Preparation method of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

Abstract

The present invention provides a preparation method of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine, the preparation method comprising: using 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine, nitrite compound and iodide as raw materials, and obtaining a target crude product through Sandmeyer reaction. The process of the present invention has safe and controllable conditions, and the raw materials and reagents involved are all easy to obtain, simple to operate, high production efficiency, high final product yield, purity of more than 99.5%, and single impurity ≤0.5%. The process is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical organic synthesis, and in particular to a method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, a key intermediate of SPH3127. Background Art

[0002] SPH3127 is a new generation of oral non-peptide small molecule renin inhibitor. It is a new class of drugs for essential hypertension. It reduces the activity of renin in plasma and inhibits the activation of the "renin-angiotensin-aldosterone system (RAS)" to achieve the effect of lowering blood pressure. As a key intermediate of SPH3127, the preparation of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine is crucial. The structure of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine is:

[0003] Patents for the synthesis of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine are currently reported in: (1) WO2015 / 122504 (2) US2017 / 0145005. The synthesis route involved is as follows:

[0004]

[0005] The specific preparation process involves a total of 7 steps, including: (1) Sodium methoxide and dichloromethane are mixed and cooled to below 4°C, and an acetone solution of ethyl formate is added dropwise. After the addition is completed, the temperature is raised to 15°C and the reaction is continued for 2 hours. Water is added and stirred for 0.5 hours to extract it. The extraction is repeated once and the aqueous phase is combined. Cyanoacetamide, acetic acid and pyridine are added to the aqueous phase in sequence, and the mixture is heated to reflux for 3 hours. After the reaction is completed, the mixture is cooled to room temperature. 6N hydrochloric acid is slowly added to the mixture under stirring to adjust the pH to about 5 to 6 and stirred for 8 to 16 hours. After filtering, the filter cake is washed with a small amount of water. After vacuum drying, a yellow solid is obtained, which is 2-hydroxy-3-cyano-6-methylpyridine, with a yield of about 72%.

[0006] (2) 2-Hydroxy-3-cyano-6-methylpyridine was mixed with phosphorus oxychloride and heated to reflux for 3 hours. Most of the phosphorus oxychloride was evaporated under reduced pressure and then added to an ice-water mixture. After stirring for 3 hours, it was filtered and dried in vacuo to obtain 2-chloro-6-methyl-1,2-dihydropyridine-3-carbonitrile. The yield was 86%.

[0007] (3) Mix 2-chloro-6-methyl-1,2-dihydropyridine-3-carbonitrile and sodium hydroxide aqueous solution, heat to 80°C, react for 2 hours, cool to room temperature, add concentrated hydrochloric acid to adjust pH to 1-2, filter and vacuum dry to obtain 2-chloro-3-carboxylic acid-6-methylpyridine. Yield: about 89%

[0008] (4) Mix 2-chloro-3-carboxylic acid-6-methylpyridine, N,O-dimethylhydroxylamine hydrochloride and dichloromethane, stir and cool. Add pyridine dropwise and stir evenly. Add water, stir to dissolve and separate the layers, and take the organic layer. Extract the water layer with dichloromethane twice, combine the organic layers, wash with water, dry and filter, and concentrate the filtrate under reduced pressure to obtain a light yellow solid, which is 2-chloro-N-methoxy-N,6-dimethylnicotinamide. The yield is about 84%.

[0009] (5) Mix 2-chloro-N-methoxy-N,6-dimethylnicotinamide with dichloromethane and cool under argon protection. Add diisobutylaluminum hydride dropwise. After the addition is complete, raise the temperature of the reaction solution to 0-10°C. Slowly add 20% ammonium chloride dropwise at this temperature. Add 3N hydrochloric acid dropwise after the addition is complete. Then add ethyl acetate and stir to separate the layers. Separate the organic layer, dry it, and filter it. The filtrate is concentrated under reduced pressure to obtain 2.94 kg of 2-chloro-3-formyl-6-methylpyridine as a light yellow oil with a yield of about 94%.

[0010] (6) Add p-toluenesulfonic acid monohydrate to 85% hydrazine hydrate at about 0°C, add 2-chloro-3-formyl-6-methylpyridine in batches while maintaining the temperature at about 0°C, raise the temperature to reflux after the addition, maintain the temperature for about 20 hours, add purified water after the reaction is complete, cool to room temperature, extract with dichloromethane, evaporate to dryness, and then slurry with a mixed solvent of n-heptane and dichloromethane for 2 hours, filter, and dry. The yield is about 61%.

[0011] (7) Add the raw materials to dimethylformamide, stir and dissolve, then add potassium carbonate, cool to about 0°C, add dropwise the dimethylformamide solution of iodine, raise the temperature to 25°C to 30°C after the addition is complete, react for about 16 hours, and after the reaction is complete, add the reaction solution in batches to an aqueous sodium sulfite solution, stir for 0.5 hours, and filter. Wash the filter cake with water, slurry it with water for 4 hours, and filter it, and dry it to obtain 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine. The yield is about 91%.

[0012] The overall yield reported for this route is around 24%.

[0013] According to the above steps of the process, the disadvantages of this route can be summarized as follows:

[0014] First, N,O-dimethylhydroxylamine hydrochloride and diisobutylaluminum hydride are relatively expensive reagents. Once industrial production is involved, cost is a key issue that is difficult to overcome. In addition, diisobutylaluminum hydride is highly flammable and explosive, and reacts violently when it comes into contact with water, which is not suitable for large-scale production.

[0015] Secondly, the elemental iodine required for the iodination process is toxic and easy to sublime, which can easily cause damage to operators and is not conducive to large-scale production.

[0016] Third, the overall reaction has as many as 7 steps, which has many problems such as long steps, complicated operation, large labor consumption, low total yield, and high economic cost.

[0017] Through the above analysis, it can be seen that the existing preparation technology has many defects such as long reaction route, high preparation cost, low total yield, and the need to use relatively dangerous reagents, which seriously restricts the subsequent commercial development of SPH3127 by researchers. Therefore, it is particularly necessary to further explore a new synthetic process route for 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine with significant technical advantages and economic value. Summary of the invention

[0018] In view of the many shortcomings of the existing synthetic route of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine, the present invention provides a preparation method of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine. The preparation method well solves the technical problems of the existing synthetic route, such as long reaction route, high preparation cost, low total yield and the need to use relatively dangerous reagents. The preparation method has the advantages of low cost, easy availability of raw materials, relatively safe reagents, short steps, simple operation, high yield, high purity and easy large-scale production.

[0019] In order to achieve the above technical objectives, the technical solutions adopted in this application are as follows:

[0020] In a first aspect, the present invention provides a method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, wherein the structure of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine is: The preparation method comprises: using 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine, a nitrite compound and an iodide as raw materials, and obtaining a target crude product through a Sandmeyer reaction, wherein the reaction equation is:

[0021]

[0022] The Sandmeyer reaction is divided into two reaction stages: in the first stage, 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine reacts with a nitrite compound to generate a diazonium salt intermediate; in the second stage, the diazonium salt intermediate reacts with an iodide to generate 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, and the target crude product is initially separated.

