CN111574392A - A kind of preparation method of 6-desmethyl-6-anhydrotetracycline - Google Patents

Abstract

The invention relates to a preparation method of 6-demethyl-6-anhydrotetracycline, which comprises the following two steps: firstly, adding demethylated aureomycin hydrochloride into purified water, dropwise adding ammonia water, adjusting the pH value to 6-8, stirring until the pH value is completely dissolved, then adding urea and a Pd/C catalyst, and reacting under the hydrogen pressure of 0.3-1.5 Mpa to generate 6-demethyltetracycline; and then adding the obtained 6-demethyltetracycline into an alcohol solvent, dropwise adding strong acid to dissolve the 6-demethyltetracycline, under the nitrogen pressure of 1-3 MPa, promoting 6-hydroxyl in 6-demethyltetracycline molecules to be combined with 5 a-hydrogen to form water, removing the water to generate double bonds, obtaining 6-demethyl-6 anhydrotetracycline reaction liquid, and purifying to obtain the purity higher than 95%. The preparation method is simple and convenient in process, and the prepared 6-demethyl-6-anhydrotetracycline can be used as a reference substance for qualitative and quantitative determination of impurities in production and also can provide a large sample for the subsequent research of converting anhydrotetracycline into deoxytetracycline.

Description

A kind of preparation method of 6-desmethyl-6-anhydrotetracycline

technical field

The present invention relates to a preparation method of 6-demethyl-6-anhydrotetracycline.

Background technique

6-Demethyl-6-anhydrotetracycline is one of the main impurities produced in the process of synthesizing sancycline. Its molecular structure is as follows:

6-Demethyl-6-anhydrotetracycline belongs to Anhydrotetracycline with high toxicity and poor antibacterial activity. The traditional preparation method is to purify the crude sancycline by column or preparative chromatography, which is cumbersome to operate, and the amount of single preparation is small. As the requirements for impurities in the Chinese Pharmacopoeia, the US Pharmacopoeia and the European Pharmacopoeia become more and more stringent, and the research on the toxicity and transformation direction of impurities continues to deepen, the demand for standard impurities has gradually increased, so high-purity, high-content impurities are prepared. The large sample impurity reference standard is becoming more and more important.

SUMMARY OF THE INVENTION

The main technical problem solved by the present invention is to provide a preparation method of 6-desmethyl-6-anhydrotetracycline which is safe, simple in process, specific in reaction, high in yield and low in cost.

Described a kind of preparation method of 6-demethyl-6-anhydrotetracycline, is characterized in that comprising the following steps:

1) First, add demethyl chlortetracycline hydrochloride into purified water, add ammonia water dropwise, adjust pH to 6-8, stir until completely dissolved, then add urea and Pd/C catalyst, under 0.3-1.5Mpa hydrogen pressure , 35～50 ℃ of temperature react for 4～6 hours, in order to carry out the reaction of removing 7-position chlorine, generate 6-desmethyltetracycline;

2) Add 6-desmethyltetracycline into an alcohol solvent, add dropwise strong acid, stir to dissolve, and react at 1-3MPa nitrogen pressure and 45-60°C temperature to promote 6-desmethyltetracycline in the molecule. The -position hydroxyl group is combined with the 5a-position hydrogen to form water and remove the double bond to obtain a 6-desmethyl-6-anhydrotetracycline reaction solution; the obtained reaction solution is post-treated to obtain a 6-desmethyl-6-anhydrotetracycline product .

The method for preparing 6-demethyl-6-anhydrotetracycline is characterized in that the mass ratio of demethyl chlortetracycline hydrochloride and urea is 1:1-3.

The method for preparing 6-desmethyl-6-anhydrotetracycline is characterized in that in the Pd/C catalyst, the mass fraction of the Pd component is 7-10%; The feeding mass ratio of the Pd/C catalyst is 1:0.01~0.1, preferably 1:0.02~0.1.

