Preparation method of inositol hexaphosphate kinase inhibitor

Abstract

The invention provides a preparation method of an inositol hexaphosphate kinase inhibitor, and provides a preparation method of a compound shown as a formula F. The reaction formula is shown as the following: # imgabs0 #, in which R1 is OMs, OTf, OTs, Cl, Br or I; comprising the following steps: (1) carrying out carbonyl insertion reaction on a compound A, ethanol and a CO source in the presence of a palladium catalyst and alkali to generate a compound B; (2) performing deprotection reaction on the compound B in a hydrochloric acid solution to generate a compound C; (3) in the presence of a reducing agent and an acid activator, carrying out reductive amination reaction on the compound C and a compound D to generate a compound E; (4) carrying out hydrolysis reaction on the compound E under an alkali condition to generate a compound F; the preparation method disclosed by the invention is simple and convenient to operate, high in yield, good in product quality, mild in reaction condition, easily available in raw materials, short in reaction time and suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to a preparation method of an phytate kinase (IP6K) inhibitor, and belongs to the technical field of medicine and chemistry. Background Art

[0002] Phytate kinase (IP6K) is a key enzyme in the synthesis of inositol pyrophosphate, which is mainly responsible for adding a β-phosphate group to the 5-position of IP6 to form 5-IP7. Phytate kinase (IP6K) phosphorylates inositol hexaphosphate (IP6) to produce inositol pyrophosphate 5-IP7, which plays an important role in glucose homeostasis, metabolic diseases, fatty liver, chronic kidney disease, neurodevelopment and psychiatric disorders.

[0003] WO2022125524A1 discloses the following representative compounds, with the following structural formula:

[0004]

[0005] Patent WO2022125524A1 of Lieber Institute Inc. discloses the use of 1'-(tert-butyloxycarbonyl)-2-oxospiro[indole-3,4'-piperidine]-5-carboxylic acid raw material, which is expensive and the penultimate reductive amination reaction takes 4 days, which is not conducive to industrial scale-up. Summary of the invention

[0006] In order to solve the technical problems in the above reports, the present invention provides a method for synthesizing an inhibitor of phytate kinase (IP6K).

[0007] In order to overcome the defects of the prior art and achieve the requirements of commercial scale-up production, the present invention adopts the following preferred technical solutions:

[0008] The first aspect of the present invention provides a method for preparing a compound of formula F, and the reaction formula is as follows:

[0009]

[0010] wherein R1 is OMs, OTf, OTs, Cl, Br or I;

[0011] The steps include:

[0012] Step (1): Compound A reacts with ethanol and a CO source in the presence of a palladium catalyst and a base to produce compound B;

[0013] Step (2): Compound B is subjected to a deprotection reaction in a hydrochloric acid solution to generate compound C;

[0014] Step (3): In the presence of a reducing agent and an acid activating agent, compound C and compound D undergo a reductive amination reaction to generate compound E;

[0015] Step (4): Compound E is hydrolyzed under alkaline conditions to generate compound F.

[0016] As a further improvement of the present invention, including but not limited to, the CO source of the reaction in step (1) is selected from carbon monoxide or a substance that can provide a carbonyl group for the reaction, and can be selected from one of Co2(CO)8, W(CO)6, and formate, preferably carbon monoxide;

[0017] As a further improvement of the present invention, including but not limited to, the base in the reaction of step (1) is selected from one or more organic bases such as triethylamine, diisopropylethylamine, pyridine, sodium ethoxide, and sodium tert-butoxide; or one or more inorganic bases such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably triethylamine;

[0018] As a further improvement of the present invention, including but not limited to, the catalyst for the reaction in step (1) is selected from one or a combination of Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, PdCl2, Pd(dba)2, preferably Pd(dppf)Cl2;

[0019] As a further improvement of the present invention, including but not limited to, the molar ratio of compound A to base in step (1) is 1:(1-5), preferably 1:(3.5-4.5);

