A pyrrolo[2,3-b]pyridine intermediate compound, and a preparation method and application thereof

Abstract

The application discloses a pyrrolo[2,3-b]pyridine intermediate compound, a preparation method and application thereof. The preparation method in the application takes 5-bromo-1H-pyrrolo[2,3-b]pyridine as a starting material, and 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine is prepared through iodine substitution, oxidation and bromine substitution reaction in a high yield. The reaction path of the preparation method is relatively simple, the active hydrogen of the pyrrole ring does not need to be protected, the atomic economy is improved, the use of dangerous lithium reagents such as sec-butyllithium is avoided, the reaction condition is mild, the danger in the scale-up production process is effectively reduced, and the production economy is improved. The reaction condition is mild, and the reaction step is simple, so the application has a good industrialization prospect. The 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine prepared in the application can be applied to the preparation of a small molecule JAK kinase inhibitor.

Description

Technical Field

[0001] This invention relates to a method for preparing pharmaceutical compound intermediates, and more particularly to a pyrrolo[2,3-b]pyridine intermediate compound, its preparation method, and its application. Background Technology

[0002] The JAK (Janus kinases) family of protein kinases is a class of non-receptor tyrosine kinases found within cells. JAKs are pivotal in the signaling processes of various cytokine receptors, playing a crucial role in cell proliferation and apoptosis. Therefore, JAKs are important targets for many emerging diseases. JAK kinase inhibitors achieve their biological activities, such as anti-cancer and immunomodulatory effects, by targeting and inhibiting JAKs. Currently, small molecule JAK inhibitors are used to treat autoimmune rheumatoid arthritis, atopic dermatitis, systemic lupus erythematosus, and ulcerative colitis; they are also used to treat myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelometra with myelofibrosis, multiple myeloma, idiopathic myelofibrosis, chronic myelodysplastic syndrome, and myelodysplastic syndrome; and they can be used to treat inflammatory diseases of the central nervous system, including epilepsy, dementia, Parkinson's disease, and depression.

[0003] Chinese patent CN 113292561A discloses a pyrrolo[2,3-b]pyridine derivative with JAK kinase inhibitory activity. This derivative uses compound 1a as a starting material, employing triisopropylsilyl ester to substituted and protect the active hydrogen atom of the pyrrole ring, followed by meta-substitution of the nitrogen atom on the pyridine ring using sec-butyllithium and iodine, and finally removal of the triisopropylsilyl ester to obtain compound 4a. The final product is then synthesized using compound 4a as an intermediate. The synthetic route of compound 4a is as follows:

[0004]

[0005] In the above synthetic method, to prevent the active hydrogen in compound 1a from participating in the subsequent iodine substitution reaction, the active hydrogen of the pyrrole ring must first be substituted and protected with triisopropylsilyl, a complex and cumbersome step. Furthermore, this method requires harsh conditions for the iodine substitution step, necessitating not only a reaction at a low temperature of -78°C but also the addition of sec-butyllithium as a reactant, which is a highly flammable and hazardous lithium reagent. Therefore, the dangerous and demanding reaction conditions limit the large-scale industrial application of this method. Summary of the Invention

[0006] Objective of this invention: The objective of this invention is to provide a novel intermediate compound for the preparation of pyrrolo[2,3-b]pyridine derivatives. Another objective of this invention is to propose a method for preparing this intermediate compound, overcoming the problems of harsh conditions and complex steps in existing synthetic routes. A third objective of this invention is to propose the application of this intermediate compound in the preparation of small molecule JAK kinase inhibitors, addressing the problem of how to use this intermediate compound to prepare pyrrolo[2,3-b]pyridine derivatives.

[0007] Technical solution: The present invention provides a pyrrolo[2,3-b]pyridine intermediate compound or a pharmaceutically acceptable salt thereof, the chemical structure of which is shown in formula (I):

[0008]

[0009] To obtain the above-mentioned pyrrolo[2,3-b]pyridine intermediate compound, the present invention provides a method for preparing the compound of formula (I), comprising the following steps:

[0010]

[0011] The molar ratio of the oxidant to compound III is 1-3 eq; the molar ratio of the acid anhydride to compound IV is 1-3 eq; and the molar ratio of the brominating agent to compound IV is 1-3 eq.

