Process for the preparation of triazole antifungal agents and intermediates thereof

Abstract

This invention provides a method for preparing triazole antifungal drugs and their intermediates, particularly a novel synthetic route for 2-methylamino-3-pyridinemethanol or its salts and isaconazole sulfate. Specifically, the method involves protecting 3-hydroxymethylpyridine with a hydroxyl group, then oxidizing and affinity-substituting the nitrogen atom on the pyridine ring, followed by methylamination at the 2-position, and finally removing the hydroxyl protecting group to obtain 2-methylamino-3-pyridinemethanol. This invention provides a method that eliminates the need for hazardous reducing agents, improving operational safety; furthermore, the raw materials are inexpensive and readily available, the multi-step reaction is telescoped, the operation is simple, and the conditions are mild, making it particularly suitable for industrial production applications.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical synthesis technology, and mainly relates to a method for preparing a triazole antifungal drug and its intermediates, especially a method for synthesizing 2-methylamino-3-hydroxymethylpyridine or its salt. Background Technology

[0002] Isavuconazonium sulfate and rivanazole are triazole antifungal drugs. Patent WO2001032652 discloses a method for preparing isavuconazine hydrochloride. The route is shown below.

[0003]

[0004] 2-Methylamino-3-hydroxymethylpyridine is a key intermediate in the preparation of isaconazole hydrochloride and isaconazole onium sulfate. WO2001032652 discloses a method for preparing 2-chloronicotinic acid chloride by reacting it with oxaloyl chloride, followed by reaction with potassium tert-butoxide to obtain tert-butyl 2-chloronicotinic acid; then reacting it with methylamine / methanol solution to obtain tert-butyl 2-methylamino-3-pyridinecarboxylate; and finally reducing it with lithium aluminum hydride to obtain the target product intermediate 2-methylamino-3-hydroxymethylpyridine. The reaction formula is as follows:

[0005]

[0006] In the above methods, methylamine reacts not only with the chlorine of 2-chloronicotinyl chloride but also with tert-butyl formate, resulting in a relatively mixed product. Furthermore, lithium aluminum hydride is not only expensive but also requires anhydrous conditions for the reaction, making it prone to spillage or explosions if handled carelessly, thus hindering scale-up.

[0007] WO2001032652 also discloses the preparation of methyl 2-aminonicotinic acid from 2-aminonicotinic acid as a starting material, reacting it with 2-chloro-1,3-dimethylimidazoline chloride; then reacting it with formic acid in acetic anhydride solution to obtain methyl 2-formamidonicotinic acid; and then reducing it with lithium aluminum hydride to obtain the target product intermediate 2-methylamino-3-hydroxymethylpyridine, as shown in the following reaction formula:

[0008]

[0009] The above method uses expensive starting material 2-aminonicotinic acid, and acetic anhydride is also a controlled chemical; moreover, lithium aluminum hydride is not only expensive, but the reaction also requires anhydrous materials, and carelessness in handling can easily lead to spillage or explosion, making it difficult to scale up.

[0010] Patent WO2010089993 discloses a method for preparing 2-methylamino-3-pyridinecarboxylic acid by reacting 2-chloronicotinic acid with methylamine hydrochloride, potassium carbonate, and cuprous bromide in DMF solvent at 100°C. The resulting product, 2-methylamino-3-hydroxymethylpyridine, is then reduced with lithium aluminum hydride to yield the target intermediate, 2-methylamino-3-hydroxymethylpyridine. The reaction formula is as follows:

[0011]

[0012] This method uses DMF, a high-boiling-point, highly polar solvent, which is cumbersome to handle and results in low yields. Furthermore, lithium aluminum hydride is not only expensive, but the reaction requires anhydrous conditions, and careless handling can easily lead to spillage or explosions, making it difficult to scale up.

[0013] CN 110317165 discloses a method for reducing tert-butyl 2-chloronicotinic acid to 2-methylamino-3-hydroxymethylpyridine using NaBH4, with a yield of 76%.