[0023] Preferably, the nitrite compound is selected from sodium nitrite, isoamyl nitrite, tert-butyl nitrite, and potassium nitrite; and further comprises: an acidic reagent one for forming nitrous acid with the nitrite compound, wherein the acidic reagent one is selected from hydrochloric acid, sulfuric acid, perchloric acid, fluoroboric acid, glacial acetic acid, and boron trifluoride ether complex; and the iodide is selected from sodium iodide, potassium iodide, iodinated ketone, and diiodomethane.

[0024] Preferably, the reaction temperature of the first stage is not higher than 4°C, more preferably -5 to -20°C; and / or, the reaction solvent one of the first stage is selected from at least one of dioxane, dichloromethane, cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, and chloroform; and / or, the reaction temperature of the second stage is 15 to 30°C; and / or, the reaction solvent two of the second stage is selected from at least one of dioxane, dichloromethane, cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, chloroform, and acetone.

[0025] Preferably, the reaction control process of the first stage comprises: mixing 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine and a nitrite compound with a reaction solvent 1 to obtain a mixed solution, adding an acidic reagent 1 to the mixed solution of 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine at a temperature below 4°C, and then further adding the mixed solution of the nitrite compound at -5 to -20°C, and reacting for 30 to 60 minutes after the addition is completed, and separating the diazonium salt intermediate after the reaction is completed; and / or, the reaction control process of the second stage The preparation process comprises: mixing iodide with reaction solvent 2, adding the diazonium salt intermediate at below 4°C, reacting at 15-30°C for 2-4h after the addition, and separating the target crude product after the reaction is completed; further preferably, the process of separating the target crude product comprises: separating the solid in the reaction solution to obtain solid 1; adding a mixed solvent of dichloromethane, ethyl acetate and methanol to the remaining separated solution after the solvent is removed, and then separating the solid, adding water to the solid part to be slurried again, separating solid 2, and the mixture of solid 1 and solid 2 is the target crude product;

[0026] More preferably, the volume ratio of dichloromethane, ethyl acetate and methanol in the mixed solvent is: 1-2:1-2:0.5-1.

[0027] Preferably, the preparation method further comprises: purifying the target crude product to obtain the target pure product; further preferably, purification is performed by recrystallization; more preferably, the recrystallization solvent is selected from at least one of dichloromethane, ethyl acetate, cyclohexane, n-heptane, dioxane, methyl tert-butyl ether, tetrahydrofuran, chloroform, petroleum ether, acetone, and methanol.

[0028] Preferably, the process of purifying the target crude product by recrystallization to obtain the target pure product comprises:

[0029] Step 1), dissolving the target crude product in at least one of the following solvents: dichloromethane, ethyl acetate, cyclohexane, n-heptane, dioxane, methyl tert-butyl ether, tetrahydrofuran, chloroform, petroleum ether, acetone, methanol, and crystallizing at -10 to -20°C for 12 to 18 hours after dissolution, separating solid three, and retaining the filtrate;

[0030] Step 4), the filtrate is concentrated to dryness and step 1) is repeated to obtain solid four, solid three and solid four which are pure products of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine.

[0031] Preferably, the preparation method of 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine comprises: using 2-chloro-6-methylnicotinonitrile and hydrazine hydrate as raw materials, and obtaining 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine through a cyclization reaction, and the reaction equation is:

[0032]

[0033] Further preferably, the cyclization reaction further comprises a catalyst: N,N-diisopropylethylamine and / or triethylamine.

[0034] Preferably, the control process of the cyclization reaction comprises: mixing 2-chloro-6-methylnicotinonitrile and a reaction solvent, adding hydrazine hydrate at a temperature below 4°C, and then adding N,N-diisopropylethylamine and / or triethylamine at a temperature of 0 to 10°C; then reacting at 75 to 80°C for 10 to 20 minutes; then reacting at 85 to 90°C for 10 to 20 minutes; then reacting at 95 to 105°C for 2 to 3 hours; adding water after the reaction is completed, and crystallizing at 10 to 20°C for 1 to 2 hours, and the separated solid is 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine;

[0035] Further preferably, the reaction solvent three is at least one selected from ethylene glycol, methanol, ethanol, isopropanol, n-butanol, tert-butanol, and water.

[0036] Preferably, the preparation method of 2-chloro-6-methylnicotinonitrile comprises: using 2-hydroxy-3-cyano-6-methylpyridine and chloride as starting materials, converting the 2-hydroxyl group of 2-hydroxy-3-cyano-6-methylpyridine into a 2-chloro group through a chlorination reaction, and the reaction equation is:

[0037] Further preferably, the halide is selected from phosphorus oxychloride, thionyl chloride, or phosphorus trichloride.

[0038] Preferably, the control process of the chlorination reaction includes: mixing 2-chloro-6-methylnicotinonitrile with chloride, reacting at 90-105° C. for 5-8 hours; concentrating the reaction mixture after the reaction is completed, and adding the concentrate to an ice-water mixture below 4° C., mixing at this temperature for 0.5-2 hours, and separating the solid as 2-chloro-6-methylnicotinonitrile.

[0039] Preferably, the preparation method of 2-hydroxy-3-cyano-6-methylpyridine comprises: using acetone, ethyl formate and cyanoacetamide as raw materials to obtain 2-hydroxy-3-cyano-6-methylpyridine through a two-step reaction, and the reaction equation is:

[0040] The first step reaction is: acetone and ethyl formate undergo condensation reaction under the catalysis of an alkaline reagent to generate an enolate compound intermediate; the second step reaction is: the enolate compound intermediate reacts with cyanoacetamide to generate 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine.

[0041] Preferably, the control process of the two-step reaction comprises: mixing ethyl formate and acetone, mixing an alkaline reagent with a reaction solvent, adding the mixed solution of ethyl formate and acetone to the mixed solution containing the alkaline reagent at -15 to 5°C, more preferably at 0±4°C, and reacting at 10 to 25°C for 6 to 12 hours after the addition; adding water at 5 to 15°C for at least one extraction after the reaction is completed, and retaining the aqueous phase; adding cyanoacetamide, acetic acid and pyridine to the aqueous phase, heating to reflux and keeping the temperature for 3 hours to 7 hours; after the reaction is completed, adding an acidic reagent II at 5 to 15°C to adjust the pH to 4 to 6, and separating the crude 2-hydroxy-3-cyano-6-methylpyridine;

[0042] More preferably, the alkaline agent is selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide and potassium hydroxide;

[0043] More preferably, the second acidic reagent is selected from at least one of hydrochloric acid, dilute sulfuric acid, and acetic acid;

[0044] More preferably, the crude 2-hydroxy-3-cyano-6-methylpyridine is slurried in at least one of the following reagents for 2 to 5 hours: methanol, ethanol, isopropanol, n-butanol, isopentanol, ethyl acetate, and dichloromethane.