[0020] As a further improvement of the present invention, including but not limited to, the molar ratio of compound A to catalyst in step (1) is 1:(0.01-0.5), preferably 1:(0.05-0.15);

[0021] As a further improvement of the present invention, including but not limited to, the volume amount of ethanol in step (1) mL is 5 to 30 times the mass amount of compound A g, preferably 6 to 25 times;

[0022] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (1) is 80 to 130° C., preferably 115 to 125° C.;

[0023] As a further improvement of the present invention, including but not limited to, the reaction time of step (1) is 9 to 32 hours, preferably 15 to 25 hours.

[0024] As a further improvement of the present invention, including but not limited to, the hydrochloric acid solution in step (2) is selected from one or a combination of concentrated hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably hydrochloric acid / dioxane solution;

[0025] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (2) is 10 to 40° C., preferably 15 to 30° C.;

[0026] As a further improvement of the present invention, including but not limited to, the reaction time of step (2) is 1 to 6 hours, preferably 2 to 5 hours.

[0027] As a further improvement of the present invention, including but not limited to, the reaction in step (3) comprises the following steps: in an organic solvent, and in the presence of a reducing agent and an acid activator, compound C and compound D undergo a reductive amination reaction to generate compound E;

[0028] As a further improvement of the present invention, including but not limited to, the molar ratio of compound C to compound D in step (3) is 1:(1-3), preferably 1:(1.5-2.5);

[0029] As a further improvement of the present invention, including but not limited to, the molar ratio of compound C to the reducing agent in step (3) is 1:(1-5), preferably 1:(3.5-4.5);

[0030] As a further improvement of the present invention, including but not limited to, the reducing agent in step (3) is selected from one or more of sodium borohydride, sodium acetate borohydride, sodium cyanoborohydride, and lithium borohydride, preferably sodium acetate borohydride;

[0031] As a further improvement of the present invention, including but not limited to, the molar ratio of the reducing agent to the acid activating agent in step (3) is 1:(1-5), preferably 1:(2-3.5);

[0032] As a further improvement of the present invention, including but not limited to, the acid activator in step (3) is selected from one of hydrochloric acid, acetic acid, formic acid, and trifluoroacetic acid, preferably acetic acid;

[0033] As a further improvement of the present invention, including but not limited to, the organic solvent in step (3) is selected from one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, dichloroethane, acetone, and dimethyl sulfoxide, preferably dichloroethane;

[0034] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (3) is 10 to 40° C., preferably 15 to 30° C.;

[0035] As a further improvement of the present invention, including but not limited to, the reaction time of step (3) is 5 to 24 hours, preferably 10 to 16 hours.

[0036] As a further improvement of the present invention, including but not limited to, the inventors use sodium acetate borohydride as a reducing agent, and when reacting in chloroform, it takes 4 days to react, and the raw materials still remain, and the yield is about 45%. However, when using the conditions of the present invention, sodium acetate borohydride is used as a reducing agent and acetic acid is used as an acid activator, when reacting in dichloroethane, the reaction can be completed in only 14 hours, and the yield can reach 60%, which solves the problem of long reaction time in the prior art and is easy to realize large-scale industrial production.

[0037] As a further improvement of the present invention, including but not limited to, the step (4) comprises the following steps: compound E is subjected to a hydrolysis reaction in a solvent in the presence of LiOH to generate compound F;

[0038] As a further improvement of the present invention, including but not limited to, the molar ratio of compound E to LiOH in step (4) is 1:(1-8), preferably 1:(3-5);