[0012] The synthetic strategy of this invention targets the para-bromine substitution of the N atom on the pyridine ring of pyrrolo[2,3-b]pyridine, rather than the halogen substitution at the meta-position of the N atom. This change in strategy allows the oxidation or bromine substitution reaction to proceed under mild conditions. The mild reaction conditions ensure that the active hydrogen on the pyrrole ring does not participate in the subsequent oxidation and bromine substitution reactions, thus eliminating the need for pre-substitution protection of the active hydrogen on the pyrrole ring.

[0013] Preferably, the molar ratio of the oxidant to compound III is 1.2-2 eq; the molar ratio of the acid anhydride to compound IV is 1.2-2 eq; and the molar ratio of the brominating agent to compound IV is 1-2 eq.

[0014] Preferably, the oxidant includes one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, and urea peroxide; the acid anhydride includes one or more of methanesulfonic anhydride, trifluoromethanesulfonic anhydride, 4-toluenesulfonic anhydride, and methanesulfonyl chloride; and the brominating agent includes one or more of potassium bromide, sodium bromide, lithium bromide, tetramethylammonium bromide, and tetrabutylammonium bromide.

[0015] Preferably, the specific method for synthesizing compound IV from compound III is as follows: compound III, oxidant and solvent are reacted at -10-50℃ and then filtered to obtain compound IV; the solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether dioxane; the liquid-to-solid ratio of the solvent to compound III is 5-30 mL / g.

[0016] Preferably, the method for preparing compound I from compound IV is as follows: compound IV, acid anhydride, brominating agent and solvent are reacted at 0-60°C, followed by water crystallization, pH adjusted to alkaline, and filtered to obtain compound I; the solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether dioxane; the liquid-to-solid ratio of the solvent to compound IV is 5-30 mL / g.

[0017] Furthermore, compound III is prepared from compound II by the following steps:

[0018]

[0019] The molar ratio of the catalyst to compound II is 0.05-1.0 eq; the molar ratio of the ligand to compound II is 0.05-1.0 eq; and the molar ratio of the iodide to compound II is 2-5 eq.

[0020] Preferably, the catalyst comprises one or more of copper, cuprous oxide, copper thiophene-2-carboxylate (I), cuprous iodide, copper acetylacetonate, cuprous bromide, and cuprous chloride; the ligand comprises L-proline, 2-pyrroleic acid, 1,10-phenanthroline, N,N-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, 8-hydroxyquinoline, 8-hydroxyquinoline-N-oxide, n-butylamine, 3,4,7,8-tetramethyl-1 The iodinated derivative comprises one or more of the following: 10-phenanthroline, 2-isobutyrylcyclohexanone, N,N-diethylethylenediamine, N,N'-dimethylethylenediamine, 2-methyl-8-hydroxyquinoline, (R,R)-(-)-N,N′-dimethyl-1,2-cyclohexanediamine, (1R,2R)-(-)-1,2-cyclohexanediamine, and L-cysteine; the iodinated derivative comprises one or more of the following: sodium iodide, potassium iodide, tetramethylammonium iodide, and tetrabutylammonium iodide.

[0021] Preferably, the method for preparing compound III from compound II is as follows: reacting compound II, catalyst, ligand, iodide and solvent at 100-200°C, cooling, and adding water to crystallize to obtain intermediate III; the solvent includes one or more of N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, n-butanol, and sulfolane, and the liquid-to-solid ratio of the solvent to compound II is 3-10 mL / g.

[0022] This invention utilizes the pyrrolo[2,3-b]pyridine intermediate compound obtained by the above method to prepare JAK kinase inhibitors, such as 1-cyclohexyl-2-(pyridin-4-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine.

[0023] Beneficial Effects: Compared with existing technologies, this invention has the following significant advantages: This invention not only avoids the use of hazardous lithium reagents such as sec-butyllithium, but also uses mild reaction conditions, eliminating the need for ultra-low temperature reactions, effectively reducing the risks during scale-up production and improving production economy. The reaction pathway of this invention is relatively simple, requiring no protection of the active hydrogen atom of the pyrrole ring, thus improving atom economy. This invention achieves high yield of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine through mild reaction conditions and simple reaction steps, demonstrating good industrialization prospects. Attached Figure Description

[0024] Figure 1 The 1H NMR spectrum of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1;

[0025] Figure 2 The carbon NMR spectrum of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1;

[0026] Figure 3 The mass spectrum of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1;

[0027] Figure 4 The HPLC chromatogram of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown.

