Preparation method of diethylaminoethyl isothiourea salt and preparation method of tiamulin

Abstract

The invention provides a preparation method of diethylaminoethyl isothiourea salt and a preparation method of tiamulin, and belongs to the technical field of organic synthesis. The invention provides a preparation method of diethylaminoethyl isothiourea salt, which comprises the following steps: mixing diethylaminoethanol and thiourea, and carrying out alkylation reaction to obtain the diethylaminoethyl isothiourea salt. The diethylaminoethyl alcohol and the thiourea are mixed for alkylation reaction to obtain the diethylaminoethyl isothiourea salt, the diethylaminoethyl isothiourea salt is prepared through a one-pot method, the preparation efficiency is high, the steps are simple, the raw materials are easy to obtain, and the cost is low. The invention further provides a preparation method of the tiamulin, the steps are simple, the method is more suitable for industrial production, and the purity of the tiamulin is improved. Data of the embodiment shows that the purity of the tiamulin prepared by the method reaches 97% or above.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a preparation method of diethylaminoethyl isothiourea salt and a preparation method of tiamulin. Background Art

[0002] The molecular formula of tiamulin fumarate is C 28 H 47 NO4S·C4H4O4, with a molecular weight of 609.8, a melting point of 147-148 °C, a boiling point of 563 °C. It is a white or off-white crystalline powder, odorless and tasteless. It is used for chronic respiratory diseases in chickens, mycoplasma pneumonia in pigs and Haemophilus pleuropneumonia, and can also be used for dysentery caused by Treponema hyodysenteriae in pigs. It has good antibacterial activity against a variety of Gram-positive cocci including most staphylococci and streptococci, a variety of mycoplasmas and certain spirochetes, and its effect on mycoplasmas is stronger than that of macrolides. Tiamulin fumarate has the advantages of rapid absorption, high blood drug concentration, wide distribution in vivo, low residue, difficult to develop drug resistance, and no pollution to the environment. It is the most widely used pleuromutilin antibiotic drug at present, and its chemical structural formula is shown in Formula I:

[0003]

[0004] Tiamulin is a semi-synthetic compound. In related technologies, diethylamine reacts with bromochloroethane, and then thiourea is added to react to generate isothiourea salt. Pleuromutilin reacts with p-toluenesulfonyl chloride to generate pleuromutilin p-toluenesulfonate ester. Adding the isothiourea salt to the pleuromutilin p-toluenesulfonate ester reacts to generate tiamulin. There are problems of many preparation steps and low efficiency of isothiourea salt. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a preparation method of diethylaminoethyl isothiourea salt and a preparation method of tiamulin. The present invention obtains diethylaminoethyl isothiourea salt by a one-pot method, with high preparation efficiency and simple steps.

[0006] To achieve the above invention purpose, the present invention provides the following technical solutions:

[0007] The present invention provides a preparation method of diethylaminoethyl isothiourea salt, including the following steps:

[0008] Mix diethylaminoethanol and thiourea for alkylation reaction to obtain the diethylaminoethyl isothiourea salt.

[0009] Preferably, the temperature of the alkylation reaction is 78-88 °C, and the reaction time is 5-8 h.

[0010] Preferably, the alkylation reaction is carried out in an acidic solvent, which is concentrated hydrochloric acid or concentrated hydrobromic acid. The mass fraction of the concentrated hydrochloric acid is 36-38%, and the mass fraction of the concentrated hydrobromic acid is 45-48%.

[0011] Preferably, the molar ratio of diethylaminoethanol to concentrated hydrochloric acid is 1:1.15-1.3.

[0012] Preferably, the molar ratio of diethylaminoethanol to thiourea is 1:1.05-1.2.

[0013] The present invention also provides a method for preparing tiamulin, comprising the following steps:

[0014] Mix diethylaminoethanol and thiourea and carry out an alkylation reaction to obtain the diethylaminoethyl isothiourea salt;

[0015] Mix the diethylaminoethyl isothiourea salt, an inorganic base and water and carry out a hydrolysis reaction to obtain the metal salt of diethylaminoethyl mercaptan;

[0016] Mix the metal salt of diethylaminoethyl mercaptan, p-methylbenzenesulfonic acid pleuromutilin ester, a two-phase catalyst and an inorganic basic solution and carry out a substitution reaction to obtain the tiamulin.

