Preparation method of 2-amino-6-hydroxypyridine compound and intermediate thereof

Abstract

The application relates to a preparation method of 2-amino-6-hydroxypyridine compounds and intermediates thereof, and belongs to the field of organic synthesis. The preparation method of the 2-amino-6-hydroxypyridine compounds comprises the following steps: 1) in a first organic solvent, compound II is reacted with a cyclic acid anhydride reagent A to prepare compound III; 2) in a second organic solvent, in the presence of an oxidizing reagent, compound III is subjected to an oxidation reaction to prepare compound IV; 3) in a third organic solvent, in the presence of an acid anhydride dehydrating reagent, compound IV is subjected to a reaction to prepare compound V; 4) in a fourth solvent, in the presence of a reducing agent, compound V is subjected to a reduction reaction to prepare compound I; and compound I is a 2-amino-6-hydroxypyridine compound. The preparation method of the 2-amino-6-hydroxypyridine compounds provided by the application can obtain a higher yield through mild reaction conditions, and is simple and convenient to operate, and is beneficial to industrial utilization.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to a method for preparing 2-amino-6-hydroxypyridine compounds and their intermediates. Background Technology

[0002] 2-Amino-6-hydroxypyridine compounds are important chemical intermediates widely used in various fields. For example, the compound of formula XII disclosed in CN 106045972A, which promotes the proliferation of neural stem cells and inhibits the activity of AChE and BuChE, is prepared from 2-amino-6-hydroxypyridine compounds; the inhibitor of mevalonate channel in vaccine adjuvants (compound XIII) disclosed in EP 3348269 A1 is also prepared from 2-amino-6-hydroxypyridine compounds.

[0003]

[0004] The preparation of 2-amino-6-hydroxypyridine compounds can be achieved by introducing a hydroxyl group or an amino group into a 2-aminopyridine compound. The paper "2,6-Diamination of Substituted Pyridines via Heterogeneous Chichibabin Reaction" (Mastalir, M., et al., Tetrahedron Letters, 57, 3, 333-336) discloses the reaction of 2-pyridinol with NaNH2 in mineral oil at 215°C to prepare 2-amino-6-hydroxypyridine in 83% yield. Although the yield is good, this reaction requires a large amount of NaNH2 (3-6 equivalents) and a very high reaction temperature (above 200°C), which is not conducive to industrial production.

[0005] A new route to 6-substituted 2,3-diaminopyridenes (Donald LB, et al., Tetrahedron Letters, 32, 45, 6503-6506) discloses a method for preparing 6-hydroxy-2,3-diaminopyridine by first protecting the amino group with cyclohexanone, then introducing a hydroxyl group at the 6-position in the presence of manganese dioxide and water, and finally removing the amino protecting group in the presence of trifluoroacetic acid, H2, and Pd / C, with an overall yield of 2.96% (47% * 30% * 21%). The reaction conditions are relatively mild, but the yield is too low.

[0006] Expanding the Genetic Alphabet: Non-Epimerizing Nucleoside with the pyDDA Hydrogen-Bonding Pattern (Daniel H. and Steven AB, J. Org. Chem. 2003, 68, 9839-9842) discloses a method for preparing 2-amino-3-nitropyridine by first forming a nitrogen oxide via m-CPBA, followed by the synthesis of 2-amino-3-nitro-6-hydroxypyridine in 14.2% yield (71% * 12%) in the presence of KOAc and Ac2O. However, this reaction has some unique characteristics. Due to the presence of the nitro group, the amino group is not oxidized even in the presence of m-chloroperoxybenzoic acid (mCPBA), and the yield remains low, making industrial application difficult. Therefore, finding a method for preparing 2-amino-6-hydroxypyridine compounds with mild reaction conditions and high yield has become an urgent problem to be solved. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the present invention provides a method for preparing 2-amino-6-hydroxypyridine compounds and its intermediates, which solves the problems of high reaction temperature, which is not conducive to industrial production and application, low product yield, and difficulty in industrial application in the prior art.