[0014]

[0015] This method suffers from steric hindrance and low reactivity of tert-butyl carboxylate during the reaction process, requiring the use of highly reactive lithium aluminum hydride or sodium borohydride as reducing agents. The reaction also involves high temperatures and harsh conditions.

[0016] CN 108822027 discloses a method for reducing 2-methylamino-3-pyridinecarboxylic acid to 2-methylamino-3-hydroxymethylpyridine using NaBH4 and FeCl3.

[0017]

[0018] CN 104961675 discloses a method for reducing 2-methylamino-3-pyridinecarboxylic acid to 2-methylamino-3-hydroxymethylpyridine in toluene by reflux reaction using red aluminum.

[0019] Existing methods for synthesizing 2-methylamino-3-hydroxymethylpyridine all require the use of highly hazardous reducing agents, such as LiAlH4, red aluminum, and boranes generated in situ using NaBH4 or KBH4. Boranes are highly toxic and explosive, posing significant safety hazards during industrial-scale production. Furthermore, the use of lithium aluminum hydride reduction requires strict anhydrous conditions, is hazardous, and results in high production costs. Summary of the Invention

[0020] To address the aforementioned problems in existing technologies, this invention provides a novel method for preparing triazole antifungal drugs and their intermediates, particularly a novel synthetic route for 2-methylamino-3-pyridinemethanol or its salts. This method offers advantages such as eliminating the need for hazardous reducing agents, improving operational safety, using readily available and inexpensive raw materials, employing telescope steps for multi-step reactions, simplifying operations, providing mild conditions, achieving high reaction yields, and being particularly suitable for industrial production applications.

[0021] Specifically, the first aspect of the present invention provides a method for preparing 2-methylamino-3-pyridinemethanol or a salt thereof, the method comprising the following steps:

[0022]

[0023] S1: React compound nt02 with an oxidizing agent to obtain compound nt03;

[0024] S2: React compound nt03 with RX to obtain compound nt04;

[0025] S3: React compound nt04 with methylamino to obtain compound nt05;

[0026] S4: Remove the hydroxyl protecting group from compound nt05 to obtain compound nta or its salt;

[0027] PG is a hydroxyl protecting group;

[0028] R is C 1～6 Alkyl or substituent C 1～6 Alkyl; the substituent is C 1-6 Any one or more of alkoxy, aryl, arylalkoxy, or trimethylsilylethoxy;

[0029] X is a halogen;

[0030] RX is the C in the R group 1～6 The hydrogen atom on the alkyl group is replaced by a halogen.

[0031] In another embodiment of the present invention, a method for preparing 2-methylamino-3-pyridinemethanol or a salt thereof is provided, comprising the following steps:

[0032]

[0033] Compound nt03 was reacted with RX to give compound nt04;

[0034] Compound nt04 was reacted with methylamino to give compound nt05;

[0035] The hydroxyl protecting group of compound nt05 was removed to obtain compound nta or its salt;

[0036] PG, R, and RX are defined as described above.

[0037] In another embodiment of the present invention, a method for preparing 2-methylamino-3-pyridinemethanol or a salt thereof is provided, comprising the following steps:

[0038]

[0039] Compound nt04 was reacted with methylamino to give compound nt05;

[0040] The hydroxyl protecting group of compound nt05 was removed to obtain compound nta or its salt;

[0041] Wherein, PG and R are as defined above.

[0042] In one embodiment of the present invention, the PG is selected from C. 1-6 Alkyl, C 1-6 Alkoxyalkyl, aryloxyalkyl, alkylsilyl, alkylsilylalkoxyalkyl, alkylcarbonyl, halogenated C 1-6 Alkyl carbonyl and aryl carbonyl, wherein Ar is a selectively substituted phenyl group, and the "substituted phenyl group" is a phenyl group selected from one or more C14 groups. 1-6 Alkyl, C 1-6 Benzene with alkoxy, halogen, and tri(chloro- or fluoro)methyl substituents.

