An intermediate of 4-cppc and a method for preparing the same

Abstract

The application belongs to the field of organic chemistry and specifically relates to a preparation method of 4-(3-carboxyphenyl)-2,5-pyridine dicarboxylic acid. The method comprises the following steps: (1) performing a Suzuki coupling reaction on compound IV and compound III in a solvent under the action of a catalyst and an inorganic base; and (2) performing a hydrolytic oxidation reaction on compound II under the action of an oxidant and a base. The reaction route is shown in the following formula: wherein X is selected from F, Cl, Br or I; and R is selected from a boronic acid group or a boronic ester group, preferably a boronic acid group or a pinacol boronic ester group or a neopentyl glycol boronic ester group or a methyl boronic ester group. According to the application, compound I is prepared from simple and readily available starting materials through a new intermediate compound II, and has the advantages of high purity, good yield, low cost, mild reaction conditions, short reaction time and simple post-treatment and purification.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a preparation method of 4-(3-carboxyphenyl)-2,5-pyridinedicarboxylic acid (4-CPPC). BACKGROUND

[0002] Dopachrome tautomerase (D-DT, or macrophage migration inhibitory factor-2 (MIF-2)) is a multifunctional protein with immunomodulatory properties and has been shown to have pathogenic roles in inflammation and cancer, associated with activation of the cell surface receptor CD74. Current studies have determined that 4-CPPC is the first small molecule inhibitor of D-DT that is potent, reversible, and selective, blocking the potency of D-DT-induced CD74 activation. In addition, 4-CPPC can be used to reveal previously unrecognized functions of MIF-1 in biological systems expressing MIF-1 and MIF-2, enriching our understanding of the MIF protein family and providing new mechanistic insights that can be used to develop potent and selective pharmacological modulators of MIF-2. However, there are few reports on the preparation of 4-CPPC, and the present application provides a new synthesis process which is simple in operation, mild in reaction conditions, simple in post-treatment and purification, high in yield, low in cost and suitable for industrial production. SUMMARY

[0003] The present application provides an industrial 4-CPPC preparation method which is easy to realize and simple, low in cost, mild in reaction conditions, simple in post-treatment and high in yield.

[0004] The present application provides a preparation method of compound II 4-CPPC intermediate, which comprises the following step (1):

[0005] (1) Suzuki coupling reaction of compound IV and compound III in a solvent under the action of a catalyst and an inorganic base, wherein the structural formula of compound IV is:

[0006]

[0007] The structure of compound III is:

[0008]

[0009] The structure of compound II is:

[0010]

[0011] wherein X is selected from F, Cl, Br or I; R is selected from boronic acid group or boronic ester group, preferably boronic acid group or pinacol boronic ester group or neopentyl glycol boronic ester group or methyl boronic ester group.

[0012] In a certain preferred embodiment, in the process for preparing the compound II, certain conditions and operations are defined as follows, and the definitions of the conditions and operations not mentioned are as described in any of the embodiments of the present application (hereinafter referred to as "in a certain preferred embodiment").

[0013] In step (1), the conditions, the types of reagents and the amounts of reagents for the Suzuki coupling reaction can be conventional conditions, types of reagents and amounts of reagents in the art, and the present application is preferably as follows.

[0014] In a certain preferred embodiment, in step (1), the molar ratio of the compound IV to the compound III is 1 : (1-5); for example, 1 : (1-1.5).

[0015] In a certain preferred embodiment, in step (1), the solvent is selected from an organic solvent or water; for example, the organic solvent is selected from one or any combination of 1,4-dioxane, toluene, tetrahydrofuran, isopropanol or ethanol.

[0016] In a certain preferred embodiment, in step (1), the mass-volume ratio (g:mL) of the compound IV to the solvent is 1 : (5-20); for example, 1 : (10-20).

[0017] In a certain preferred embodiment, in step (1), the volume ratio of the organic solvent to water is (1-10) : (1-3); for example, the volume ratio of the organic solvent to water is 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 9:2, 7:2, 5:2, 3:2 or 1:2.

[0018] In a certain preferred embodiment, in step (1), the catalyst is selected from at least one of Pd(PPh3)4, Pd(dppf)Cl2, 1,1'-bis(di-tert-butylphosphino) ferrocene dichloropalladium, PdCl2, Pd(dba)2, Pd2(dba)3, Pd(TFA)2 or PdCl2(PPh3)2.

[0019] In a certain preferred embodiment, in step (1), the molar ratio of the compound IV to the catalyst is 1 : (1-0.1); for example, 1 : (1-0.05).

[0020] In a certain preferred embodiment, in step (1), the inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, potassium fluoride or cesium fluoride.