[0039] As a further improvement of the present invention, including but not limited to, the solvent in step (4) is at least one of an ether solvent, a halogenated alkane solvent, a ketone solvent, an aromatic hydrocarbon solvent, a nitrile solvent, an ester solvent, an alcohol solvent, a sulfone solvent, an amide solvent, and water, preferably an ether solvent, or a mixed solvent of an alcohol solvent and water; the ether solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran, and dioxane, preferably tetrahydrofuran; the halogenated alkane solvent may be one or more of dichloromethane, dichloroethane, and chloroform, preferably dichloromethane; the ketone solvent may be acetone; the aromatic hydrocarbon solvent is preferably toluene; the nitrile solvent is preferably acetonitrile; the ester solvent may be one or more of ethyl acetate, ethyl formate, and isopropyl acetate, preferably ethyl acetate; the sulfone solvent is preferably dimethyl sulfoxide; the amide solvent is preferably N,N-dimethylformamide; the alcohol solvent is one or more of methanol, ethanol, and isopropanol, preferably methanol; further preferably tetrahydrofuran, a mixed solvent of methanol and water;

[0040] As a further improvement of the present invention, including but not limited to, the solvent in step (4) is selected from a mixed solvent of tetrahydrofuran, methanol and water, and further the volume ratio of tetrahydrofuran: methanol: water is 2:1:1;

[0041] As a further improvement of the present invention, including but not limited to, the reaction temperature of step (4) is 30 to 70° C., preferably 50 to 60° C.;

[0042] As a further improvement of the present invention, including but not limited to, the reaction time of step (4) is 5 to 24 hours, preferably 12 to 16 hours.

[0043] As further improvements of the present invention, including but not limited to, when the inventors use NaOH for hydrolysis, the ethyl ester of the present invention generates 25% by-products and the yield is only 32%; however, when the LiOH conditions of the present invention are used for hydrolysis, the yield can be increased by about 60%, which greatly reduces the production cost and is conducive to industrial production.

[0044] The second aspect of the present invention provides a compound C having the following structure:

[0045]

[0046] The present invention has the following beneficial effects:

[0047] (1) The synthesis route of the present invention is simple, the preparation method is easy to operate, the yield is high, the product quality is good, the reaction conditions are mild, the raw materials are easily available, the reaction time is short, and it is suitable for industrial scale-up production.

[0048] (2) When the inventors use the LiOH hydrolysis conditions of the present invention, the yield can be increased by more than 60%, greatly reducing the production cost.

[0049] (3) The inventors use a reducing agent (e.g., sodium acetate borohydride) and an acid activator (e.g., acetic acid) system to carry out a reductive amination reaction, which can greatly shorten the reaction time and achieve a yield of 60%, which is at least 15% higher than the yield of the prior art. The problem of the prior art of long reaction time is also solved, making it easier to achieve large-scale industrial production. DETAILED DESCRIPTION

[0050] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0051] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0052] Example 1

[0053] Synthesis of compound B:

[0054]

[0055] Compound A (5 g, 13.1 mmol) was added to an autoclave, ethanol (100 mL) was added to dissolve, and then Pd(dppf)Cl2 (0.96 g, 1.3 mmol) and TEA (5.3 g, 52.5 mmol) were added in sequence. The gas was replaced three times by decompression method, CO (4 MPa) was charged, and the temperature was raised to 120°C for reaction for 24 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was rinsed with ethanol several times, the filtrate was concentrated and purified to obtain a white solid compound B (4.5 g, yield 91.6%).

[0056] Example 2

[0057] Synthesis of compound C:

[0058]

[0059] Compound B (3 g, 8.0 mmol) was added to 4 mol / L HCl / dioxane (50 mL) and stirred at room temperature for 3 hours. Solids precipitated during the reaction. The reaction solution was directly evaporated to dryness. The residue was slurried with methyl tert-butyl ether, filtered with suction, and the filter cake was dried to obtain a white solid compound C (2.37 g, yield 95.2%).