[0043] The R is selected from: C 1～6 alkyl and aryl substituted C 1～6 alkyl;

[0044] X is F, Cl, Br, or I;

[0045] The oxidant is m-chloroperoxybenzoic acid, peracetic acid, or hydrogen peroxide;

[0046] In one embodiment of the present invention, the PG is selected from: the PG is selected from C 1-6 Alkyl, C 1-6 Alkoxyalkyl, aryloxyalkyl, alkylsilyl, alkylsilylalkoxyalkyl, alkylcarbonyl, halogenated C 1-6 Alkyl carbonyl and aryl carbonyl, wherein Ar is a selectively substituted phenyl group, and the "substituted phenyl group" is a phenyl group selected from one or more C14 groups. 1-6 Alkyl, C 1-6 Alkyl, halogen, and tri(chloro- or fluoro)methyl substituted phenyl groups;

[0047] More preferably, the PG is selected from: methyl, ethyl, benzyl, acetyl, trifluoroacetyl, benzoyl, MOM, MEM, TMS, TBDPS, TIPS, TBDMS, benzyloxymethyl and trimethylsilylethoxymethyl;

[0048] More preferably, the PG is selected from any one of MOM, MEM, TBDPS, TIPS, and TBDMS.

[0049] In one embodiment of the present invention, R is selected from: methyl, ethyl, propyl, isopropyl, benzyl, and triphenylmethyl.

[0050] In one embodiment of the present invention, X is selected from Cl, Br or I.

[0051] In one embodiment of the present invention, a method for preparing 2-methylamino-3-pyridinemethanol or a salt thereof is provided, the method comprising the following steps:

[0052]

[0053] S1: React compound nt02 with an oxidizing agent to obtain compound nt03;

[0054] S2: React compound nt03 with RX to obtain compound nt04;

[0055] S3: React compound nt04 with methylamino to obtain compound nt05;

[0056] S4: Remove the hydroxyl protecting group from compound nt05 to obtain compound nta or its salt;

[0057] Among them, PG is selected from C 1-6 Alkyl, C 1-6 Alkoxyalkyl, aryloxyalkyl, alkylsilyl, alkylsilylalkoxyalkyl, alkylcarbonyl, halogenated C 1-6 Alkyl carbonyl and aryl carbonyl, wherein the aryl group is a selectively substituted phenyl group, and the "substituted phenyl group" is a phenyl group selected from one or more C14 groups. 1-6 Alkyl, C 1-6 Alkyl, halogen, and tri(chloro- or fluoro)methyl substituted phenyl groups;

[0058] The C 1-6 Alkyl groups include: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.

[0059] The alkylsilyl groups include, but are not limited to, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS or TBS), tert-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS);

[0060] The alkyl carbonyl group is preferably C. 1-6 Alkyl carbonyl groups, such as acetyl and propionyl groups;

[0061] The aryl carbonyl benzoyl group, p-methoxybenzoyl group, methylbenzoyl group, chlorobenzoyl group, etc.

[0062] The alkylsilylalkoxyalkyl group is preferably trimethylsilylethoxymethyl, etc.

[0063] The aryloxyalkyl group, such as benzyloxymethyl, etc.;

[0064] The halogenated C 1-6 Alkyl carbonyl, preferably trifluoroacetyl, chloroacetyl, etc.

[0065] More preferably, the PG is selected from: methyl, ethyl, benzyl, acetyl, trifluoroacetyl, benzoyl, MOM, MEM, TMS, TIPS, TBDMS, TBDPS, benzyloxymethyl and trimethylsilylethoxymethyl;

[0066] More preferably, the PG is selected from any one of MOM, MEM, TBDPS, TIPS, and TBDMS.

[0067] R is methyl, ethyl, propyl, isopropyl, benzyl, or triphenylmethyl; preferably, R is methyl or ethyl.

[0068] The RX is iodomethane, iodoethane, bromomethane, or bromoethane;

[0069] The oxidant is m-chloroperoxybenzoic acid, peracetic acid, or hydrogen peroxide.

