CN116425674A - Preparation method of 2, 6-diamino-3, 5-difluoropyridine - Google Patents

Preparation method of 2, 6-diamino-3, 5-difluoropyridine Download PDF

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CN116425674A
CN116425674A CN202210006291.XA CN202210006291A CN116425674A CN 116425674 A CN116425674 A CN 116425674A CN 202210006291 A CN202210006291 A CN 202210006291A CN 116425674 A CN116425674 A CN 116425674A
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reaction
acid
agent
anhydride
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王仲清
黎利军
范文进
唐鹏飞
郑金付
漆春辉
肖毅
吴警
黎义绍
黄芳芳
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to a novel method for preparing 2, 6-diamino-3, 5-difluoropyridine, which takes 2, 6-diaminopyridine as a starting material, adopts the steps of nitration, reduction, diazotization, substitution and the like to prepare a target compound, does not need high-temperature and high-pressure conditions in each reaction step, has low requirements on reaction equipment, is simple and convenient to operate, and is suitable for industrialized amplified production. In addition, the purity of the 2, 6-diamino-3, 5-difluoropyridine obtained by the method is more than 95 percent, and the total yield can reach 70 to 95 percent. The preparation method disclosed by the invention is simple to operate, convenient to post-treat in each step and high in intermediate purity.

Description

Preparation method of 2, 6-diamino-3, 5-difluoropyridine
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of 2, 6-diamino-3, 5-difluoropyridine.
Background
2, 6-diamino-3, 5-difluoropyridine is an important chemical drug intermediate for synthesizing a new generation of broad-spectrum fluoroquinolone antibiotics delafloxacin. Delafloxacin is more effective against gram-positive bacteria than other quinolone antibacterial agents, particularly methicillin-resistant staphylococcus aureus (MRSA) which is resistant to other quinolone antibacterial agents. Delafloxacin is useful for treating acute bacterial skin and skin structure infections caused by susceptible bacteria.
The structural formula of the 2, 6-diamino-3, 5-difluoropyridine is as follows:
Figure BDA0003455579540000011
document (Journal of Fluorine Chemistry,2009,130,461-465) discloses a process for the preparation of 2, 6-diamino-3, 5-difluoropyridine by reacting 2,3,5, 6-tetrafluoropyridine with aqueous ammonia at 150 ℃ in an autoclave for 67 hours, the synthetic route being as follows. The method needs high-temperature high-pressure reaction, has harsh synthesis conditions and high requirements on reaction equipment, and is not suitable for industrial production.
Figure BDA0003455579540000012
CN109251167a discloses a preparation method of 2, 6-diamino-3, 5-difluoropyridine, 2,3,4,5, 6-pentachloropyridine is used as raw material, and the 2, 6-diamino-3, 5-difluoropyridine is prepared through three steps of reduction, fluoro and ammonolysis, and the synthetic route is as follows. The first two steps of the method are used for preparing 2,3,5, 6-tetrafluoropyridine, distillation purification is needed, the requirements on equipment and technology are high, and the final step of aminolysis needs closed reaction, so that the method is not beneficial to industrial production.
Figure BDA0003455579540000013
Therefore, a new method for preparing 2, 6-diamino-3, 5-difluoropyridine needs to be developed, the synthesis condition is mild, the requirement on reaction equipment is low, and the method is suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a novel method for preparing 2, 6-diamino-3, 5-difluoropyridine, which takes 2, 6-diaminopyridine as a starting material, adopts the steps of nitration, reduction, diazotization, substitution and the like to prepare a target compound, does not need high-temperature and high-pressure conditions in each reaction step, has low requirements on reaction equipment, is simple and convenient to operate, and is suitable for industrialized amplified production.
In order to achieve the above object, the present invention provides the following technical solutions.