[0008] The first aspect of this invention provides a method for preparing 2-amino-6-hydroxypyridine compounds, comprising:

[0009] 1) Compound II is reacted with cyclic anhydride reagent A in a first organic solvent to prepare compound III;

[0010]

[0011] 2) In a second organic solvent, in the presence of an oxidizing agent, compound III undergoes an oxidation reaction to prepare compound IV;

[0012]

[0013] 3) In a third organic solvent, in the presence of an acid anhydride dehydrating agent, compound IV reacts to prepare compound V;

[0014]

[0015] 4) In the fourth solvent, in the presence of a reducing agent, compound V undergoes a reduction reaction to prepare compound I; compound I is a 2-amino-6-hydroxypyridine compound;

[0016]

[0017] Among them, R 1 R 2 R 3 Selected independently from H or C 1- C6 alkyl; R 5 and R 6 Independently selected from H or C1-C3 alkyl; or R 5 R 6 Together with the carbon atom it is bonded to, they form C6-C. 10 Aryl.

[0018] A second aspect of the present invention provides a compound VI, having the following structural formula: Among them, R 1 R 2 R 3 Selected independently from H or C 1- C6 alkyl, and not all of them are H.

[0019] The above technical solution has the following beneficial effects:

[0020] Using 2-aminopyridine compounds as raw materials, and through mild reaction conditions and a new intermediate compound V, the yield of 2-amino-6-hydroxypyridine compounds prepared from 2-aminopyridine compounds as raw materials was increased by 30%, and the entire reaction process was simple and convenient to operate, which is conducive to industrial application. Attached Figure Description

[0021] Figure 1 It is compound V-1 in Example 1 of this invention. 1 HNMR image. Detailed Implementation

[0022] The following details the preparation method of the disclosed 2-amino-6-hydroxypyridine compounds and the implementation of their intermediates.

[0023] Terminology Definition

[0024] Unless otherwise stated, the following words, phrases and symbols used in this specification generally have the meanings described below.

[0025] Generally, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including those for cell culture, organic chemistry, analytical chemistry, and pharmacology) are those well-known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. Additionally, in the claims and / or description, the term “a” or “an” used in conjunction with the term “comprising” or a noun may mean “one,” but also is consistent with the meanings of “one or more,” “at least one,” and “one or more.” Similarly, the term “another” or “other” may mean at least a second or more.

[0026] It should be understood that whenever this document uses the terms “comprising” or “including” to describe a particular aspect, other similar aspects described by “consisting of” and / or “substantially consisting of” are also provided.

[0027] In this document, the term "alkyl" as used alone or in combination may be straight-chain or branched, and the number of carbon atoms may be, for example, C1-C2. 10 C1-C4. For example, alkyl groups include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, cyclopentylmethyl, cyclohexylmethyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, 1-ethyl-propyl, 1,1-dimethyl-propyl, isohexyl, 4-methylhexyl, and 5-methylhexyl.

[0028] The first aspect of this invention provides a method for preparing 2-amino-6-hydroxypyridine compounds, comprising:

[0029] 1) Compound II is reacted with cyclic anhydride reagent A in a first organic solvent to prepare compound III;

[0030]

[0031] 2) In a second organic solvent, in the presence of an oxidizing agent, compound III undergoes an oxidation reaction to prepare compound IV;

[0032]

[0033] 3) In a third organic solvent, in the presence of an acid anhydride dehydrating agent, compound IV reacts to prepare compound V;

[0034]

[0035] 4) In a fourth solvent, in the presence of a reducing agent, compound V undergoes a reduction reaction to prepare compound I; said compound I is a 2-amino-6-hydroxypyridine compound;

[0036]

[0037] In compound IV, R 1 R 2 R 3 They are independently selected from H or C1-C6 alkyl groups;

[0038] R 5 and R 6 Independently selected from H or C1-C3 alkyl; or R 5 and R 6 Together with the carbon atom it is attached to, they form C6-C. 10 Aryl.

[0039] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 1 Selected from H.

[0040] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 1 Selected from C1-C6 alkyl groups. Optionally, R 1 Selected from C1-C5 alkyl groups, C1-C4 alkyl groups, and C1-C3 alkyl groups. Further optionally, R 1 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0041] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 2 Selected from H.

[0042] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 2 Selected from C1-C6 alkyl groups, optionally, R 2 Selected from C1-C5 alkyl groups, C1-C4 alkyl groups, and C1-C3 alkyl groups. Further optionally, R 2It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0043] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 3 Selected from H.