[0045] In a second aspect, the present invention provides the use of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine obtained by the preparation method described in the first aspect in the preparation of SPH3127 related substance standards.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] The process conditions of the invention are safe and controllable, the raw materials and reagents involved are easily available, the operation is simple, the production efficiency is high, the yield of the final product is high, the purity after refining reaches more than 99.5%, and the single impurity is ≤0.5%. The whole process is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1This is the thermal analysis curve of the diazonium salt intermediate in Example 1 of the present invention.

[0049] Figure 2 This is the DSC curve of the diazonium salt intermediate in Example 1 of the present invention.

[0050] Figure 3 This is the exothermic curve of the first stage of the Sandmeyer reaction in Example 1 of the present invention.

[0051] Figure 4 This is the exothermic curve of the second stage of the Sandmeyer reaction in Example 1 of the present invention.

[0052] Figure 5 This is the mass spectrum of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine obtained in Example 1 of the present invention.

[0053] Figure 6 This is the H NMR spectrum of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine obtained in Example 1 of the present invention.

[0054] Figure 7 This is the HPLC spectrum of the pure 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine obtained in Example 1 of the present invention.

[0055] Figure 8 This is the HPLC spectrum of the pure 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine obtained in Example 2 of the present invention.

[0056] Fig. 9 This is the HPLC spectrum of the pure 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine obtained in Example 3 of the present invention.

[0057] Fig.10 This is the HPLC spectrum of the pure 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine obtained in Example 4 of the present invention. DETAILED DESCRIPTION

[0058] In the description of the present invention, it should be noted that, if the specific conditions are not specified in the examples, the experiments were carried out according to conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0059] The specific embodiment of the present invention provides a preparation method of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine, using acetone as the starting material, undergoing 5 reactions and 4 process steps to obtain 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine, with a total yield of 31-40%, a product purity of more than 99.5%, and a single impurity of ≤0.5%. The reaction process involved is shown in the following formula:

[0060]

[0061] The method comprises the following steps:

[0062] (1) Cyclization reaction: Acetone, ethyl formate and cyanoacetamide are used as raw materials to undergo cyclization reaction to generate intermediate 1 (2-hydroxy-3-cyano-6-methylpyridine).

[0063] (2) Chlorination reaction: Intermediate 1 is chlorinated with phosphorus oxychloride to generate intermediate 2.

[0064] (3) Intermediate 2 is cyclized with hydrazine hydrate to generate intermediate 3.

[0065] (4) Intermediate 3 is subjected to diazotization and iodination reaction to generate crude 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine, which is then recrystallized from ethyl acetate to obtain the finished 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine.

[0066] In step (1), acetone and ethyl formate are used as starting materials, and under the condition of -15°C to 5°C, preferably 0±4°C, the acetone solution of ethyl formate is slowly added dropwise to sodium methoxide (which can also be replaced by sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or a mixture of two, three, four or five of the above) in cyclohexane, n-heptane, petroleum ether, chloroform, tetrahydrofuran, dichloromethane, preferably dichloromethane. For the selection of solvents for mixing sodium methoxide, the present invention has investigated a variety of polar solvents and non-polar solvents, and finally selected these solvents to mix sodium methoxide, which has a diluting effect on sodium methoxide, so that the reaction proceeds gently. In addition, among these solvents, dichloromethane is used as a mixed solvent, showing relatively few impurity peaks. In this step of the reaction, the early feeding rate is relatively safe under the condition of -15°C to 5°C, and the reaction rate can be ensured to be moderate. After the addition is completed, the temperature is raised to 10 to 25°C, preferably 15°C, and the reaction is continued for 6 to 12h, preferably 8h. After the system is cooled to 5-15°C, preferably 10°C, water is added and stirred for 0.5-2h to extract it. After repeated extraction, the aqueous phase is combined. The reaction raw material cyanoacetamide and the catalyst acetic acid and pyridine are added to the aqueous phase in sequence, and the mixture is heated to reflux for 3h-7h, preferably 4h. After the reaction is completed, the temperature is lowered to 5-15°C, preferably 10°C, and 6N hydrochloric acid (which can also be replaced by dilute sulfuric acid or acetic acid) is slowly added thereto under stirring conditions to adjust the pH to about 5 (4-6) and stirred for 8-16h. After filtering, the filter cake is washed with a small amount of water to obtain a yellow solid, and methanol, ethanol, isopropanol, n-butanol, isoamyl alcohol, ethyl acetate, dichloromethane are added, preferably ethanol, and the mixture is slurried for 2-5h and filtered. The filter cake is washed with a small amount of ethanol to obtain a light yellow solid, 2-hydroxy-3-cyano-6-methylpyridine, with a yield of more than 83%.

[0067] In step (2), compound 1 (2-hydroxy-3-cyano-6-methylpyridine) is added to phosphorus oxychloride (which can also be replaced by dichlorothionyl or phosphorus trichloride) under stirring conditions of 0-10°C, preferably 0°C, and heated to 90-105°C, preferably 100°C, for reaction for 5-8h. After the reaction is completed, the mixture is cooled to room temperature (25°C), and concentrated under reduced pressure until the system still has fluidity. The residue is slowly added to the ice-water mixture, and the temperature of the reaction liquid must not exceed 4°C during the addition process. The mixture is stirred at this temperature for 0.5-2h, and the filter cake is filtered and washed with a small amount of water to obtain a brown solid, thereby obtaining compound 2: 2-chloro-6-methylnicotinonitrile, with a yield of more than 87%.

[0068] In step (3), ethylene glycol is added to the reaction bottle, compound 2 (2-chloro-6-methylnicotinonitrile) is added under stirring, and after cooling to -5 to 0°C, hydrazine hydrate is slowly added dropwise. The reaction temperature must not exceed 4°C during the addition. After the addition is completed, the reaction liquid temperature is cooled to 0°C, and the acid binding agent N, N-diisopropylethylamine and / or triethylamine is slowly added dropwise. After the addition is completed, stirring is continued for 5 minutes, and the temperature is gradually increased. The reaction is carried out at 75 to 80°C for 10 to 20 minutes; then at 85 to 90°C for 10 to 20 minutes; and then at 95 to 105°C for 2 to 3 hours (TLC is used to detect whether the reaction is complete). After the reaction is completed, the reaction solution is cooled to room temperature, and water is added to the reaction solution, cooled to 10-20°C, preferably 15°C, and stirred for 1 hour. The solution is filtered and the filter cake is washed with a small amount of water to obtain a brown solid to obtain compound 3: 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine, with a yield of more than 87%.