[0028] Figure 5 The 1H NMR spectrum of compound III 5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1;

[0029] Figure 6 The mass spectrum of compound III 5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1;

[0030] Figure 7 The HPLC chromatogram of compound III 5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1;

[0031] Figure 8 The 1H NMR spectrum of compound IV 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide obtained in Example 1;

[0032] Figure 9 The mass spectrum of compound IV 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide obtained in Example 1;

[0033] Figure 10 The HPLC chromatogram of compound IV 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide obtained in Example 1 is shown. Detailed Implementation

[0034] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0035] Example 1: A pyrrolo[2,3-b]pyridine intermediate compound, the structure of which is as follows:

[0036]

[0037] The preparation method of this pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0038] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0039]

[0040] In a reaction flask, starting material II (5-bromo-1H-pyrrolo[2,3-b]pyridine, 5 g, 25.4 mmol), cuprous iodide (0.484 g, 2.54 mmol), N,N'-dimethylethylenediamine (0.224 g, 2.54 mmol), sodium iodide (7.61 g, 50.8 mmol) and 50 mL of sulfolane were added. The mixture was reacted at 110–120 °C for 6–10 hours. After the reaction was completed, the temperature was lowered to 40–60 °C, 500 mL of water was added to induce crystallization, and the mixture was cooled, filtered, and purified to obtain compound III (5-iodo-1H-pyrrolo[2,3-b]pyridine) 5.0 g, with a yield of 80%.

[0041] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0042]

[0043] Compound III (5-iodo-1H-pyrrolo[2,3-b]pyridine, 8 g, 32.8 mmol), m-chloroperoxybenzoic acid (8.5 g, 49.2 mmol) and 160 mL of ethyl acetate were added to a reaction flask and reacted at 0–10 °C for 15–20 h. After the reaction was completed, sodium sulfite aqueous solution (0.087 g / mL) was added, stirred, concentrated to remove ethyl acetate, and triethylenediamine aqueous solution (0.11 g / mL) was added, stirred, filtered, and 7 g of compound IV (5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide) was obtained, with a yield of 82%.

[0044] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0045]

[0046] Compound IV (5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide, 4 g, 15.4 mmol), p-toluenesulfonic anhydride (15 g, 46.1 mmol), tetrabutylammonium bromide (9.9 g, 30.8 mmol), and 40 mL of N,N-dimethylformamide were added to a reaction flask and reacted at 25–35 °C for 2–4 hours. After the reaction was completed, water was added to crystallize the mixture, and the crystals were filtered to obtain 3.7 g of the pyrrolo[2,3-b]pyridine intermediate compound shown in Formula I, with a yield of 75%.

[0047] Example 2: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0048] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0049]

[0050] In a reaction flask, starting material II (5-bromo-1H-pyrrolo[2,3-b]pyridine, 10 g, 50.8 mmol), cuprous iodide (4.8 g, 25.4 mmol), 8-hydroxyquinoline (3.7 g, 25.4 mmol), sodium iodide (15.2 g, 101.6 mmol) and 50 mL of n-butanol were added. The reaction was carried out at 110–120 °C for 6–10 hours. After the reaction was completed, the temperature was lowered to 20–30 °C, 500 mL of water was added to induce crystallization, the temperature was lowered, and the mixture was filtered to obtain compound III (5-iodo-1H-pyrrolo[2,3-b]pyridine) 10.8 g, with a yield of 87%.

[0051] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0052]

[0053] Compound III, 5-iodo-1H-pyrrolo[2,3-b]pyridine (5 g, 20.5 mmol), m-chloroperoxybenzoic acid (6 g, 34.8 mmol) and 160 mL of isopropyl acetate were added to a reaction flask and reacted at 0–10 °C for 15–20 h. After the reaction was completed, sodium sulfite aqueous solution (0.087 g / mL) was added, stirred, concentrated to remove isopropyl acetate, and triethylenediamine aqueous solution (0.11 g / mL) was added, stirred, and filtered to obtain 4.5 g of compound IV (5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide), with a yield of 83%.