[0044] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 3 Selected from C1-C6 alkyl groups, optionally, R 3 Selected from C1-C5 alkyl groups, C1-C4 alkyl groups, and C1-C3 alkyl groups. Further optionally, R 3 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0045] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 5 R 6 Each is selected from H.

[0046] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 5 R 6 Alkyl groups selected from C1-C3. Further optionally, R 5 R 6 They are selected from methyl, ethyl, n-propyl, and isopropyl, respectively.

[0047] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, compound IV may also have the following characteristic: R 5 and R 6 Together with the carbon atom attached to it, they form phenyl and naphthyl groups.

[0048] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, step 1) involves reacting compound II with cyclic anhydride reagent A in a first organic solvent to obtain compound III. Specifically: the first organic solvent, compound II, and cyclic anhydride reagent A are added to a reaction flask, stirred, heated, kept at a constant temperature, and a sample is taken for HPLC monitoring (compound II ≤ 0.5%). The mixture is then slowly cooled, water is added, filtered, and dried to obtain compound III.

[0049] In step 1) of this invention, the cyclic anhydride reagent A is maleic anhydride or phthalic anhydride, preferably phthalic anhydride.

[0050] In step 1) of this invention, the first organic solvent is dimethylformamide, acetonitrile, or dimethylacetamide, preferably dimethylformamide.

[0051] In step 1) of the present invention, the mass-volume ratio of compound II to the first organic solvent is 1g:(3-5)mL, which can be selected as 1g:(3-4)mL or 1g:(4-5)mL, and is preferably 1g:4mL.

[0052] In step 1) of the present invention, the molar ratio of compound II to cyclic anhydride reagent A is 1:(1-3), which can be 1:(1-1.2), 1:(1.2-2), or 1:(2-3), and is preferably 1:(1.2-2).

[0053] In step 1) of this invention, the reaction temperature is 110-120℃, which can be 110-115℃ or 115-120℃; the holding time is 8-12h, which can be 8-10h or 10-12h.

[0054] In step 1) of this invention, the temperature is reduced to 20-30℃, which can be selected as 20-25℃ or 25-30℃.

[0055] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, step 2) involves the oxidation of compound III in a second organic solvent in the presence of an oxidizing agent to obtain compound IV. Specifically: compound III and the second organic solvent are added to a reaction flask, heated, and an oxidizing agent is slowly added dropwise to carry out the oxidation reaction. A sample is taken and analyzed by HPLC (compound III ≤ 2.0%). The flask is quenched with an inorganic salt solution, filtered, and the filtrate is collected. An aqueous solution of sodium bicarbonate is added to adjust the pH. The organic phase is separated, concentrated, and then slurried with an organic compound. The mixture is filtered and dried to obtain compound IV.

[0056] In step 2) of this invention, the second organic solvent is dichloromethane, 1,2-dichloroethane, or tetrahydrofuran.

[0057] In step 2) of this invention, the oxidizing agent is a mixture of hydrogen peroxide and phthalic anhydride or m-chloroperoxybenzoic acid, preferably a mixture of hydrogen peroxide and phthalic anhydride. The mass fraction of the hydrogen peroxide is 1%-50%, optionally 1%-30%, 30%-50%, or 20%-40%, preferably 30%.

[0058] In step 2) of the present invention, the mass-volume ratio of compound III to the second organic solvent is 1g:(9-11)mL, which can be selected as 1g:(9-10)mL or 1g:(10-11)mL, and is preferably 1g:10mL.

[0059] In step 2) of this invention, the molar ratio of compound III to phthalic anhydride is 1:(1-3), which can be 1:(1-2) or 1:(2-3).

[0060] In step 2) of this invention, the mass ratio of compound III to hydrogen peroxide is 1:(1-3), which can be 1:(1-2) or 1:(2-3).

[0061] In step 2) of this invention, the temperature of the oxidation reaction is 30-40℃, which can be selected as 30-35℃, 35-37℃ or 37-40℃.

[0062] In step 2) of this invention, the oxidation reaction time is 10-16h, which can be 10-13h or 13-16h.

[0063] In step 2) of this invention, the reducing inorganic salt solution is a sulfite aqueous solution, and the mass fraction of the sulfite aqueous solution is 1-50%, which can be selected as 1-10%, 10-30%, 30-50%, 5-20%, and preferably 10%.