[0070] In one specific embodiment of the present invention, a method for preparing compound ntO3 is provided, comprising adding compound ntO2 to a suitable solvent (such as dichloromethane), adding an oxidant in batches or slowly under suitable temperature conditions (such as 0°C), preferably reacting at room temperature (20-25°C) to obtain compound ntO3; further, preferably after the reaction is completed, adding sodium thiosulfate solution to the reaction solution to neutralize excess oxidant, then removing the aqueous phase and separating to obtain an organic phase; preferably, the organic phase is concentrated and directly used in the next reaction step; further preferably, the molar ratio of compound ntO2 to oxidant is preferably 1:1-2, more preferably 1:1.2-1.5.

[0071] In one specific embodiment of the present invention, a method for preparing compound nt04 is provided, comprising adding compound nt03 to a suitable solvent (such as dichloromethane), then adding RX (preferably iodoethane), and reacting under suitable temperature (such as room temperature) conditions to obtain compound nt04; preferably, the molar ratio of compound nt03 to RX (preferably iodoethane) is 1:2 to 5, more preferably 1:3 to 4.

[0072] In one specific embodiment of the present invention, a method for preparing compound nt05 is provided, comprising adding compound nt04 to an organic solvent of methylamine (preferably THF), then adding a base (such as sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate), and reacting under suitable temperature (such as room temperature) to obtain compound nt05; preferably, the molar ratio of compound nt04 to methylamine is 1:5 to 15, more preferably 1:8 to 10; further preferably, the molar ratio of compound nt04 to base is 1:2 to 5, more preferably 1:3 to 4.

[0073] In one specific embodiment of the present invention, a method for preparing compound NTA or its salt is provided, comprising: dissolving compound nt05a in a suitable organic solvent (preferably dioxane), adding an acid or base solution, reacting at a suitable temperature (preferably 30-60°C), and removing the hydroxyl protecting group PG to obtain compound NTA or its salt; preferably, reacting with HCl / Diox to obtain compound NTA or its salt. The hydroxyl protecting group PG in compound nt05 can be removed under acidic or alkaline conditions. When PG is alkylsilyl, it can also be removed with tetraalkylammonium fluoride; for example, when PG is alkylsilyl, MEM, MOM, or benzyl, it can be removed using an HCl-MeOH or HCl-Diox system. In this case, the hydroxyl protecting group is removed by compound nt05 to obtain compound NTA hydrochloride. Compound NTA can be prepared from compound NTA salt, such as NTA hydrochloride, using conventional acid-base neutralization reactions, for example, by adding a base such as sodium hydroxide to neutralize, to obtain free compound NTA. Preferably, after removing the hydroxyl protecting group from compound nt05 using an HCl-MeOH or HCl-Diox system, sodium hydroxide is added to the reaction solution for neutralization to obtain compound nta.

[0074] Therefore, in one specific embodiment of the present invention, the method further includes the step of converting the salt of the obtained compound nta into compound nt0a.

[0075] The compound nt02 described in this invention can be prepared from 3-hydroxymethylpyridine by hydroxyl protection, for example, by reacting 3-hydroxymethylpyridine with a hydroxyl protecting agent under acidic or alkaline conditions.

[0076] In the above embodiments of the present invention, after the reaction in preferred steps S1 and / or S2 is completed, the reaction solution can be directly used for the next reaction after simple filtration, concentration and other operations.

[0077] Another aspect of the present invention provides a method for preparing isaconazole sulfate, which includes the method for preparing the compound nta or its salt described in the present invention.

[0078] In another aspect, the present invention also provides the following compounds:

[0079]

[0080] The present invention also provides the use of the above-mentioned compounds nt03a, nt04a, and nt04a in the preparation of compounds methylamino-3-hydroxymethylpyridine and isaconazole sulfate.

[0081] The hydroxyl protecting group as used in this invention is a known general term that refers to a group that protects a hydroxyl group from chemical reactions but is easily removed after the desired chemical reaction has occurred elsewhere in the molecule. Typical such groups include unsubstituted or substituted aryl, aralkyl, or acyl groups, as well as alkyl groups. Those having 1-20, particularly 1-10, carbon atoms are preferred. Representative hydroxyl protecting groups include, for example, C... 1-6 Alkyl, C 1-6 Alkoxyalkyl, aryloxyalkyl, alkylsilyl, alkylsilylalkoxyalkyl, alkylcarbonyl, halogenated C 1-6 Alkyl carbonyl and aryl carbonyl groups, wherein Ar is a selectively substituted phenyl group. The term "substituted phenyl" refers to a group having one or more C14 groups selected from C14. 1-6 Alkyl, C 1-6 The phenyl group is alkoxy, hydroxyl, nitro, halogen, or a tri(chloro- or fluoro)methyl substituent. Methyl is preferred.