[0017] Preferably, the temperature of the hydrolysis reaction is 22-32 °C and the time is 3-5 h.

[0018] Preferably, the temperature of the substitution reaction is 55-65 °C and the time is 1-2 h. During the substitution reaction, the pH value of the reaction system is not less than 12.

[0019] Preferably, the p-methylbenzenesulfonic acid pleuromutilin ester is prepared by an esterification reaction of pleuromutilin and p-toluenesulfonyl chloride.

[0020] Preferably, the two-phase catalyst includes tetrabutylammonium bromide. The mass of the tetrabutylammonium bromide is 1%-2% of the mass of pleuromutilin. The inorganic basic solution includes a sodium hydroxide solution. The mass fraction of the sodium hydroxide solution is 32%, and the volume of the sodium hydroxide solution is 40%-50% of the volume of pleuromutilin.

[0021] The present invention provides a method for preparing a diethylaminoethyl isothiourea salt, comprising the following steps: Mix diethylaminoethanol and thiourea and carry out an alkylation reaction to obtain the diethylaminoethyl isothiourea salt.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] The present invention uses a mixture of diethylaminoethanol and thiourea for alkylation reaction to obtain the diethylaminoethyl isothiourea salt. The diethylaminoethyl isothiourea salt is prepared by a one-pot method, with high preparation efficiency, simple steps, readily available raw materials, and low cost.

[0024] The present invention also provides a preparation method of tylosin, with simple steps, more suitable for industrial production, and improved purity of tylosin. The data of the examples show that the purity of the tylosin prepared by the present invention reaches more than 97%. Detailed implementation manners

[0025] The present invention provides a preparation method of diethylaminoethyl isothiourea salt, comprising the following steps:

[0026] Mix diethylaminoethanol and thiourea for alkylation reaction to obtain the diethylaminoethyl isothiourea salt.

[0027] In the present invention, unless otherwise specified, the raw materials used are commercially available products in the art.

[0028] In the present invention, the temperature of the alkylation reaction is preferably 78 - 88°C, specifically can be 78, 80, 82, 84, 85, 87 or 88°C, and the reaction time is preferably 5 - 8 h, specifically can be 5, 6, 7 or 8 h; controlling the parameters of the alkylation reaction within the above ranges can ensure the completion of the reaction and stable quality.

[0029] In the present invention, the alkylation reaction is preferably carried out in an acidic solvent. The acidic solvent is preferably concentrated hydrochloric acid or concentrated hydrobromic acid. The mass fraction of the concentrated hydrochloric acid is preferably 36 - 38%, specifically can be 36%, 37% or 38%, and the mass fraction of the concentrated hydrobromic acid is preferably 45 - 48%, specifically can be 45%, 46% or 48%; controlling the mass fraction of the acidic solvent within the above ranges can ensure the requirements of the pH value of the reaction system and facilitate the completion of the alkylation reaction.

[0030] In the present invention, the molar ratio of diethylaminoethanol to concentrated hydrochloric acid is preferably 1:1.15 - 1.3, specifically can be 1:1.15, 1:1.2, 1:1.25 or 1:1.3. Controlling the molar ratio of diethylaminoethanol to concentrated hydrochloric acid within the above ranges can ensure the requirements of the pH value of the reaction system and facilitate the completion of the alkylation reaction.

[0031] In the present invention, the molar ratio of diethylaminoethanol to thiourea is preferably 1:1.05 - 1.2, specifically can be 1:1.05, 1:1.15 or 1:1.2. Controlling the molar ratio of diethylaminoethanol to thiourea within the above ranges can ensure the completion of the alkylation reaction and stable quality.

[0032] After the alkylation reaction is completed, the present invention preferably does not perform post-treatment on the obtained alkylation product and directly uses it in the next step to prepare tylosin.