[0021] In a preferred embodiment, the molar ratio of compound IV to inorganic base in step (1) is 1:(1-5); for example, 1:(1-2).

[0022] In a preferred embodiment, the reaction temperature in step (1) is 70–100°C, for example, 70–90°C.

[0023] In a preferred embodiment, the reaction progress of the Suzuki coupling reaction in step (1) can be monitored using conventional monitoring methods in the art (e.g., TLC or LC-MS), generally with the disappearance of compound IV or the cessation of reaction as the reaction endpoint. The reaction time can be 2–7 h, for example 2–5 h, or even 3 h.

[0024] In a preferred embodiment, after the Suzuki coupling reaction in step (1) is completed, the following post-processing steps are included. The post-processing steps are conventional post-processing operations for such reactions in the art, such as cooling, filtration, rinsing, evaporation, and purification.

[0025] The cooling can be reduced to room temperature; the elution solution can be ethyl acetate; the purification can be performed by silica gel column chromatography, and the eluent can be petroleum ether and ethyl acetate in a volume ratio of 3:1.

[0026] A second aspect of the present invention provides a method for preparing compound I 4-CPPC, wherein the method for preparing compound I includes the following step (2):

[0027] (2) Compound II undergoes hydrolysis and oxidation reactions under the action of oxidizing agents and bases. The structural formula of compound II is:

[0028]

[0029] The structure of compound I is as follows:

[0030]

[0031] The oxidant is potassium permanganate, and the molar ratio of potassium permanganate to compound II is (5-10):1.

[0032] In a preferred embodiment, compound I in step (2) is prepared by a one-pot method using compound II under the action of an oxidant and a base.

[0033] In a preferred embodiment, the molar ratio of compound II to oxidant in step (2) is 1:(1-10); for example, 1:(1-5).

[0034] In a preferred embodiment, the base in step (2) is selected from inorganic bases, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0035] In a certain preferred embodiment, the progress of the hydroxylation reaction in step (2) is monitored by using the conventional monitoring methods in the art (such as TLC or LC-MS) to take the disappearance of the compound II or no longer reaction as the end point of the reaction. The reaction time can be 1-24 h, for example, 1-20 h, and further for example, 3-16 h.

[0036] In a certain preferred embodiment, after the completion of the hydroxylation reaction in step (2), the following post-treatment steps are further included, which are the post-treatment operations of the reaction in the art, for example, one or more of the following: filtration, washing, adjusting pH with hydrochloric acid, beating, and drying, to obtain a product with high purity.

[0037] The washing solution can be water; the hydrochloric acid for adjusting pH can be 6 mol / L hydrochloric acid to adjust pH = 2; and the beating can be beating with methanol.

[0038] In a certain preferred embodiment, the preparation method of the compound I in step (2) further includes the preparation method of the compound II, which includes the preparation method of the compound II in the first aspect.

[0039] The third aspect of the present application provides a compound II 4-CPPC intermediate, which has the following structure:

[0040]

[0041] The fourth aspect of the present application provides the use of a compound I 4-CPPC in inhibiting the activity of D-DT.

[0042] Without departing from the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, that is, to obtain each preferred example of the present application.

[0043] The reagents and raw materials used in the present application are commercially available.

[0044] The present application provides a preparation method of a compound I, which is prepared from simple and readily available starting materials through a new intermediate compound II by ingenious design, and has the advantages of high purity, good yield, low cost, mild reaction conditions, short reaction time, and simple post-treatment and purification. The present application has low cost and simple operation, and the two-step yield is more than 80%, which is increased by nearly 50% compared with the two-step yield of 23% in the prior art Biophysical Journal (2023), 122(7), 1268-1276. The obtained product has good properties and a purity of ≥99.6%. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 It is the nuclear magnetic hydrogen spectrum of the compound II in Example 1.

[0046] Figure 2 is the HPLC spectrum of Example 2 Compound I.

[0047] Figure 3 is the HPLC spectrum of Example 2 Compound I. DETAILED DESCRIPTION

[0048] Example 1

[0049]

[0050] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonyl phenyl boronic acid, 20 mL of dioxane / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of Pd(PPh3)4 after blowing argon for 5 min. Then, after blowing argon for another 5 min, seal the tube, and react in an oil bath at 90 °C for 3 h. After TLC spot plate monitoring, the reaction is completed. After cooling to room temperature, filter through celite, elute with ethyl acetate, spin dry, and purify through a silica gel column (PE:EA = 3:1) to obtain 1.5 g of the product, Compound II, with a yield of 97.6%. NMR 1 H NMR (400 MHz, DMSO-d6) hydrogen spectrum is shown in Figure 1 .

