Preparation method of pyrimidinopyrrole compound

Abstract

The invention relates to a preparation method of a pyrimidopyrrole compound, and particularly discloses a preparation method of a compound as shown in a formula I. The preparation method comprises a method 1 or a method 2, and the method 1 comprises the following steps: in a solvent, in the presence of alkoxide of alkali metal, reacting a compound 1 with a compound 2 or hydrochloride of the compound 2 to generate the compound as shown in the formula I; the method 2 comprises the following steps: in a solvent, in the presence of a copper salt catalyst, a ligand and an alkaline reagent, reacting a compound 1 and a compound 2 or hydrochloride of the compound 2 to generate the compound as shown in the formula I, the preparation method is mild in reaction condition and simple and convenient to operate, the pyrimidine and pyrrole compound can be obtained through one-step reaction, and the preparation method is more suitable for industrial large-scale production of # imgabs0 #.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compounds and relates to a method for preparing pyrimidopyrrole compounds. Background Art

[0002] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (ester) or 2-thiomethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (ester) is an important intermediate in pharmaceutical synthesis and can be used to synthesize two CDK4 / 6 inhibitor drugs, Trilaciclib and Ribociclib. Among them, Trilaciclib (trade name Cosela) is the world's first innovative drug developed by G1 that is administered before chemotherapy and has a full-line bone marrow protection effect; Ribociclib (trade name Kisqali) is a drug developed by Novartis for the treatment of breast cancer. At present, these two new drugs have been approved for marketing in China and have broad application prospects. Therefore, it is very necessary to develop a simple and efficient route. The pyrimidine pyrrole compounds involved in the invention of this application can be used to prepare Trilaciclib and Ribociclib at the same time, which is undoubtedly of great value.

[0003] At present, only two documents report the preparation methods of pyrimidopyrrole compounds involved in the present invention. One is the method disclosed by Nanjing Yaoshi Technology Co., Ltd. in patent CN110016024A (Route 1), and the other is the method developed by Sanofi in patent WO2022263472A1 (Route 2). It is not difficult to find that the existing methods are relatively long, with medium yields, and some steps have harsh conditions (such as the need to -100 o C reaction), and is therefore not suitable for large-scale production.

[0004] Summary of the invention

[0005] In view of the defects of the preparation method of pyrimidopyrrole compounds in the prior art, such as a long route and harsh reaction conditions, the present invention provides a preparation method of pyrimidopyrrole compounds. The preparation method has mild reaction conditions, simple and convenient operation, and pyrimidopyrrole compounds can be obtained in one-step reaction, which is more suitable for industrial scale-up production.

[0006] The present invention provides a method for preparing a compound as shown in formula I, which comprises method 1 or method 2;

[0007] Method 1:

[0008] In a solvent, in the presence of an alkali metal alkoxide, reacting compound 1 and compound 2, or the hydrochloride of compound 2, to generate the compound shown in formula I;

[0009] Method 2:

[0010] In a solvent, in the presence of a copper salt catalyst, a ligand and an alkaline agent, compound 1 and compound 2, or the hydrochloride of compound 2, are reacted to generate the compound shown in formula I;

[0011] ;

[0012] X is halogen or -SC 1~6 alkyl;

[0013] R is H, C 1~6 Alkyl or C 6~10 Aryl.

[0014] In X, the halogen is F, Cl, Br or I; for example, Cl.

[0015] X and R, the C 1~6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; for example methyl or ethyl.

[0016] R, C 6~10 Aryl is phenyl or naphthyl.

[0017] X is Cl or -S-CH3.

[0018] R is -CH2CH3.

[0019] In method 1, the solvent may be a conventional solvent for such reactions in the art, preferably selected from one or more of sulfone solvents, amide solvents, pyrrolidone solvents, aromatic hydrocarbon solvents, ether solvents, nitrile solvents and alcohol solvents; for example, selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol and tert-butanol; preferably, the solvent is a nitrile solvent; for example, acetonitrile.

[0020] In method 1, the alkali metal alkoxide is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium tert-amylate and sodium tert-amylate; preferably potassium tert-butoxide.