[0082] The halogen used in this invention is F, Cl, Br or I, preferably Br or I.

[0083] The C described in this invention 1～6 Alkyl refers to a straight-chain or branched alkyl group having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, etc., preferably methyl, ethyl, propyl or isopropyl.

[0084] The "C substituted with aryl group" described in this invention 1～6 "alkyl" refers to C 1-6 One or more hydrogen atoms on an alkyl group are replaced by an aryl group, preferably a phenyl group, as described in this invention. 1～6 "alkyl" is preferably benzyl or triphenylmethyl.

[0085] In this invention, RX refers to the C in the R group. 1～6 At least one hydrogen atom on the alkyl group is substituted with a halogen. In this invention, R is selected from: C 1～6 alkyl and aryl substituted C 1～6 Alkyl groups, where RX is selected from halogenated C3 groups. 1～6 Alkyl groups, such as iodomethane, iodoethane, bromomethane, or bromoethane, or halogenated aryl-substituted C4 groups. 1～6 Alkyl groups, such as bromotriphenylmethyl, iodotriphenylmethyl, bromotriphenylmethyl, bromobenzyl or iodobenzyl, wherein iodomethane, iodoethane or bromoethane are preferred.

[0086] The "2-methylamino-3-pyridinemethanol or its salt" described in this invention includes a salt formed by 2-methylamino-3-pyridinemethanol and an inorganic acid, wherein the inorganic acid includes hydrochloric acid, sulfuric acid, hydrosulfuric acid, hydrobromic acid, or phosphoric acid, preferably a hydrochloride salt; or a salt formed by 2-methylamino-3-pyridinemethanol and an organic acid, wherein the organic acid may include, for example, acetic acid, formic acid, etc. In a specific embodiment of this invention, the salt formed by the 2-methylamino-3-pyridinemethanol salt depends mainly on the acid used in the process of removing the hydroxyl protecting group from compound nt05. For example, when hydrochloric acid is used for the dehydroxyl protecting group reaction, compound nt05 hydrochloride salt is obtained.

[0087] Explanation of abbreviations:

[0088] THF: Tetrahydrofuran;

[0089] DCM: Dichloromethane;

[0090] MOM: Methoxymethyl

[0091] MEM: Methoxyethoxymethyl;

[0092] BOM: Benzyloxymethyl;

[0093] TBDPS: tert-butyldiphenylsilyl;

[0094] TIPS: Triisopropylsilyl;

[0095] TBDMS: tert-butyldimethylsilane

[0096] m-CPBA: m-chloroperoxybenzoic acid;

[0097] Diox: 1,4-Dioxane.

[0098] The beneficial effects of this invention are:

[0099] First, this invention provides a novel synthetic route for preparing 2-methylamino-3-pyridinemethanol and isaconazole sulfate. Compared with existing technologies, this method does not require the use of dangerous reducing agents (such as lithium aluminum hydride, borane, sodium borohydride, etc.), thus improving operational safety.

[0100] Secondly, the synthetic route provided by this invention uses inexpensive and readily available raw materials; the intermediate multi-step reactions are telescope steps (i.e., "continuous casting" steps), which are simple to operate and have mild conditions.

[0101] Third, the method for preparing compound nt0a or its salt provided by the present invention significantly improves the reaction yield. Detailed Implementation

[0102] The technical solutions and advantages of the present invention will be further explained below with reference to specific embodiments. It should be noted that, unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other. Unless otherwise specified, the reagents used in the present invention are commercially available.

