Process for the preparation of a minocycline intermediate

Abstract

The application discloses a preparation method of a minocycline intermediate, which comprises the following steps: carrying out a dechlorination reaction on a starting material of demethylchlortetracycline hydrochloride in a mixed solvent of alcohol and water under the action of a catalyst in an ammonium formate and alkali system under normal pressure and in a non-hydrogen environment to obtain the intermediate 6-demethyltetracycline; the alcohol is C1-C3 alcohol; and the alkali is one or more of the following: ammonia water, methylamine solution, dimethylamine solution, triethylamine and the like. The preparation method is a normal-pressure non-hydrogen dechlorination method, and has the advantages of simple process, few side reactions, high purity, high yield, simple post-treatment, high safety factor and suitability for industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing 6-nortetracycline, belonging to the field of semi-synthetic technology of antibiotic drugs. Background Technology

[0002] 6-Desmethyltetracycline, also known as 7-dechlorodesmethylchlortetracycline, is an important intermediate in the preparation of minocycline hydrochloride. Its appearance is a yellow-green powder. Its English chemical name is (4S,4aS,5aS,6S)-4-(Dimethylamino)-3,6,10,12,12a-pentahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide, CAS Registry Number is 987-02-0, and its molecular formula is C2. 21 H 22 N₂O₈ has the following chemical structural formula:

[0003]

[0004] The existing methods for preparing 6-nortetracycline mainly involve high-pressure hydrogenation dechlorination: 6-nortetracycline is prepared by high-pressure hydrogenation dechlorination using demethylchlorinium hydrochloride as a raw material in a suitable solvent and under a heavy metal catalyst. Representative literature includes the following:

[0005] 1. The master's thesis of Zhejiang University, "Study on the Synthesis Process of Minocycline Hydrochloride", reported that dechlorinated chlortetracycline was prepared by using dechlorinated chlortetracycline hydrochloride as raw material, methanol as solvent, in the presence of organic base (triethylamine), at a reaction temperature of 55℃, a hydrogen pressure of 0.8MPa, and 5% palladium on carbon as catalyst for dechlorination and hydrogenation reaction for more than 3 hours.

[0006] 2. Patent CN111574392 discloses a method for removing the chlorine at the C7 position of 6-nortetracycline using demethylchlortetracycline as raw material, purified water as solvent, and ammonia as alkali, under the action of urea and palladium on carbon and a hydrogen pressure of 0.3-1.5 MPa, with a yield of 81.2% and a purity of 96.8%.

[0007] 3. The master's thesis of Hebei University of Science and Technology, "Development of a New Process for Minocycline", reported the preparation of 6-nortetracycline by using demethylchlortetracycline hydrochloride as raw material, distilled water as solvent, 25% sodium hydroxide as base, 5% palladium on carbon as catalyst, adding 2-3 drops of defoamer, and reacting under hydrogen pressure of about 0.8 MPa to remove chlorine at the C7 position.

[0008] 4. The literature “Research on the Synthesis of 7-Dimethylamino-6-demethyl-6-deoxytetracycline” (Fujian Light Textile, 2009, 5: 52-56) describes the preparation of 6-demethyltetracycline by hydrogenation of demethylchlortetracycline hydrochloride in anhydrous ethanol, with triethylamine as the base, 10% palladium on carbon as the catalyst, and 4.0 MPa hydrogen pressure at room temperature, with a yield of 86.7%.

[0009] 5. Patent CN106831479 reports that in ethanol solvent, triethylamine is used as a base, 5% palladium on carbon is used as a catalyst, and under hydrogen pressure of 1.0MPa to 1.5MPa and temperature of 40°C, the chlorine at the C7 position of the raw material demethylchlortetracycline hydrochloride is removed to obtain 6-nortetracycline with a yield of 85% and a purity of 96.5%.

[0010] These methods generally require pressurized and hydrogenated operating environments, using high-pressure hydrogenation equipment and processes, which pose significant safety hazards. Furthermore, these methods exhibit drawbacks such as complex processes, numerous control points, many operational steps, and high requirements for industrial production. Summary of the Invention

[0011] The main technical problem solved by this invention is to provide a simple method for preparing 6-nortetracycline via a non-hydrogen dechlorination reaction at atmospheric pressure, in order to avoid the high-pressure hydrogenation reaction in existing methods for preparing 6-nortetracycline. The preparation method of this invention features a simple process, few side reactions, high yield, simple post-processing, high safety, and ease of industrialization.