[0021] In method 1, the molar volume ratio of the compound 1 to the solvent can be a conventional molar volume ratio for such reactions in the art, preferably (0.2-3) mol / L; for example (0.7-1.5) mol / L; for example 1 mol / L.

[0022] In method 1, the molar ratio of the compound 1 to the compound 2 can be a conventional molar ratio for such reactions in the art, preferably 1:(0.5-3); for example 1:(0.7-1.5); for example 1:1.

[0023] In method 1, the molar ratio of the compound 1 to the alkali metal alkoxide is 1:(0.8-9); preferably 1:(2-5); for example 1:3.

[0024] In method 1, the reaction temperature is 15 o C~120 o C; preferably 20 o C~80 o C; for example, 25 o C or 65 o C.

[0025] In method 1, the progress of the reaction can be detected by conventional monitoring methods for such reactions in the art (e.g., HPLC, LCMS), and the reaction endpoint is generally taken as the disappearance or no-reaction of compound 1. The reaction time can be the conventional reaction time for such reactions in the art, for example, 8 to 16 hours, preferably 11 hours.

[0026] In method 1, the reaction preferably comprises the following steps: under nitrogen protection, mixing the compound 2, the alkali metal alkoxide, the compound 1 and the solvent at room temperature, raising the temperature to 65 o C reacts.

[0027] In method 1, the materials for the reaction are the compound 2, the alkali metal alkoxide, the compound 1 and the solvent.

[0028] In method 1, after the reaction is completed, the following post-treatment steps are preferably included: adding acid to the reaction solution to adjust the pH, extracting with an ester solvent, concentrating the organic phase to obtain a crude product, recrystallizing the crude product, and drying to obtain the compound shown in formula I.

[0029] In one embodiment, the acid is a dilute hydrochloric acid solution.

[0030] In one embodiment, the pH is 6-7.

[0031] In one embodiment, the ester solvent is ethyl acetate.

[0032] In one embodiment, the solvent used for the recrystallization is an ether solvent or an ester solvent, preferably methyl tert-butyl ether or ethyl acetate.

[0033] In a certain scheme, the post-treatment step is preferably: adding the reaction solution to a dilute hydrochloric acid solution, adjusting the pH to 6-7, extracting with ethyl acetate, concentrating the organic phase to obtain a crude product, recrystallizing the crude product with methyl tert-butyl ether or ethyl acetate, and drying to obtain the compound shown in Formula I.

[0034] In method 2, the solvent may be a conventional solvent for such reactions in the art, preferably selected from one or more of sulfone solvents, amide solvents, pyrrolidone solvents, aromatic hydrocarbon solvents, ether solvents, nitrile solvents and alcohol solvents; for example, selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol and tert-butanol; preferably, the solvent is a sulfone solvent, preferably dimethyl sulfoxide.

[0035] In method 2, the copper salt catalyst is a monovalent copper salt; preferably cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide; for example, cuprous iodide.

[0036] In method 2, the alkaline agent is an organic base or an inorganic base, preferably selected from one or more of alkali metal hydroxides, alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, alkali metal hydrides, alkali metal organic acid salts, heterocyclic organic bases and pyridine organic bases; for example, selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium hydride, potassium acetate, 1,8-diazacyclo[5,4,0]undecene-7 and pyridine; for example, cesium carbonate.

[0037] In method 2, the ligand is selected from one or more of alcohol ligands, 1,2-diamine ligands, amino acid ligands, bipyridine ligands and oxalamide ligands; preferably, the ligand is selected from one or more of ethylene glycol, cyclohexanediamine, proline, 2,2'-bipyridine and BPPO (N,N'-bis(2-biphenyl)oxalamide).

[0038] In method 2, the molar volume ratio of the compound 1 to the solvent can be a conventional molar volume ratio for such reactions in the art, preferably (0.2-3) mol / L; preferably (0.7-1.5) mol / L; for example, 1 mol / L.

[0039] In method 2, the molar ratio of compound 1 to compound 2 is 1:(0.5-2); preferably 1:(0.7-1.5); for example 1:1.

[0040] In method 2, the molar ratio of the compound 1 to the alkaline reagent is 1:(0.5-6); preferably 1:(1-3); for example 1:2.