[0054] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0055]

[0056] Compound IV (5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide, 4.5 g, 17.3 mmol), methanesulfonic anhydride (6 g, 34.6 mmol), tetrabutylammonium bromide (8.3 g, 25.9 mmol), and 45 mL of N,N-dimethylformamide were added to a reaction flask. The reaction was carried out at 25–35 °C for 2–4 hours. After the reaction was completed, water was added to crystallize and purified to obtain 4.4 g of the pyrrolo[2,3-b]pyridine compound shown in Formula I, with a yield of 78%.

[0057] Example 3: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0058] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0059] Everything else is the same as in Example 2, except that:

[0060] The catalyst was replaced by copper instead of cuprous iodide; the molar ratio of copper to compound II was 0.05 eq.

[0061] The ligand was replaced by L-proline at a molar ratio of 1.0 eq with that of compound II;

[0062] The iodinated derivative is equivalently replaced by potassium iodide instead of sodium iodide; the molar ratio of this iodinated derivative to compound II is 2 eq;

[0063] The solvent was replaced by N-methylpyrrolidone instead of n-butanol; the liquid-to-solid ratio of this solvent to compound II was 3 ml / g.

[0064] The reaction temperature in step one is 100-110℃, and after the reaction is complete, the temperature is lowered to 30-40℃. Yield: 63%.

[0065] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0066] Everything else is the same as in Example 2, except that:

[0067] The oxidant was replaced by hydrogen peroxide instead of m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 1 eq.

[0068] The solvent was replaced by dichloromethane instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 5 ml / g.

[0069] The reaction temperature in step two is -10 to 0°C. Yield: 70%.

[0070] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0071] Everything else is the same as in Example 2, except that:

[0072] The acid anhydride was replaced by a trifluoromethanesulfonic anhydride; the molar ratio of this acid anhydride to compound IV was 1 eq.

[0073] The brominating agent was replaced by potassium bromide instead of tetrabutylammonium bromide; the molar ratio of this brominating agent to compound IV was 1 eq.

[0074] The solvent was replaced by N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 5 ml / g.

[0075] The reaction temperature in step three is 0-10℃. Yield: 33%.

[0076] Example 4: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0077] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0078] Everything else is the same as in Example 2, except that:

[0079] The catalyst was replaced by cuprous oxide instead of cuprous iodide; the molar ratio of cuprous oxide to compound II was 1.0 eq.

[0080] The ligand was replaced by 2-pyrrolic acid, which was equivalent to 8-hydroxyquinoline; the molar ratio of this ligand to compound II was 1.0 eq.

[0081] The iodinated derivative is equivalently replaced by tetramethylammonium iodide with sodium iodide; the molar ratio of this iodinated derivative to compound II is 5 eq;

[0082] The solvent was replaced by dimethyl sulfoxide instead of n-butanol; the liquid-to-solid ratio of this solvent to compound II was 10 ml / g.

[0083] The reaction temperature in step one is 120–130°C, and after the reaction is complete, the temperature is lowered to 50–60°C. Yield: 69%.

[0084] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0085] Everything else is the same as in Example 2, except that:

[0086] The oxidant was replaced by urea peroxide, which was equivalent to m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 3 eq.

[0087] The solvent was replaced by ethyl acetate instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 30 ml / g.

[0088] The reaction temperature in step two is 10-20℃. Yield: 81%.

[0089] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0090] Everything else is the same as in Example 2, except that:

[0091] The acid anhydride was replaced by 4-toluenesulfonic anhydride; the molar ratio of this acid anhydride to compound IV was 3 eq;

[0092] The brominating agent was replaced by sodium bromide, which was equivalent to tetrabutylammonium bromide; the molar ratio of this brominating agent to compound IV was 3 eq.

[0093] The solvent was replaced by N-methylpyrrolidone instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 30 ml / g.

[0094] The reaction temperature in step three is 10-20℃. Yield: 68%.