[0033] The present invention preferably adds the diethylaminoethanol to the reactor first and then adds concentrated hydrochloric acid and thiourea to carry out the alkylation reaction.

[0034] The present invention obtains diethylaminoethyl isothiourea salt by a one-pot method, with high preparation efficiency, simple steps, easily available raw materials, and low cost.

[0035] The present invention also provides a method for preparing tylosin, which includes the following steps:

[0036] Mix diethylaminoethanol and thiourea to carry out an alkylation reaction to obtain the diethylaminoethyl isothiourea salt;

[0037] Mix the diethylaminoethyl isothiourea salt, inorganic base and water to carry out a hydrolysis reaction to obtain the metal salt of diethylaminoethyl mercaptan;

[0038] Mix the metal salt of diethylaminoethyl mercaptan, p-methylbenzenesulfonic acid pleuromutilin ester, two-phase catalyst and inorganic basic solution to carry out a substitution reaction to obtain the tylosin.

[0039] The present invention preferably uses the same process as the above scheme for preparing the diethylaminoethyl isothiourea salt, which will not be elaborated here.

[0040] After obtaining the diethylaminoethyl isothiourea salt, the present invention mixes the diethylaminoethyl isothiourea salt, inorganic base and water to carry out a hydrolysis reaction to obtain the metal salt of diethylaminoethyl mercaptan.

[0041] In the present invention, the temperature of the hydrolysis reaction is preferably 22 - 32 °C, specifically it can be 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 °C, and the time is preferably 3 - 5 h, specifically it can be 3, 4 or 5 h. Controlling the temperature and time of the hydrolysis reaction within the above range can control the hydrolysis progress and the completion of the hydrolysis reaction.

[0042] In the present invention, the inorganic base is preferably sodium hydroxide, and the sodium hydroxide is preferably added in the form of a sodium hydroxide solution, and the mass percentage of the sodium hydroxide solution is preferably 32%; when the inorganic base is preferably sodium hydroxide, the obtained metal salt of diethylaminoethyl mercaptan is the sodium salt of diethylaminoethyl mercaptan.

[0043] In the present invention, the molar ratio of diethylaminoethanol to sodium hydroxide is preferably 1:1.3 to 1.6, specifically it can be 1:1.3, 1:1.4, 1:1.45 or 1:1.6. Controlling the molar ratio of diethylaminoethanol to sodium hydroxide within the above range can ensure the requirements of the pH value of the reaction system and is conducive to the full completion of the hydrolysis reaction.

[0044] In the present invention, the mass ratio of diethylaminoethanol to water is preferably 1:1.0 to 1.2, specifically it can be 1:1.0, 1:1.1, 1:1.14 or 1:1.2. Controlling the molar ratio of diethylaminoethanol to water within the above range can control the concentration of the reactants and is conducive to the full completion of the hydrolysis reaction.

[0045] After the hydrolysis reaction is completed, the present invention preferably does not perform post-treatment on the obtained hydrolysis product and directly uses it for the next step of preparing tiamulin.

[0046] The present invention preferably adds an inorganic base and water to the diethylaminoethyl isothiourea salt for the hydrolysis reaction.

[0047] After obtaining the metal salt of diethylaminoethanethiol, the present invention mixes the metal salt of diethylaminoethanethiol, p-methylbenzenesulfonic acid pleuromutilin ester, a two-phase catalyst and an inorganic alkaline solution for a substitution reaction to obtain the tiamulin.

[0048] In the present invention, the temperature of the substitution reaction is preferably 55 to 65 °C, specifically it can be 55, 58, 61, 63 or 65 °C, the time is preferably 1 to 2 h, and the pH value of the reaction system during the substitution reaction is preferably not lower than 12, specifically it can be 12 or 13.

[0049] In the present invention, the p-methylbenzenesulfonic acid pleuromutilin ester is preferably prepared by an esterification reaction of pleuromutilin and p-toluenesulfonyl chloride, and preferably includes the following steps: First, add a ketone or ester organic solvent to a reactor, and then add pleuromutilin, p-toluenesulfonyl chloride and an inorganic base. The temperature of the esterification reaction does not exceed 50 °C (specifically it can be 42, 45 or 46 °C), control the pH value of the reaction system not to be lower than 12, the reaction time is 1 to 2 h, and then wash the esterification product with water and discard the aqueous phase to obtain a solution of p-methylbenzenesulfonic acid pleuromutilin ester.