[0064] In step 2) of this invention, the pH of the reaction solution is adjusted to 4-5 by using sodium bicarbonate aqueous solution.

[0065] In step 2) of this invention, the organic compound is any one or more of methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane, preferably methyl tert-butyl ether.

[0066] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, step 3) involves reacting compound IV in a third organic solvent in the presence of an acid anhydride dehydrating agent to obtain compound V. Specifically: compound IV and the third organic solvent are placed in a reaction vessel, cooled once, and an acid anhydride dehydrating agent is added dropwise. After the reaction is completed, the temperature is raised and stirred, and a sample is taken for HPLC analysis (compound IV ≤ 1.0%). The mixture is then cooled a second time, quenched with water, filtered, and compound V is obtained.

[0067] In step 3) of this invention, the third organic solvent is dimethylformamide or dimethylacetamide.

[0068] In step 3) of the present invention, the acid anhydride dehydrating agent is trifluoroacetic anhydride, acetic anhydride or phthalic anhydride, preferably trifluoroacetic anhydride.

[0069] In step 3) of the present invention, the mass-volume ratio of compound IV to the third organic solvent is 1g:(2-10)mL, which can be selected as 1g:(2-2.4)mL, 1g:(2.4-6)mL, 1g:(4-6)mL, 1g:(6-8)mL or 1g:(8-10)mL.

[0070] In step 3) of the present invention, the molar ratio of compound IV to the acid anhydride dehydrating agent is 1:(2-4), which can be selected as 1:(2-3) or 1:(3-4), and is preferably 1:3.

[0071] In step 3) of this invention, the temperature is cooled down to 0-10℃.

[0072] In step 3) of this invention, the temperature is raised to 30-45℃, which can be selected as 30-35℃, 35-40℃ or 40-45℃.

[0073] In step 3) of this invention, the reaction time is 12-16 hours, which can be 12-14 hours or 14-16 hours.

[0074] In step 3) of this invention, the secondary cooling to a temperature of 5-15℃ is optional, specifically 5-10℃ or 10-15℃.

[0075] In the preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention, step 4) involves the reduction of compound V in a fourth solvent in the presence of a reducing agent to obtain compound I; compound I is a 2-amino-6-hydroxypyridine compound. Specifically: compound V, the fourth solvent, and the reducing agent are added to a reaction flask, heated, refluxed, and sampled for HPLC analysis (compound V ≤ 2.0%), cooled, filtered, and slurried with water to obtain compound I.

[0076] In step 4) of this invention, the fourth solvent is a mixture of alcohol and water.

[0077] In step 4) of this invention, the alcohol solvent is methanol or ethanol.

[0078] In step 4) of this invention, the mass ratio of the alcohol solvent to water is 1:(2-4), which can be 1:(2-3) or 1:(3-4).

[0079] In step 4) of the present invention, the mass ratio of compound V to alcohol solvent is 1:(1-3), which can be selected as 1:(1-1.3), 1:(1.3-1.6), 1:(1.6-2) or 1:(2-3).

[0080] In step 4) of the present invention, the reducing agent is hydrazine hydrate, and the content of the hydrazine hydrate is 80%-90%, which can be selected as 80%-85% or 85%-90%, preferably 85%.

[0081] In step 4) of the present invention, the molar ratio of compound V to the reducing agent is 1:(1-3), which can be selected as 1:(1-2) or 1:(2-3).

[0082] In step 4) of the present invention, the temperature is raised to 70-80℃, preferably 80℃.

[0083] In step 4) of this invention, the reflux time is 3-5 hours, which can be 3-4 hours or 4-5 hours.

[0084] In step 4) of the present invention, the temperature is reduced to 10-15℃, which can be selected as 10-12℃ or 12-15℃.

[0085] A second aspect of the present invention provides a compound VI, the structural formula of which is

[0086] Among them, R 1 R 2 R 3 They are independently selected from H or C1-C6 alkyl groups, and not all of them are H.

[0087] The preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention may also have the following characteristic: R 1 Selected from H.

[0088] The preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention may also have the following characteristic: R 1 Selected from C1-C6 alkyl groups, optionally, R 1 Selected from C1-C5 alkyl groups, C1-C4 alkyl groups, and C1-C3 alkyl groups. Further optionally, R 1 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0089] The preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention may also have the following characteristic: R 2 Selected from H.

