as S- (+) mandelic acid), and carrying out butt joint and demethylation reaction on the compound IX and 1-fluoronaphthalene to obtain the duloxetine.

The chiral compound IX obtained by the above process, however, results in a large amount of R-isomer upon resolution, which production results in high waste solids disposal costs.

Disclosure of Invention

The purpose of the invention is as follows: provides a preparation and purification method of duloxetine hydrochloride impurities. In the reaction for preparing duloxetine hydrochloride, we have unexpectedly found two new impurities (compound I and compound II) which affect the quality of duloxetine hydrochloride. We also investigated methods for analyzing impurities in duloxetine to further control the formation and handling of impurities.

The invention provides two duloxetine hydrochloride intermediate impurities, wherein the structural formulas of a compound I and a compound II are as follows:

the preparation method of the compound I comprises the following steps:

in the first step, firstly adding alkali 1 and a compound III, after hydrolysis reaction, adding alkali 2 to react with a compound IV to obtain a mixture of a compound V and a compound VI; in the second step, adding alkali 3; purifying the compound I by column chromatography and then purifying by using n-heptane.

In the first step, the base 1 is preferably potassium hydroxide or sodium hydroxide, and the base 2 is preferably N, N-diisopropylethylamine.

In the first step, the molar ratio of the compound III to the alkali 1 to the compound IV to the alkali 2 is 1: 2.0-6.0: 1.0-2.5: 1.0-3.0; the temperature of the hydrolysis reaction is 10-20 ℃, and the reaction temperature of the demethylation reaction is 50-65 ℃.

The assay for compound I was as follows: the chromatographic column is a chromatographic column taking octadecylsilane chemically bonded silica as a packed column, the detection wavelength is 230nm, the mobile phase A is acetonitrile, the mobile phase B is 0.1% ammonia water solution, and the elution gradient is as follows:

time (min)	A(％)	B(％)
			0	10	90
10	50	50
			25	70	30
30	90	10
			35	10	90
45	10	90

。

The preparation method of the compound II comprises the following steps:

in the first step, firstly adding alkali 1 and a compound III, after hydrolysis reaction, adding alkali 2 to react with a compound IV to obtain a mixture of a compound V and a compound VI; in the second step, adding alkali 3; and (3) purifying the compound II by column chromatography and then purifying by using n-heptane to obtain n-heptane, and recrystallizing to obtain the compound II.

In the first step, the alkali 1 is selected from potassium hydroxide or sodium hydroxide, and the alkali 2 is selected from N, N-diisopropylethylamine.

In the first step, the molar ratio of the compound III to the alkali 1 to the compound IV to the alkali 2 is 1: 2.0-6.0: 1.0-2.5: 1.0-3.0; the temperature of the hydrolysis reaction is 10-20 ℃, and the reaction temperature of the demethylation reaction is 50-65 ℃.

Analytical method for compound II, as follows: the chromatographic column is a chromatographic column taking octadecylsilane chemically bonded silica as a packed column, the detection wavelength is 230nm, the mobile phase A is acetonitrile, the mobile phase B is 0.1% ammonia water solution, and the elution gradient is as follows:

time (min)	A(％)	B(％)
			0	10	90
10	50	50
			25	70	30
30	90	10
			35	10	90
45	10	90

。

Advantageous effects

The invention provides a preparation and purification method of a newly discovered duloxetine hydrochloride impurity (a compound I and a compound II). The discovery of the two impurities, which are related to the analytical methods of the impurities studied at the same time, can better control the quality of duloxetine hydrochloride.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, are included to provide a further understanding of the invention and are not to be construed as limiting the invention in any way:

FIG. 1 shows a NMR spectrum of compound I as an impurity of duloxetine hydrochloride intermediate;

FIG. 2 shows a mass spectrum of compound I as an impurity of duloxetine hydrochloride intermediate of the present invention;

FIG. 3 shows a NMR spectrum of compound II as an impurity in duloxetine hydrochloride intermediate;

FIG. 4 shows a mass spectrum of compound II as an impurity in the duloxetine hydrochloride intermediate of the present invention;

FIG. 5 shows a high performance liquid chromatogram of the reaction solution of step one in example 1 of duloxetine hydrochloride according to the present invention;

FIG. 6 shows a high performance liquid chromatogram of the reaction solution of step two in example 1 of duloxetine hydrochloride according to the present invention.

