A method for synthesizing delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine

Abstract

The application belongs to the technical field of medical intermediate synthesis, and particularly relates to a synthesis method of delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine, which comprises the following steps: stirring and reacting compound II with ammonia / methanol solution to obtain compound III; heating and reacting compound III under the action of sodium hypochlorite and alkali to obtain compound IV; reacting compound IV with sodium nitrite solution until solid is precipitated, filtering the solid, adding fluoroboric acid into the solid in batches, and heating and reacting to obtain compound V; and heating and reacting compound V with ammonia water in a reaction autoclave to obtain compound I. The method avoids harsh synthesis conditions of raw material 2,3,5,6-tetrafluoropyridine, uses raw material 2,6-dichloro-5-fluoronicotinic acid (compound II) as a starting material, reduces equipment cost, and is easy to be industrialized and enlarged.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing 3,5-difluoro-2,6-diaminopyridine, an intermediate of delafloxacin. Background Technology

[0002] Delafloxacin is a new-generation broad-spectrum fluoroquinolone antibiotic developed by Wakunaga Pharmaceuticals. In 2017, the FDA approved delafloxacin (brand name Baxdela™) for the treatment of acute bacterial skin and skin structure infections caused by susceptible bacteria. Unlike quinolones such as levofloxacin, ciprofloxacin, and moxifloxacin, which have separated positive and negative charge centers, delafloxacin has a weakly basic amine at the C7 position. Therefore, the entire delafloxacin molecule is weakly acidic (pKa 5.4). In heterolysosomes (pH 5–5.5), delafloxacin exists primarily in a neutral molecular form, which facilitates its penetration through cell membranes into bacteria. Compared to other fluoroquinolone antibacterial drugs, delafloxacin exhibits superior activity against Gram-positive bacteria. Studies have shown that delafloxacin has the potential to be an alternative treatment for various serious infections, including complicated skin infections, acquired pneumonia, endocarditis, and other severe infectious diseases.

[0003] 3,5-Difluoro-2,6-diaminopyridine, as an important intermediate of delafloxacin, has attracted the attention of chemists due to the presence of fluorine and amino groups in its molecular structure.

[0004]

[0005] Currently reported methods for preparing 3,5-difluoro-2,6-diaminopyridine mainly involve synthesis from 2,3,5,6-tetrafluoropyridine as a starting material.

[0006] Method 1: Journal of Fluorine Chemistry, 2009, 130, 461-465. The authors in this paper reacted 2,3,5,6-tetrafluoropyridine and ammonia in a high-pressure reactor at 150°C for 67 hours. This method requires high temperature and pressure, and is highly corrosive to the reactor.

[0007] The conditions are quite demanding, and the yield is low, making it unsuitable for industrial production.

[0008]

[0009] Method 2: Patent WO200615194. In this patent, the authors used 2,3,5,6-tetrafluoropyridine as a raw material, first reacting it with benzylamine to generate N... 2 N 6The method involves dibenzyl-3,5-difluoro-2,6-diaminopyridine, followed by hydrogenation with 20% palladium hydroxide to obtain the target product 3,5-difluoro-2,6-diaminopyridine. This method uses an expensive palladium catalyst, and the first step of the reaction requires a high temperature of 150–170 °C, making it unsuitable for industrial production.

[0010]

[0011] Method 3: Patent CN110218180 reports a method using 2,3,5,6-tetrafluoropyridine as a raw material, which yields intermediate (VI) through a nucleophilic reaction with sulfonamide. The intermediate is then subjected to a removal reaction to obtain 3,5-difluoro-2,6-diaminopyridine (compound I). While this method is easy to control, has relatively mild conditions, and achieves high yields, enabling stable industrial production, it requires 2,3,4,5,6-pentafluoropyridine to prepare the raw material 2,3,5,6-tetrafluoropyridine.

[0012]

[0013] The methods reported in the above literature all require the raw material 2,3,5,6-tetrafluoropyridine, which in turn requires 2,3,4,5,6-pentafluoropyridine. The preparation of 2,3,4,5,6-pentafluoropyridine requires the reaction of 2,3,4,5,6-pentachloropyridine with potassium fluoride under high temperature and high pressure catalyst conditions. The reaction conditions are quite harsh, the equipment requirements are high, and the cost is relatively high.

[0014] Summary of the Invention

[0015] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing the intermediate 3,5-difluoro-2,6-diaminopyridine, which is a delafloxacin. This method avoids the use of the raw material 2,3,5,6-tetrafluoropyridine, which has harsh synthesis conditions, and uses 2,6-dichloro-5-fluoronicotinic acid (compound II), which is readily available, as the starting material, thereby reducing equipment costs and facilitating industrial-scale production.

[0016] This invention provides a method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine, comprising:

[0017]

[0018] In the step of synthesizing compound III from compound II, compound II reacts with ammonia-methanol solution by stirring to obtain compound III; in the step of synthesizing compound IV from compound III, compound III reacts with sodium hypochlorite and alkali by heating to obtain compound IV; in the step of synthesizing compound I from compound V, compound V reacts with ammonia water by heating in a high-pressure reactor to obtain compound I.