[0051] Example 2

[0052]

[0053] In a 100 mL round-bottom flask, add 1.5 g (5.3 mmol, 1 eq) of the product from the previous step, 30 mL of water, 4.5 g (28.5 mmol, 5.4 eq) of potassium permanganate, and 10 mL of 10% aqueous NaOH solution. Reflux overnight, and then monitor the reaction completion by TLC spot plate. After cooling to room temperature, filter through celite, rinse the filter cake with water, adjust the pH of the filtrate to 2 with 6 mol / L hydrochloric acid, and then filter. The filter cake is slurried with methanol, filtered, and dried to obtain 1.28 g of the pure product, with a yield of 85% and a purity of 99.6%. NMR 1 H NMR (400 MHz, DMSO-d6) hydrogen spectrum is shown in Figure 2 . Figure 3 HPLC spectrum is shown in

[0054] Comparative Example 1

[0055] In a sealed tube, add 1.9 g (10 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 2.2 g (12 mmol, 1.2 eq) of 3-methoxycarbonyl phenyl boronic acid, 2.8 g (20 mmol, 2 eq) of potassium carbonate, DME / H2O (40 / 10 mL), and then add 0.05 eq of tetrakis(triphenylphosphine)palladium under argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 85 °C for 3 h. After cooling, filter, and then extract the filtrate with 50 mL of EA twice, and then wash the organic phase with water and saturated brine, and then dry over anhydrous sodium sulfate, and then rotary evaporate to dryness, and then purify on a silica gel column to obtain 2.1 g of the product, with a yield of 72%.

[0056] Comparative Example 2

[0057] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonyl phenyl boronic acid, 20 mL of a dioxane / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of Pd(dppf)Cl2 under argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90 °C for 3 h, and then cool to room temperature, and then filter through celite, and then elute with ethyl acetate, and then rotary evaporate to dryness, and then purify on a silica gel column (PE:EA = 3:1) to obtain 1.3 g of compound II, with a yield of 84.4%.

[0058] Comparative Example 3

[0059] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonyl phenyl boronic acid, 20 mL of a dioxane / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of Pd(OAc)2 under argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90 °C for 3 h, and then cool to room temperature, and then filter through celite, and then elute with ethyl acetate, and then rotary evaporate to dryness, and then purify on a silica gel column (PE:EA = 3:1) to obtain 0.8 g of compound II, with a yield of 52%.

[0060] Comparative Example 4

[0061] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonyl phenyl boronic acid, 20 mL of dioxane / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of PdCl2(PPh3)2 after argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90°C for 3 h. After TLC spotting plate shows that the raw material is completely reacted, cool to room temperature, and then filter through celite, elute with ethyl acetate, spin dry, and then purify through a silica gel column (PE:EA = 3:1) to obtain 1.4 g of compound II, with a yield of 91%.

[0062] Comparative Example 5

[0063] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonyl phenyl boronic acid, 20 mL of dioxane / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of PdCl2(PPh3)2 after argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90°C for 3 h. After TLC spotting plate shows that the raw material is completely reacted, cool to room temperature, and then filter through celite, elute with ethyl acetate, spin dry, and then purify through a silica gel column (PE:EA = 3:1) to obtain 1.4 g of compound II, with a yield of 91%.

[0064] Comparative Example 6

[0065] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonyl phenyl boronic acid, 20 mL of dioxane / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of PdCl2(PPh3)2 after argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90°C for 3 h. After TLC spotting plate shows that the raw material is completely reacted, cool to room temperature, and then filter through celite, elute with ethyl acetate, spin dry, and then purify through a silica gel column (PE:EA = 3:1) to obtain 1.4 g of compound II, with a yield of 91%.

[0066] Comparative Example 7

[0067] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methylnicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonylphenylboronic acid, 20 mL of acetonitrile / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of Pd(PPh3)4 after argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90°C for 3 h. After TLC spotting plate shows that the starting material has been consumed, cool to room temperature, and then filter through celite, and then elute with acetonitrile, and then dry by rotary evaporation, and then purify by silica gel column (PE:EA = 3:1) to obtain 0.7 g of compound II, with a yield of 45.5%.

[0068] Comparative Example 8

[0069] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methylnicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonylphenylboronic acid, 20 mL of N-methylpyrrolidone / water (4:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of Pd(PPh3)4 after argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90°C for 3 h. After TLC spotting plate shows that the starting material has been consumed, cool to room temperature, and then filter through celite, and then elute with ethyl acetate, and then add 100 mL of water, and then extract 3 times with 30 mL of ethyl acetate each time, and then dry the organic phase over anhydrous sodium sulfate, and then dry by rotary evaporation, and then purify by silica gel column (PE:EA = 3:1) to obtain 0.8 g of compound II, with a yield of 52%.