[0069] In step (4), 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine is mixed with dioxane, dichloromethane, cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, chloroform, preferably tetrahydrofuran, and cooled to below 0°C, and then boron trifluoride etherate (which can also be replaced by hydrochloric acid, sulfuric acid, perchloric acid, fluoroboric acid, glacial acetic acid) is slowly added dropwise. During the addition, the temperature of the reaction solution shall not exceed 4°C. After the addition is completed, After the reaction liquid is cooled to -5 to -20°C, slowly drop isoamyl nitrite (which can also be replaced by sodium nitrite, tert-butyl nitrite, potassium nitrite) in dioxane, dichloromethane, cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, chloroform, preferably tetrahydrofuran solution. During the dropwise addition, the temperature of the reaction liquid must not exceed -5°C. After the dropwise addition is completed, keep the reaction warm for 30 to 60 minutes (TLC is used to detect whether the reaction is complete). The mixed solvent of 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine and isoamyl nitrite is selected as an aprotic solvent, and tetrahydrofuran shows that the impurity peaks in the reaction process are relatively small. After the reaction is completed, filter with suction, wash the filter cake with a small amount of acetone, and obtain the wet diazonium salt product. Sodium iodide (which can also be replaced by potassium iodide, iodide ketone, diiodomethane) is added to dioxane, dichloromethane, tetrahydrofuran, chloroform, acetone, preferably acetone, and stirred to dissolve. After cooling to below 0°C, the wet diazonium salt is slowly added thereto. The temperature of the reaction solution must not exceed 4°C during the addition process. After the addition is completed, the temperature is raised to 15-30°C and reacted for 2-4 hours (TLC is used to detect whether the reaction is complete). After the reaction is completed, the filter is filtered, and the filter cake is washed with a small amount of acetone. After vacuum drying, a brown solid crude product 1 is obtained. The filtrate is concentrated to dryness under reduced pressure, and a mixed solvent of dichloromethane, ethyl acetate, and methanol (1:1:0.5V) is added to pulp for one hour and then filtered. The filter cake is washed with a small amount of dichloromethane, and then 5V water is added to pulp for 1 hour and then filtered. The filter cake is washed with a small amount of water to obtain a reddish-brown solid crude product 2. Combine crude products 1 and 2, add dichloromethane, ethyl acetate, dioxane, tetrahydrofuran, chloroform, acetone, preferably ethyl acetate, stir and heat and reflux until all solids are dissolved, the solution volume is 25-60V / g crude product, preferably 30V / g crude product. Maintain the temperature, place a certain amount of diatomaceous earth in the suction funnel for hot filtration. Cool to -10--20℃ for crystallization for 12-18h. Filter and vacuum dry to obtain 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine finished product 1. The filtrate is concentrated to dryness, weighed and repeated the above recrystallization process to obtain 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine finished product 2. After merging, the total yield is more than 31%, the purity is more than 99.5%, and the single impurity is ≤0.5%.

[0070] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, which are intended to explain the present invention rather than to limit it.

[0071] Example 1

[0072] This embodiment provides a method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine, which comprises the following steps:

[0073] (1) Preparation of Compound 1

[0074] Dissolve 102g sodium methoxide in 800ml dichloromethane and cool to below 0℃. Mix 102g ethyl formate and 130g acetone evenly and then add dropwise to the sodium methoxide dichloromethane solution. Control the reaction temperature ≤4℃. After adding dropwise, heat to 15℃ and react for 8h. After cooling to below 5℃, add 400ml water and stir for 0.5h. Separate and collect the aqueous phase. Extract the organic phase with 200ml water. Combine the aqueous phases and place them in a reaction bottle. Add 145g cyanoacetamide, 30ml glacial acetic acid and 41ml pyridine. Heat to above 90℃ and react for 4h. Detect by TLC (DCM: MeOH = 20: 1). After the reaction is completed, cool to below 5℃, add 190ml 6N HCl to adjust the pH to about 5. Keep the temperature ≤5℃ during the addition. After adding dropwise, heat to room temperature and stir for more than 12h and filter. Wash the filter cake with a small amount of water. The wet product was added with 500 ml of ethanol and slurried for 3 h, then filtered. The filter cake was washed with a small amount of ethanol and dried in vacuo to obtain 160 g of a light yellow solid compound 1.

[0075] (2) Preparation of Compound 2

[0076] 459 ml POCl 3 Add to the reaction bottle and cool to below 0°C, add 153 g of compound 1, heat to above 95°C for 5 h, and detect by TLC (PE:EA=5:1). After the reaction is completed, cool to room temperature and concentrate most of the POCl 3 The system still has fluidity. Slowly add the distillation residue into the ice-water mixture, keep the temperature ≤5°C, continue stirring for 0.5h, filter, wash the filter cake with a small amount of water, and vacuum dry to obtain 155g of brown solid.

[0077] (3) Preparation of Compound 3

[0078] 155g of compound 2 was added to 465ml of ethylene glycol, cooled to below 0°C, 76.5g of hydrazine hydrate (98%) was slowly added dropwise to control the temperature ≤4°C, and 131g of N,N-diisopropylethylamine was added dropwise to control the temperature ≤4°C after the addition was completed. After the addition was completed, the temperature was slowly raised, and the reaction was carried out at 75-80°C for 15min; then at 85-90°C for 15min; then at 95-100°C for 3h, and detected by TLC (PE:EA=5:1). After the reaction was completed, the temperature was lowered to room temperature, 620ml of water was added, stirred for 1h, and then filtered. The filter cake was vacuum dried to obtain 134g of brown solid.

[0079] (4) Preparation of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0080] 121g of compound 3 was mixed with 968ml of tetrahydrofuran and cooled to below 0℃. 207ml of boron trifluoride ether was added dropwise, and the temperature was controlled at ≤0℃. After the addition was completed, the temperature was cooled to below -10℃. 124g of isoamyl nitrite and 242ml of tetrahydrofuran were added dropwise, and the temperature was controlled at ≤-5℃. After the addition was completed, stirring was continued for 0.5h. TLC (DCM: MeOH = 20: 1) was used for detection. After the reaction was completed, the filter was filtered and the filter cake was washed with a small amount of acetone to obtain a wet diazonium salt product. 159g of sodium iodide was weighed and dissolved in 1815ml of acetone and cooled to below 0℃. The wet diazonium salt product was slowly added to the acetone solution of sodium iodide, and the temperature was maintained at ≤4℃. After the addition was completed, the reaction was heated to room temperature for 2h, and TLC (DCM: MeOH = 20: 1) was used for detection. After the reaction was completed, the filter was filtered and the filter cake was washed with a small amount of acetone. After vacuum drying, 132g of brown solid was obtained.

[0081] The filtrate was concentrated to dryness under reduced pressure, and 100 ml of dichloromethane, 100 ml of ethyl acetate, and 50 ml of methanol were added, and the mixture was beaten for 1 hour before filtering. 500 ml of water was added to continue beating for 1 hour before filtering. After vacuum drying, 45 g of brown solid was obtained. Combined with the above 132 g, a total of 177 g was added, and 5310 ml of ethyl acetate was added. The mixture was heated to reflux to dissolve, and after hot filtration, the mixture was cooled to -10°C and stirred for crystallization for more than 12 hours. Filtered, and the filter cake was washed with a small amount of ethyl acetate. Vacuum drying gave 104 g of light yellow solid. The filtrate was concentrated to dryness under reduced pressure, and the ethyl acetate refining process was repeated. Filtered and vacuum dried to give 12 g of light yellow solid. The total yield was 37.9%, and the purity was 99.79% (as Figure 7 ), the maximum single impurity ≤0.5%.