[0090] The preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention may also have the following characteristic: R 2 Selected from C1-C6 alkyl groups, optionally, R 2 Selected from C1-C5 alkyl groups, C1-C4 alkyl groups, and C1-C3 alkyl groups. Further optionally, R 2 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0091] The preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention may also have the following characteristic: R 3 Selected from H.

[0092] The preparation method of 2-amino-6-hydroxypyridine compounds provided by this invention may also have the following characteristic: R 3 Selected from C1-C6 alkyl groups, optionally, R 3 Selected from C1-C5 alkyl groups, C1-C4 alkyl groups, and C1-C3 alkyl groups. Further optionally, R 3 It is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0093] Compound VI described in this invention is

[0094] To make the technical means, creative features, objectives and effects of this invention easy to understand, the invention will be specifically described below in conjunction with embodiments and accompanying drawings.

[0095] In the following examples, unless otherwise stated, all reactants are commercially available products.

[0096] Example 1

[0097] Preparation method of compound I-1

[0098] Step 1:

[0099]

[0100] 14 L of dimethylformamide, 3.5 kg of 2-amino-3-methylpyridine (32.37 mol, 1.0 eq), and 5.75 kg of phthalic anhydride (38.84 mol, 1.2 eq) were added to a reaction flask. The mixture was stirred and heated to 110-120 °C and kept at this temperature for 8-12 h. HPLC analysis was performed on a sample (2-amino-3-methylpyridine ≤ 0.5%). The mixture was then slowly cooled to 20-30 °C, and 280 kg of water was added dropwise. The mixture was filtered and dried to obtain 5.5 kg of compound III-1, with a yield of 71.42% and a purity of 99.65%.

[0101] Step 2:

[0102]

[0103] 50 g of compound III-1 (0.21 mol, 1.0 eq), 62.2 g of phthalic anhydride (0.42 mol, 2.0 eq), and 500 mL of dichloromethane were added to a reaction flask and heated to 35-37 °C. 30 wt% hydrogen peroxide (47.6 g, 2.0 eq) was slowly added dropwise, and the reaction was allowed to proceed for 10-16 h. Samples were taken, and HPLC analysis was performed. Compound III-1 was ≤2.0%. The reaction was quenched with a 10 wt% sodium bisulfite aqueous solution, filtered, and the filtrate was added to a sodium bicarbonate aqueous solution to adjust the pH to 4-5. The organic phase was separated, concentrated, and then slurried with methyl tert-butyl ether. After filtration and drying, 40.58 g of compound IV-1 was obtained, with a yield of 76.0% and a purity of 99.80%.

[0104] Step 3:

[0105]

[0106] 2.1 kg of compound IV-1 (8.26 mol, 1.0 eq) and 12.6 L of dimethylformamide were added to a 100 L reactor. The mixture was cooled to 0-10 °C, and 5.2 kg of trifluoroacetic anhydride (24.76 mol, 3.0 eq) was added dropwise. After this, the mixture was heated to 35 °C and stirred for 16 h. HPLC analysis showed that compound IV-1 was ≤1.0%. The mixture was then cooled to 5-15 °C, quenched with water, and filtered to obtain 1.68 kg of compound V-1, with a yield of 80% and a purity of 94.0%.

[0107] Step 4:

[0108]

[0109] 50 g of compound V-1 (0.2 mol, 1.0 eq), 80 g of ethanol, 250 g of water, and 23.5 g of hydrazine hydrate (85% purity, 0.4 mol, 2.0 eq) were added to a reaction flask. The mixture was heated to 80 °C and refluxed for 4 h. HPLC analysis showed that compound V-1 was ≤ 2.0%. The mixture was cooled to 10-15 °C, filtered, and slurried with water to obtain 20.5 g of compound I-1, with a yield of 82.6% and a purity of 95.2%.

[0110] Example 2

[0111] Preparation method of compound I-2

[0112] Step 1:

[0113]

[0114] 200 mL of dimethylformamide, 50 g of 2-aminopyridine (0.53 mol, 1.0 eq), and 94.2 g of phthalic anhydride (0.64 mol, 1.2 eq) were added to a reaction flask. The mixture was stirred and heated to 110-120 °C and kept at this temperature for 8-12 h. The sample was monitored by HPLC (2-aminopyridine ≤ 0.5%). The mixture was then slowly cooled to 20-30 °C, quenched with a large amount of water, filtered, and dried to obtain 88.9 g of compound III-2, with a yield of 74.8% and a purity of 99.4%.