A process for preparing 2, 6-diamino-3, 5-difluoropyridine comprising:
step a: leading the compound II and a nitrifying agent to carry out nitration reaction in the presence of a dehydrating agent to obtain a compound III;
step b: carrying out substitution reaction on the compound III and an amino protecting reagent to obtain a compound IV;
step c: the compound IV and a reducing agent are subjected to reduction reaction in the presence of a catalyst to obtain a compound V;
step d: diazotizing a compound V with nitrite in the presence of acid, and performing fluoridation on the obtained product and a fluoridation agent to obtain a compound VI; and
step e: removing the amino protecting group from compound VI to give a 2, 6-diamino-3, 5-difluoropyridine of formula I:
Figure BDA0003455579540000021
wherein the radicals R 1 And R is 2 Independently of one another, can be C 1 -C 6 Acyl, cbz, tos, bn, PMB, boc, fmoc, alloc, teoc, pht, tfa or Trt.
Preferably, the nitrating agent in step a may be nitric acid, nitrous oxide or a mixture thereof; the dehydrating agent may be concentrated sulfuric acid, acetic anhydride, or mixtures thereof.
Preferably, the molar ratio of compound II to nitrating agent may be 1 (2-3.5), preferably 1 (2.5-3.5). For example, the molar ratio of compound II to nitrating agent may be 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, or 1:3.5.
Preferably, the reaction temperature of step a may be from-10 ℃ to 0 ℃; the reaction time can be 2-10h.
After the reaction of step a is completed, the reaction liquid may be dropped into ice water, filtered and dried.
Preferably, the amino protecting agent in step b may be acetic anhydride, propionic anhydride, isopropyl anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride, hexanoic anhydride, acetyl chloride, cbz-Cl, tos-Cl, bn-Br, PMB-Br, boc 2 O, fmoc-Cl, alloc-Cl, teoc-Cl, phthalimide-NCO 2 Et, trifluoroacetic anhydride, phthalimide-NCO 2 CF 3 Or Trt-Cl.
Preferably, the molar ratio of compound III to amino protecting agent may be 1 (2-3.5), preferably 1 (2.2-3). For example, the molar ratio of compound III to amino protecting reagent may be 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, or 1:3.5.
Preferably, the reaction of step b may be carried out in a solvent which may be one or more of water, 2, 4-dioxane, ethanol, methanol, chloroform, toluene, tetrahydrofuran, acetonitrile and dichloromethane. The organic solvent is not particularly limited as long as it can dissolve the raw materials and does not participate in the reaction. The reaction temperature in step b may be 0-150 ℃; the reaction time may be 1 to 24 hours, preferably 1 to 10 hours.
Preferably, the substitution reaction of step b may be carried out in the presence of a base or an acid. The base may be: organic bases such as triethylamine, pyridine, tetramethylammonium hydroxide, 4-Dimethylaminopyridine (DMAP) or N, N-Diisopropylethylamine (DIPEA); carbonates such as sodium carbonate, barium carbonate, calcium carbonate or potassium carbonate; bicarbonate salts such as potassium bicarbonate or sodium bicarbonate; or acetates, such as potassium acetate or sodium acetate. The acid may be acetic acid, sulfuric acid or hydrochloric acid. The person skilled in the art will be able to choose exactly the substitution reaction to carry out step b in the presence of an acid or in the presence of a base, depending on the amino protecting agent used. Of course, the substitution reaction of step b may also be carried out under neutral conditions.
After the reaction in step b is completed, the resulting reaction solution is subjected to post-treatment. The post-processing includes: dropwise adding water or NaCl water solution, filtering and drying; or comprises: dropwise adding water or NaCl water solution, separating liquid and distilling under reduced pressure.
Preferably, the reducing agent in step c may be hydrazine hydrate.
Preferably, the catalyst in step c may be a mixture of ferric chloride and activated carbon. The mixture of ferric chloride and active carbon is used as the catalyst in the step c, so that the production cost can be reduced.
Preferably, the molar ratio of compound IV to reducing agent may be 1 (2-3.5), preferably 1 (2.5-3). For example, the molar ratio of compound IV to reducing agent may be 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, or 1:3.5.