[0012] This invention provides a method for preparing 6-nortetracycline, which includes the following steps: in a mixed solvent of alcohol and water, under normal pressure and non-hydrogen atmosphere, in the presence of a catalyst, dechlorination reaction is carried out on demethylchlortetracycline hydrochloride as the starting material to obtain the intermediate 6-nortetracycline.

[0013]

[0014] This invention discloses a method for preparing a minocycline intermediate, comprising the following steps: adding demethylchlortetracycline hydrochloride to alcohol, water, catalyst, ammonium formate, and liquid alkali, stirring to dissolve, and carrying out a dechlorination reaction to obtain the minocycline intermediate 6-demethyltetracycline; wherein the alcohol is a C1-C3 alcohol; and the catalyst is a palladium-on-carbon catalyst.

[0015] Furthermore, the liquid alkali is one or more of ammonia, methylamine solution, dimethylamine solution, triethylamine, etc., the C1-C3 alcohol is one or more of methanol, ethanol, isopropanol, etc., and the reaction temperature is 30-50°C.

[0016] Furthermore, the mass-to-volume ratio of the hydrochloric acid to the alcohol (g / ml) is 1:3 to 10, preferably 1:6.

[0017] Furthermore, the volume ratio of the alcohol to water is 1:1 to 5, preferably 1:2.

[0018] Furthermore, the molar ratio of demethylchlortetracycline hydrochloride to ammonium formate is 1:2 to 10, preferably 1:6.

[0019] Furthermore, the molar ratio of the liquid alkali to demethylchlortetracycline hydrochloride is 1 to 5:1, preferably 1.5:1.

[0020] Furthermore, the palladium in the palladium-on-carbon catalyst contains 5% to 10% by mass.

[0021] Furthermore, the weight ratio of the dry palladium carbon to demethylchlortetracycline hydrochloride is 1:5 to 50, preferably 1:10.

[0022] The preparation method of the present invention includes a post-processing step: adjusting the reaction solution to alkaline with alkali, filtering to remove the palladium-carbon catalyst, and then adjusting the acid to precipitate the solid.

[0023] Furthermore, the alkali includes, but is not limited to, organic alkalis such as methylamine solution, dimethylamine, and triethylamine; inorganic alkalis such as ammonia, sodium hydroxide, and potassium hydroxide; and basic inorganic salts such as sodium bicarbonate, sodium carbonate, potassium sodium bicarbonate, and potassium carbonate; the acid is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, and oxalic acid.

[0024] The beneficial effects of this invention are as follows: This invention employs an atmospheric pressure non-hydrogen dechlorination method, resulting in high product yield, few side reactions, and a purity of over 98% for the obtained product, 6-nortetracycline. Furthermore, the process is simple, post-processing is convenient, catalyst and solvent recovery is easy, the safety factor is high, environmental impact is low, and it is suitable for industrial production. Attached Figure Description

[0025] Figure 1 HPLC chromatogram of 6-nortetracycline.

[0026] Figure 2 Mass spectrum of 6-nortetracycline. Detailed Implementation

[0027] The following embodiments further illustrate the present invention, but do not limit the invention to the scope of these embodiments. Experimental methods in the following embodiments, where specific conditions are not specified, were selected according to conventional methods and conditions. Without departing from common knowledge in the art, the various preferred conditions can be arbitrarily combined to obtain various preferred embodiments of the present invention. The raw materials and reagents used in the present invention are all conventional commercially available products.

[0028] Example 1

[0029] 20 g (0.04 mol) of demethylchlortetracycline hydrochloride, 60 ml of methanol, 60 ml of purified water, 5.0 g (0.08 mol) of ammonium formate, 0.4 g of 5% palladium on carbon (dry weight), and 4.9 ml (0.04 mol) of methylamine solution were stirred at room temperature until homogeneous. The temperature was then raised to 30 ± 3 °C with stirring. A sample was taken for monitoring. The reaction was stopped when the residual reactants were ≤ 5%, and the temperature was lowered to room temperature. The reaction mixture was adjusted to alkaline with methylamine, stirred for 10 min, filtered to remove the palladium on carbon, washed with 8 ml of water, and dried under vacuum. The filtrate was adjusted to acidic with 1 N hydrochloric acid, stirred for 1 h, filtered under vacuum, washed with 10 ml of water, and dried under vacuum. The wet product was dried under vacuum at 40 ± 5 °C to obtain 15.32 g of a yellow-green solid, with a yield of 89.2% and a purity of 98.36%.