[0050] In the present invention, the ketones preferably include methyl isobutyl ketone or methyl ethyl ketone, the esters preferably include ethyl acetate or propyl acetate, the inorganic base is preferably a sodium hydroxide solution with a mass fraction of 32%, the molar ratio of pleuromutilin to diethylaminoethanol is preferably 0.80 - 0.85:1, the added volume (mL) of the 32% sodium hydroxide solution is 50% - 60% of the weight (g) of pleuromutilin, the molar ratio of p-toluenesulfonyl chloride to pleuromutilin is preferably 1.1 - 1.3:1, and specifically can be 1.1:1, 1.2:1 or 1.3:1.

[0051] In the present invention, the two-phase catalyst preferably includes tetrabutylammonium bromide, and the mass of the tetrabutylammonium bromide is preferably 1% - 2% of the mass of pleuromutilin, and specifically can be 1%, 1.5% or 2%. Controlling the dosage of the tetrabutylammonium bromide within the above range can facilitate the full reaction of the two-phase substances.

[0052] In the present invention, the inorganic alkaline solution preferably includes a sodium hydroxide solution, the mass fraction of the sodium hydroxide solution is preferably 32%, the volume of the sodium hydroxide solution is preferably 40% - 50% of the volume of pleuromutilin, and specifically can be 40%, 45% or 50%. Controlling the dosage of the sodium hydroxide solution within the above range can ensure the pH value requirement of the reaction system and facilitate the full completion of the reaction.

[0053] In the present invention, the solution of diethylaminoethyl mercaptan metal salt is preferably added to the pleuromutilin p-toluenesulfonate solution, and then the tetrabutylammonium bromide and the inorganic alkaline solution are added to carry out the substitution reaction.

[0054] After the substitution reaction is completed, in the present invention, water is preferably added to the obtained substitution product for washing, and then the aqueous phase is discarded to obtain a tylosin reaction solution, and then extraction is carried out to obtain the tylosin.

[0055] In the present invention, the extraction preferably includes the following steps: adding phosphoric acid to the tylosin reaction solution to adjust the pH value to 6.8 - 7.1 (specifically can be 6.8, 7 or 7.1), then discarding the aqueous phase, adding water for washing and then discarding the aqueous phase, and finally removing the solvent by vacuum distillation to obtain the tylosin.

[0056] The present invention has no special limitation on the concentration and dosage of the phosphoric acid, and commercially available products well-known to those skilled in the art can be used.

[0057] The present invention has no special limitation on the specific parameters of the vacuum distillation, and the method well-known to those skilled in the art can be used.

[0058] The preparation method of tylosin in the present invention has simple steps, is more suitable for industrial production, and the purity of tylosin is high.

[0059] The technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0060] Example 1

[0061] 13.5 g of diethylaminoethanol was added into a reactor with stirring. Then, 12 mL of concentrated hydrochloric acid (mass fraction 37%) and 10 g of thiourea were added in sequence. Then, the alkylation reaction was maintained at 85 °C for 5 h. Then, the reaction solution was naturally cooled to room temperature to obtain a solution of diethylaminoethyl isothiourea hydrochloride.

[0062] 15 mL of water and 16 mL of sodium hydroxide solution with a mass fraction of 32% were added to the diethylaminoethyl isothiourea salt solution. The molar ratio of diethylaminoethanol to sodium hydroxide in the sodium hydroxide solution was 1:1.45. Then, the hydrolysis reaction was maintained at 28 °C for 4 h to generate sodium diethylaminoethyl mercaptide for use.

[0063] 190 mL of methyl isobutyl ketone and 38 g of pleuromutilin (content 94.2 wt%) were added into a reactor with stirring. Then, 21 g of p-toluenesulfonyl chloride and 19 mL of sodium hydroxide solution with a mass fraction of 32% were added. The reaction temperature was controlled at 46 °C, and the esterification reaction was maintained for 1 h. During the reaction process, the pH value of the reaction system was controlled not to be lower than 12. After the reaction, it was washed with water and then the aqueous phase was discarded to obtain a solution of pleuromutilin p-toluenesulfonate.