Preferably, the reaction of step c may be carried out in an organic solvent which may be one or more of ethanol, toluene, tetrahydrofuran, acetonitrile and dichloromethane. The organic solvent is not particularly limited as long as it can dissolve the raw materials and does not participate in the reaction. Preferably, the reaction temperature of step c may be from 40 to 100 ℃, preferably from 60 to 80 ℃; the reaction time may be 2 to 10 hours, preferably 5 to 7 hours.
After the reaction in step c is completed, reduced pressure distillation is performed, and the obtained residue is mixed with water, pulped, filtered and dried.
Preferably, the diazotisation and fluorination reactions of step d are carried out in a one-pot process, and compound VI is obtained directly without isolation of intermediates. The one-pot reaction is more economically and environmentally friendly.
Preferably, the nitrite in step d may be sodium nitrite, potassium nitrite or a mixture thereof. Specifically, in some embodiments, the nitrite in step d is sodium nitrite. The acid in step d may be one or more of hydrochloric acid, sulfuric acid, hydrobromic acid and acetic acid. Specifically, in some embodiments, the acid in step d is hydrochloric acid.
Preferably, the molar ratio of compound V to nitrite may be 1 (2-5), preferably 1 (3-4.5). For example, the molar ratio of compound V to nitrite may be 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, or 1:5. Preferably, the molar ratio of compound V to acid may be 1 (2-5.5), preferably 1 (2-5). For example, the molar ratio of compound V to acid may be 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5.1, 1:5.2, 1:5.3, 1:5.4, or 1:5.5.5.
Preferably, the diazotisation reaction of step d may be carried out in a solvent which may be water, or a mixture of water and other organic solvents. The other organic solvent may be one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile and dichloromethane. The temperature of the diazotisation reaction of step d may be from 0 ℃ to 10 ℃, preferably from 0 ℃ to 5 ℃; the reaction time may be 1 to 10 hours, preferably 1 to 5 hours.
Preferably, the fluorinating agent in step d may be one of fluoroboric acid, chlorine trifluoride, magnesium fluoride or copper fluoride. In particular, in some embodiments, the fluorinating agent in step d may be fluoroboric acid.
Preferably, the molar ratio of compound V to fluorinating agent may be 1 (2-3), preferably 1 (2-2.5). For example, the molar ratio of compound V to fluorinating agent can be 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, or 1:3.
Preferably, the fluorination reaction in step d may be carried out in a solvent, which may be water, or a mixture of water and other organic solvents. The other organic solvent may be one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile and dichloromethane. Preferably, the temperature of the fluorination reaction in step d may be 0-10 ℃; the reaction time may be 1 to 10 hours, preferably 1 to 5 hours.
And d, after the fluoro reaction in the step is completed, filtering, cleaning the obtained filter cake, mixing the filter cake with ethanol and water, heating and stirring, cooling to room temperature, filtering and drying. In the present invention, room temperature means a temperature of 20 to 30 ℃.
In step e, the reagent for removing the amino protecting group may be selected according to the kind of amino protecting group, and such selection is well known to those skilled in the art. For example, when R 1 Is C 1 -C 6 In the case of acyl groups, the reaction of step e may be carried out in the presence of a base, which may be K, or an acid 2 CO 3 、Na 2 CO 3 NaOH and NaHCO 3 The acid may be hydrochloric acid. When R is 1 In the case of Cbz, the reaction of step e may be carried out in a mixture of hydrobromic acid and acetic acid. When R is 1 In the case of Tos, the reaction of step e may be carried out in a mixture of hydrobromic acid and acetic acid or in a mixture of hydrobromic acid and phenol.
Preferably, the reaction temperature of step e may be from 20 to 150 ℃. The reaction time may be 1 to 24 hours.