[0041] In method 2, the molar ratio of the compound 1 to the ligand is 1:(0.05-0.6); preferably 1:(0.1-0.4); for example 1:0.12 or 1:0.2.

[0042] In method 2, the reaction temperature is 50 oC~120 o C; preferably 70 o C~100 o C; for example, 80 o C.

[0043] In method 2, the progress of the reaction can be detected by conventional monitoring methods for such reactions in the art (e.g., HPLC, LCMS), and the reaction endpoint is generally taken as the disappearance or no-reaction of compound 1. The reaction time can be the conventional reaction time for such reactions in the art, for example, 8 to 16 hours, preferably 10 hours.

[0044] In method 2, the reaction preferably comprises the following steps: under nitrogen protection, the compound 2, the copper salt catalyst, the ligand, the alkaline reagent, the compound 1 and the solvent are reacted at 80 o C reacts.

[0045] In method 2, the materials for the reaction are the compound 2, the copper salt catalyst, the ligand, the alkaline reagent, the compound 1 and the solvent.

[0046] In method 2, after the reaction is completed, the following post-treatment steps are preferably included: adding acid to the reaction solution to adjust the pH, extracting with an ester solvent, washing the obtained organic phase with a disodium ethylenediaminetetraacetic acid aqueous solution and a saturated sodium chloride solution, respectively, concentrating the organic phase to obtain a crude product, recrystallizing the crude product, and drying to obtain the compound shown in Formula I.

[0047] In one embodiment, the acid is a dilute hydrochloric acid solution.

[0048] In one embodiment, the pH is 6-7.

[0049] In one embodiment, the ester solvent is ethyl acetate.

[0050] In a certain embodiment, the concentration of the disodium ethylenediaminetetraacetic acid aqueous solution is 2-10 wt %; preferably 5 wt %, where wt % represents the ratio of the mass of disodium ethylenediaminetetraacetic acid to the total mass of the disodium ethylenediaminetetraacetic acid aqueous solution.

[0051] In a certain embodiment, the solvent used for the recrystallization is an ether solvent, preferably methyl tert-butyl ether.

[0052] In method 2, the post-treatment step is preferably: adding the reaction solution to a dilute hydrochloric acid solution, adjusting the pH to 6-7, extracting with ethyl acetate, washing the obtained organic phase with a 5 wt% disodium ethylenediaminetetraacetic acid aqueous solution and saturated sodium chloride, respectively, concentrating the organic phase to obtain a crude product, recrystallizing the crude product with methyl tert-butyl ether, and drying to obtain the compound shown in Formula I.

[0053] The compound shown in formula I can be used for the preparation of CDK4 / 6 inhibitor drugs treraciclib and ribociclib, and the reaction scheme is as follows:

[0054]

[0055] In the present invention, room temperature refers to 10~40 o C, for example 25 o C.

[0056] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0057] The reagents and raw materials used in the present invention are commercially available.

[0058] The positive and progressive effects of the present invention are:

[0059] (1) Raw materials are easily available;

[0060] (2) The reaction conditions are mild, the operation is simple and convenient, and it is suitable for industrial scale-up production;

[0061] (3) The key intermediates of two CDK4 / 6 inhibitor drugs can be obtained through a one-step reaction. DETAILED DESCRIPTION

[0062] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0063] Example 1

[0064] Synthesis of ethyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0065]

[0066] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by potassium tert-butoxide (3.37 g, 30 mmol), anhydrous acetonitrile (10 mL) and 2,4-dichloro-5-pyrimidinecarboxaldehyde (1.77 g, 10 mmol) and stirred at room temperature for 10 hours. Finally, the mixture was heated to 65 °C. o C for 1 hour. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x2 mL). The organic phases were combined and the solvent was removed by vortexing to obtain a crude product; the crude product was recrystallized from methyl tert-butyl ether, filtered and dried to obtain a yellow solid (1.47 g, 65%, purity 99.5%).1 HNMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.99 (s, 1H), 7.25 (s, 1H), 4.47 (q, J= 12.0 Hz, 8.0H), 1.44 (t, J = 8.0 Hz, 3H).