[0060] Example 3

[0061] Synthesis of compound E:

[0062]

[0063] Compound C (2.37 g, 7.6 mmol) was added to dichloroethane (250 mL), followed by compound D (2.67 g, 15.3 mmol), sodium acetate borohydride (6.47 g, 30.5 mmol), and acetic acid (5.2 mL, 91.5 mmol), and the mixture was reacted at room temperature for 14 hours. An appropriate amount of saturated NaHCO3 solution was added to the reaction solution, and the mixture was extracted with dichloroethane, concentrated, and purified to obtain compound E (2 g, yield 60.5%) as a white solid.

[0064] Example 4

[0065] Synthesis of compound F:

[0066]

[0067] Compound E (2 g, 4.6 mmol) was dissolved in 200 mL THF: MeOH: H2O at a volume ratio of 2: 1: 1, and LiOH (442.1 mg, 18.5 mmol) was added, and the mixture was reacted at 55°C for 14 hours. The reaction solution was evaporated to dryness, H2O was added to the residue, and the mixture was washed with ethyl acetate, the aqueous phase was filtered, 2M HCl was added to the filtrate, pH = 1, and the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was dried to obtain a white solid compound F (1.7 g, yield 90.9%, purity 98.95%).

[0068] Comparative Example 1

[0069] Synthesis of compound E:

[0070]

[0071] C (2.37 g, 7.6 mmol) was added to 250 mL CHCl3, and D (2.66 g, 15.2 mmol) and sodium acetate borohydride (6.47 g, 30.5 mmol) were added in sequence and stirred at room temperature for 4 days. An appropriate amount of 5% Na2CO3 solution was added to the reaction solution, and the mixture was extracted with CHCl3 until there was no product in the aqueous phase. The organic phase was dried, evaporated, and purified to obtain white solid compound E (1.5 g, yield 45.4%).

[0072] Comparative Example 2

[0073] Synthesis of compound F:

[0074]

[0075] Compound E (2 g, 4.6 mmol) was dissolved in MeOH (200 mL), 1 mol / L NaOH (23 mL) solution was added, and the mixture was reacted at 55°C for 22 hours. Methanol was evaporated from the reaction solution, H2O was added to the residue, and the mixture was washed with ethyl acetate, the aqueous phase was filtered, 2 mol / L HCl was added to the filtrate, pH = 1, the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was dried to obtain a white solid compound F (600 mg, yield 32%).

Claims

1. A method for preparing a compound of formula F, the reaction formula is as follows: in, R1 is OMs, OTf, OTs, Cl, Br or I; The steps include: Step (1): Compound A reacts with ethanol and a CO source in the presence of a palladium catalyst and a base to produce compound B; Step (2): Compound B is subjected to a deprotection reaction in a hydrochloric acid solution to generate compound C; Step (3): In the presence of a reducing agent and an acid activating agent, compound C and compound D undergo a reductive amination reaction to generate compound E; Step (4): Compound E is hydrolyzed under alkaline conditions to generate compound F.

2. The preparation method according to claim 1, characterized in that: The CO source of the step (1) reaction is selected from carbon monoxide or a substance that can provide a carbonyl group for the reaction, and can be selected from one of Co2(CO)8, W(CO)6, and formate, preferably carbon monoxide.

3. The preparation method according to any one of claims 1 or 2, characterized in that: The preparation method of step (1) satisfies one or more of the following conditions: 1) The base used in the reaction of step (1) is selected from one or more organic bases such as triethylamine, diisopropylethylamine, pyridine, sodium ethoxide, sodium tert-butoxide; or sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, One or more of lithium hydroxide, sodium hydroxide, potassium hydroxide and other inorganic bases, preferably triethylamine; 2) The catalyst for the reaction in step (1) is selected from one or a combination of Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, PdCl2, Pd(dba)2, preferably Pd(dppf)Cl2; 3) In step (1), the molar ratio of compound A to base is 1:(1-5), preferably 1:(3.5-4.5); 4) In step (1), the molar ratio of compound A to catalyst is 1:(0.01-0.5), preferably 1:(0.05-0.15); 5) The volume of ethanol in step (1) is 5 to 30 times, preferably 6 to 25 times, the mass of compound A. 6) The reaction temperature of step (1) is 80-130°C, preferably 115-125°C; 7) The reaction time of step (1) is 9 to 32 hours, preferably 15 to 25 hours.

