Preparation method of amacycline intermediate

Abstract

The invention provides a preparation method of an ompacycline intermediate, which comprises the following steps: by taking minocycline hydrochloride and N-hydroxymethyl phthalimide as starting raw materials, directionally generating a 9-site substituent through a catalyst, and then synthesizing 9-aminomethyl minocycline. The method has the advantages of simple process operation, few side reaction products, high purity of the obtained intermediate, and suitableness for the production of the OMM.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and in particular, the present application relates to a preparation method of an Omadacycline intermediate. BACKGROUND

[0002] Omadacycline tosylate, chemical name (4S, 4aS, 5aR, 12aS)-4, 7-bis (dimethylamino)-9- (2, 2-dimethylpropylaminomethyl)-3, 10, 12, 12a-tetrahydroxy-1, 11-dioxo-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-tetracene-2-carboxamide p-toluenesulfonate, is a semisynthetic derivative of minocycline, belonging to the aminomethylcycline drug, which can bind to the 30S subunit of bacterial ribosomes, thereby inhibiting protein synthesis, and is effective against a variety of gram-positive bacteria, gram-negative bacteria and atypical pathogens, especially for the treatment of drug-resistant bacterial infections.

[0003] The marketed preparation of Omadacycline tosylate is named NuTyram, and its dosage forms include lyophilized powder for injection and oral tablets. It was approved for marketing in China in December 2021, and its indications are as follows: 1. Community-acquired bacterial pneumonia (CABP); 2. Acute bacterial skin and skin structure infection (ABSSSI) caused by sensitive microorganisms.

[0004] The synthesis of Omadacycline tosylate usually takes minocycline as the starting material, and 9-aminomethyl minocycline is obtained by methylation of the 9-position amino group, and then Omadacycline tosylate is prepared by salt formation. At present, due to the generation of a large number of complex by-products in the preparation process of Omadacycline tosylate, the post-treatment and purification are difficult, and means such as preparative liquid phase need to be used, and the yield is low. As a key intermediate for the synthesis of Omadacycline tosylate, the purity of 9-aminomethyl minocycline has a great influence on the synthesis and quality of subsequent Omadacycline tosylate. Various preparation methods thereof are disclosed in the prior art.

[0005] Patent application CN200810096219.0 discloses a synthesis route and preparation method of Omadacycline tosylate, as shown in Route 1 below. In this method, minocycline is subjected to alkylation with N-hydroxymethylphthalimide to obtain 2, 9-di-aminomethylphthalimide minocycline, which is subjected to ammonolysis to obtain 2, 9-di-aminomethyl minocycline, and the 2, 9-di-aminomethyl minocycline is subjected to acidolysis to obtain 9-aminomethyl minocycline. This method needs to use high-temperature reaction to generate 2, 9-di-aminomethylphthalimide minocycline which is difficult to be completely ammonolyzed, resulting in a large amount of residue, affecting the quality of the product, and a large amount of 2-substituted and tri-substituted substances; strong acids such as sulfuric acid and trifluoroacetic acid are used, which have strong corrosion and cause great pollution; at the same time, the overall yield of the reaction is low, which is not conducive to industrial production.

[0006]

[0007] Patent application CN202210168628.7 reported the synthesis route and preparation method of omadacycline intermediate, as shown in Route 2 below. The method alkylates minocycline with N-hydroxymethyl phthalimide to obtain 2,9-di-aminomethyl phthalimido minocycline, and 2,9-di-aminomethyl phthalimido minocycline is subjected to ammonolysis to obtain 2,9-di-aminomethyl minocycline. This method still generates a large amount of 2,9-di-aminomethyl phthalimido minocycline substituted at the 2 and 9 positions, and although the amount of by-products generated in each step is reduced, a large amount of 2-substituted, 9-substituted and tri-substituted products still exist. These existing by-products will be partially converted into target products in subsequent reactions, but a considerable amount of by-products will not be converted into target products or will further react to derive more impurities in subsequent reactions and are difficult to remove, resulting in poor atom economy. In addition, the ammonolysis reaction will generate a large amount of 2,9-di-aminomethyl minocycline, which will generate a large amount of impurities in subsequent reactions, resulting in poor product quality.