After the deamination reaction in step e is completed, water is added, dichloromethane extraction is used, the pH of the water phase is adjusted to 9-10 by NaOH, and the water phase is filtered and dried in vacuum.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides a novel method for preparing 2, 6-diamino-3, 5-difluoropyridine, which takes 2, 6-diaminopyridine as a starting material, adopts the steps of nitration, reduction, diazotization, substitution and the like to prepare a target compound, does not need high-temperature and high-pressure conditions in each reaction step, has low requirements on reaction equipment, is simple and convenient to operate, and is suitable for industrialized amplified production. In addition, the purity of the 2, 6-diamino-3, 5-difluoropyridine obtained by the method is more than 95 percent, and the total yield can reach 70 to 95 percent.
2. The preparation method disclosed by the invention is simple to operate, convenient to post-treat in each step and high in intermediate purity.
Detailed Description
In order to make the contents of the present invention more easily understood, the technical scheme of the present invention will be further described with reference to the specific embodiments, but the present invention is not limited thereto. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention. Unless otherwise indicated, the raw materials and reagents used in the examples were all commercially available. The reagents, instruments or procedures not described herein are those routinely determinable by one of ordinary skill in the art.
The following abbreviations are used throughout the present invention:
Figure BDA0003455579540000061
note that: * Represents the site of attachment to other groups.
Example 1: synthesis of Compound III
To a 50mL single-necked flask, 2, 6-diaminopyridine (5.00 g,45.83 mmol) and concentrated sulfuric acid (15 mL) were added at room temperature, the mixture was transferred to a low-temperature tank at-5℃and fuming nitric acid (8.66 g,137.49 mmol) was added dropwise, and after the completion of the dropwise addition, the mixture was stirred at a constant temperature for 2 hours.
After the reaction was completed, the reaction solution was slowly dropped into ice water. After the dripping is finished, the mixture is stirred for 1h under heat preservation. Filtration and vacuum drying of the filter cake at 60℃for 12h gave 8.91g of 2, 6-diamino-3, 5-dinitropyridine as a yellow solid with an HPLC purity of 99.4% and a yield of 97.6%.
Example 2: synthesis of Compound IV
To a 50mL single-necked flask, the compound III (2.00 g,10.05 mmol) produced in example 1, acetic anhydride (3.08 g,30.14 mmol) and acetic acid (10 mL) were added and reacted at 110℃for 6h.
After the reaction, the reaction mixture was cooled to 0℃and water (30 mL) was added dropwise. After the dripping is finished, the mixture is stirred for 1h under heat preservation. Filtration and vacuum drying of the filter cake at 50℃for 12h gave 2.79g of yellow solid with a HPLC purity of 99.1% and a yield of 98.1%.
Example 3: synthesis of Compound IV
To a 50mL single-necked flask, a solution of compound III (2.00 g,10.05 mmol) obtained in example 1, potassium carbonate (7.25 g,52.46 mmol) and toluene (10 mL) was added, the temperature was lowered to 0℃and a toluene (6 mL) solution of Cbz-Cl (5.14 g,30.13 mmol) was added dropwise thereto to react at 0℃for 5 hours.
After the completion of the reaction, water (20 mL) was added dropwise. After the dripping is finished, the mixture is stirred for 1h under heat preservation. The mixture was allowed to stand and separated, the organic layer was washed with 2% aqueous HCl (20 mL) and water (10 mL), and the obtained organic layer was evaporated to dryness under reduced pressure at 45-55℃to give 4.53g of a yellow solid with a HPLC purity of 98.8% and a yield of 96.4%.
Example 4: synthesis of Compound IV
To a 50mL single-necked flask, a solution of compound III (2.00 g,10.05 mmol) prepared in example 1, tetrahydrofuran (10 mL) and triethylamine (3.05 g,30.14 mmol) was added, the temperature was lowered to 0℃and p-toluenesulfonyl chloride (4.22 g,22.14 mmol) in tetrahydrofuran (6 mL) was added dropwise to react at 0℃for 2 hours.
After the reaction was completed, 25% aqueous NaCl solution (10 mL) was added thereto, and the mixture was stirred at a constant temperature for 0.5h. Standing for layering, washing the organic layer with 25% NaCl aqueous solution for 1 time, and evaporating the obtained organic layer at 40-50 ℃ under reduced pressure to obtain yellow solid with 5.05g, HPLC purity of 98.3% and yield of 99.0%.