[0082] The light yellow solid was subjected to mass spectrometry and H NMR analysis. Figure 5 and Figure 6 As shown, the structure analysis is as follows:

[0083] 1) 1 H NMR (400MHz, DMSO-d6) δ13.95(s,1H),7.78(d,J=8.2Hz,1H),7.13(d,J=8.3Hz,1H),2.65(s,3H).

[0084] 2)Exact mass for C 7 H 6 IN 3 :258.96, found m / z=259.50[M+H]+.

[0085] The reaction process and product of Example 1 were further tested as follows:

[0086] (I) Step (4) Reaction Safety

[0087] The stability of the Sandmeyer reaction and the diazonium salt intermediates involved in the reaction were investigated using thermogravimetric analyzer (TGA), differential scanning calorimeter (DSC) and synthetic reaction calorimeter.

[0088] (1) Investigation of diazonium salt stability: Weigh a diazonium salt sample (2.4 mg) and perform a TGA experiment (heating rate 10°C / min) using a thermogravimetric analyzer (TGA500 Tsushima). Figure 1 As shown by Figure 1 It can be seen that the diazonium salt intermediate can exist stably at room temperature to 50°C; when the temperature is higher than 50°C, the diazonium salt intermediate begins to gradually decompose.

[0089] (2) DSC experiment (temperature range: 0-50°C): Weigh 2.7 mg of diazonium salt and perform DSC experiment using a differential calorimeter (DSC1 Shimadzu). Figure 2 It can be seen that when the temperature rises from 0 to 50°C, the heat flow rate drops from 0.5mW to -0.7mW, which means that the diazonium salt sample has a slight heat release during this process.

[0090] (3) Investigation of the safety of Sandmeyer reaction:

[0091] The Sandmeyer reaction is carried out in two stages. In the first stage, 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine is used to generate a diazonium salt intermediate. In the second stage, sodium iodide is used to iodize the diazonium salt. The heat release of the two reaction stages was detected by a commercially available synthetic reaction calorimeter. The results are as follows: Figure 3 and Figure 4 shown.

[0092] In the first stage, Figure 3 It can be seen that when a solution of boron trifluoride ether (13 mL) is slowly added to a tetrahydrofuran solution of 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine (7.5 g), the whole process releases 2.6891 KJ of heat. After the addition is completed, when the reaction liquid reaches -10°C, a solution of isoamyl nitrite (7.7 g) in tetrahydrofuran is slowly added. The whole process releases 3.8267 KJ of heat, and there is a slight accumulation of reactants.

[0093] The results of the heat release integration in the first stage of the reaction are shown in Table 1:

[0094] Table 1 Results of thermal integration in the first stage

[0095] name Start time End Time Heat release Baseline Type Adiabatic temperature change 1 00：10：30 00：22：30 2.6891KJ Proportional to conversion 13.043K 2 01：35：12 02：06：16 3.8267KJ Proportional to conversion 17.351K

[0096] Note: 1 represents the exothermic stage of adding boron trifluoride etherate, and 2 represents the exothermic stage of adding isoamyl nitrite.

[0097] As shown in Table 1, the adiabatic temperature rise in the first stage of the Sandmeyer reaction is: ΔTad = 13.043K + 17.351K = 30.394K. According to GB / T 42300-2022 "Specifications for Safety Risk Assessment of Fine Chemical Reactions", when ΔTad < 50K, the severity level can be ignored, the thermal hazard of the reaction process is low, and the reaction safety can be ensured by relying on the cooling capacity of the reactor.

[0098] In the second stage, Figure 4 It can be seen that when the wet diazonium salt (12.5 g) is slowly added in batches to the sodium iodide (10 g) acetone solution, the whole process releases 6.4821 KJ of heat.

[0099] The results of the heat release integration in the second stage of the reaction are shown in Table 2:

[0100] Table 2 Second stage thermal integration results

[0101] name Start time End Time Heat release Baseline Type Adiabatic temperature change 1 01：21：16 02：05：58 6.4821KJ Proportional to conversion 25.749K

[0102] It can be seen from Table 2 that the adiabatic temperature rise in the second stage of the Sandmeyer reaction is: ΔTad = 25.749 K. According to GB / T42300-2022 "Specifications for Safety Risk Assessment of Fine Chemical Reactions", when ΔTad < 50 K, the severity level can be ignored, the thermal hazard of the reaction process is low, and the reaction safety can be ensured by relying on the cooling capacity of the reactor.

[0103] In summary, there is slight exotherm in both stages of the Sandmeyer reaction. Since the adiabatic temperature rise - ΔTad - in both stages is less than 50K, the thermal risk of the reaction is low and the reaction can be safely carried out by relying on the cooling capacity of the reactor.

[0104] Example 2

[0105] This embodiment provides a method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, which comprises the following steps:

[0106] (1) Preparation of Compound 1

[0107] Dissolve 91.8g sodium methoxide in 800ml dichloromethane and cool to below 5℃. Mix 91.8g ethyl formate and 130g acetone evenly and then add dropwise to the sodium methoxide dichloromethane solution. Control the reaction temperature ≤4℃. After adding dropwise, heat to 20℃ and react for 6h. After cooling to below 0℃, add 500ml water and stir for 2h. Separate and collect the aqueous phase. Extract the organic phase with 200ml water. Combine the aqueous phases and place them in a reaction bottle. Add 118g cyanoacetamide, 15ml glacial acetic acid, and 50ml pyridine. Heat to above 70℃ and react for 7h. Detect by TLC (DCM: MeOH = 20: 1). After the reaction is completed, cool to below 5℃, add 180ml concentrated HCl to adjust the pH to about 5. Keep the temperature ≤5℃ during the addition. After adding dropwise, heat to room temperature and stir for more than 15h to filter. Wash the filter cake with a small amount of water. The wet product was added with 450 ml of ethanol and slurried for 3 h, then filtered. The filter cake was washed with a small amount of ethanol and vacuum dried to obtain 141 g of a light yellow solid.

[0108] (2) Preparation of Compound 2

[0109] 420 ml POCl 3 Add to the reaction bottle and cool to below 0°C, add 132 g of the intermediate, heat to above 90°C for 6 h, and detect by TLC (PE:EA=5:1). After the reaction is completed, cool to room temperature and concentrate most of the POCl 3 The system still has fluidity. Slowly add the distillation residue into the ice-water mixture, keep the temperature ≤5°C, continue stirring for 2 hours, filter, wash the filter cake with a small amount of water, and vacuum dry to obtain 140g of brown solid.