[0095] Example 5: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0096] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0097] Everything else is the same as in Example 2, except that:

[0098] The catalyst was replaced by copper iodide with copper thiophene-2-carboxylate (I); the molar ratio of copper thiophene-2-carboxylate (I) to compound II was 0.1 eq;

[0099] The ligand was replaced by 1,10-phenanthroline at a molar ratio of 0.1 eq with compound II.

[0100] The iodide is replaced by an equivalent of sodium iodide with tetrabutylammonium iodide; the molar ratio of this iodide to compound II is 3 eq;

[0101] The solvent was replaced by n-butanol with N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound II was 5 ml / g.

[0102] The reaction temperature in step one is 130–140°C, and after the reaction is complete, the temperature is lowered to 70–80°C. Yield: 74%.

[0103] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0104] Everything else is the same as in Example 2, except that:

[0105] The oxidant was replaced by hydrogen peroxide instead of m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 1.2 eq.

[0106] The solvent was replaced by n-hexane instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 10 ml / g.

[0107] The reaction temperature in step two is 30-40℃. Yield: 57%.

[0108] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0109] Everything else is the same as in Example 2, except that:

[0110] The acid anhydride was replaced by methanesulfonic anhydride with methanesulfonyl chloride; the molar ratio of this acid anhydride to compound IV was 1.2 eq;

[0111] The brominating agent was replaced by an equivalent of tetrabutylammonium bromide with lithium bromide; the molar ratio of this brominating agent to compound IV was 2 eq;

[0112] The solvent was replaced by dimethyl sulfoxide instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 8 ml / g.

[0113] The reaction temperature in step three is 20–30°C. Yield: 73%.

[0114] Example 6: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0115] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0116] Everything else is the same as in Example 2, except that:

[0117] The catalyst was replaced by copper acetylacetonate instead of cuprous iodide; the molar ratio of copper acetylacetonate to compound II was 0.5 eq.

[0118] The ligand was replaced by n-butylamine at a molar ratio of 0.5 eq with compound II;

[0119] The iodide is replaced by an equivalent of sodium iodide with tetrabutylammonium iodide; the molar ratio of this iodide to compound II is 2.5 eq;

[0120] The solvent was replaced by n-butanol with N,N-dimethylacetamide; the liquid-to-solid ratio of this solvent to compound II was 5 ml / g.

[0121] The reaction temperature in step one is 140–150°C, and after the reaction is complete, the temperature is lowered to 60–70°C. Yield: 56%.

[0122] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0123] Everything else is the same as in Example 2, except that:

[0124] The oxidant was replaced by urea peroxide, which was equivalent to m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 2 eq.

[0125] The solvent was replaced by cyclohexane instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 20 ml / g.

[0126] The reaction temperature in step two is 40-50℃. Yield: 67%.

[0127] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0128] Everything else is the same as in Example 2, except that:

[0129] The acid anhydride was replaced by methanesulfonic anhydride with methanesulfonyl chloride; the molar ratio of this acid anhydride to compound IV was 2 eq;

[0130] The brominating agent was replaced by tetramethylammonium bromide; the molar ratio of this brominating agent to compound IV was 1.5 eq.

[0131] The solvent was replaced by ethylene glycol dimethyl ether instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 15 ml / g.

[0132] The reaction temperature in step three is 30–40°C. Yield: 69%.

[0133] Example 7: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0134] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0135] Everything else is the same as in Example 2, except that:

[0136] The catalyst was replaced by cuprous bromide; the molar ratio of cuprous bromide to compound II was 0.3 eq.

[0137] The ligand was replaced by 2-isobutyrylcyclohexanone, with 8-hydroxyquinoline being replaced by 2-isobutyrylcyclohexanone; the molar ratio of this ligand to compound II was 0.4 eq.

[0138] The iodinated derivative is equivalently replaced by tetramethylammonium iodide with sodium iodide; the molar ratio of this iodinated derivative to compound II is 2.5 eq;

[0139] The solvent was replaced by dioxane instead of n-butanol; the liquid-to-solid ratio of this solvent to compound II was 8 ml / g.

[0140] The reaction temperature in step one is 150–160°C, and after the reaction is complete, the temperature is lowered to 40–50°C. Yield: 37%.