[0019] In the step of synthesizing compound III from compound II, the concentration of the ammonia / methanol solution is 7 mol / L; the molar ratio of compound II to ammonia is 1:1.1 to 1.3.

[0020] In the step of synthesizing compound IV from compound III, the base is sodium hydroxide; the molar ratio of compound III: sodium hypochlorite: sodium hydroxide is 1:1 to 1.1:3 to 3.1.

[0021] In the step of synthesizing compound IV from compound III, the reaction temperature range is 40–60 °C.

[0022] In the step of synthesizing compound V from compound IV, compound IV reacts with sodium nitrite solution until a solid precipitates out, the solid is filtered off, and fluoroboric acid is added in batches to react with the solid and heated to obtain compound V.

[0023] In the step of synthesizing compound V from compound IV, the molar ratio of compound IV: sodium nitrite: fluoroboric acid is 1:1.8~2:9~10.

[0024] In the step of synthesizing compound V from compound IV, the reaction temperature range is 70–90 °C.

[0025] In the step of synthesizing compound I from compound V, the molar ratio of compound V to ammonia is 1:4 to 5.

[0026] In the step of synthesizing compound I from compound V, the reaction temperature range is 100–105 °C; the reaction time is 4–5 h.

[0027] This invention provides a method for synthesizing the intermediate 3,5-difluoro-2,6-diaminopyridine, which avoids the harsh synthesis conditions of the raw material 2,3,5,6-tetrafluoropyridine and the production of corrosive hydrogen fluoride. It uses readily available raw material 2,6-dichloro-5-fluoronicotinic acid (compound II) as the starting material, which reduces equipment costs, facilitates operation and post-processing, and is easy to scale up for industrial production, with an overall yield of 66%. Attached Figure Description

[0028] To more clearly illustrate the technical solution of this application, the drawings used in the embodiments will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0029] Figure 1 It is 3,5-difluoro-2,6-diaminopyridine (compound I) 1 H NMR spectrum. Detailed Implementation

[0030] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0031] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0032] In this document, all features defined by numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0033] For the sake of brevity, not all possible combinations of the technical features in each implementation scheme or embodiment are described herein. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each implementation scheme or embodiment can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[0034] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0035] The following examples use instruments and equipment conventional in the art. Experimental methods in the following examples, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. All raw materials used in the following examples are conventional commercially available products with specifications conventional in the art. In this specification and the following examples, unless otherwise specified, "%" refers to weight percentage, "parts" refers to parts by weight, and "ratio" refers to weight.

[0036] The following specific embodiments further illustrate the synthesis method of 3,5-difluoro-2,6-diaminopyridine, an intermediate of delafloxacin provided in this application.

[0037] Example 1

[0038] Synthesis of 2,6-dichloro-3-carboxamide-5-fluoropyridine (compound III):

[0039]

[0040] In a 1000 mL flask, compound II (105.0 g, 0.5 mol) and ammonia / methanol solution (7 mol / L, 86 mL) were added. The mixture was stirred at 25 °C for 3 hours. The starting material disappeared on the TLC plate. The solvent was evaporated to obtain the crude product. After recrystallization with 95% ethanol, a white solid 2,6-dichloro-3-carboxamide-5-fluoropyridine (99.3 g, 95%) was obtained.

[0041] Synthesis of 2,6-dichloro-5-fluoro-3-aminopyridine (compound IV):

[0042]

[0043] In a 500 mL flask, 90 g of 2,6-dichloro-3-carboxamide-5-fluoropyridine (0.43 mol), 213 g of 15% sodium hypochlorite solution (0.43 mol), and 258 g of 20% sodium hydroxide solution (1.29 mol) were added. The mixture was stirred at 50 °C for 5 hours. The starting material disappeared when the mixture was spotted on a TLC plate. The aqueous solution was distilled off, and the solution was extracted with dichloromethane to remove the solvent and obtain the crude product. The crude product was then recrystallized from 95% ethanol to obtain 68.5 g of 2,6-dichloro-5-fluoro-3-aminopyridine (88%).

[0044] Synthesis of 2,6-dichloro-3,5-difluoropyridine (compound V):

[0045]

[0046] In a 500 mL flask, 2,6-dichloro-5-fluoro-3-aminopyridine (60 g, 0.33 mol) and sodium nitrite (46 g, 0.6 mol) dissolved in 100 mL of water were added dropwise to the reaction flask. A solid precipitated out and was filtered to obtain a brown solid. Fluoroboric acid (200 mL) was added in portions. The mixture was heated to 80 °C, cooled, and extracted with dichloromethane to remove the solvent, yielding a crude product. The crude product was recrystallized from ethanol to obtain 2,6-dichloro-3,5-difluoropyridine (50.5 g, 83%).