The method for preparing 6-desmethyl-6-anhydrotetracycline is characterized in that in step 2), the alcohol solvent is an organic alcohol aqueous solution with a volume concentration of 85% to 95%, and the organic alcohol is C1～95%. C4 alcohol, preferably methyl alcohol, ethanol or isopropanol; The mass ratio of demethyl chlortetracycline hydrochloride and described alcoholic solvent is 1: 2～4.

The method for preparing 6-demethyl-6-anhydrotetracycline is characterized in that in step 2), the strong acid is concentrated sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or hydrofluoric acid; The mass ratio of methyltetracycline and strong acid is 1:0.2～2, preferably 1:0.5～2.

The described preparation method of 6-desmethyl-6-anhydrotetracycline is characterized in that the post-processing step of the reaction solution is as follows: cooling the reaction solution to -5～10°C, and then slowly adding concentrated sulfuric acid drop by drop Adjust the pH to 1-2 (so that the crude 6-desmethyltetracycline crystallizes in the form of sulfate), stir and crystallize for 1-3 h, filter, add the filter cake to anhydrous lower alcohol, add DMF, and adjust with ammonia water The pH is adjusted to 7 to 8, and the mixture is kept at -5 to 5° C. and stirred for 1 to 3 h to obtain the 6-desmethyl-6-anhydrotetracycline product.

The method for preparing 6-demethyl-6-anhydrotetracycline is characterized in that the mass ratio of 6-demethyltetracycline to DMF is 1:0.1-0.5.

Described a kind of preparation method of 6-demethyl-6-anhydrotetracycline, it is characterized in that in parts by weight, specifically comprises the following steps:

1) Add 1 part of demethyl chlortetracycline hydrochloride to soft water, adjust the pH to 6-8 with ammonia water, stir to dissolve, then add 1-3 parts of urea and mix evenly, add 0.015-0.025 parts of Pd mass fraction of 7~10% Pd/C catalyst, react at 0.3~1.5Mpa hydrogen pressure and 35~50℃ temperature for 4~6 hours to generate 6-desmethyltetracycline;

2) Then add the obtained 6-desmethyltetracycline into 2-4 parts of an organic alcohol aqueous solution with a volume concentration of 85%-95%, control the temperature at 0-5°C, add 0.5-2 parts of a strong acid, and stir until Completely soluble; under the nitrogen pressure of 1-3Mpa, react at 45-60 ℃ for 3-5 hours to promote the combination of the 6-position hydroxyl group and the 5a-position hydrogen in the 6-desmethyltetracycline molecule to form water and remove it to obtain 6-demethyl-6-anhydrotetracycline reaction solution; the obtained reaction solution is cooled to -5～10° C., 0.2～1 part of concentrated sulfuric acid is added dropwise, and the pH of the reaction solution is adjusted to 1～2 to obtain 6-demethylation -6-anhydrotetracycline sulfate; then add 6-demethyl-6-anhydrotetracycline sulfate to 3-5 parts of anhydrous lower alcohol, cool to 0-5 ℃, add 0.1-0.5 part of DMF, Adjust the pH to 7-8 with ammonia water, keep stirring for 2 hours, and filter the obtained 6-desmethyl-6-anhydrotetracycline product.

The reaction process of the present invention is monitored by HPLC, and in the two-step reaction process of the present invention: the first step is generally that the content of the raw material demethyl chlortetracycline in the reaction solution is below 0.5%, and the reaction ends; the second step is generally The reaction is terminated when the content of the raw material 6-demethyltetracycline in the reaction solution is less than 1%.

The synthetic route of the present invention is as follows:

The beneficial effects obtained by the present invention are as follows:

1. The technological process of the present invention is simple and convenient, and the prepared 6-demethyl-6-anhydrotetracycline can be used as a reference substance for qualitative and quantitative impurities in the production of sancycline, and can also be used for the subsequent research that anhydrotetracycline is converted into deoxytetracycline. Great sample.

