CN111718344A - Tadalafil refining method - Google Patents

Abstract

The invention discloses a tadalafil refining process, which comprises the following steps: dissolving or suspending the crude tadalafil product in a solvent, adding malic acid or benzoic acid, heating to dissolve the crude tadalafil product, cooling, and adding water to separate out the crystal so as to obtain a refined tadalafil crystal form I product. The obtained crystal has high yield, high chemical purity and good chemical stability.

Description

Tadalafil refining method

Technical Field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for refining a tadalafil medicament.

Background

Tadalafil, chemical name: (6R,12aR) -6- (1, 3-benzodioxolan-5-yl) -2-methyl-2, 3,6,7,12,12 a-hexahydropyrazino [1',2' -1,6] -pyrido [3,4-b ] indole-1, 4-dione (trade name Cialis) having the following structural formula:

tadalafil is a selective and reversible inhibitor of oral long-acting specific phosphodiesterase 5(PDE5) developed by both Li Lai company and Icos company, is used for treating ED, has the characteristics of quick response, convenient taking and obvious curative effect, and particularly has the sustained drug effect of 36h, so that a patient can freely schedule the administration time.

Most of the existing tadalafil synthesis processes reported in the literature use D-tryptophan and piperonal as starting materials, the D-tryptophan is esterified to generate D-tryptophan methyl ester, the D-tryptophan methyl ester and the piperonal are subjected to cyclization reaction, then amidation reaction is carried out to obtain (1R,3R) -1- (1, 3-benzodioxolane-5-yl) -2- (chloroacetyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-B ] indole-3-carboxylic acid methyl ester (T1 for short), and finally T1 is subjected to methylamine substitution and condensation ring closure to obtain a crude tadalafil product. The process can be known that the tadalafil crude product contains residues of process impurities such as methylamine and T1, wherein the toxicity of methylamine and T1 is high, and needs to be strictly controlled, so that a refining process of the tadalafil crude product, which is convenient for industrial mass production, needs to be found.

US5859006 discloses a tadalafil purification process by flash chromatography followed by methanol crystallization, which is expensive and not conducive to industrial production.

Chinese patent CN105272981A discloses a refining process of tadalafil crystal form I, which comprises introducing an isopropanol solution of a crude tadalafil product into an adsorption tower carrying a solid adsorbent bed for recrystallization purification. But the concentration of the tadalafil solution is only 0.1-1 Wt%, the stirring and crystallization time is 2-8 h, and special adsorption equipment is needed.

Chinese patent CN106674223A discloses a method for refining tadalafil, which comprises dispersing crude tadalafil into a mixed solvent of methanol and acetic acid, heating to dissolve the crude product, evaporating part of the solvent, separating out crystals, filtering, washing, drying to obtain tadalafil crystal form a, wherein acetic acid is used in the method, tadalafil is easy to form tadalafil acetic acid complex with acetic acid, and the obtained product contains impurity residues.

Chinese patent CN102367253B discloses a method for preparing tadalafil crystal form by directly cooling and crystallizing in a binary mixed solvent containing C1-C4 alcohol and acetic acid or a ternary mixed solvent containing C1-C4 alcohol, acetic acid and water, but the yield of the method is only 50% lower, tadalafil is easy to form a compound with acetic acid, and the obtained product also contains impurity residues.

Chinese patent CN101128463A discloses a refining method of crude tadalafil, which dissolves or suspends the crude tadalafil in C₂-C₆Aliphatic alcohols and ketones, or nitriles with hydroxy solventsHeating the mixture to 25-140 ℃, and cooling for crystallization. However, the method uses a large amount of solvent, and the mass/volume ratio of tadalafil to the solvent is 1 g: 80mL, and the heating temperature needs to be 125 ℃, and two types of solvents acetonitrile with higher toxicity are also used.

In the refinement process of tadalafil, the acid substance is added to effectively remove the residual organic base methylamine in the crude tadalafil product, but the tadalafil contains an imine structure and is alkalescent, so that the tadalafil is easy to form a solvate with acetic acid, hydrochloric acid and the like which are conventionally used in the purification process. The existing methods for removing process impurities such as T1 and the like comprise column chromatography, recrystallization and the like, but the production cost of the column chromatography is high, or a second solvent with high toxicity, such as acetonitrile, is used for recrystallization, so that the industrial production is not facilitated, and therefore, the refining process of tadalafil is further researched, and the method has a high practical application value.

Disclosure of Invention

The invention aims to provide a method for refining tadalafil, which solves the technical problem of low product purity in the existing refining method and is more economical and practical.

The technical scheme of the tadalafil refining method is as follows:

dissolving or suspending the crude tadalafil product in a solvent, adding malic acid or benzoic acid, heating to dissolve the crude tadalafil product, cooling, and adding water to separate out the crystal so as to obtain a refined tadalafil crystal form I product.