[0064] The sodium diethylaminoethyl mercaptide prepared in the above step was added to the solution of pleuromutilin p-toluenesulfonate. Then, 0.5 g of tetrabutylammonium bromide and 16 mL of sodium hydroxide solution with a mass fraction of 32% were added. The reaction temperature was controlled at 58 °C, and the substitution reaction was maintained for 1 h. During the reaction process, the pH value of the reaction system was controlled not to be lower than 12. After the reaction, it was washed with water and then the aqueous phase was discarded to obtain the reaction solution of tiamulin.

[0065] The pH value of the tiamulin reaction solution was adjusted to 6.8 - 7.1 with phosphoric acid. Then, the aqueous phase was discarded. After washing with water again, the aqueous phase was discarded. The solvent was distilled off under reduced pressure to obtain 56.8 g of tiamulin, and the detected purity was 97.6%.

[0066] Example 2

[0067] 14 g of diethylaminoethanol was added into a reactor with stirring. Then, 13 mL of concentrated hydrochloric acid (mass fraction 37%) and 11 g of thiourea were added in sequence. Then, the alkylation reaction was maintained at 82 °C for 7 h. Then, the reaction solution was naturally cooled to room temperature to obtain a solution of diethylaminoethyl isothiourea hydrochloride.

[0068] 16 mL of water and 16 mL of a 32% sodium hydroxide solution were added to the diethylaminoethyl isothiourea salt solution. The molar ratio of diethylaminoethanol to sodium hydroxide in the sodium hydroxide solution was 1:1.4. Then, the hydrolysis reaction was maintained at 30 °C for 5 h to produce sodium diethylaminoethyl mercaptide for use.

[0069] 190 mL of methyl isobutyl ketone and 38 g of pleuromutilin (content 94.2 wt%) were added to a reactor equipped with stirring. Then, 21 g of p-toluenesulfonyl chloride and 19 mL of a 32% sodium hydroxide solution were added. The reaction temperature was controlled at 42 °C, and the esterification reaction was maintained for 1 h. During the reaction process, the pH value of the reaction system was controlled not to be lower than 12. After the reaction ended, it was washed with water and then the aqueous phase was discarded to obtain a solution of pleuromutilin p-toluenesulfonate.

[0070] The sodium diethylaminoethyl mercaptide prepared in the above step was added to the solution of pleuromutilin p-toluenesulfonate. Then, 0.5 g of tetrabutylammonium bromide and 16.5 mL of a 32% sodium hydroxide solution were added. The reaction temperature was controlled at 61 °C, and the substitution reaction was maintained for 1 h. During the reaction process, the pH value of the reaction system was controlled not to be lower than 12. After the reaction ended, it was washed with water and then the aqueous phase was discarded to obtain a tylosin reaction solution.

[0071] The pH value of the tylosin reaction solution was adjusted to 6.8 - 7.1 with phosphoric acid. Then, the aqueous phase was discarded. After washing with water again, the aqueous phase was discarded. The solvent was evaporated under reduced pressure to obtain 57.3 g of tylosin, and the detected purity was 97.4%.

[0072] Example 3

[0073] 14 g of diethylaminoethanol was added to a reactor equipped with stirring. 13 mL of concentrated hydrochloric acid (mass fraction 37%) and 10.5 g of thiourea were added in sequence. Then, the alkylation reaction was maintained at 87 °C for 6 h. Then, the reaction solution was naturally cooled to room temperature to obtain a diethylaminoethyl isothiourea hydrochloride solution.

[0074] 16 mL of water and 16 mL of a 32% sodium hydroxide solution were added to the diethylaminoethyl isothiourea salt solution. The molar ratio of diethylaminoethanol to sodium hydroxide in the sodium hydroxide solution was 1:1.4. Then, the hydrolysis reaction was maintained at 29 °C for 4 h to produce sodium diethylaminoethyl mercaptide for use.