[0070] Comparative Example 9

[0071] In a sealed tube, add 1 g (5.4 mmol, 1 eq) of 4-chloro-6-methylnicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) of 3-methoxycarbonylphenylboronic acid, 20 mL of water, 1.5 g (10.9 mmol, 2 eq) of potassium carbonate, and then add 0.05 eq of Pd(PPh3)4 after argon blowing for 5 min, and then seal the tube, and then react in an oil bath at 90°C for 3 h. After TLC spotting plate shows no reaction, the reaction fails.

[0072] Comparative Example 10

[0073] In a sealed tube, add 1 g (5.4 mmol, 1 eq) 4-chloro-6-methyl nicotinic acid methyl ester, 1.5 g (8.3 mmol, 1.5 eq) 3-methoxycarbonyl phenyl boronic acid, 20 mL dioxane / water (3:1 by volume) solution, 1.5 g (10.9 mmol, 2 eq) potassium carbonate, and then add 0.05 eq Pd(PPh3)4 after blowing argon for 5 min, and then blow argon for another 5 min, seal the tube, and then react in an oil bath at 90 ℃ for 3 h. TLC spot plate shows that the raw material is completely reacted. After cooling to room temperature, filter with celite, elute with ethyl acetate, spin dry, and then purify with a silica gel column (PE:EA = 3:1) to obtain 1.4 g of compound II with a yield of 91.1%.

Claims

1. A method for preparing intermediate compound II, characterized in that, The preparation method of compound II includes the following steps (1): (1) Compound IV and Compound III undergo a Suzuki coupling reaction in a solvent under the action of a catalyst and an inorganic base. The structural formula of Compound IV is as follows: The structure of compound III is as follows: The structure of compound II is as follows: Wherein, X is selected from F, Cl, Br or I; R is selected from borate group or borate ester group; In step (1), the catalyst is selected from at least one of Pd(PPh3)4, Pd(dppf)Cl2, 1,1'-bis(di-tert-butylphosphine)ferrocene dichloropalladium, PdCl2, Pd(dba)2, Pd2(dba3), Pd(TFA)2 or PdCl2(PPh3)2; The reaction in step (1) is carried out in an organic solvent and water; the organic solvent is selected from one or any combination of 1,4-dioxane, toluene, tetrahydrofuran, isopropanol or ethanol; the volume ratio of the organic solvent to water in step (1) is 4:1 or 3:

1. In step (1), the inorganic base is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, potassium fluoride, or cesium fluoride.

2. The preparation method according to claim 1, characterized in that, The boronic acid ester group is pinacol boronic acid ester group, neopentyl glycol boronic acid ester group, or methyl boronic acid ester group.

3. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound IV to compound III is 1:(1~5).

4. The preparation method according to claim 3, characterized in that, In step (1), the molar ratio of compound IV to compound III is 1:(1~1.5).

5. The preparation method according to claim 1, characterized in that, In step (1), the mass-to-volume ratio of compound IV to solvent, g: mL, is 1: (5~20).

6. The preparation method according to claim 5, characterized in that, In step (1), the mass-to-volume ratio of compound IV to solvent, g: mL, is 1: (10~20).

7. According to the preparation method of claim 1, the molar ratio of compound IV to catalyst in step (1) is 1:(1~0.1).

8. According to the preparation method of claim 1, the molar ratio of compound IV to catalyst in step (1) is 1:(1~0.05).

9. The preparation method according to any one of claims 1 to 8, wherein the molar ratio of compound IV to inorganic base in step (1) is 1:(1 to 5), and the reaction temperature is 70 to 100°C.

10. The preparation method according to claim 9, wherein the molar ratio of compound IV to inorganic base in step (1) is 1:(1~2), and the reaction temperature is 70~90℃.

11. A method for preparing compound I, characterized in that, The preparation method of compound I includes the following steps (2): (2) Compound II undergoes hydrolysis and oxidation under the action of an oxidizing agent and a base. The structural formula of compound II is: The structure of compound I is as follows: The oxidant is potassium permanganate, and the molar ratio of potassium permanganate to compound II is (5~10):

1.

12. The preparation method according to claim 11, characterized in that, In step (2), compound I is prepared by compound II in a one-pot process under the action of an oxidant and an alkali.

13. The preparation method according to claim 11, characterized in that, The alkali in step (2) is an inorganic alkali.

14. The preparation method according to claim 13, characterized in that, The inorganic base is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide.

15. The preparation method according to any one of claims 11 to 14, characterized in that, The reaction in step (2) also includes simple post-processing: filtration, rinsing, pH adjustment with hydrochloric acid, pulping, and drying.

16. An intermediate compound II, characterized in that, The structure is as follows: 。

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