[0008]

[0009] The above preparation method generates a large amount of intermediate by-products, which are difficult to completely remove in the subsequent preparation of omadacycline. Omadacycline prepared by using the above intermediate preparation method needs to be purified by preparative liquid phase or column purification, etc., which is a complex process with low yield and high energy consumption, and the purification process is also prone to generate oxidation impurities and isomerization impurities. As disclosed in CN202180041465.X specification

[0005] paragraph, crude omadacycline needs to be separated and purified by high performance liquid chromatography (HPLC), and the purified omadacycline fraction is collected and concentrated.

[0010] When minocycline hydrochloride reacts with N-hydroxymethyl phthalimide, the target product is the 9-substituted product (Int1), but the existing preparation method usually generates a large amount of other by-products, such as 2-substituted products, disubstituted products and trisubstituted products. Among them, the 2-substituted product will generate minocycline in the subsequent reaction, which has poor atom economy and greatly affects the product quality; although the disubstituted and trisubstituted products will be converted into products in the subsequent reaction, the reaction will be prolonged, the cost will be increased, and other impurities may be generated.

[0011]

[0012] The impurities in the omadacycline intermediate (9-aminomethyl minocycline) obtained by the prior art are low in purity, and the omadacycline prepared therefrom contains more impurities, and the purification process is complex, the yield is low, and oxidation impurities and isomerization impurities are generated, thereby affecting the quality and yield of omadacycline tosylate. How to reduce the content of impurities in the key intermediate, thereby reducing the impurities in omadacycline, thereby reducing the difficulty of subsequent HPLC purification and reducing the time, and even avoiding the use of time-consuming HPLC purification method, thereby further reducing the generation of impurities and improving the quality of the drug is a problem to be solved.

[0013] The present application is directed to the above situation, and a method for directional generation of 9-substituted product (Int1) and 9-aminomethyl minocycline (Int2) is developed through trial, which is simple in process operation, less in by-products, good in atom economy, and suitable for large-scale production. SUMMARY

[0014] The present application is directed to the above situation, and a method for directional generation of 9-substituted product (Int1) and 9-aminomethyl minocycline (Int2) is developed through trial, which is simple in process operation, less in by-products, good in atom economy, and suitable for large-scale production.

[0015] The present application provides a preparation method of omadacycline intermediate (formula Int2), and the chemical reaction equation is as follows:

[0016]

[0017] The method comprises the following steps:

[0018] Step 1): SM1 and SM2 are subjected to alkylation reaction under the action of a catalyst to obtain Int1;

[0019] Step 2): Int1 is subjected to ammonolysis reaction with methylamine under the action of a base reagent to obtain Int2.

[0020] The preparation method has the characteristics that in step 1), the catalyst is selected from one or more of yttrium triflate, scandium triflate, aluminum triflate and lanthanum triflate.

[0021] The preparation method has the characteristics that in step 1), the weight ratio of SM1: catalyst: trifluoromethanesulfonic acid is 1: (0.02-0.1): (3.5-5.5).

[0022] In the preparation method, SM1 is minocycline hydrochloride, and SM2 is N-hydroxymethyl phthalimide.

[0023] The preparation method has the characteristics that in step 1), the molar ratio of SM1: SM2 is 1: (1.1-1.6), and the reaction temperature is 20-40℃.

[0024] The preparation method described above, characterized in that, in step 1), the operation method is to add the catalyst to trifluoromethanesulfonic acid for activation, then add SM1, and finally add SM2; after adding SM2, control the vacuum value (gauge pressure of the vacuum gauge) to -0.03 to -0.07 MPa, and react at 20 to 40°C.

[0025] Controlling the vacuum degree during the reaction can timely and continuously remove the volatile gases (such as HCl gas) and heat in the reaction system, which can promote the system to fully react while avoiding or inhibiting the generation of side reactions, thereby significantly improving the efficiency of the main reaction and the yield of the product Int1. The vacuum degree control is one of the key process parameters for realizing high quality and high yield of this step, and the vacuum value is relatively stable for the product quality and yield when it is -0.03 to -0.07 MPa.