Detailed Description

The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Example 1

Step one (preparation of compound V and compound VI):

adding water (2L) into a reaction kettle, adding potassium hydroxide solid (593.2g, 10.573mol, 5.0eq.) with stirring, and stirring until the mixture is clear; the reaction internal temperature was controlled to about 15 ℃, toluene (4L) was added to the reaction vessel with stirring, and then compound III (849.0g, 2.115mol, 1.0eq.) was added and stirred until a white solid was dissolved. Standing for 30 minutes under the condition of heat preservation for layering, separating liquid, taking an upper organic phase, and treating a lower aqueous phase according to waste liquid; the organic phase was washed twice with water (2L) added. The organic phase was dried over anhydrous sodium sulfate.

Adding the organic phase into a reaction kettle, adding N, N-diisopropylethylamine (314.3g, 2.432mol, 1.15eq.) while stirring, and dropwise adding an ethyl chloroformate compound IV (482.0g, 4.441mol, 2.1eq.) at the temperature of 60 ℃ in the reaction kettle; after the dropwise addition, the reaction is carried out for 3 hours under the condition of heat preservation, and sampling and controlling are carried out (standard: compound III is less than or equal to 1.0%).

Cooling the inner temperature to about 15 ℃, dropwise adding 10% sodium hydroxide aqueous solution, adjusting the pH to 14, stirring after dropwise adding, standing for layering, separating liquid, and taking an upper organic phase. And (3) controlling the temperature in the reaction kettle to be reduced to 5-15 ℃, dropwise adding 1N hydrochloric acid solution to adjust the pH to 2-3, stirring after dropwise adding, standing for layering, and taking an upper organic phase. Controlling the temperature in the reaction kettle to be reduced to 15-25 ℃, and dropwise adding a sodium bicarbonate water solution to wash until the pH value is 8-10; after the addition, stirring for 20 minutes, standing, layering, taking an upper organic phase, and treating a lower aqueous phase according to the wastewater. Concentration under reduced pressure gave 770.0g of crude compound V, containing compound VI.

Step two (preparation of compound VII, compound I and compound II):

preparing a potassium hydroxide/water solution (2.108kg/5.506kg), and stirring the solution at the temperature of 10-25 ℃ until the solution is clear for later use. Adding the crude product (2.720kg) of the compound V obtained by the method in the step one into a reaction kettle, adding dimethyl sulfoxide (9.108kg), and uniformly stirring. Adding the aqueous solution of potassium hydroxide into the dimethyl sulfoxide solution of the compound V, controlling the internal temperature to be about 96 ℃, and carrying out heat preservation reaction. HPLC is used to monitor the end of the reaction (standard: Compound V. ltoreq.3.0%).

And cooling the internal temperature to 15-35 ℃, adding process water (15.120kg) and toluene (11.951kg) under the condition of heat preservation, stirring and extracting, standing and separating, temporarily storing an upper organic phase, adding toluene (11.954kg) into a water layer, stirring and extracting, standing and separating, and removing the water layer. The two organic layers were combined, washed twice with process water (5.520kg × 2) and concentrated. After the concentration is finished, adding isopropanol (16.250kg) into the reaction kettle, heating the reaction kettle to about 60 ℃, stirring the mixture for dissolution, adding medicinal activated carbon (207.1g), and keeping the temperature and stirring the mixture for 1 hour; the hot activated carbon was filtered off.