2. The present invention adopts a two-step method. When preparing 6-demethyltetracycline in the first step, urea is used as an acid binding agent, and the pH of the system is maintained at 6 to 8, which reduces the occurrence of C ring being destroyed. The resulting 6-desmethyltetracycline forms a double salt, which improves both the yield and the purity. In the preparation of 6-desmethyl-6-anhydrotetracycline in the second step, nitrogen pressure was used to promote the removal of a molecule of water from the hydroxyl group at the C6 position and the hydrogen at the C5a position. The refined DMF can dissolve most of the organic impurities and improve the The purity of 6-desmethyl-6-anhydrotetracycline sulfate was determined.

Detailed ways

The present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.

Example 1:

Cool 100g of soft water to 25°C, add 27g of chlortetracycline hydrochloride, adjust the pH to 8.0 with ammonia, stir to dissolve completely, add 30g of urea, stir for 10 minutes, mix the above mixture and 0.5g of 10% Pd/C (After drying) put into a 500ml hydrogenation reactor. It was replaced with 0.2MPa nitrogen and 0.2MPa hydrogen three times respectively to exhaust the air in the hydrogenation reaction kettle. Under the hydrogen pressure of 1.0 MPa, the temperature was controlled at 35~40 °C, and the reaction was carried out for 6 h, and the content of the raw material demethyl chlortetracycline in the reaction solution was controlled to be 0.3%. The material was discharged, cooled to 25°C, 15 g of concentrated hydrochloric acid with a mass concentration of 36% was added dropwise, stirred for 15 minutes until the precipitated material was completely dissolved, and then Pd/C was filtered. The filtrate was collected, 24 g of liquid caustic soda with a mass concentration of 40% was added dropwise, crystallization at 25°C for 1 h, suction filtration to obtain 6-demethyltetracycline, and dried to obtain 19.6 g with a purity of 98.5% and a yield of 84.77%.

19.6g of 6-demethyltetracycline was added to 100g of methanol aqueous solution with a volume concentration of 85%, 10g of methanesulfonic acid was added at 35°C, and after dissolving, it was put into a 500ml autoclave, and replaced 3 times with 0.4MPa nitrogen. Under the nitrogen gas of 2.5MPa, the temperature is controlled at 45~50°C, and the content of 6-desmethyltetracycline in the reaction solution is controlled to be 0.8%, the reaction is completed, and the nitrogen gas is released. The obtained reaction solution was cooled to 0°C, 2 g of DMF was added, the pH was adjusted to 1 with 98% concentrated sulfuric acid, stirred at a temperature for 2 h, and filtered to obtain 38.9 g of a wet cake. The wet filter cake was added to 60g of anhydrous methanol, and then adjusted to pH 7.5 with ammonia water, stirred at 5°C for 2h, filtered to obtain high-purity 6-desmethyl-6-anhydrotetracycline, and dried to obtain 15.1g of yellow powder , the purity is 94.2%, and the yield is 78%.

Example 2:

Cool 100g of soft water to 25°C, add 30g of chlortetracycline hydrochloride, adjust the pH to 7.5 with ammonia, stir to dissolve completely, add 30g of urea, stir for 10 minutes, mix the above mixed solution and 0.7g of 10% Pd/C (After drying) put into a 500ml hydrogenation reactor. It was replaced three times with 0.2MPa nitrogen and 0.2MPa hydrogen respectively. Under the hydrogen pressure of 0.8MPa, the temperature was controlled at 35~40℃, and the reaction was carried out for 6h, and the content of the raw material demethyl chlortetracycline in the reaction solution was controlled to be 0.6%. The material was discharged, cooled to 15°C, 15 g of concentrated hydrochloric acid with a mass concentration of 36% was added dropwise, stirred until the material was completely dissolved, and the Pd/C was filtered. The filtrate was collected, 28 g of liquid caustic soda with a mass concentration of 40% was added dropwise, 15°C was kept for crystallization for 1 h, and suction filtered to obtain 6-desmethyltetracycline, which was dried to obtain 20 g, with a purity of 97.1% and a yield of 79.1%.