[0026] The preparation method described above, characterized in that, in step 2), the base reagent is one or more of sodium methoxide, sodium ethoxide, potassium methoxide, and potassium tert-butoxide.

[0027] The preparation method described above, characterized in that, in step 2), the molar ratio of Int1: base reagent: methylamine is 1: (0.1 to 0.5): (8 to 15).

[0028] The preparation method described above, characterized in that, in step 2), the methylamine is an ethanol solution of methylamine or a methanol solution of methylamine, and the ethanol solution of methylamine is preferred.

[0029] The preparation method described above, characterized in that, in step 2), the reaction temperature is 10 to 25°C, and the reaction time is 1 to 5 h.

[0030] The preparation method described above, characterized in that, in step 1), the specific operation method is to add the catalyst to trifluoromethanesulfonic acid, add SM1 under stirring, add SM2 after nitrogen protection and stirring dissolution, control the vacuum value to -0.03 MPa to -0.07 MPa for reaction for 2 h, add the reaction solution to water at 0 to 10°C for crystallization, filter, dissolve the filter cake in acetone, adjust the pH to neutral with ammonia water, add water to cool to 0 to 10°C for crystallization, filter, wash the filter cake with isopropyl alcohol and isopropyl ether, and then dry under reduced pressure to obtain Int1.

[0031] The preparation method described above, characterized in that, in step 2), the specific operation method is to add the base reagent to the methylamine solution, control the temperature to 10°C, add Int1 under stirring for 3 h, and then filter, add the filtrate to methyl tert-butyl ether, control the temperature to 0 to 10°C for crystallization, filter, and dry to obtain Int2.

[0032] The preparation method described above is characterized in that, in the step 2), the methylamine solution is an alcohol solution of methylamine, which can be selected from methylamine ethanol (an ethanol solution of methylamine), methylamine methanol (a methanol solution of methylamine), and preferably methylamine ethanol.

[0033] The obtained omadacycline intermediate of the application has less impurities and high purity detected by an HPLC method, and when used for further preparation of omadacycline, the impurities of omadacycline can be significantly reduced and the purity can be significantly improved, the pressure of HPLC purification can be reduced, and even the conventional recrystallization purification method can be selected instead of HPLC purification.

[0034] The HPLC detection method described above can use the detection method disclosed in the pharmacopoeia or the prior art, or the following detection method: reverse phase high performance liquid chromatography, the chromatographic column uses octadecylsilane bonded silica gel as the filler, and the mobile phase is phosphate buffer-acetonitrile, the mobile phase A is 30 mmol / L phosphate buffer, and the mobile phase B is 2 mmol / L acetonitrile. The flow rate of the mobile phase is 0.8-1.2 ml / min, and the elution gradient is:

[0035] Time min Mobile phase A % (V / V) Mobile phase B % (V / V) 0 85 15 30 65 35 45 35 65 50 85 15

[0036] The application provides a preparation method of a key intermediate of omadacycline, which has the characteristics of green environmental protection, easy-to-obtain raw materials, simple operation, high yield, few impurities, and high product purity compared with prior art techniques. Specifically, the following is provided:

[0037] 1) In the preparation process of Int1, a catalyst is used to induce the reaction process, direct the generation of 9-substituted products, effectively reduce or avoid the generation of 2-substituted products, disubstituted products, and trisubstituted products, and thus improve the conversion rate; at the same time, under the action of the catalyst, the reaction progresses faster, which can effectively save costs and improve product quality.

[0038] 2) In the preparation process of Int2, by adding an alkaline reagent, the ammonia of Int1 can be catalyzed to be faster, so that the reaction is more complete; at the same time, under the action of the alkaline reagent, the activity and solubility of the byproduct phthalimide can be reduced to facilitate removal, and the product quality is effectively improved.