[0075] Add 190 mL of methyl isobutyl ketone and 38 g of pleuromutilin (content 94.2 wt%) to a reactor with stirring. Then add 21 g of p-toluenesulfonyl chloride and 19 mL of a sodium hydroxide solution with a mass fraction of 32%. Control the reaction temperature at 45 °C and maintain the esterification reaction for 1 h. During the reaction, control the pH value of the reaction system to be not lower than 12. After the reaction, wash with water and then discard the aqueous phase to obtain a pleuromutilin p-toluenesulfonate solution.

[0076] Add the sodium salt of 2-diethylaminoethanethiol prepared in the above step to the pleuromutilin p-toluenesulfonate solution. Then add 0.6 g of tetrabutylammonium bromide and 17 mL of a sodium hydroxide solution with a mass fraction of 32%. Control the reaction temperature at 63 °C and maintain the substitution reaction for 1 h. During the reaction, control the pH value of the reaction system to be not lower than 12. After the reaction, wash with water and then discard the aqueous phase to obtain a tylosin reaction solution.

[0077] Adjust the pH value of the tylosin reaction solution to 6.8 - 7.1 using phosphoric acid. Then discard the aqueous phase, wash with water again and discard the aqueous phase. Evaporate the solvent under reduced pressure to obtain 57.1 g of tylosin, and the detected purity is 97.7%.

[0078] The above is only the preferred embodiment of the present invention and does not impose any form of limitation on the present invention. It should be noted that for those of ordinary skill in the art of this technology, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A preparation method of diethylaminoethyl isothiourea salt, characterized in that, It includes the following steps: Mix diethylaminoethanol and thiourea for alkylation reaction to obtain the diethylaminoethyl isothiourea salt.

2. The preparation method according to claim 1, wherein The temperature of the alkylation reaction is 78 - 88 °C, and the reaction time is 5 - 8 h.

3. The preparation method according to claim 1, characterized in that, The alkylation reaction is carried out in an acidic solvent, and the acidic solvent is concentrated hydrochloric acid or concentrated hydrobromic acid. The mass fraction of the concentrated hydrochloric acid is 36 - 38%, and the mass fraction of the concentrated hydrobromic acid is 45 - 48%.

4. The preparation method according to claim 3, characterized in that, The molar ratio of diethylaminoethanol to concentrated hydrochloric acid is 1:1.15 - 1.

3.

5. The preparation method according to claim 1, wherein The molar ratio of diethylaminoethanol to thiourea is 1:1.05 - 1.

25.

6. A preparation method of tiamulin, characterized in that, It includes the following steps: Mix diethylaminoethanol and thiourea for alkylation reaction to obtain the diethylaminoethyl isothiourea salt; Mix the diethylaminoethyl isothiourea salt, inorganic base and water for hydrolysis reaction to obtain the metal salt of diethylaminoethyl mercaptan; Mix the metal salt of diethylaminoethyl mercaptan, p-methylbenzenesulfonic acid pleuromutilin ester, two-phase catalyst and inorganic basic solution for substitution reaction to obtain the tylosin.

7. The preparation method according to claim 6, characterized in that, The temperature of the hydrolysis reaction is 22 - 32 °C, and the time is 3 - 5 h.

8. The preparation method according to claim 6, characterized in that, The temperature of the substitution reaction is 55 - 65 °C, and the time is 1 - 2 h. The pH value of the reaction system during the substitution reaction is not lower than 12.

9. The preparation method according to claim 6, characterized in that, The p-methylbenzenesulfonic acid pleuromutilin ester is prepared by an esterification reaction of pleuromutilin and p-toluenesulfonyl chloride.

10. The preparation method according to claim 9, characterized in that, The two-phase catalyst includes tetrabutylammonium bromide. The mass of the tetrabutylammonium bromide is 1% - 2% of the mass of pleuromutilin. The inorganic basic solution includes sodium hydroxide solution. The mass fraction of the sodium hydroxide solution is 32%, and the volume of the sodium hydroxide solution is 40% - 50% of the volume of pleuromutilin.

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