[0103] Example 1: Preparation method of compound (6):

[0104]

[0105] Synthesis of compound (2)

[0106] 5.45 g of 3-hydroxymethylpyridine (50 mmol, 1.0 eq.) was dissolved in 55 mL of tetrahydrofuran. 2.20 g of 60% NaH (55 mmol, 1.1 eq.) was added in portions at 0 °C. After stirring at 0 °C for 30 minutes until no more bubbles were released, 4.23 g of MOMCl (52.5 mmol, 1.05 eq.) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 6 hours, and TLC showed complete conversion of the starting material. The reaction was quenched by adding 0.8 mL of saturated ammonium chloride solution. The reaction mixture was washed twice with 20% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the resulting product was used directly in the next reaction step.

[0107] Synthesis of compound (3)

[0108] 7.65 g of compound 2 (50 mmol, 1.0 eq.) was dissolved in 77 mL of dichloromethane, and 17.26 g of 75% m-CPBA (75 mmol, 1.5 eq.) was added in portions at 0 °C. After stirring the reaction mixture at room temperature for 18 hours, TLC showed complete conversion of the starting material. 20 mL of 20% sodium thiosulfate solution was added and stirred for 0.5 hours, followed by separation to remove the aqueous phase. The organic phase was washed with saturated sodium carbonate solution (20 mL x 3), then with 20% sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the resulting product was used directly in the next reaction step.

[0109] Synthesis of compound (4)

[0110] 8.46 g of compound 3 (50 mmol, 1.0 eq.) was dissolved in 85 mL of dry dichloromethane, followed by the addition of 23.40 g of iodoethane (150 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 18 hours, and TLC showed complete conversion of the starting material. The reaction mixture was filtered, and the filter cake was washed three times with ethyl acetate and dried to give 15.77 g of a white solid (yield: 97%).

[0111] Synthesis of compound (5)

[0112] 1.63 g of compound 4 (5 mmol, 1.0 eq.) was suspended in 20 mL of 2.0 M methylamine in tetrahydrofuran (40 mmol, 1.0 mL).

[0113] 8.0 eq.) of potassium carbonate (15 mmol, 3.0 eq.) was added. The reaction mixture was stirred at room temperature for 22 hours, and then filtered to remove the potassium carbonate. The filtrate was concentrated and purified by silica gel column chromatography to give 0.79 g of product (yield: 87%).

[0114] Synthesis of compound (6)

[0115] 0.363 g of compound 5 (2 mmol, 1.0 eq.) was dissolved in 4 mL of dioxane, and 4 mL of 4 M HCl / Dioxane was added. The reaction mixture was stirred at 40 °C for 2 hours, and then concentrated to dryness under reduced pressure to give 0.347 g of compound 6 (yield: 100%).

[0116] Example 2: Preparation method of compound (6):

[0117]

[0118] Synthesis of compound (nt02a)

[0119] 5.45 g of 3-hydroxymethylpyridine (50 mmol, 1.0 eq.) was dissolved in 55 mL of tetrahydrofuran. 2.20 g of 60% NaH (55 mmol, 1.1 eq.) was added in portions at 0 °C. After stirring at 0 °C for 30 minutes until no more bubbles were released, 6.42 g of MEMCl (51.5 mmol, 1.03 eq.) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 9 hours, and TLC showed complete conversion of the starting material. The reaction was quenched by adding 0.8 mL of saturated ammonium chloride solution. The reaction mixture was washed twice with 20% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the resulting product was used directly in the next reaction step.

[0120] Synthesis of compound (nt03a)

[0121] 9.86 g of compound nt02a (50 mmol, 1.0 eq.) was dissolved in 100 mL of dichloromethane, and 28.52 g of 20% peracetic acid (75 mmol, 1.5 eq.) was added in portions at 0 °C. After stirring the reaction mixture at room temperature for 18 hours, TLC showed complete conversion of the starting material. 20 mL of 20% sodium thiosulfate solution was added and stirred for 0.5 hours, followed by separation to remove the aqueous phase. The organic phase was washed with saturated sodium carbonate solution (20 mL x 3), then with 20% sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the resulting product was used directly in the next reaction step.