[0067] Example 2

[0068] Synthesis of ethyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0069]

[0070] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by cuprous iodide (0.19 g, 1 mmol), ethylene glycol (0.12 g, 2 mmol), cesium carbonate (6.52 g, 20 mmol), anhydrous dimethyl sulfoxide (10 mL) and 2,4-dichloro-5-pyrimidinecarboxaldehyde (1.77 g, 10 mmol) and then heated to 80 °C. o C for 10 hours. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x3 mL), and the organic phases were combined and washed with 5 wt% disodium ethylenediaminetetraacetate aqueous solution (10x2 mL) and saturated sodium chloride (20 mL) in sequence, and the solvent was removed by rotation to obtain a crude product; the crude product was recrystallized from methyl tert-butyl ether, filtered and dried to obtain a yellow solid (1.76 g, 78%, purity 99.9%). 1 H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.99 (s, 1H), 7.25 (s,1H), 4.47 (q, J = 12.0 Hz, 8.0H), 1.44 (t, J = 8.0 Hz, 3H).

[0071] Example 3

[0072] Synthesis of ethyl 2-thiomethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0073]

[0074] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by potassium tert-butoxide (3.37 g, 30 mmol), anhydrous acetonitrile (10 mL) and 4-chloro-2-(methylthio)pyrimidine-5-carboxaldehyde (1.89 g, 10 mmol) and stirred at room temperature for 10 hours. Finally, the mixture was heated to 65 °C. o C for 1 hour. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x2 mL). The organic phases were combined and the solvent was removed by vortexing to obtain a crude product; the crude product was recrystallized from ethyl acetate, filtered and dried to obtain a yellow solid (1.66 g, 70%, purity 99.8%). 1 H NMR (400 MHz, CDCl3): δ 11.94 (s, 1H), 8.89 (s, 1H), 7.10 (s, 1H), 4.25 (q,J = 12 Hz, 2H), 2.73 (s, 3H),1.31 (t, J = 8.0 Hz, 3H).

[0075] Example 4

[0076] Synthesis of ethyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0077]

[0078] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by cuprous iodide (0.19 g, 1 mmol), cyclohexanediamine (0.22 g, 2 mmol), cesium carbonate (6.52 g, 20 mmol), anhydrous dimethyl sulfoxide (10 mL) and 2,4-dichloro-5-pyrimidinecarboxaldehyde (1.77 g, 10 mmol) and then heated to 80 °C. o C for 10 hours. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x3 mL), and the organic phases were combined and washed with 5 wt% disodium ethylenediaminetetraacetate aqueous solution (10x2 mL) and saturated sodium chloride (20 mL) in sequence, and the solvent was removed by rotation to obtain a crude product; the crude product was recrystallized from methyl tert-butyl ether, filtered and dried to obtain a yellow solid (1.52 g, 67%, purity 99.5%). 1H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.99 (s, 1H), 7.25 (s, 1H), 4.47 (q, J = 12.0 Hz, 8.0H), 1.44 (t, J = 8.0 Hz, 3H).

[0079] Example 5

[0080] Synthesis of ethyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0081]

[0082] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by cuprous iodide (0.19 g, 1 mmol), proline (0.23 g, 2 mmol), cesium carbonate (6.52 g, 20 mmol), anhydrous dimethyl sulfoxide (10 mL) and 2,4-dichloro-5-pyrimidinecarboxaldehyde (1.77 g, 10 mmol) and then heated to 80 °C. o C for 10 hours. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x3 mL), and the organic phases were combined and washed with 5 wt% disodium ethylenediaminetetraacetate aqueous solution (10x2 mL) and saturated sodium chloride (20 mL) in sequence, and the solvent was removed by rotation to obtain a crude product; the crude product was recrystallized from methyl tert-butyl ether, filtered and dried to obtain a yellow solid (1.58 g, 70%, purity 99.6%). 1 H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.99 (s, 1H), 7.25 (s,1H), 4.47 (q, J = 12.0 Hz, 8.0H), 1.44 (t, J = 8.0 Hz, 3H).