[0110] (3) Preparation of Compound 3

[0111] 140g of compound was added to 430ml of ethylene glycol, cooled to below -5℃, 75g of hydrazine hydrate (85%) was slowly added dropwise to control the temperature ≤4℃, and 120g of diisopropylethylamine was added dropwise to control the temperature ≤4℃ after the addition was completed. After the addition was completed, the temperature was slowly raised, and the reaction was carried out at 75-80℃ for 15min; then at 85-90℃ for 15min; then at 95℃-100℃ for 3h, and detected by TLC (PE:EA=5:1). After the reaction was completed, the temperature was lowered to room temperature, 570ml of water was added, stirred for 2h, filtered, and vacuum dried to obtain 120g of brown solid.

[0112] (4) Preparation of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0113] 112g of compound 3 was mixed with 1000ml of dichloromethane and cooled to below -5°C. 185ml of boron trifluoride ether was added dropwise, and the temperature was controlled at ≤5°C. After the addition was completed, the temperature was cooled to below -5°C. 110g of isoamyl nitrite and 200ml of dichloromethane were added dropwise, and the temperature was controlled at ≤-5°C. After the addition was completed, stirring was continued for 2h. TLC (DCM: MeOH = 20: 1) was used for detection. After the reaction was completed, the filter was filtered and the filter cake was washed with a small amount of acetone to obtain a wet diazonium salt product. 142g of sodium iodide was weighed and dissolved in 1500ml of dichloromethane and cooled to below 0°C. The wet diazonium salt product was slowly added to the dichloromethane solution of sodium iodide, and the temperature was maintained at ≤4°C. After the addition was completed, the reaction was heated to room temperature for 2h and then detected by TLC (DCM: MeOH = 20: 1). After the reaction was completed, the filter was filtered and the filter cake was washed with a small amount of dichloromethane. After vacuum drying, 122g of brown solid was obtained.

[0114] The filtrate was concentrated to dryness under reduced pressure, and 150 ml of dichloromethane, 150 ml of ethyl acetate, and 50 ml of methanol were added for 1 hour of beating, and then filtered. 400 ml of water was continued for 1 hour of beating, and then filtered. After vacuum drying, 31 g of brown solid was obtained. Combined with the above 122 g, a total of 153 g, 4590 ml of dichloromethane was added, heated to reflux to dissolve, and the diatomaceous earth was hot filtered and cooled to -10 ° C and stirred for crystallization for more than 12 hours. Filter, and wash the filter cake with a small amount of dichloromethane. Vacuum drying gave 91 g of light yellow solid. The filtrate was concentrated to dryness under reduced pressure, and the dichloromethane refining process was repeated. Filter and vacuum dry to give 16 g of light yellow solid.

[0115] The total yield was 38%, the purity was 99.79% (such as Figure 8 ). The maximum single impurity is ≤0.5%.

[0116] Example 3

[0117] This example provides a method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, which is a small-scale scale-up process, and the specific steps are as follows:

[0118] (1) Preparation of Compound 1

[0119] Dissolve 1.02kg sodium methoxide in 800ml dichloromethane and cool to below 0℃. Mix 1.02kg ethyl formate and 1.3kg acetone evenly and then add dropwise to the sodium methoxide dichloromethane solution. Control the reaction temperature ≤4℃. After adding dropwise, heat to 15℃ and react for 8h. After cooling to below 5℃, add 4L water and stir for 0.5h. Separate and collect the aqueous phase. Extract the organic phase with 2L water. Combine the aqueous phases and place them in a reaction bottle. Add 1.45kg cyanoacetamide, 300ml glacial acetic acid, and 410ml pyridine. Heat to above 90℃ and react for 4h. Detect by TLC (DCM: MeOH = 20: 1). After the reaction is completed, cool to below 5℃. Add 1900ml 6N HCl to adjust the pH to about 5. Keep the temperature ≤5℃ during the addition. After adding dropwise, heat to room temperature and stir for more than 12h to filter. Wash the filter cake with a small amount of water. The wet product was added with 500 ml of ethanol and slurried for 3 hours, then filtered. The filter cake was washed with a small amount of ethanol and vacuum dried to obtain 1.305 kg of a light yellow solid compound.

[0120] (2) Preparation of Compound 2

[0121] 3.9LPOCl 3 Add to the reaction bottle and cool to below 0°C, add 1.3 kg of compound 1, heat to above 95°C for 5 h, and detect by TLC (PE:EA=5:1). After the reaction is completed, cool to room temperature and concentrate most of the POCl 3 The system still has fluidity. Slowly add the distillation residue into the ice-water mixture, keep the temperature ≤5°C, continue stirring for 0.5h, filter, wash the filter cake with a small amount of water, and vacuum dry to obtain 1.245kg of brown solid.

[0122] (3) Preparation of Compound 3

[0123] 1.2 kg of compound 2 was added to 3.6 L of ethylene glycol, cooled to below 0 ° C, 0.983 hydrazine hydrate (98%) was slowly added dropwise to control the temperature ≤ 4 ° C, and 1.02 kg of N, N-diisopropylethylamine was added dropwise to control the temperature ≤ 4 ° C. After the addition was completed, the temperature was slowly raised, and the reaction was carried out at 75-80 ° C for 15 min; then at 85-90 ° C for 15 min; then at 95 ° C to 100 ° C for 3 h, and TLC (PE: EA = 5: 1) was used for detection. After the reaction was completed, the temperature was lowered to room temperature, 4.8 L of water was added, stirred for 1 h, and then filtered. The filter cake was vacuum dried to obtain 0.955 kg of brown solid.

[0124] (4) Preparation of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0125] 0.9 kg of compound 3 was mixed with 7.2 L of tetrahydrofuran and cooled to below 0 ° C. 1.725 kg of boron trifluoride ether was added dropwise, and the temperature was controlled at ≤ 0 ° C. After the addition was completed, the temperature was cooled to below -10 ° C. 0.925 kg of a mixture of isoamyl nitrite and 1.8 L of tetrahydrofuran was added dropwise, and the temperature was controlled at ≤ -5 ° C. After the addition was completed, stirring was continued for 0.5 h. TLC (DCM: MeOH = 20: 1) was used for detection. After the reaction was completed, the filter was filtered and the filter cake was washed with a small amount of acetone to obtain a wet diazonium salt product. 1.184 kg of sodium iodide was weighed and dissolved in 13.5 L of acetone and cooled to below 0 ° C. The wet diazonium salt product was slowly added to the acetone solution of sodium iodide, and the temperature was maintained at ≤ 4 ° C. After the addition was completed, the reaction was heated to room temperature for 2 h. TLC (DCM: MeOH = 20: 1) was used for detection. After the reaction was completed, the filter was filtered and the filter cake was washed with a small amount of acetone. After vacuum drying, 1.207 kg of brown solid was obtained.