And (3) reducing the temperature in the feed liquid to 3-7 ℃, and dropwise adding concentrated hydrochloric acid to a pH value of 4-5. And after the dropwise addition is finished, keeping the temperature of the inner temperature at 0-5 ℃, stirring until solid is separated out, keeping the temperature, stirring for 2 hours, filtering, leaching a filter cake with isopropanol (4.867kg), filtering to obtain a wet product, and collecting filtrate for further treatment.

Adjusting the pH of the collected filtrate to be neutral by using solid sodium bicarbonate, carrying out rotary evaporation at 45-50 ℃, adding 2L of methyl tert-ether and 2L of water into the concentrate after the concentration is finished, carrying out liquid separation and water washing (1L 1), carrying out liquid separation, adjusting the pH to be 2-3 by using 1N diluted hydrochloric acid, controlling the temperature to be 0-10 ℃, carrying out liquid separation, extracting an aqueous phase by using 1.5L of methyl tert-ether, combining organic phases, washing (1L 2), and carrying out rotary evaporation on the organic phase at 40 ℃ to obtain 90.20g of brownish red oily matter.

Adding 500mL of methyl tert-ether into the concentrate, performing column chromatography, eluting PE-PE with EA being 30: 1-EA to obtain two main impurities, and HNMR shows that the crude product of the compound I (20.00g, the purity is 90%); crude product of Compound II (14.00g, 80% pure).

Then, 20.00g of crude compound I was eluted by column chromatography PE-PE with EA being 15:1 to give 14.00g of brown oil, 50mL of n-heptane was added, the mixture was heated to 50 ℃, the solution was poured into a 100mL separatory funnel, the product was not completely dissolved and settled down, the brown oil was separated and washed with n-heptane (50mL × 3), and the lower brown oil was rotary evaporated to give 12.50g of compound I brown oil.

A compound I: the detection data are as follows: HPLC: 97.14 percent; MS: 307.0+/M + 23; 1H-NMR (400MHz, DMSO) δ (ppm)8.22-8.24(m, 1H), 7.83-7.85(m, 1H), 7.50-7.52(m, 2H), 7.42-7.45(m, 2H), 7.31-7.35(m, 1H), 7.22-7.23(m, 1H), 7.04-7.06(d, 1H, J ═ 7.20Hz), 6.97-6.99(dd, 1H, J1 ═ 3.60Hz, J2 ═ 5.20Hz), 5.98-6.01(dd, 2H, J1 ═ 5.60Hz, J2 ═ 7.60Hz), 4.70-4.72(t, 1H, J ═ 4.80Hz), 3.56-3.66(m, 2H), 2.39H (m, 2H), 2H (39H ).

And (3) performing column chromatography and PE elution on the crude product (14.00g, with the purity of 80%) of the compound II, performing spin drying to obtain about 10.00g of a colorless oily substance, adding 40mL of n-heptane into the concentrate, performing cooling crystallization by dry ice ethanol, performing suction filtration to obtain a white solid, adding 30mL of n-heptane, heating to complete dissolution, performing natural cooling crystallization, and performing suction filtration to obtain 5.32g of a compound II white solid. Compound II: 1H-NMR (400MHz, DMSO) δ (ppm)1.68-1.69(d, 3H, J ═ 7.00Hz), 6.04-6.09 (q, 1H, J ═ 7.00Hz), 6.83-6.85(d, 1H, J ═ 7.56Hz), 6.93-6.95(dd, 1H, J ═ 3.72Hz, J ═ 4.96Hz), 7.09-7.10(d, 1H, J ═ 3.12Hz), 7.32-7.36(t, 1H, J ═ 7.88Hz), 7.38-7.39(m, 1H), 7.54-7.56(d, 1H, J ═ 8.24Hz), 7.58-7.64(m, 2H), 7.93-7.95(m, 1H), 8.35-1H (m, 8.38H, 1H).