[0122] Synthesis of compound (nt04a)

[0123] 10.66 g of compound nt03a (50 mmol, 1.0 eq.) was dissolved in 101 mL of dry dichloromethane, followed by the addition of 21.29 g of iodomethane (150 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 18 hours, and TLC showed complete conversion of the starting material. The reaction mixture was filtered, and the filter cake was washed three times with ethyl acetate and dried to give 17.40 g of a white solid (yield: 98%).

[0124] Synthesis of compound (nt05a)

[0125] 1.14 g of compound nt04a (5 mmol, 1.0 eq.) was suspended in 25 mL of 2.0 M methylamine in tetrahydrofuran (50 mmol, 10.0 eq.), and 2.07 g of potassium carbonate (15 mmol, 3.0 eq.) was added. The reaction mixture was stirred at room temperature for 22 hours, and the potassium carbonate was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography to give 1.04 g of the product (yield: 92%).

[0126] Synthesis of compound (6)

[0127] 0.453 g of compound nt05a (2 mmol, 1.0 eq.) was dissolved in 4 mL of dioxane, and 4 mL of 4 M HCl / Dioxane was added. The reaction mixture was stirred at 40 °C for 2 hours, and then concentrated to dryness under reduced pressure to give 0.349 g of compound 6 (yield: 100%).

[0128] Example 3: Preparation method of compound nta:

[0129]

[0130] Synthesis of compound (nt02b)

[0131] 5.45 g of 3-hydroxymethylpyridine (50 mmol, 1.0 eq.) was dissolved in 55 mL of dichloromethane. 3.74 g of imidazole (55 mmol, 1.1 eq.) and 8.29 g of TBDMSCl (55.0 mmol, 1.1 eq.) were added at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 14 hours, and TLC showed complete conversion of the starting material. The reaction was quenched by adding 0.8 mL of saturated ammonium chloride solution. The reaction mixture was washed twice with 20% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the resulting product was used directly in the next reaction step.

[0132] Synthesis of compound (nt03b)

[0133] 11.17 g of compound nt02b (50 mmol, 1.0 eq.) was dissolved in 115 mL of ethanol, and 0.065 g of methylrhenium trioxide (0.25 mmol, 0.005 eq.) was added. 8.50 g of 30% hydrogen peroxide (75 mmol, 1.5 eq.) was added dropwise at 0 °C. After stirring the reaction mixture at room temperature for 3 hours, TLC showed complete conversion of the starting material. 20 mL of 20% sodium thiosulfate solution was added and stirred for 0.5 hours, followed by separation to remove the aqueous phase. The organic phase was washed with saturated sodium carbonate solution (20 mL x 3), washed with 20% sodium chloride solution (20 mL x 1), dried over anhydrous sodium sulfate, concentrated, and the resulting product was used directly in the next reaction step.

[0134] Synthesis of compound (nt04b)

[0135] 11.97 g of compound nt03b (50 mmol, 1.0 eq.) was dissolved in 120 mL of dry dichloromethane, followed by the addition of 16.35 g of bromoethane (150 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 21 hours, and TLC showed complete conversion of the starting material. The reaction mixture was filtered, and the filter cake was washed three times with ethyl acetate and dried to give 16.20 g of a white solid (yield: 92%).

[0136] Synthesis of compound (nt05b)

[0137] 1.74 g of compound nt04b (5 mmol, 1.0 eq.) was suspended in 25 mL of 2.0 M methylamine in tetrahydrofuran (50 mmol, 10.0 eq.), and 2.07 g of potassium carbonate (15 mmol, 3.0 eq.) was added. The reaction mixture was stirred at room temperature for 22 hours, and the potassium carbonate was removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography to give 1.15 g of the product (yield: 91%).

[0138] Synthesis of compound (nta)

[0139] 0.505 g of compound nt05b (2 mmol, 1.0 eq.) was dissolved in 4 mL of dioxane, and 4 mL of 4M HCl / Diox was added. The reaction mixture was stirred at 40 °C for 2 hours, then dried under reduced pressure. The residue was dissolved in 10 mL of water, washed with ethyl acetate (5 mL x 2), and then the pH was adjusted to 9 with 10% NaOH solution. The mixture was then extracted with ethyl acetate (10 mL x 2). The combined organic phases were concentrated to dryness under reduced pressure to give 0.265 g of compound nta (yield: 96%).