Example 5: synthesis of Compound V
To a 50mL single-necked flask, the compound IV (2.00 g,7.06 mmol) prepared in example 2, ethanol (20 mL), ferric chloride (0.023 g,0.14 mmol) and activated carbon (0.2 g, 10%) were added at room temperature. 80% hydrazine hydrate (1.33 g, 21.19mmol of hydrazine hydrate) was added dropwise at room temperature, and after the completion of the addition, the reaction was carried out at 70℃for 6 hours.
After the reaction was completed, distillation was carried out at 40℃under reduced pressure until it was dried. Water (20 mL) was added to the residue, slurried at room temperature for 1h, filtered, and the filter cake dried under vacuum at 60℃for 12h to give 1.51g of a brown solid with 98.9% HPLC purity in 95.8% yield.
Example 6: synthesis of Compound V
To a 50mL single-necked flask was added compound IV (3.30 g,7.06 mmol) obtained in example 3, ethanol (20 mL), ferric chloride (0.023 g,0.14 mmol) and activated carbon (0.2 g, 6%) at room temperature, 80% hydrazine hydrate (1.33 g, the amount of hydrazine hydrate was 21.19 mmol) at room temperature, and after the completion of the addition, the mixture was heated to 70℃and reacted for 6 hours.
After the reaction was completed, distillation was carried out at 35℃under reduced pressure to dryness. Water (20 mL) was added to the residue, slurried at room temperature for 1h, filtered, and the filter cake dried under vacuum at 60℃for 12h to give 2.73g of a brown solid with 98.1% HPLC purity in 94.9% yield.
Example 7: synthesis of Compound V
To a 50mL single-necked flask was added compound IV (3.60 g,7.09 mmol) obtained in example 4, ethanol (20 mL), ferric chloride (0.023 g,0.14 mmol) and activated carbon (0.2 g, 5.5%) at room temperature, 80% hydrazine hydrate (1.33 g, the amount of hydrazine hydrate was 21.19 mmol) at room temperature, and after the completion of the addition, the mixture was heated to 70℃and reacted for 6 hours.
After the reaction was completed, distillation was carried out at 35℃under reduced pressure to dryness. Water (20 mL) was added to the residue, slurried at room temperature for 1h, filtered, and the filter cake dried under vacuum at 60℃for 12h to give 3.00g of a brown solid with 98.4% HPLC purity in 94.5% yield.
Example 8: synthesis of Compound VI
To a 50mL single flask at room temperature was added 10% aqueous HCl (7.40 g,20.27 mmol), cooled to 0 to 5℃and then added compound V (1.50 g,6.72 mmol) obtained in example 5, followed by dropwise addition of 10% aqueous sodium nitrite (5.20 g, the amount of sodium nitrite was 7.54 mmol) and the reaction was continued for 3 hours.
After the completion of the reaction, 40% aqueous fluoroboric acid (3.25 g, the amount of fluoroboric acid substance was 14.80 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was carried out for 2 hours to precipitate a solid. Filtering, and washing the filter cake with water until the pH=7 to obtain a wet product.
To the wet product was added 10% aqueous ethanol (9 ml), and the mixture was stirred at 40℃for 5 hours. After cooling to room temperature, filtration and vacuum drying of the filter cake at 60℃for 12h gave 1.22g of a white solid with an HPLC purity of 99.71% and a yield of 79.21%.
Example 9: synthesis of Compound VI
To a 50mL single-necked flask was added 10% aqueous HCl (7.40 g,20.27 mmol) at room temperature, cooled to 0 to 5℃and then added compound V (2.75 g,6.75 mmol) obtained in example 6, followed by dropwise addition of 10% aqueous sodium nitrite (5.20 g, the amount of sodium nitrite was 7.54 mmol) and the reaction was continued for 3 hours.