20g 6-demethyltetracycline is added in the 85% ethanol aqueous solution in 100g volume concentration, and 10g mass concentration is 48% hydrobromic acid aqueous solution in 35 ℃, throws into the autoclave of 500ml after dissolving, uses 0.2MPa Nitrogen replacement 3 times. Under the nitrogen of 2.0MPa, the temperature is controlled at 45~50°C, and the content of 6-desmethyltetracycline in the reaction solution is controlled to be 0.6%, the reaction is completed, and the nitrogen gas is released. The obtained reaction solution was cooled to 0°C, adjusted to pH 1 with 98% concentrated sulfuric acid, kept stirring for 2 hours, and filtered to obtain 42.0 g of wet cake. The wet filter cake was added to 60g of anhydrous methanol, 2.5g of DMF was added, the pH was adjusted to 7.3 with ammonia water, stirred at 5°C for 2h, filtered to obtain high-purity 6-desmethyl-6-anhydrotetracycline, and dried. 14.6 g of yellow powder were obtained with a purity of 95.6% and a yield of 76.8%.

Example 3:

Cool 100g of soft water to 10°C, add 30g of chlortetracycline hydrochloride, adjust the pH to 7.8 with ammonia, stir to dissolve completely, add 35g of urea, stir for 10 minutes, mix the above mixture and 0.7g of 10% Pd/C (After drying) put into a 500ml hydrogenation reactor. It was replaced three times with 0.2MPa nitrogen and 0.2MPa hydrogen respectively. Under the hydrogen pressure of 1.0 MPa, the temperature was controlled at 35~40 °C, and the reaction was carried out for 6 h, and the content of the raw material demethyl chlortetracycline in the reaction solution was controlled to be 0.9%. The material was discharged, cooled to 5°C, 16 g of concentrated hydrochloric acid with a mass concentration of 36% was added dropwise, stirred until the material was completely dissolved, and the Pd/C was filtered. The filtrate was collected, 27.6 g of liquid caustic soda with a mass concentration of 40% was added dropwise, crystallization was maintained at 5°C for 1 h, suction filtration was performed to obtain 6-desmethyltetracycline, and 22.4 g was obtained by drying, with a purity of 96.8% and a yield of 81.2%.

22.4g of 6-demethyltetracycline was added to 100g of isopropanol aqueous solution with a volume concentration of 85%, 11g of p-toluenesulfonic acid was added at 35°C, and after dissolving, it was thrown into a 500ml autoclave, and replaced with 0.2MPa nitrogen for 3 Second-rate. Under the nitrogen gas of 3.0MPa, the temperature is controlled at 50~55°C, and the content of 6-desmethyltetracycline in the reaction solution is controlled to be 0.87%, the reaction is completed, and the nitrogen gas is released. The obtained reaction solution was cooled to -5°C, adjusted to pH 1 with 98% concentrated sulfuric acid, kept stirring for 2 hours, and filtered to obtain 40.1 g of wet cake. The wet filter cake was added to 60g of anhydrous methanol, 3g of DMF was added, the pH was adjusted to 7.6 with ammonia water, stirred at -5°C for 2h, filtered to obtain high-purity 6-desmethyl-6-anhydrotetracycline, and dried to obtain 15.1 g of yellow powder with a purity of 94.8% and a yield of 70.3%.

The content described in this specification is only an enumeration of the realization forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms stated in the embodiments.

Claims (8)

1. A method for preparing 6-demethyl-6-anhydrotetracycline, characterized by comprising the steps of:

1) firstly, adding demethylated aureomycin hydrochloride into purified water, dropwise adding ammonia water, adjusting the pH value to 6-8, stirring until the mixture is completely dissolved, then adding urea and a Pd/C catalyst, and reacting for 4-6 hours at the hydrogen pressure of 0.3-1.5 Mpa and the temperature of 35-50 ℃ to perform a reaction for removing 7-site chlorine, so as to generate 6-demethyltetracycline;

2) adding 6-demethyltetracycline into an alcohol solvent, dropwise adding strong acid, stirring to dissolve, reacting under the nitrogen pressure of 1-3 MPa and the temperature of 45-60 ℃, promoting 6-hydroxyl in 6-demethyltetracycline molecules to combine with 5 a-hydrogen to form water, and removing to generate double bonds, thereby obtaining 6-demethyl-6-anhydrotetracycline reaction liquid; the obtained reaction solution is post-treated to obtain the 6-demethyl-6-anhydrotetracycline product.