[0115] Step 2:

[0116]

[0117] 50 g of compound III-2 (0.22 mol, 1.0 eq), 65.17 g of phthalic anhydride (0.44 mol, 2.0 eq), and 500 mL of dichloromethane were added to a reaction flask and heated to 35-37 °C. 30 wt% hydrogen peroxide (49.9 g, 2.0 eq) was slowly added dropwise, and the reaction was allowed to proceed for 10-16 h. Samples were taken, and HPLC analysis showed that compound III-2 was ≤2.0%. The reaction was quenched with a 10 wt% sodium bisulfite aqueous solution, filtered, and the filtrate was added to a sodium bicarbonate aqueous solution to adjust the pH to 4-5. The organic phase was separated, concentrated, and then slurried with methyl tert-butyl ether. After filtration and drying, 39.4 g of compound IV-2 was obtained, with a yield of 74.5% and a purity of 99.70%.

[0118] Step 3:

[0119]

[0120] 50 g of compound IV-2 (0.21 mol, 1.0 eq) and 120 mL of dimethylformamide were added to a 1 L reactor. The mixture was cooled to 0-10 °C, and 132 g of trifluoroacetic anhydride (0.63 mol, 3.0 eq) was added dropwise. After this process, the mixture was heated to 40 °C and stirred for 16 h. HPLC analysis showed that compound IV-2 was ≤1.0%. The mixture was then cooled to 5-15 °C, quenched with water, and filtered to obtain 41.9 g of compound V-2, with a yield of 83.0% and a purity of 96.7%.

[0121] Step 4:

[0122]

[0123] 38.4 g of compound V-2 (0.16 mol, 1.0 eq), 50 g of ethanol, 150 g of water, and 18.8 g of hydrazine hydrate (85% purity, 0.32 mol, 2.0 eq) were added to a reaction flask, heated to 80 °C and refluxed for 4 h. HPLC analysis showed that compound V-2 was ≤2.0%. The mixture was cooled to 10-15 °C, filtered, and slurried with water to obtain 14.9 g of compound I-2, with a yield of 85% and a purity of 96.0%.

[0124] The role and effect of the embodiments

[0125] Using 2-aminopyridine compounds as raw materials, and through mild reaction conditions and a new intermediate compound V, the yield of 2-amino-6-hydroxypyridine compounds prepared from 2-aminopyridine compounds as raw materials was increased by 30%, and the entire reaction process was simple and convenient to operate, which is conducive to industrial application.

[0126] The above embodiments are preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention.

[0127] The applicant declares that the present invention illustrates the preparation method of the 2-amino-6-hydroxypyridine compounds and their intermediates through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0128] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0129] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing a 2-amino-6-hydroxypyridine compound, characterized in that, Includes the following steps: 1) Compound II is reacted with cyclic anhydride reagent A in a first organic solvent to prepare compound III; 2) In a second organic solvent, in the presence of an oxidizing agent, compound III undergoes an oxidation reaction to prepare compound IV; 3) In a third organic solvent, in the presence of an acid anhydride dehydrating agent, compound IV reacts to prepare compound V; 4) In a fourth solvent, in the presence of a reducing agent, compound V undergoes a reduction reaction to prepare compound I; compound I is a 2-amino-6-hydroxypyridine compound; Among them, R 1 R 2 R 3 Selected independently from H or C 1- C6 alkyl; R 5 and R 6 Independently selected from H or C1-C3 alkyl groups; Or R 5 R 6 Together with the carbon atom it is bonded to, they form C6-C. 10 Aryl.