Example 2

Detection of duloxetine hydrochloride impurities:

example 1 detection of liquid chromatography of reaction solution for synthesizing duloxetine hydrochloride (Compound VII) in step two

The detection method comprises the following steps: and (3) using a reversed-phase liquid chromatography column, using an ultraviolet detector as a detector, using acetonitrile and an ammonia water solution as mobile phases, and performing detection according to a gradient elution program.

And (3) testing conditions are as follows: using a chromatographic column: xbridge C184.6 × 150mm, 5um, detection wavelength: 230nm, the mobile phase A is acetonitrile, and the mobile phase B is 0.1% ammonia water solution.

The mobile phase was eluted with the following gradient:

time (min)	A(％)	B(％)
			0	10	90
10	50	50
			25	70	30
30	90	10
			35	10	90
45	10	90

And (3) testing results: as shown in fig. 6. FIG. 6 shows a liquid chromatogram of a reaction solution of duloxetine hydrochloride VII according to the present invention. The duloxetine intermediate impurity compound I, the compound II and duloxetine can be simultaneously detected by a liquid chromatography detection method, and the three have good separation degrees. The content of intermediate impurities and the content of other impurities in the preparation process of duloxetine can be detected by liquid chromatography, so that qualitative and quantitative analysis of duloxetine intermediates and duloxetine can be facilitated, and the quality of duloxetine hydrochloride can be better improved.

Claims (10)

1. A duloxetine hydrochloride intermediate impurity, Compound I, having the structural formula:

2. a duloxetine hydrochloride intermediate impurity, compound II, having the structural formula:

3. a process for the preparation of compound I according to claim 1, characterized in that:

in the first step, firstly adding alkali 1 and a compound III, after hydrolysis reaction, adding alkali 2 to react with a compound IV to obtain a mixture of a compound V and a compound VI; and step two, adding alkali 3, purifying the compound I by column chromatography and then purifying by n-heptane to obtain the compound I.

4. A process for the preparation of compound I according to claim 3, characterized in that: in the first step, the alkali 1 is selected from potassium hydroxide or sodium hydroxide, and the alkali 2 is N, N-diisopropylethylamine.

5. A process for the preparation of compound I according to claim 3, characterized in that: in the first step, the molar ratio of the compound III to the alkali 1 to the compound IV to the alkali 2 is 1: 2.0-6.0: 1.0-2.5: 1.0-3.0.

6. A method of assaying compound I, characterized by:

the chromatographic column is a chromatographic column taking octadecylsilane chemically bonded silica as a packed column, the detection wavelength is 230nm, the mobile phase A is acetonitrile, the mobile phase B is 0.1% ammonia water solution, and the elution gradient is as follows:

time (min) A(％) B(％) 0 10 90 10 50 50 25 70 30 30 90 10 35 10 90 45 10 90

。

7. A process for the preparation of compound II according to claim 2, characterized in that:

in the first step, firstly adding alkali 1 and a compound III, after hydrolysis reaction, adding alkali 2 to react with a compound IV to obtain a mixture of a compound V and a compound VI; and step two, adding the alkali 3, purifying the compound II, and performing column chromatography and then recrystallizing with n-heptane to obtain the compound II.

8. A process for the preparation of compound II according to claim 7, characterized in that: in the first step, the alkali 1 is selected from potassium hydroxide or sodium hydroxide, and the alkali 2 is N, N-diisopropylethylamine.

9. A process for the preparation of compound II according to claim 7, characterized in that: in the first step, the molar ratio of the compound III to the alkali 1 to the compound IV to the alkali 2 is 1: 2.0-6.0: 1.0-2.5: 1.0-3.0.

10. A method for analyzing a compound II, comprising:

the chromatographic column is a chromatographic column taking octadecylsilane chemically bonded silica as a packed column, the detection wavelength is 230nm, the mobile phase A is acetonitrile, the mobile phase B is 0.1% ammonia water solution, and the elution gradient is as follows:

time (min) A(％) B(％) 0 10 90 10 50 50 25 70 30 30 90 10 35 10 90 45 10 90

。

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