2. The process for preparing 6-demethyl-6-anhydrotetracycline according to claim 1, wherein the feed mass ratio of demethylated aureomycin hydrochloride to urea is 1: 1 to 3.

3. The method for preparing 6-demethyl-6-anhydrotetracycline according to claim 1, wherein the mass fraction of Pd in the Pd/C catalyst is 7-10%; the feeding mass ratio of the demethyl aureomycin hydrochloride to the Pd/C catalyst is 1: 0.01-0.1, and preferably 1: 0.02-0.1.

4. The method for preparing 6-demethyl-6-anhydrotetracycline according to claim 1, wherein in step 2), the alcoholic solvent is an aqueous solution of an organic alcohol with a volume concentration of 85% to 95%, and the organic alcohol is a C1-C4 alcohol, preferably methanol, ethanol or isopropanol; the feeding mass ratio of the demethyl aureomycin hydrochloride to the alcohol solvent is 1: 2-4.

5. The process according to claim 1, wherein in the step 2), the strong acid is concentrated sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or hydrofluoric acid; the feeding mass ratio of the 6-demethyltetracycline to the strong acid is 1: 0.2 to 2, preferably 1: 0.5 to 2.

6. The process for producing 6-desmethyl-6-anhydrotetracycline according to claim 1, characterized in that the step of post-treating the reaction solution is: cooling the reaction liquid to-5-10 ℃, dropwise and slowly dripping concentrated sulfuric acid to adjust the pH value to 1-2, stirring and crystallizing for 1-3 h, filtering, adding a filter cake into anhydrous lower alcohol, adding DMF, adjusting the pH value to 7-8 by using ammonia water, keeping the temperature and stirring for 1-3 h at-5 ℃, filtering and drying to obtain the 6-demethyl-6-anhydrotetracycline product with the purity of more than 95%.

7. The process according to claim 6, wherein the mass ratio of 6-demethyltetracycline to DMF is 1: 0.1 to 0.5.

8. The preparation method of 6-demethyl-6-anhydrotetracycline according to claim 1, which comprises the following steps in parts by weight:

1) adding 1 part of demethylated aureomycin hydrochloride into soft water, adjusting the pH value to 6-8 by using ammonia water, stirring to dissolve the mixture clearly, adding 1-3 parts of urea, uniformly mixing, adding 0.015-0.025 part of Pd/C catalyst with the mass fraction of 7-10%, and reacting for 4-6 hours at the temperature of 35-50 ℃ under the hydrogen pressure of 0.3-1.5 Mpa to generate 6-demethyltetracycline;

2) then adding the obtained 6-demethyltetracycline into 2-4 parts of organic alcohol aqueous solution with volume concentration of 85% -95%, controlling the temperature at 0-5 ℃, adding 0.5-2 parts of strong acid, and stirring until the solution is completely dissolved; reacting for 3-5 hours at 45-60 ℃ under the nitrogen pressure of 1-3 Mpa to promote 6-hydroxyl and 5 a-hydrogen in 6-demethyltetracycline molecules to combine to form water and remove, so as to obtain 6-demethyl-6-anhydrotetracycline reaction liquid;

3) cooling the obtained reaction liquid to-5-10 ℃, dropwise adding 0.2-1 part of concentrated sulfuric acid, and adjusting the pH of the reaction liquid to 1-2 to obtain 6-demethyl-6-anhydrotetracycline sulfate; and then adding 6-demethyl-6-anhydrotetracycline sulfate into 3-5 parts of anhydrous lower alcohol, cooling to 0-5 ℃, adding 0.1-0.5 part of DMF, adjusting the pH to 7-8 with ammonia water, stirring for 2 hours under heat preservation, filtering, and drying to obtain a 6-demethyl-6-anhydrotetracycline product with the purity of more than 95%.