[0141] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0142] Everything else is the same as in Example 2, except that:

[0143] The molar ratio of the oxidant m-chloroperoxybenzoic acid to compound III is 2 eq;

[0144] The solvent was replaced by cyclohexane instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 15 ml / g.

[0145] The reaction temperature in step two is 30-35℃. Yield: 85%.

[0146] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0147] Everything else is the same as in Example 2, except that:

[0148] The acid anhydride was replaced by 4-toluenesulfonic anhydride; the molar ratio of this acid anhydride to compound IV was 1.8 eq.

[0149] The brominating agent was replaced by tetrabutylammonium bromide; the molar ratio of this brominating agent to compound IV was 1.5 eq.

[0150] The solvent was replaced by ethylene glycol monomethyl ether dioxane instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 11 ml / g.

[0151] The reaction temperature in step three is 40–50°C. Yield: 71%.

[0152] Example 8: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0153] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0154] Everything else is the same as in Example 2, except that:

[0155] The catalyst was replaced by cuprous chloride instead of cuprous iodide; the molar ratio of cuprous chloride to compound II was 0.2 eq.

[0156] The ligand was replaced by (R,R)-(-)-N,N′-dimethyl-1,2-cyclohexanediamine; the molar ratio of this ligand to compound II was 0.3 eq.

[0157] The iodinated derivative is equivalently replaced by sodium iodide with tetramethylammonium iodide; the molar ratio of this iodinated derivative to compound II is 4 eq;

[0158] The solvent was replaced by dimethyl sulfoxide instead of n-butanol; the liquid-to-solid ratio of this solvent to compound II was 4 ml / g.

[0159] The reaction temperature in step one is 160–170°C, and after the reaction is complete, the temperature is lowered to 35–45°C. Yield: 43%.

[0160] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0161] Everything else is the same as in Example 2, except that:

[0162] The oxidant was replaced by hydrogen peroxide instead of m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 2.5 eq.

[0163] The solvent was replaced by n-hexane instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 25 ml / g.

[0164] The reaction temperature in step two is 45-50℃. Yield: 68%.

[0165] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0166] Everything else is the same as in Example 2, except that:

[0167] The acid anhydride was replaced by a trifluoromethanesulfonic acid anhydride; the molar ratio of this acid anhydride to compound IV was 1.3 eq.

[0168] The brominating agent was replaced by sodium bromide, which was equivalent to tetrabutylammonium bromide; the molar ratio of sodium bromide to compound IV was 1.4 eq.

[0169] The solvent was replaced by ethylene glycol monomethyl ether dioxane instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 25 ml / g.

[0170] The reaction temperature in step three is 50–60°C. Yield: 43%.

[0171] Example 9: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0172] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0173] Everything else is the same as in Example 2, except that:

[0174] The catalyst was replaced by copper acetylacetonate instead of cuprous iodide; the molar ratio of copper acetylacetonate to compound II was 0.8 eq.

[0175] The ligand was replaced by (1R,2R)-(-)-1,2-cyclohexanediamine; the molar ratio of this ligand to compound II was 0.5 eq.

[0176] The iodinated derivative is equivalently replaced by sodium iodide with tetramethylammonium iodide; the molar ratio of this iodinated derivative to compound II is 3 eq;

[0177] The solvent was replaced by dioxane instead of n-butanol; the liquid-to-solid ratio of this solvent to compound II was 5 ml / g.

[0178] The reaction temperature in step one is 190–200℃, and after the reaction is complete, the temperature is lowered to 55–65℃. Yield: 37%.

[0179] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0180] Everything else is the same as in Example 2, except that:

[0181] The oxidant was replaced by urea peroxide, which was equivalent to m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 1.6 eq.

[0182] The solvent was replaced by ethyl acetate instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 10 ml / g.

[0183] The reaction temperature in step two is 10-20℃. Yield: 73%.

[0184] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0185] Everything else is the same as in Example 2, except that:

[0186] The acid anhydride was replaced by trifluoromethanesulfonic anhydride; the molar ratio of this acid anhydride to compound IV was 1.9 eq.

[0187] The brominating agent was replaced by tetrabutylammonium bromide; the molar ratio of this brominating agent to compound IV was 1.1 eq.

[0188] The solvent was replaced by ethylene glycol dimethyl ether instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 20 ml / g.