After the completion of the reaction, 40% aqueous fluoroboric acid (3.25 g, the amount of fluoroboric acid substance was 14.80 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was carried out for 2 hours to precipitate a solid. Filtering, and washing the filter cake with water until the pH=7 to obtain a wet product.
To the wet product was added 10% aqueous ethanol (12 ml), and the mixture was stirred at 40℃for 5 hours. After cooling to room temperature, filtration and vacuum drying of the filter cake at 60℃for 12h gave 2.35g of a white solid with an HPLC purity of 99.13% and a yield of 84.22%.
Example 10: synthesis of Compound VI
To a 50mL single-necked flask was added 10% aqueous HCl (7.40 g,20.27 mmol) at room temperature, cooled to 0 to 5℃and then added compound V (3.00 g,6.70 mmol) obtained in example 7, followed by dropwise addition of 10% aqueous sodium nitrite (5.20 g, the amount of sodium nitrite was 7.54 mmol) and the reaction was continued for 3 hours.
After the completion of the reaction, 40% aqueous fluoroboric acid (3.25 g, the amount of fluoroboric acid substance was 14.80 mmol) was added dropwise. After the completion of the dropwise addition, the reaction was carried out for 2 hours to precipitate a solid. Filtering, and washing the filter cake with water until the pH=7 to obtain a wet product.
To the wet product was added 10% aqueous ethanol (12 mL) and stirred at 40℃for 5h. After cooling to room temperature, filtration and vacuum drying of the filter cake at 60 ℃ for 12h gave 2.70g of white solid with 99.46% hplc purity in 88.86%.
Example 11: synthesis of Compound I
Figure BDA0003455579540000091
To a 50mL single-necked flask, the compound VI (1.20 g,5.24 mmol) obtained in example 8 and 36% concentrated hydrochloric acid (5.00 g,49.32 mmol) were added and the mixture was refluxed at 100℃for 5 hours at room temperature.
After the reaction was completed, the mixture was extracted 2 times with methylene chloride (6 ml), the pH of the aqueous phase was adjusted to 9 to 10 with a 10% NaOH solution, and the mixture was filtered, and the cake was dried under vacuum at 60℃for 12 hours to give 0.73g of Compound I as a white solid, 99.57% pure by HPLC and 96.0% yield.
LC-MS:M+H＝146.2；
1 H NMR(400MHz,DMSO)δ6.61(s,1H),5.45(br,4H)。
Example 12: synthesis of Compound I
Figure BDA0003455579540000101
To a 50mL single-necked flask was added compound VI (2.20 g,5.32 mmol) obtained in example 9, 48% hydrobromic acid (4.00 g, the amount of hydrobromic acid was 23.73 mmol) and acetic acid (1.90 g,31.64 mmol) at room temperature, and the mixture was reacted at room temperature for 3 hours.
After the reaction was completed, water (11 ml) was added, extraction was performed 2 times with methylene chloride (11 ml), the pH of the aqueous phase was adjusted to 9 to 10 with 10% NaOH solution, filtration was performed, and the cake was dried under vacuum at 60℃for 12 hours to obtain 0.75g of Compound I as a white solid with an HPLC purity of 99.42% and a yield of 97.15%.
LC-MS:M+H＝146.2；
1 H NMR(400MHz,DMSO)δ6.61(s,1H),5.45(br,4H)。
Example 13: synthesis of Compound I
Figure BDA0003455579540000102
To a 50mL single-necked flask was added compound VI (2.40 g,5.29 mmol) prepared in example 10, 48% hydrobromic acid (4.00 g, the amount of hydrobromic acid was 23.73 mmol) and phenol (3.00 g,31.88 mmol) at room temperature, and reacted at 130℃for 8 hours.
After the reaction was completed, the temperature was lowered to room temperature, water (12 ml) was added, extraction was performed 2 times with methylene chloride (12 ml), the pH of the aqueous phase was adjusted to 9 to 10 with 10% NaOH solution, filtration was performed, and the cake was dried under vacuum at 60℃for 12 hours to give 0.70g of Compound I as a white solid, with a purity of 99.17% by HPLC and a yield of 91.18%.