In the method, the solvent is a ternary mixed solvent containing water, ethyl acetate and C1-C4 alcohol; the volume ratio of water, ethyl acetate and C1-C4 alcohol in the ternary mixed solvent is 1: 1-2: 1-4; the C1-C4 alcohol can be selected from methanol, ethanol, isopropanol, and n-butanol.

For the selection of the amount of crude tadalafil, experiments have shown that the preferred range of amounts is: the mass/volume ratio of the crude tadalafil product to the ternary mixed solvent is 1 g: 30-70 mL, wherein the molar ratio of the tadalafil crude product to malic acid or benzoic acid is 1: 1-1: 2, the mass/volume ratio of the crude tadalafil product to water is 1 g: 10-30 mL.

Further, the method for refining tadalafil comprises the following steps:

(1) dissolving or suspending the crude tadalafil product in a ternary mixed solvent of water, ethyl acetate and C1-C4 alcohol, and stirring;

(2) adding malic acid or benzoic acid, heating to 60-80 ℃, stirring, and dissolving;

(3) slowly cooling, and adding water to separate out crystals;

(4) filtering, washing, separating and drying to obtain the tadalafil crystal form I.

The stirring time after the temperature is raised to 60-80 ℃ in the step (2) is preferably 0.5-1 h.

The tadalafil crystal form I obtained by the method (example 1) adopts Cu-K α₁The following X-ray powder diffraction patterns, measured with radiation and expressed in terms of the crystal spacing d, bragg angle 2 theta, intensity and relative intensity (expressed in percentage with respect to the most intense radiation), demonstrate that the tadalafil crystalline form I obtained using the process of the present invention has the following characteristics.

TABLE 1X-ray powder diffraction peak relative intensity of Tadalafil crystal form I prepared by the present invention

The invention further considers the stability effect of the tadalafil crystal form I obtained by the method (example 1) of the invention, and the test results are as follows:

table 2 stability test results of Tadalafil crystal form I prepared by the invention

Conditions of standing	Appearance of the productTraits	Content (%)	Related substance (%)
				Day 0	White powder	99.4	Not detected out
60 ℃ for 10 days	White powder	99.5	0.02
				RH 92.5% for 10 days	White powder	99.2	0.02
Illuminating for 10 days	White powder	99.1	0.02

Through detection, the total impurities of related substances of a tadalafil finished product in the light, heat and wet sample retention process are only 0.02 percent, the content is more than 99 percent, the tadalafil finished product meets the requirements of pharmacopoeias of various countries, and acetic acid used in the prior art is easy to form a solvate with tadalafil, so that the technical effect of the application cannot be realized.

The results prove that the tadalafil crystal form I is a good crystal with uniform particle size distribution, has stable property, is not easy to absorb moisture, is easy to store and prepare into a corresponding preparation.

More importantly, the influence of the purity of tadalafil on the quality of the final medicine is very critical, the control on related substances in the product is very strict, and the related substance standard of tadalafil in European pharmacopoeia and United states pharmacopoeia is that the maximum single impurity content is not more than 0.1%, the total impurity content is not more than 0.3%, and the content limit is 97.5-102.5%.

In the prior art, acetic acid is commonly used for removing organic bases with high toxicity, such as methylamine and the like, contained in a crude product of tadalafil, but because the structure of tadalafil contains imine, which is alkalescent and is easy to form a compound with an acid substance, the prior art method uses acetic acid, so that the technical problems of high impurity content and low yield of the obtained product occur.

The method creatively changes the defects, can effectively control the residue of organic alkali such as methylamine and the like with high toxicity of tadalafil by using organic acid such as malic acid, benzoic acid and the like, and obtains a tadalafil finished product with high purity because the benzoic acid and the malic acid are not salified with tadalafil.

The method comprises the steps of performing linear gradient elution by using high performance liquid chromatography, using octadecylsilane chemically bonded silica as a filling agent, using 0.1% trifluoroacetic acid solution and acetonitrile as mobile phases according to the following table, and detecting related substances of tadalafil with the detection wavelength of 285 nm.

TABLE 3 gradient elution Table for related substances

Time (minutes)	0.1% trifluoroacetic acid solution	Acetonitrile
			0-3	85	15
3-30	85→5	15→95
			30-33	5	95

The method comprises the steps of performing isocratic elution by using high performance liquid chromatography, using octadecylsilane chemically bonded silica as a filler, using 0.1% trifluoroacetic acid solution (55%) -acetonitrile (45%) as a mobile phase, detecting the wavelength of 285nm, and determining the content of tadalafil. The detection results of related substances and content of tadalafil crystal form I obtained by different methods are shown in the following table.