[0030] Example 2

[0031] 20 g (0.04 mol) of demethylchlortetracycline hydrochloride, 60 ml of ethanol, 300 ml of purified water, 25.2 g (0.4 mol) of ammonium formate, 4.0 g of 5% palladium on carbon (dry weight), and 8 ml (0.04 mol) of dimethylamine solution were stirred until homogeneous at room temperature. The temperature was then raised to 40 ± 3 °C with stirring. A sample was taken for monitoring. The reaction was stopped when the residual reactants were ≤ 5%, and the temperature was lowered to room temperature. The reaction mixture was adjusted to alkaline with dimethylamine, stirred for 10 min, filtered to remove the palladium on carbon, washed with 8 ml of water, and dried under vacuum. The filtrate was adjusted to acidic with 1N sulfuric acid, stirred for 1 h, filtered under vacuum, washed with 10 ml of water, and dried under vacuum. The wet product was dried under vacuum at 40 ± 5 °C to obtain 14.85 g of a yellow-green solid, with a yield of 86.5% and a purity of 99.18%.

[0032] Example 3

[0033] 20 g (0.04 mol) of demethylchlortetracycline hydrochloride, 200 ml of methanol, 200 ml of purified water, 15.1 g (0.24 mol) of ammonium formate, 2.0 g of 5% palladium on carbon (dry weight), and 5.5 ml (0.04 mol) of triethylamine were stirred at room temperature until homogeneous. The temperature was then raised to 50 ± 3 °C with stirring. A sample was taken for monitoring. The reaction was stopped when the residual reactants reached ≤ 5%, and the temperature was lowered to room temperature. The reaction mixture was adjusted to alkaline with triethylamine, stirred for 10 min, filtered to remove the palladium on carbon, washed with 10 ml of water, and dried under vacuum. The filtrate was adjusted to acidic with aqueous acetic acid, stirred for 1 h, filtered under vacuum, washed with 10 ml of water, and dried under vacuum. The wet product was dried under vacuum at 40 ± 5 °C to obtain 15.66 g of a yellow-green solid, with a yield of 91.2% and a purity of 98.28%.

[0034] Example 4

[0035] 20 g (0.04 mol) of demethylchlortetracycline hydrochloride, 100 ml of isopropanol, 500 ml of purified water, 25.2 g (0.4 mol) of ammonium formate, 0.4 g of 10% palladium on carbon (dry weight), and 30.7 ml (0.2 mol) of ammonia were stirred at room temperature until homogeneous. The temperature was then raised to 35 ± 3 °C with stirring. A sample was taken for monitoring. The reaction was stopped when the residual reactant was ≤ 5%, and the temperature was lowered to room temperature. The reaction mixture was adjusted to alkaline with ammonia, stirred for 10 min, filtered to remove the palladium on carbon, washed with 10 ml of water, and dried under vacuum. The filtrate was adjusted to acidic with oxalic acid solution, stirred for 1 h, filtered under vacuum, washed with 10 ml of water, and dried under vacuum. The wet product was dried under vacuum at 40 ± 5 °C to obtain 15.22 g of a yellow-green solid, with a yield of 88.6% and a purity of 99.17%.

[0036] Example 5

[0037] 20 g (0.04 mol) of demethylchlortetracycline hydrochloride, 120 ml of ethanol, 240 ml of purified water, 15.1 g (0.24 mol) of ammonium formate, 2.0 g of 10% palladium on carbon (dry weight), and 7.3 ml (0.06 mol) of methylamine solution were stirred until homogeneous at room temperature. The temperature was then raised to 45 ± 3 °C with stirring. A sample was taken for monitoring. The reaction was stopped when the residual reactants were ≤5%, and the temperature was lowered to room temperature. The reaction mixture was adjusted to alkaline with sodium hydroxide aqueous solution, stirred for 10 min, filtered to remove palladium on carbon, washed with 10 ml of water, and dried under vacuum. The filtrate was adjusted to acidic with formic acid aqueous solution, stirred for 1 h, filtered under vacuum, washed with 10 ml of water, and dried under vacuum. The wet product was dried under vacuum at 40 ± 5 °C to obtain 16.02 g of a yellow-green solid, with a yield of 93.3% and a purity of 99.43%.