[0039] 3) The reaction conditions of each step are mild, the operation is simple, the power cost is greatly reduced, and it is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 : MS chart of omadacycline Int2 in Example 1 DETAILED DESCRIPTION

[0041] The technical solutions of the present application will be further described in combination with specific embodiments, which are only exemplary and do not constitute any limitation on the scope of the present application; all the embodiments need not and cannot be exhausted by the skilled in the art. The skilled in the art should understand that the details and forms of the technical solutions of the present application can be modified or replaced without departing from the spirit and scope of the present application, and such modifications and replacements fall within the protection scope of the present application. The experimental methods in the following examples without specific experimental conditions are usually carried out according to the conventional conditions or the conditions recommended by the manufacturers.

[0042] Example 1

[0043] Yttrium triflate (0.40 g, 0.746 mmol) was added to trifluoromethanesulfonic acid (70.0 g, 0.466 mol) and stirred at 20 °C for 30 min. SM1 (20.0 g, 0.04049 mol) was added in portions and dissolved by stirring under nitrogen protection for 1 h. Then SM2 (7.891 g, 0.04454 mol) was added, and the reaction was carried out at 20 °C for 2 h under the control of vacuum value (vacuum gauge gauge pressure) -0.03 MPa. The reaction solution was added dropwise to water (200 ml) at 0-10 °C, and the temperature was controlled at 0-10 °C for crystallization for 1 h, and then filtered. The filter cake was added to acetone (140 ml), and the temperature was controlled at 20-30 °C for dissolution. The pH was adjusted to neutral with ammonia water, and then 200 ml of water was added. The temperature was lowered to 0-10 °C for crystallization for 1 h, and then filtered. The filter cake was washed with isopropyl alcohol (60 ml) and isopropyl ether (60 ml) in sequence, and then dried at 50 °C under reduced pressure to obtain yellow solid Int1 (22.89 g) with a yield of 91.7%.

[0044] Sodium methoxide (0.176 g, 0.00326 mol) was added to 32% methylamine ethanol (methylamine ethanol solution) (47.22 g, 0.487 mol) and stirred at 10 °C for 30 min. Then Int1 (20.0 g, 0.03243 mol) was added and stirred at 10 °C for 3 h. The mixture was filtered, and the filtrate was added to methyl tert-butyl ether (400 ml) and crystallized at 0-10 °C for 1 h. The mixture was filtered, and the filter cake was dried at 30 °C to obtain light green solid Int2 (13.14 g) with a yield of 83.3%.

[0045] Example 2

[0046] Scandium triflate (2.0 g, 4.064 mmol) was added to trifluoromethanesulfonic acid (110.0 g, 0.733 mol) and stirred at 40 °C for 30 min. SM1 (20.0 g, 0.04049 mol) was added in portions and stirred for 1 h under nitrogen protection until dissolved. SM2 (11.477 g, 0.06478 mol) was added and the reaction was carried out at 40 °C for 2 h under vacuum at -0.07 MPa. The reaction solution was added dropwise to water (200 ml) at 0-10 °C, and the temperature was controlled at 0-10 °C for 1 h to crystallize. The filter cake was dissolved in acetone (140 ml) at 20-30 °C, and the pH was adjusted to neutral with ammonia water. Then 200 ml of water was added, and the temperature was lowered to 0-10 °C for 1 h to crystallize. The filter cake was washed with isopropyl alcohol (60 ml) and isopropyl ether (60 ml) in sequence, and dried at 50 °C under reduced pressure to obtain Int1 (22.69 g) as a yellow solid with a yield of 90.9%.

[0047] Sodium ethoxide (1.103 g, 0.01621 mol) was added to 32% methylamine ethanol (25.19 g, 0.2595 mol) and stirred at 10 °C for 30 min. Int1 (20.0 g, 0.03243 mol) was added and stirred at 25 °C for 3 h. The filter cake was dissolved in methyl tert-butyl ether (400 ml) at 0-10 °C for 1 h to crystallize. The filter cake was washed with isopropyl alcohol (60 ml) and isopropyl ether (60 ml) in sequence, and dried at 30 °C to obtain Int2 (13.33 g) as a light green solid with a yield of 84.5%.