4. The preparation method according to claim 1, characterized in that: The preparation method of step (2) satisfies one or more of the following conditions: The hydrochloric acid solution in step (2) is selected from one or a combination of concentrated hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, and hydrochloric acid / methanol solution, preferably a hydrochloric acid / dioxane solution; The reaction temperature of step (2) is 10-40°C, preferably 15-30°C; The reaction time of step (2) is 1 to 6 hours, preferably 2 to 5 hours.

5. The preparation method according to claim 1, characterized in that: The preparation method of step (3) satisfies one or more of the following conditions: The reaction in step (3) comprises the following steps: in an organic solvent and in the presence of a reducing agent and an acid activator, compound C and compound D undergo a reductive amination reaction to generate compound E; The molar ratio of compound C to compound D in step (3) is 1:(1-3), preferably 1:(1.5-2.5); The molar ratio of compound C to the reducing agent in step (3) is 1:(1-5), preferably 1:(3.5-4.5); The reducing agent in step (3) is selected from one or more of sodium borohydride, sodium acetate borohydride, sodium cyanoborohydride, and lithium borohydride, preferably sodium acetate borohydride; The molar ratio of the reducing agent to the acid activating agent in step (3) is 1:(1-5), preferably 1:(2-3.5); The acid activator in step (3) is selected from hydrochloric acid, acetic acid, formic acid, and trifluoroacetic acid, preferably acetic acid; The organic solvent in step (3) is selected from one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, dichloroethane, acetone, and dimethyl sulfoxide, preferably dichloroethane; The reaction temperature in step (3) is 10 to 40°C, preferably 15 to 30°C; The reaction time of step (3) is 5 to 24 hours, preferably 10 to 16 hours.

6. The preparation method according to claim 1, characterized in that: The step (4) comprises the following steps: Compound E is subjected to a hydrolysis reaction in a solvent in the presence of LiOH to generate Compound F.

7. The preparation method according to claim 6, characterized in that: The molar ratio of compound E to LiOH in step (4) is 1:(1-8), preferably 1:(3-5).

8. The preparation method according to claim 6, characterized in that: The solvent in step (4) is at least one of an ether solvent, a halogenated alkane solvent, a ketone solvent, an aromatic hydrocarbon solvent, a nitrile solvent, an ester solvent, an alcohol solvent, a sulfone solvent, an amide solvent, and water, preferably an ether solvent, or a mixed solvent of an alcohol solvent and water; the ether solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran, and dioxane, preferably tetrahydrofuran; the halogenated alkane solvent may be one or more of dichloromethane, dichloroethane, and chloroform, preferably dichloromethane; the ketone solvent may be acetone; the aromatic hydrocarbon solvent is preferably toluene; the nitrile solvent is preferably acetonitrile; the ester solvent may be one or more of ethyl acetate, ethyl formate, and isopropyl acetate, preferably ethyl acetate; the sulfone solvent is preferably dimethyl sulfoxide; the amide solvent is preferably N,N-dimethylformamide; the alcohol solvent is one or more of methanol, ethanol, and isopropanol, preferably methanol; and tetrahydrofuran, a mixed solvent of methanol and water is further preferred; And / or, preferably, the solvent in step (4) is selected from a mixed solvent of tetrahydrofuran, methanol and water, and further the volume ratio of tetrahydrofuran:methanol:water is 2:1:

1.

9. The preparation method according to claim 8, characterized in that: The reaction temperature in step (4) is 30-70°C, preferably 50-60°C; And / or, preferably, the reaction time of step (4) is 5 to 24 hours, preferably 12 to 16 hours.

10. A compound C having the following structure:

Images