[0038] Example 6

[0039] 20 g (0.04 mol) of demethylchlortetracycline hydrochloride, 160 ml of ethanol, 480 ml of purified water, 7.6 g (0.12 mol) of ammonium formate, 0.4 g of 10% palladium on carbon (dry weight), and 27.7 ml (0.2 mol) of triethylamine were stirred at room temperature until homogeneous. The temperature was then raised to 50 ± 3 °C with stirring. A sample was taken for monitoring. The reaction was stopped when the residual reactants reached ≤ 5%, and the temperature was lowered to room temperature. The reaction mixture was adjusted to alkaline with potassium hydroxide aqueous solution, stirred for 10 min, filtered to remove the palladium on carbon, washed with 10 ml of water, and dried under vacuum. The filtrate was adjusted to acidic with 1 N hydrochloric acid, stirred for 1 h, filtered under vacuum, washed with 10 ml of water, and dried under vacuum. The wet product was dried under vacuum at 40 ± 5 °C to obtain 14.87 g of a yellow-green solid, with a yield of 86.6% and a purity of 99.21%.

Claims

1. A method for preparing a minocycline intermediate, characterized in that... Includes the following steps: Demethylchlortetracycline hydrochloride was added to alcohol, water, catalyst, ammonium formate and liquid alkali, stirred and dissolved, and carried out a dechlorination reaction to obtain minocycline intermediate 6-demethyltetracycline; the alcohol was a C1 to C3 alcohol; the catalyst was a palladium-on-carbon catalyst.

2. The preparation method according to claim 1, characterized in that, The liquid alkali is one or more of ammonia, methylamine solution, dimethylamine solution, triethylamine, etc., and the C1-C3 alcohol is one or more of methanol, ethanol, isopropanol, etc. The reaction temperature is 30-50℃.

3. The preparation method according to claim 2, characterized in that: The mass-to-volume ratio of the hydrochloric acid to the alcohol (g / ml) is 1:3 to 10, and the volume ratio of the alcohol to the water is 1:1 to 5.

4. The preparation method according to claim 3, characterized in that: The mass-to-volume ratio of the hydrochloric acid to the alcohol (g / ml) is 1:6, and the volume ratio of the alcohol to the water is 1:

2.

5. The preparation method according to claim 1, characterized in that: The molar ratio of demethylchlortetracycline hydrochloride to ammonium formate is 1:2 to 10, and the molar ratio of liquid alkali to demethylchlortetracycline hydrochloride is 1 to 5:

1.

6. The preparation method according to claim 5, characterized in that: The molar ratio of demethylchlortetracycline hydrochloride to ammonium formate is 1:6, and the molar ratio of liquid alkali to demethylchlortetracycline hydrochloride is 1.5:

1.

7. The preparation method according to claim 1, characterized in that: The palladium-on-carbon catalyst contains 5% to 10% palladium by mass, and the weight ratio of the dry palladium-on-carbon catalyst to demethylchlortetracycline hydrochloride is 1:5 to 50.

8. The preparation method according to claim 7, characterized in that: The weight ratio of the dry palladium carbon to demethylchlortetracycline hydrochloride is 1:

10.

9. The preparation method according to claim 1, characterized in that: The preparation method includes a post-processing step: adjusting the reaction solution to alkaline with alkali, filtering to remove the palladium-carbon catalyst, adjusting the acid to precipitate the solid.

10. The preparation method according to claim 9, characterized in that: The alkali includes, but is not limited to, organic alkalis such as methylamine solution, dimethylamine, and triethylamine; inorganic alkalis such as ammonia, sodium hydroxide, and potassium hydroxide; and basic inorganic salts such as sodium bicarbonate, sodium carbonate, sodium bicarbonate potassium, and potassium carbonate. The acid is one or more of hydrochloric acid, sulfuric acid, formic acid, acetic acid, and oxalic acid.

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