[0048] Example 3:

[0049] Aluminum triflate (1.2 g, 2.531 mmol) was added to trifluoromethanesulfonic acid (80.0 g, 0.533 mol) and stirred at 30 °C for 30 min. SM1 (20.0 g, 0.04049 mol) was added in portions and stirred for 1 h under nitrogen protection until dissolved. SM2 (9.325 g, 0.05264 mol) was added and the reaction was carried out at 30 °C for 2 h under vacuum at -0.05 MPa. The reaction solution was added dropwise to water (200 ml) at 0-10 °C, and the temperature was controlled at 0-10 °C for 1 h to crystallize. The filter cake was dissolved in acetone (140 ml) at 20-30 °C, and the pH was adjusted to neutral with ammonia water. Then 200 ml of water was added, and the temperature was lowered to 0-10 °C for 1 h to crystallize. The filter cake was washed with isopropyl alcohol (60 ml) and isopropyl ether (60 ml) in sequence, and dried at 50 °C under reduced pressure to obtain Int1 (23.20 g) as a yellow solid with a yield of 92.9%.

[0050] Potassium methoxide (0.682 g, 0.00973 mol) was added to 32% methylamine ethanol (37.78 g, 0.3892 mol) and stirred at 10 °C for 30 min. Int 1 (20.0 g, 0.03243 mol) was added and stirred at 20 °C for 3 h. The filtrate was added to methyl tert-butyl ether (400 ml) and crystallized at 0-10 °C for 1 h. The filtrate was filtered and the filter cake was dried at 30 °C to give Int 2 (13.54 g) as a light green solid in a yield of 85.8%.

[0051] Example 4:

[0052] Lanthanum triflate (1.2 g, 2.047 mmol) was added to trifluoromethanesulfonic acid (80.0 g, 0.533 mol) and stirred at 30 °C for 30 min. SM 1 (20.0 g, 0.04049 mol) was added in portions and dissolved by stirring for 1 h under nitrogen. SM 2 (9.325 g, 0.05264 mol) was added and reacted at 30 °C for 2 h under a vacuum of -0.05 MPa. The reaction solution was added to water (200 ml) at 0-10 °C and crystallized at 0-10 °C for 1 h. The filtrate was filtered and the filter cake was added to acetone (140 ml) and dissolved at 20-30 °C. The pH was adjusted to neutral with ammonia water, 200 ml of water was added, and crystallized at 0-10 °C for 1 h. The filtrate was filtered, washed with isopropyl alcohol (60 ml) and isopropyl ether (60 ml) in sequence, and the filter cake was dried at 50 °C under reduced pressure to give Int 1 (23.27 g) as a yellow solid in a yield of 93.2%.

[0053] Potassium tert-butoxide (1.09 g, 0.00971 mol) was added to 32% methylamine ethanol (37.78 g, 0.3892 mol) and stirred at 10 °C for 30 min. Int 1 (20.0 g, 0.03243 mol) was added and stirred at 20 °C for 3 h. The filtrate was added to methyl tert-butyl ether (400 ml) and crystallized at 0-10 °C for 1 h. The filtrate was filtered and the filter cake was dried at 30 °C to give Int 2 (13.65 g) as a light green solid in a yield of 86.5%.

[0054] Comparative Example 1 (prepared according to CN200810096219.0):

[0055] Minocycline hydrochloride (20 g) and N-hydroxymethyl phthalimide (10 g) were added to trifluoroacetic acid (100 ml) and stirred to dissolve. Sulfuric acid (20 ml) and N-hydroxymethyl amine (10 g) were added and reacted at 45 °C for 5 h. The reaction solution was added to acetone (400 ml) and crystallized. The filtrate was filtered and the filter cake was added to a mixed solvent of methanol (100 ml) and methyl tert-butyl ether (200 ml). The pH was adjusted to 3 with triethylamine and filtered to give 2,9-di-aminomethyl phthalimide minocycline in a yield of 72.2%.