2. The method for preparing the 2-amino-6-hydroxypyridine compound as described in claim 1, characterized in that, It also includes at least one of the following technical features: A1) The first organic solvent mentioned in step 1) is dimethylformamide, acetonitrile, or dimethylacetamide; A2) The mass-to-volume ratio of compound II in step 1) to the first organic solvent is 1 g: (3-5) mL; A3) The cyclic anhydride reagent A mentioned in step 1) is maleic anhydride or phthalic anhydride; A4) The molar ratio of compound II to cyclic anhydride reagent A in step 1) is 1:(1-3); A5) The reaction temperature described in step 1) is 110-120℃, and the holding time is 8-12h; A6) The second organic solvent mentioned in step 2) is dichloromethane, 1,2-dichloroethane or tetrahydrofuran; A7) The oxidizing agent mentioned in step 2) is a mixture of hydrogen peroxide and phthalic anhydride or m-chloroperoxybenzoic acid; A8) The mass-to-volume ratio of compound III to the second organic solvent in step 2) is 1 g: (9-11) mL; A9) The oxidation reaction described in step 2) is at a temperature of 30-40℃; The oxidation reaction described in step 2) of A10) takes 10-16 hours.

3. The method for preparing 2-amino-6-hydroxypyridine compounds as described in claim 2, characterized in that, Includes one or more of the following features: A71) The molar ratio of compound III to hydrogen peroxide in step 2) is 1:(1-3); A72) The molar ratio of compound III to phthalic anhydride in step 2) is 1:(1-3).

4. The method for preparing the 2-amino-6-hydroxypyridine compound as described in claim 1, characterized in that, It also includes at least one of the following technical features: B1) The third organic solvent mentioned in step 3) is dimethylformamide or dimethylacetamide; B2) The acid anhydride dehydrating agent mentioned in step 3) is trifluoroacetic anhydride, acetic anhydride or phthalic anhydride; B3) The mass-to-volume ratio of compound IV in step 3) to the third organic solvent is 1 g: (2-10) mL; B4) The molar ratio of compound IV to the acid anhydride dehydrating agent in step 3) is 1:(2-4); B5) The reaction temperature described in step 3) is 30-45℃; B6) The reaction time described in step 3) is 12-16 hours; B7) The fourth solvent mentioned in step 4) is a mixed solvent of alcohol and water; B8) The reducing agent mentioned in step 4) is hydrazine hydrate; B9) The molar ratio of compound V to the reducing agent in step 4) is 1:(1-3); The reaction temperature described in step 4) of B10 is 70-80℃; The reaction described in step 4) of B11 needs to be refluxed for 3-5 hours.

5. The method for preparing the 2-amino-6-hydroxypyridine compound as described in claim 4, characterized in that, Includes one or more of the following features: B71) The alcohol solvent mentioned in step 4) is methanol or ethanol; B72) The mass ratio of the alcohol solvent to water in step 4) is 1:(2-4); In step 4) of B73), the mass ratio of compound V to the alcohol solvent is 1:(1-3).

6. The method for preparing the 2-amino-6-hydroxypyridine compound as described in claim 1, characterized in that, It also includes at least one of the following technical features: C1) After the reaction described in step 1), the process also includes cooling, adding water, filtering, and drying to obtain compound III; C2) After the oxidation reaction described in step 2), the process also includes adding a reducing inorganic salt solution to quench the reaction, filtering the filtrate, adjusting the pH, separating the organic phase, concentrating the filtrate, adding an organic compound to slurry, filtering, and drying to obtain compound IV. C3) After the reaction described in step 3), the process also includes cooling, quenching with water, and filtration to obtain compound V; Following the reaction described in step 4), C4) further includes cooling, filtration, adding water and slurrying to obtain compound I.

7. The method for preparing the 2-amino-6-hydroxypyridine compound as described in claim 6, characterized in that, It also includes at least one of the following technical features: C11) Characteristic C1) Cooling down to 20-30℃; The reducing inorganic salt solution described in characteristic C2) is an aqueous solution of sulfite; In C22), adjust the pH to 4-5. C23) The organic compound described in feature C2) is any one or more of methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane; C31) Characteristic C3) Cooling down to 5-15℃; C41) characteristic C4) cooling to 10-15℃.

8. The method for preparing the 2-amino-6-hydroxypyridine compound as described in claim 1, characterized in that, It also includes any of the following features: D1)R 1 R 2 R 3 They are selected independently from H; D2)R 1 R 2 R 3 Selected independently from H or C 1- C6 alkyl, and not all of them are H.

9. A compound VI, characterized in that, The structural formula of compound VI is as follows: Among them, R 1 R 2 R 3 Selected independently from H or C 1- C6 alkyl, and not all of them are H.

10. Compound VI as claimed in claim 9, characterized in that, The compound VI is

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