[0140] Example 4: Synthesis of Compound (NTA) 0.453 g of compound nt05a (2 mmol, 1.0 eq.) was dissolved in 4 mL of dioxane, and 4 mL of 4M HCl / Dioxane was added. The reaction mixture was stirred at 40 °C for 2 hours, then concentrated to dryness under reduced pressure to give 0.349 g of compound 6 (yield: 100%). Compound 6 was dissolved in 10 mL of water, and the pH was adjusted to 9 with 10% NaOH solution. The mixture was then extracted with ethyl acetate. The organic phases were combined and concentrated to dryness under reduced pressure to give 0.276 g of compound NTA, yield 100%.

Claims

A method for preparing 1,2-methylamino-3-pyridinemethanol or a salt thereof, characterized in that, Includes the following steps: S1: React compound nt02 with an oxidizing agent to obtain compound nt03; S2: React compound nt03 with RX to obtain compound nt04; S3: React compound nt04 with methylamino to obtain compound nt05; S4: Remove the hydroxyl protecting group from compound nt05 to obtain compound nta or its salt; PG is a hydroxyl protecting group; R is C 1～6 alkyl or C 1～6 alkyl; X is a halogen; R-X is C 1～6 hydrogen on an alkyl group is replaced by halogen. A method for preparing 2,2-methylamino-3-pyridinemethanol or a salt thereof, characterized in that, Includes the following steps: Compound nt03 was reacted with RX to give compound nt04; Compound nt04 was reacted with methylamino to give compound nt05; The hydroxyl protecting group of compound nt05 was removed to obtain compound nta or its salt; Wherein, PG, R, X, RX are as defined in claim 1. A method for preparing 3,2-methylamino-3-pyridinemethanol or a salt thereof, characterized in that, Includes the following steps: Compound nt04 was reacted with methylamino to give compound nt05; The hydroxyl protecting group of compound nt05 was removed to obtain compound nta or its salt; Wherein, PG, R, X are as defined in claim 1.

4. The method according to any one of claims 1 to 3, characterized in that, The PG is selected from C. 1～6 Alkyl, C 1～6 Alkoxyalkyl, aryloxyalkyl, alkylsilyl, alkylsilylalkoxyalkyl, alkylcarbonyl, halogenated C 1～6 Alkyl carbonyl and aryl carbonyl, wherein the aryl group is an optionally substituted phenyl group, and the "substituted phenyl group" is a phenyl group selected from one or more C16 groups. 1～6 Alkyl, C 1～6 Alkoxy, halogen, and trichloromethyl or trifluoromethyl substituted phenyl groups.

5. The method according to any one of claims 1 to 3, characterized in that, The PG is selected from: methyl, ethyl, benzyl, acetyl, trifluoroacetyl, benzoyl, MOM, MEM, TMS, TIPS, TBDMS, benzyloxymethyl and trimethylsilylethoxymethyl.

6. The method according to any one of claims 1 to 3, characterized in that, The PG is selected from any one of MOM, MEM, TMS, TIPS, and TBDMS.

7. The method according to any one of claims 1 to 3, characterized in that, R is methyl, ethyl, propyl, isopropyl, benzyl, or triphenylmethyl.

8. The method according to any one of claims 1 to 3, characterized in that, R is ethyl.

9. The method according to claim 1, characterized in that, The oxidant is m-chloroperoxybenzoic acid, peracetic acid, or hydrogen peroxide.

10. The method according to any one of claims 1 to 3, characterized in that, PG is MOM, MEM or benzyl; R is C 1～6 alkyl.

11. The method according to claim 1, characterized in that, The PG is MOM, MEM, or benzyl; RX is iodomethane, iodoethane, bromomethane, or bromoethane; R is methyl or ethyl; The oxidizing agent is m-chloroperoxybenzoic acid, peracetic acid, or hydrogen peroxide.

12. A method for preparing isaconazole sulfate, characterized in that, Includes the method described in any one of claims 1 to 11.

13. A compound, characterized in that, It has the following structure: or .

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