[0047] Synthesis of 3,5-difluoro-2,6-diaminopyridine (compound I):

[0048]

[0049] In a 1-liter autoclave, 50 g (0.27 mol) of 2,6-dichloro-3,5-difluoropyridine and 200 mL of ammonia were added. The mixture was heated to 100°C and reacted for 5 hours until complete. Dichloromethane was added for extraction, and the solvent was evaporated to obtain a crude product. Recrystallization from ethanol yielded 3,5-difluoro-2,6-diaminopyridine (35.5 g, 95%, mp: 155–159°C). Figure 1 As shown, 1 HNMR(CDCl3)δ7.04(s,1H),4.23(s,4H).

[0050] Example 2

[0051] Synthesis of 2,6-dichloro-3-carboxamide-5-fluoropyridine (compound III):

[0052]

[0053] In a 1000 mL flask, compound II (105.0 g, 0.5 mol) and ammonia / methanol solution (7 mol / L, 92 mL) were added. The mixture was stirred at 25 °C for 3 hours. The starting material disappeared when the TLC plate was drawn. The solvent was evaporated to obtain the crude product. After recrystallization with 95% ethanol, a white solid 2,6-dichloro-3-carboxamide-5-fluoropyridine (97.2 g, 93%) was obtained.

[0054] Synthesis of 2,6-dichloro-5-fluoro-3-aminopyridine (compound IV):

[0055]

[0056] In a 500 mL flask, 90 g of 2,6-dichloro-3-carboxamide-5-fluoropyridine (0.43 mol), 234 g of 15% sodium hypochlorite solution (0.47 mol), and 266 g of 20% sodium hydroxide solution (1.33 mol) were added. The mixture was stirred at 60 °C for 5 hours. The starting material disappeared when the mixture was spotted on a TLC plate. The aqueous solution was distilled off, and the solution was extracted with dichloromethane to remove the solvent and obtain the crude product. The crude product was then recrystallized from 95% ethanol to obtain 68.5 g of 2,6-dichloro-5-fluoro-3-aminopyridine (88%).

[0057] Synthesis of 2,6-dichloro-3,5-difluoropyridine (compound V):

[0058]

[0059] In a 500 mL flask, 2,6-dichloro-5-fluoro-3-aminopyridine (60 g, 0.33 mol) and sodium nitrite (46 g, 0.6 mol) dissolved in 100 mL of water were added dropwise to the reaction flask. A solid precipitated out and was filtered to obtain a brown solid. Fluoroboric acid (200 mL) was added in portions. The mixture was heated to 90 °C, cooled, and extracted with dichloromethane to remove the solvent, yielding a crude product. The crude product was recrystallized from ethanol to obtain 2,6-dichloro-3,5-difluoropyridine (48.7 g, 80%).

[0060] Synthesis of 3,5-difluoro-2,6-diaminopyridine (compound I):

[0061]

[0062] In a 1-liter autoclave, 50 g (0.27 mol) of 2,6-dichloro-3,5-difluoropyridine and 200 mL of ammonia were added. The mixture was heated to 105 °C and reacted for 4 hours until complete. Dichloromethane was added for extraction, and the solvent was evaporated to obtain a crude product. Recrystallization from ethanol yielded 3,5-difluoro-2,6-diaminopyridine (35.5 g, 95%, mp: 155–159 °C). Figure 1 As shown, 1 HNMR(CDCl3)δ7.04(s,1H),4.23(s,4H).

[0063] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine, characterized in that, include:

2. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound III from compound II, compound II reacts with ammonia-methanol solution by stirring to obtain compound III; in the step of synthesizing compound IV from compound III, compound III reacts with sodium hypochlorite and alkali by heating to obtain compound IV; in the step of synthesizing compound I from compound V, compound V reacts with ammonia water by heating in a high-pressure reactor to obtain compound I.

3. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound III from compound II, the concentration of the ammonia / methanol solution is 7 mol / L; the molar ratio of compound II to ammonia is 1:1.1 to 1.

3.

4. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound IV from compound III, the base is sodium hydroxide; the molar ratio of compound III: sodium hypochlorite: base is 1:1 to 1.1:3 to 3.

1.

5. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound IV from compound III, the reaction temperature range is 40–60 °C.

6. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound V from compound IV, compound IV reacts with sodium nitrite solution until a solid precipitates out, the solid is filtered off, and fluoroboric acid is added in batches to react with the solid and heated to obtain compound V.

7. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound V from compound IV, the molar ratio of compound IV: sodium nitrite: fluoroboric acid is 1:1.8~2:9~10.

8. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound V from compound IV, the reaction temperature range is 70–90 °C.

9. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound I from compound V, the molar ratio of compound V to ammonia is 1:4 to 5.

10. The method for synthesizing the delafloxacin intermediate 3,5-difluoro-2,6-diaminopyridine according to claim 1, characterized in that, In the step of synthesizing compound I from compound V, the reaction temperature range is 100–105 °C; the reaction time is 4–5 h.

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