Table 4, related substances of Tadalafil crystal form I obtained by different methods and content detection results

Method of producing a composite material	Selection of acid	Related substance (%)	Content (%)	Yield (%)
					Example 2	Benzoic acid	Not detected out	99.4	79
Example 1	Malic acid	Not detected out	99.0	65
					Comparative example	Acetic acid	0.03	86.1	51

The method has the technical effects that: on one hand, the organic base residue with high toxicity of tadalafil is effectively controlled by using malic acid and benzoic acid, so that impurities can be effectively avoided, and the yield is obviously improved; on the other hand, because two to three low-toxicity organic solvents such as methanol, ethanol and the like are simultaneously used, the method is green and environment-friendly and is more suitable for industrial production

Drawings

Figure 1 is an X-ray powder diffraction pattern of tadalafil form I.

Detailed Description

The technical solutions of the present invention are described below by specific examples, but the scope of the present invention is not limited thereto.

Example 1

Adding 10g of tadalafil, 10ml of distilled water, 20ml of ethyl acetate and 40ml of absolute ethyl alcohol into a three-necked bottle with a stirring device at room temperature, stirring, adding 5g of malic acid, heating in a water bath to 80 ℃, keeping the temperature and stirring for 30min, cooling, adding 290ml of water, separating out white solid, stirring for 2H at room temperature, performing suction filtration, washing with a small amount of water, performing suction drying, and drying to obtain 6.5g of white tadalafil crystal form I with the yield of about 65% (elemental analysis: C% 66.75, H% 4.89, N% 10.64, and HPLC: no impurity detected).

Example 2

Adding 10g of tadalafil, 10ml of distilled water, 20ml of ethyl acetate and 30ml of absolute ethyl alcohol into a three-necked flask with a stirring device at room temperature, stirring, adding 5g of benzoic acid, heating in a water bath to 70 ℃, keeping the temperature and stirring for 1H, cooling, adding 140ml of water, separating out white solid, stirring for 2H at room temperature, performing suction filtration, washing with a small amount of water, performing suction drying, and drying to obtain 7.9g of white tadalafil crystal form I with the yield of about 79% (elemental analysis: C% 67.51, H% 4.96, N% 10.79, HPLC: impurities are not detected).

Example 3

Adding 10g of tadalafil, 10ml of distilled water, 10ml of ethyl acetate and 10ml of absolute ethyl alcohol into a three-necked flask with a stirring device at room temperature, stirring, adding 3g of benzoic acid, heating in a water bath to 60 ℃, keeping the temperature and stirring for 45min, cooling, adding 90ml of water, separating out white solid, stirring for 2H at room temperature, performing suction filtration, washing with a small amount of water, performing suction drying, and drying to obtain 7.0g of white tadalafil crystal form I with the yield of about 70% (elemental analysis: C% 66.28, H% 4.75, N% 10.52, HPLC: no impurity detected).

Claims (9)

1. A method for refining tadalafil is characterized by comprising the following steps: dissolving or suspending the crude tadalafil product in a solvent, adding malic acid or benzoic acid, heating to dissolve the crude tadalafil product, cooling, and adding water to separate out the crystal so as to obtain a refined tadalafil crystal form I product.

2. The method of claim 1, wherein the solvent is a ternary mixed solvent comprising water, ethyl acetate, and a C1-C4 alcohol.

3. The method according to claim 2, wherein the volume ratio of water, ethyl acetate and the C1-C4 alcohol in the ternary mixed solvent is 1: 1-2: 1 to 4.

4. The method according to claim 2, wherein the mass/volume ratio of the crude tadalafil product to the ternary mixed solvent is 1 g: 30-70 mL.

5. The method according to claim 2, wherein the C1-C4-containing alcohol is selected from the group consisting of methanol, ethanol, isopropanol, and n-butanol.

6. The method of claim 1, wherein the molar ratio of the crude tadalafil product to malic acid or benzoic acid is 1: 1-1: 2.

7. the process according to claim 2, characterized in that the mass/volume ratio of crude tadalafil to water is 1 g:

10～30mL。

8. the method according to claim 1, characterized by comprising the steps of:

(1) dissolving or suspending the crude tadalafil product in a ternary mixed solvent of water, ethyl acetate and C1-C4 alcohol, and stirring;

(2) adding malic acid or benzoic acid, heating to 60-80 ℃, stirring, and dissolving;

(3) slowly cooling, and adding water to separate out crystals;

(4) filtering, washing, separating and drying to obtain the tadalafil crystal form I.

9. The method according to claim 8, wherein the stirring time after the temperature is raised to 60 to 80 ℃ in the step (2) is 0.5 to 1 hour.

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