[0056] 2,9-di-aminomethylphthalimido minocycline (10 g) was added to 2M methylamine methanol solution (10 eq), stirred at room temperature for 3h. The reaction solution was added to methyl tert-butyl ether (50 ml) to crystallize, filtered and dried to obtain 2,9-di-aminomethyl minocycline. The 2,9-di-aminomethyl minocycline was added to a mixture of water (2 ml) / methanol (18 ml), and trifluoroacetic acid was added to adjust the pH to 3, and reacted at 40°C for 1h. The temperature was lowered, and triethylamine was added to adjust the pH to 7, and isopropyl alcohol (20 ml) was added to crystallize, filtered and dried to obtain 9-aminomethyl minocycline, with a yield of 45.7%.

[0057] Test Example 1: The products prepared in Examples 1-4 and Comparative Example 1 were tested, and the test results are shown in the following table:

[0058]

[0059] The present application has the advantages of providing a new preparation method, and further optimizing the scheme to achieve the purpose of being more economical and environmentally friendly. The above is only to explain the typical embodiments of the present application, and those skilled in the art can make various modifications and changes to the reaction conditions and post-treatment of each step based on the disclosure of the present application, such as changing the feeding ratio of the reaction raw materials, changing the reaction temperature, using similar alternative reagents, etc., all of which are within the scope of the present application.

Claims

1. A method for preparing an omadacycline intermediate represented by formula Int2, wherein the chemical reaction equation is as follows: The method comprises the following steps: Step 1): SM1 and SM2 undergo alkylation reaction in the presence of a catalyst to obtain Int1; Step 2): Int1 undergoes aminolysis reaction with methylamine in the presence of an alkaline reagent to obtain Int2.

2. The preparation method according to claim 1, characterized in that In the step 1), the catalyst is selected from one or more of yttrium trifluoromethanesulfonate, scandium trifluoromethanesulfonate, aluminum trifluoromethanesulfonate, and lanthanum trifluoromethanesulfonate.

3. The preparation method according to claim 1, characterized in that In the step 1), the weight ratio of SM1:catalyst:trifluoromethanesulfonic acid is 1:(0.02-0.1):(3.5-5.5).

4. The preparation method according to claim 1, wherein In the step 1), the molar ratio of SM1:SM2 is 1:(1.1-1.6).

5. The preparation method according to any one of claims 1 to 4, characterized in that: The operation method of step 1) is to first add the catalyst to trifluoromethanesulfonic acid for activation, then add SM1, and finally add SM2. After adding SM2, the vacuum value is controlled at -0.03 to -0.07 MPa, and the reaction is carried out at 20 to 40°C.

6. The preparation method according to claim 1, characterized in that The alkaline reagent in step 2) is selected from one or more of sodium methoxide, sodium ethoxide, potassium methoxide, and potassium tert-butoxide.

7. The preparation method according to claim 1, characterized in that In the step 2), the molar ratio of Int1: alkaline reagent: methylamine is 1: (0.1-0.5): (8-15).

8. The preparation method according to claim 7, characterized in that The methylamine in step 2) is an ethanol solution of methylamine or a methanol solution of methylamine, preferably an ethanol solution of methylamine; the reaction temperature is 10-25° C., and the reaction time is 1-5 hours.

9. The preparation method according to claim 1, characterized in that In the step 1), the specific operation method is as follows: adding the catalyst to trifluoromethanesulfonic acid, adding SM1 under stirring, protecting with nitrogen and stirring to dissolve, then adding SM2, controlling the vacuum value to -0.03MPa to -0.07MPa, and reacting for 2h, adding the reaction solution to water at 0 to 10°C for crystallization and filtration, dissolving the filter cake with acetone, adjusting the pH to neutral with ammonia water, adding water and cooling to 0 to 10°C for crystallization and filtration, washing the filter cake with isopropyl alcohol and isopropyl ether, and then drying under reduced pressure to obtain Int1.

10. The preparation method according to claim 1, characterized in that In the step 2), the specific operation method is: add the alkaline reagent to the methylamine solution, add Int1 under stirring at 10°C, stir for 3 hours, and then filter, add the filtrate to methyl tert-butyl ether, control the temperature at 0-10°C for crystallization, filter and dry to obtain Int2.

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