[0189] The reaction temperature in step three is 35–40°C. Yield: 42%.

[0190] Example 10: The preparation method of the pyrrolo[2,3-b]pyridine intermediate compound is as follows:

[0191] Step 1: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine

[0192] Everything else is the same as in Example 2, except that:

[0193] The catalyst was replaced by copper iodide with copper thiophene-2-carboxylate (I); the molar ratio of copper thiophene-2-carboxylate (I) to compound II was 0.5 eq;

[0194] The ligand may be replaced by any one of N,N-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, 8-hydroxyquinoline-N-oxide, 3,4,7,8-tetramethyl-1,10-phenanthroline, N,N-diethylethylenediamine, N,N'-dimethylethylenediamine, 2-methyl-8-hydroxyquinoline, or L-cysteine; the optional molar ratio of the ligand to compound II is 0.6 eq.

[0195] The molar ratio of sodium iodide to compound II is 3 eq;

[0196] The solvent was replaced by an equivalent of n-butanol with N-methylpyrrolidone; the liquid-to-solid ratio of this solvent to compound II was 5 ml / g.

[0197] The reaction temperature in step one is 180–190°C, and after the reaction is complete, the temperature is lowered to 65–70°C. Yield: 63%.

[0198] Step 2: Preparation of 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide

[0199] Everything else is the same as in Example 2, except that:

[0200] The oxidant was replaced by hydrogen peroxide instead of m-chloroperoxybenzoic acid; the molar ratio of this oxidant to compound III was 1.4 eq.

[0201] The solvent was replaced by dichloromethane instead of isopropyl acetate; the liquid-to-solid ratio of this solvent to compound III was 20 ml / g.

[0202] The reaction temperature in step two is 20-30℃. Yield: 76%.

[0203] Step 3: Preparation of 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine

[0204] Everything else is the same as in Example 2, except that:

[0205] The acid anhydride was replaced by 4-toluenesulfonic anhydride; the molar ratio of this acid anhydride to compound IV was 2 eq;

[0206] The brominating agent was replaced by sodium bromide, which was equivalent to tetrabutylammonium bromide; the molar ratio of this brominating agent to compound IV was 2 eq.

[0207] The solvent was replaced by N-methylpyrrolidone instead of N,N-dimethylformamide; the liquid-to-solid ratio of this solvent to compound IV was 15 ml / g.

[0208] The reaction temperature in step three is 25–35°C. Yield: 71%.

[0209] Example 11: Using compound I prepared in Example 1 as the starting material, compound 1-cyclohexyl-2-(pyridin-4-yl)-1,6-dihydrodipyrrolo[2,3-b:2',3'-d]pyridine was prepared according to the preparation method disclosed in Example 39 of Chinese Patent CN113292561A, with a yield of 36%.

[0210] Structural confirmation of compounds I, III, and IV:

[0211] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The units (ppm) are given. NMR measurements were performed using a Bruker Avance NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard. Other starting materials disclosed in this invention can be synthesized according to methods known in the art or derived from commercially available products.

[0212] The 1H NMR spectrum of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown in the appendix. Figure 1 : 1 H NMR (400MHz, DMSO-d6) δ12.19 (s, 1H), 8.50 (s, 1H), 7.60 (t, J = 3.0 Hz, 1H), 6.43 (t, J = 2.7 Hz, 1H).

[0213] The carbon NMR spectrum of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown in the appendix. Figure 2 : 13 C NMR (101MHz, DMSO-d6) δ149.40,147.13,130.47,128.70,123.43,101.26,90.95.

[0214] The mass spectrum of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown in the appendix. Figure 3 MS(ESI): 322.6(M+H) + .

[0215] The 1H NMR spectrum of intermediate compound III 5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown in the appendix. Figure 5 : 1H NMR (400MHz, DMSO-d6) δ11.82 (s, 1H), 8.34 (dd, J = 11.6, 2.0 Hz, 2H), 7.52-7.45 (m, 1H), 6.41 (dd, J = 3.5, 1.7 Hz, 1H).

[0216] The mass spectrum of intermediate compound III 5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown in the appendix. Figure 6 MS(ESI): 244.8(M+H) + .