[0126] The filtrate was concentrated to dryness under reduced pressure, and 750 ml of dichloromethane, 750 ml of ethyl acetate and 380 ml of methanol were added, and the mixture was beaten for 1 hour and then filtered. 3.8 L of water was used to continue beating for 1 hour and then filtered. After vacuum drying, 269 g of brown solid was obtained. Combined with the above 1.207 kg, a total of 1.476 kg was added, and 44.28 L of ethyl acetate was added. The mixture was heated to reflux to dissolve, and after hot filtration, the mixture was cooled to -10 °C and stirred for crystallization for more than 12 hours. Filtered, the filter cake was washed with a small amount of ethyl acetate. Vacuum drying gave 960 g of light yellow solid. Purity 99.51% (such as Fig. 9 ), the maximum single impurity ≤ 0.5%. After the mother liquor was evaporated to dryness, the above purification process was repeated to obtain 188g of solid. The total yield was 32.2%.

[0127] Example 4

[0128] This example provides a method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, which is a small-scale scale-up process, and the specific steps are as follows:

[0129] (1) Scale-up 2: Preparation of compound 1

[0130] Dissolve 0.918kg sodium methoxide in 8L dichloromethane and cool to below 0-5℃. Mix 0.918kg ethyl formate and 1.3kg acetone evenly and then add dropwise to the sodium methoxide dichloromethane solution. Control the reaction temperature ≤4℃. After adding dropwise, heat to 20℃ and react for 6h. After cooling to below 0℃, add 5L water and stir for 2h. Separate and collect the aqueous phase. Extract the organic phase with 2L water. Combine the aqueous phases and place them in a reaction bottle. Add 1.18kg cyanoacetamide, 150ml glacial acetic acid, and 500ml pyridine. Heat to above 70℃ and react for 7h. Detect by TLC (DCM: MeOH = 20: 1). After the reaction is completed, cool to below 5℃. Add 0.8L concentrated HCl to adjust the pH to about 5. Keep the temperature ≤5℃ during the addition. After adding dropwise, heat to room temperature and stir for more than 15h. Filter and wash the filter cake with a small amount of water. The wet product was added with 4.5 L of ethanol and slurried for 3 h, then filtered. The filter cake was washed with a small amount of ethanol and vacuum dried to obtain 1.45 kg of light yellow solid.

[0131] (2) Preparation of Compound 2

[0132] 4.2LPOCl 3 Add to the reaction bottle and cool to below -5°C, add 1.45 kg of the intermediate, heat to above 90°C for 6 hours, and detect by TLC (PE:EA=5:1). After the reaction is completed, cool to room temperature and concentrate most of the POCl 3 The system still has fluidity. Slowly add the distillation residue into the ice-water mixture, keep the temperature ≤5°C, continue stirring for 2 hours, filter, wash the filter cake with a small amount of water, and vacuum dry to obtain 1.45 kg of brown solid.

[0133] (3) Preparation of Compound 3

[0134] 1.45 kg of compound was added to 4 L of ethylene glycol, cooled to below -5 °C, 1.18 kg of hydrazine hydrate (85%) was slowly added dropwise to control the temperature ≤ 4 °C, and 1.23 kg of diisopropylethylamine was added dropwise to control the temperature ≤ 4 °C after the addition was completed. After the addition was completed, the temperature was slowly raised, and the reaction was carried out at 75-80 °C for 15 min; then at 85-90 °C for 15 min; then at 95-100 °C for 2 h, and detected by TLC (PE: EA = 5: 1). After the reaction was completed, the temperature was lowered to room temperature, 5.8 L of water was added, stirred for 2 h, and then filtered. After vacuum drying, 1.26 kg of brown solid was obtained.

[0135] (4) Preparation of 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine

[0136] 1.26 kg of compound 3 was mixed with 8.9 L of dichloromethane and cooled to below -5 °C. 2.41 kg of boron trifluoride ether was added dropwise, and the temperature was controlled at ≤5 °C. After the addition was completed, the temperature was cooled to below -5 °C. 1.28 kg of isoamyl nitrite and 2.57 L of dichloromethane were added dropwise, and the temperature was controlled at ≤-5 °C. After the addition was completed, stirring was continued for 2 h. TLC (DCM: MeOH = 20: 1) was used for detection. After the reaction was completed, the mixture was filtered and the filter cake was washed with a small amount of acetone to obtain a wet diazonium salt product. 1.66 kg of sodium iodide was weighed and dissolved in 17.5 L of dichloromethane and cooled to below 0 °C. The wet diazonium salt product was slowly added to the dichloromethane solution of sodium iodide, and the temperature was maintained at ≤4 °C. After the addition was completed, the mixture was heated to room temperature for 2 h and then detected by TLC (DCM: MeOH = 20: 1). After the reaction was completed, the mixture was filtered and the filter cake was washed with a small amount of dichloromethane. After vacuum drying, 1.52 kg of brown solid was obtained.

[0137] The filtrate was concentrated to dryness under reduced pressure, and 175 ml of dichloromethane, 60 ml of ethyl acetate and 35 ml of methanol were added, and the mixture was beaten for 1 hour and then filtered. 470 ml of water was added to continue beating for 1 hour and then filtered. After vacuum drying, 0.36 kg of brown solid was obtained. Combined with the above 1.52 kg, a total of 1.88 kg, 56 L of dichloromethane was added, and the mixture was heated to reflux to dissolve. After hot filtration on diatomaceous earth, the temperature was lowered to -10°C and stirred for crystallization for more than 12 hours. Filter, and wash the filter cake with a small amount of dichloromethane. Vacuum drying gave 1.18 kg of light yellow solid. After evaporating the mother liquor, the above refining process was repeated to obtain 120 g of solid. The total yield was 40%, and the purity was 99.52% (such as Fig.10 ), the maximum single impurity ≤0.5%.

[0138] In summary, the advantages of the present invention are:

[0139] (1) Compared with the original process, this process route has only 4 steps, is simple to operate, greatly improves production efficiency, and is suitable for large-scale production.

[0140] (2) The process is easy to purify, the reaction conditions are safe and controllable, and the product purity can reach above 99.5%, with single impurity ≤ 0.5%.

[0141] (3) The yield is high, the total yield can reach 31%, and the highest can reach 40%, which greatly reduces the cost and improves the production efficiency. It is an ideal new process for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-b]pyridine with high promotion potential.

[0142] (4) The 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine obtained by the present invention can also be used to prepare SPH3127 related substance standards for the quality control process of SPH3127 raw materials.

[0143] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, wherein the structure of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine is: It is characterized in that The preparation method comprises: using 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine, a nitrite compound and an iodide as raw materials, and obtaining a target crude product through a Sandmeyer reaction, wherein the reaction equation is: The Sandmeyer reaction is divided into two reaction stages: in the first stage, 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine reacts with a nitrite compound to generate a diazonium salt intermediate; in the second stage, the diazonium salt intermediate reacts with an iodide to generate 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine, and the target crude product is initially separated.

2. The preparation method according to claim 1, characterized in that: The nitrite compound is selected from sodium nitrite, isoamyl nitrite, tert-butyl nitrite, and potassium nitrite; it also includes: an acidic reagent one for forming nitrous acid with the nitrite compound, the acidic reagent one is selected from hydrochloric acid, sulfuric acid, perchloric acid, fluoroboric acid, glacial acetic acid, and boron trifluoride ether complex; the iodide is selected from sodium iodide, potassium iodide, iodinated ketone, and diiodomethane.