LC-MS:M+H＝146.2；
1 H NMR(400MHz,DMSO)δ6.61(s,1H),5.45(br,4H)。
The present invention is not limited to the above-mentioned embodiments, and any changes or substitutions that can be easily understood by those skilled in the art within the technical scope of the present invention are intended to be included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A process for the preparation of 2, 6-diamino-3, 5-difluoropyridine comprising:
step a: leading the compound II and a nitrifying agent to carry out nitration reaction in the presence of a dehydrating agent to obtain a compound III;
step b: carrying out substitution reaction on the compound III and an amino protecting reagent to obtain a compound IV;
step c: the compound IV and a reducing agent are subjected to reduction reaction in the presence of a catalyst to obtain a compound V;
step d: diazotizing a compound V with nitrite in the presence of acid, and performing fluoridation on the obtained product and a fluoridation agent to obtain a compound VI; and
step e: removing the amino protecting group from compound VI to give a 2, 6-diamino-3, 5-difluoropyridine of formula I:
Figure FDA0003455579530000011
wherein the radicals R 1 And R is 2 Independently of one another C 1 -C 6 Acyl, cbz, tos, bn, PMB, boc, fmoc, alloc, teoc, pht, tfa or Trt.
2. The process according to claim 1, wherein in step a, the nitrating agent is nitric acid, dinitrogen pentoxide or a mixture thereof; the dehydrating agent is concentrated sulfuric acid, acetic anhydride or their mixture.
3. The process according to claim 1 or 2, wherein in step a, the molar ratio of compound II to nitrating agent is 1 (2-3.5); the reaction temperature in the step a is-10 ℃ to 0 ℃.
4. The process according to claim 1 or 2, wherein in step b, the amino protecting agent is acetic anhydride, propionic anhydride, isopropyl anhydride, butyric anhydride, isobutyric anhydride, pivalic anhydride, hexanoic anhydride, acetyl chloride, cbz-Cl, tos-Cl, bn-Br, PMB-Br, boc 2 O, fmoc-Cl, alloc-Cl, teoc-Cl, phthalimide-NCO 2 Et, trifluoroacetic anhydride, phthalimide-NCO 2 CF 3 Or Trt-Cl.
5. The process according to claim 1 or 2, wherein in step b, the molar ratio of compound III to amino protecting agent is 1 (2-3.5);
the reaction temperature in the step b is 0-150 ℃; the reaction time is 1-24h.
6. The method according to claim 1 or 2, wherein in step c, the reducing agent is hydrazine hydrate; the catalyst is a mixture of ferric chloride and active carbon;
the mol ratio of the compound IV to the reducing agent is 1 (2-3.5);
the reaction temperature in the step c is 40-100 ℃; the reaction time is 2-10h.
7. The preparation method according to claim 1 or 2, wherein the diazotisation and fluoridation of step d are carried out using a one-pot process.
8. The method according to claim 1 or 2, wherein in step d, the nitrite is sodium nitrite, potassium nitrite or a mixture thereof; the acid is one or more of hydrochloric acid, sulfuric acid, hydrobromic acid and acetic acid;
the molar ratio of the compound V to the nitrite is 1 (2-5);
the molar ratio of the compound V to the acid is 1 (2-5.5);
the temperature of the diazotization reaction in the step d is 0-10 ℃; the reaction time is 1-10h.
9. The method of claim 1 or 2, wherein the fluorinating agent in step d is fluoroboric acid, chlorine trifluoride, magnesium fluoride or copper fluoride;
the molar ratio of the compound V to the fluorinating agent is 1 (2-3);
the temperature of the fluoro reaction in the step d is 0-10 ℃; the reaction time is 1-10h.
10. The process according to claim 1 or 2, wherein the reaction temperature in step e is 20-150 ℃; the reaction time is 1-24h.
CN202210006291.XA 2022-01-04 2022-01-04 Preparation method of 2, 6-diamino-3, 5-difluoropyridine Pending CN116425674A (en)

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