[0217] The 1H NMR spectrum of the intermediate compound IV 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide obtained in Example 1 is attached. Figure 7 : 1 H NMR (400MHz, DMSO-d6) δ 12.64 (s, 1H), 8.41 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 3.3 Hz, 1H), 6.52 (d, J = 3.3 Hz, 1H).

[0218] The mass spectrum of the intermediate compound IV 5-iodo-1H-pyrrolo[2,3-b]pyridine-7-oxide obtained in Example 1 is attached. Figure 8 MS(ESI): 260.7(M+H) + 520.5 (2M+H) + 542.5 (2M+Na) + .

[0219] The HPLC chromatogram of the final product 4-bromo-5-iodo-1H-pyrrolo[2,3-b]pyridine obtained in Example 1 is shown in the appendix. Figure 4 The purity is 98.01%.

[0220] After structural confirmation, the compounds obtained in Examples 2-9 were found to have the same structure as compounds I, III, and IV in Example 1.

Claims

1. A method for preparing a pyrrolo[2,3-b]pyridine intermediate compound, characterized in that, Includes the following steps: ， The molar ratio of the oxidant to compound III is 1-3 eq; the molar ratio of the acid anhydride to compound IV is 1-3 eq; the molar ratio of the brominating agent to compound IV is 1-3 eq; the oxidant is one or more of hydrogen peroxide, m-chloroperoxybenzoic acid, and urea peroxide; the acid anhydride is one or more of methanesulfonic anhydride, trifluoromethanesulfonic anhydride, and 4-toluenesulfonic anhydride; and the brominating agent is one or more of potassium bromide, sodium bromide, lithium bromide, tetramethylammonium bromide, and tetrabutylammonium bromide.

2. The method for preparing the pyrrolo[2,3-b]pyridine intermediate compound according to claim 1, characterized in that, The molar ratio of the oxidant to compound III is 1.2-2 eq; the molar ratio of the acid anhydride to compound IV is 1.2-2 eq; and the molar ratio of the brominating agent to compound IV is 1-2 eq.

3. The method for preparing the pyrrolo[2,3-b]pyridine intermediate compound according to claim 1, characterized in that, The method for preparing compound I from compound IV is as follows: compound IV, acid anhydride, brominating agent and solvent are reacted at 0-60℃, followed by water crystallization, pH adjusted to alkaline, and filtered to obtain compound I; the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and ethylene glycol dimethyl ether; the liquid-to-solid ratio of the solvent to compound IV is 5-30 mL / g.

4. The method for preparing the pyrrolo[2,3-b]pyridine intermediate compound according to claim 1, characterized in that, Compound III was prepared from compound II, as follows: ， The molar ratio of the catalyst to compound II is 0.05-1.0 eq; the molar ratio of the ligand to compound II is 0.05-1.0 eq; the molar ratio of the iodide to compound II is 2-5 eq; the catalyst is one or more of copper, cuprous oxide, copper thiophene-2-carboxylate (I), cuprous iodide, copper acetylacetonate, cuprous bromide, and cuprous chloride; the ligand is L-proline, 2-pyrrolic acid, 1,10-phenanthroline, N,N-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, 8-hydroxyl... The iodinated derivative is one or more of the following: methylquinoline, 8-hydroxyquinoline-N-oxide, n-butylamine, 3,4,7,8-tetramethyl-1,10-phenanthroline, 2-isobutyrylcyclohexanone, N,N-diethylethylenediamine, N,N'-dimethylethylenediamine, 2-methyl-8-hydroxyquinoline, (R,R)-(-)-N,N′-dimethyl-1,2-cyclohexanediamine, (1R,2R)-(-)-1,2-cyclohexanediamine, and L-cysteine; the iodinated derivative is one or more of sodium iodide, potassium iodide, tetramethylammonium iodide, and tetrabutylammonium iodide.

5. The method for preparing the pyrrolo[2,3-b]pyridine intermediate compound according to claim 4, characterized in that, The method for preparing compound III from compound II is as follows: compound II, catalyst, ligand, iodide and solvent are reacted at 100-200℃ and then cooled, and water is added to crystallize and obtain intermediate III; the solvent is one or more of N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, n-butanol and sulfolane, and the liquid-to-solid ratio of the solvent to compound II is 3-10 mL / g.

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