3. The preparation method according to claim 2, characterized in that: The reaction temperature of the first stage is not higher than 4°C, preferably -5 to -20°C; and / or, the reaction solvent one of the first stage is selected from at least one of dioxane, dichloromethane, cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, and chloroform; and / or, the reaction temperature of the second stage is 15 to 30°C; and / or, the reaction solvent two of the second stage is selected from at least one of dioxane, dichloromethane, cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, tetrahydrofuran, chloroform, and acetone.

4. The preparation method according to claim 3, characterized in that: The reaction control process of the first stage comprises: mixing 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine and a nitrite compound with a reaction solvent 1 to obtain a mixed solution, adding an acidic reagent 1 to the mixed solution of 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine at a temperature below 4° C., and then further adding the mixed solution of the nitrite compound at a temperature of -5 to -20° C., and reacting for 30 to 60 minutes after the addition is completed, and separating a diazonium salt intermediate after the reaction is completed; and / or, the reaction control process of the second stage The preparation process comprises: mixing iodide with reaction solvent 2, adding the diazonium salt intermediate at below 4°C, reacting at 15-30°C for 2-4h after the addition, and separating the target crude product after the reaction is completed; preferably, the process of separating the target crude product comprises: separating the solid in the reaction solution to obtain solid 1; adding a mixed solvent of dichloromethane, ethyl acetate and methanol to the remaining separated solution after the solvent is removed, and then separating the solid, adding water to the solid part to be slurried again, separating solid 2, and the mixture of solid 1 and solid 2 is the target crude product; More preferably, the volume ratio of dichloromethane, ethyl acetate and methanol in the mixed solvent is: 1-2:1-2:0.5-1.

5. The method according to any one of claims 1 to 4, characterized in that: The preparation method further comprises: purifying the target crude product to obtain the target pure product; preferably, the purification is performed by recrystallization; more preferably, the recrystallization solvent is selected from at least one of dichloromethane, ethyl acetate, cyclohexane, n-heptane, dioxane, methyl tert-butyl ether, tetrahydrofuran, chloroform, petroleum ether, acetone, and methanol.

6. The preparation method according to claim 5, characterized in that: The process of purifying the target crude product by recrystallization to obtain the target pure product includes: Step 1), dissolving the target crude product in at least one of the following solvents: dichloromethane, ethyl acetate, cyclohexane, n-heptane, dioxane, methyl tert-butyl ether, tetrahydrofuran, chloroform, petroleum ether, acetone, methanol, and crystallizing at -10 to -20°C for 12 to 18 hours after dissolution, separating solid three, and retaining the filtrate; Step 4), the filtrate is concentrated to dryness and step 1) is repeated to obtain solid four, solid three and solid four which are pure products of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The preparation method of 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine comprises: using 2-chloro-6-methylnicotinonitrile and hydrazine hydrate as raw materials, and obtaining 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine through a cyclization reaction, and the reaction equation is: Preferably, the cyclization reaction further comprises a catalyst: N,N-diisopropylethylamine and / or triethylamine.

8. The preparation method according to claim 7, characterized in that: The control process of the cyclization reaction comprises: mixing 2-chloro-6-methylnicotinonitrile and a reaction solvent, adding hydrazine hydrate at a temperature below 4° C., and then adding N,N-diisopropylethylamine and / or triethylamine at a temperature of 0 to 10° C.; then reacting at 75 to 80° C. for 10 to 20 minutes; then reacting at 85 to 90° C. for 10 to 20 minutes; then reacting at 95 to 105° C. for 2 to 3 hours; adding water after the reaction is completed, and crystallizing at 10 to 20° C. for 1 to 2 hours, and the separated solid is 6-methyl-1H-pyrazolo[3,4-b]pyridine-3-amine; Preferably, the reaction solvent three is selected from at least one of ethylene glycol, methanol, ethanol, isopropanol, n-butanol, tert-butanol and water.

9. The preparation method according to claim 7 or 8, characterized in that: The preparation method of 2-chloro-6-methylnicotinonitrile comprises: using 2-hydroxy-3-cyano-6-methylpyridine and chloride as starting materials, converting the 2-hydroxyl group of 2-hydroxy-3-cyano-6-methylpyridine into a 2-chloro group through a chlorination reaction, and the reaction equation is: Preferably, the halide is selected from phosphorus oxychloride, thionyl chloride, or phosphorus trichloride.

10. The preparation method according to claim 9, characterized in that: The control process of the chlorination reaction comprises: mixing 2-chloro-6-methylnicotinonitrile with chloride, reacting at 90-105° C. for 5-8 hours; concentrating the reaction mixture after the reaction, adding the concentrate to an ice-water mixture at below 4° C., keeping warm and mixing for 0.5-2 hours, and separating out the solid 2-chloro-6-methylnicotinonitrile.

11. The preparation method according to claim 9 or 10, characterized in that: The preparation method of 2-hydroxy-3-cyano-6-methylpyridine comprises: using acetone, ethyl formate and cyanoacetamide as raw materials to obtain 2-hydroxy-3-cyano-6-methylpyridine through a two-step reaction, and the reaction equation is: The first step reaction is: acetone and ethyl formate undergo condensation reaction under the catalysis of an alkaline reagent to generate an enolate compound intermediate; the second step reaction is: the enolate compound intermediate reacts with cyanoacetamide to generate 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine.

12. The preparation method according to claim 11, characterized in that: The control process of the two-step reaction comprises: mixing ethyl formate and acetone, mixing an alkaline reagent with a reaction solvent, adding the mixed solution of ethyl formate and acetone to the mixed solution containing the alkaline reagent at -15 to 5°C, preferably at 0±4°C, and reacting at 10 to 25°C for 6 to 12 hours; after the reaction is completed, adding water at 5 to 15°C for at least one extraction, and retaining the aqueous phase; adding cyanoacetamide, acetic acid and pyridine to the aqueous phase, heating to reflux and keeping the temperature for 3 hours to 7 hours; after the reaction is completed, adding an acidic reagent II at 5 to 15°C to adjust the pH to 4 to 6, and separating the crude 2-hydroxy-3-cyano-6-methylpyridine; Preferably, the alkaline reagent is selected from at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide and potassium hydroxide; preferably, the acidic reagent is selected from at least one of hydrochloric acid, dilute sulfuric acid and acetic acid; Preferably, the crude 2-hydroxy-3-cyano-6-methylpyridine is slurried in at least one of the following reagents for 2 to 5 hours: methanol, ethanol, isopropanol, n-butanol, isopentanol, ethyl acetate, and dichloromethane.

13. Use of 3-iodo-6-methyl-1H-pyrazolo[3,4-B]pyridine obtained by the preparation method according to any one of claims 1 to 12 in the preparation of SPH3127 related substance standards.

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