[0083] Example 6

[0084] Synthesis of ethyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0085]

[0086] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by cuprous iodide (0.19 g, 1 mmol), BPPO (0.47 g, 1.2 mmol), cesium carbonate (6.52 g, 20 mmol), anhydrous dimethyl sulfoxide (10 mL) and 2,4-dichloro-5-pyrimidinecarboxaldehyde (1.77 g, 10 mmol) and then heated to 80 °C. o C for 10 hours. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x3 mL), and the organic phases were combined and washed with 5 wt% disodium ethylenediaminetetraacetate aqueous solution (10x2 mL) and saturated sodium chloride (20 mL) in sequence, and the solvent was removed by rotation to obtain a crude product; the crude product was recrystallized from methyl tert-butyl ether, filtered and dried to obtain a yellow solid (1.31 g, 58%, purity 99.7%). 1 H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.99 (s, 1H), 7.25 (s,1H), 4.47 (q, J = 12.0 Hz, 8.0H), 1.44 (t, J = 8.0 Hz, 3H).

[0087] Example 7

[0088] Synthesis of ethyl 2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate

[0089]

[0090] Under nitrogen protection, glycine ethyl ester hydrochloride (1.40 g, 10 mmol) was added to the reaction vessel, followed by cuprous iodide (0.19 g, 1 mmol), bipyridine (0.31 g, 2 mmol), cesium carbonate (6.52 g, 20 mmol), anhydrous dimethyl sulfoxide (10 mL) and 2,4-dichloro-5-pyrimidinecarboxaldehyde (1.77 g, 10 mmol) and then heated to 80 °C. o C for 10 hours. After returning to room temperature, dilute hydrochloric acid solution was added to adjust the pH to 6-7, followed by extraction with ethyl acetate (10x3 mL), and the organic phases were combined and washed with 5 wt% disodium ethylenediaminetetraacetate aqueous solution (10x2 mL) and saturated sodium chloride (20 mL) in sequence, and the solvent was removed by rotation to obtain a crude product; the crude product was recrystallized from methyl tert-butyl ether, filtered and dried to obtain a yellow solid (1.56 g, 69%, purity 99.5%). 1H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.99 (s, 1H), 7.25 (s,1H), 4.47 (q, J = 12.0 Hz, 8.0H), 1.44 (t, J = 8.0 Hz, 3H)。

Claims

1. A method for preparing a compound as shown in formula I, characterized in that: It includes method 1 or method 2; Method 1: In a solvent, in the presence of an alkali metal alkoxide, compound 1 and compound 2, or the hydrochloride of compound 2, are reacted to generate the compound shown in formula I; Method 2: In a solvent, in the presence of a copper salt catalyst, a ligand and an alkaline agent, compound 1 and compound 2, or the hydrochloride of compound 2, are reacted to generate the compound shown in formula I; ； X is halogen or -SC 1~6 alkyl; R is H, C 1~6 Alkyl or C 6~10 Aryl.

2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) In X, the halogen is F, Cl, Br or I; for example, Cl; (2) Among X and R, the C 1~6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; for example, methyl or ethyl; (3) R, C 6~10 Aryl is phenyl or naphthyl; Preferably, it satisfies one or both of the following conditions: (1) X is Cl or -S-CH3; (2) R is -CH2CH3.

3. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In method 1, the solvent is selected from one or more of sulfone solvents, amide solvents, pyrrolidone solvents, aromatic hydrocarbon solvents, ether solvents, nitrile solvents and alcohol solvents; (2) In method 1, the alkali metal alkoxide is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, potassium tert-amylate and sodium tert-amylate; (3) In method 1, the molar volume ratio of the compound 1 to the solvent is (0.2-3) mol / L; (4) In method 1, the molar ratio of compound 1 to compound 2 is 1:(0.5-3); (5) In method 1, the molar ratio of the compound 1 to the alkali metal alkoxide is 1:(0.8-9); (6) In method 1, the reaction temperature is 15 o C~120 o C; (7) In method 1, the materials for the reaction are the compound 2, the alkali metal alkoxide, the compound 1 and the solvent; (8) In method 1, after the reaction is completed, the following post-treatment steps are included: adding acid to the reaction solution to adjust the pH, extracting with an ester solvent, concentrating the organic phase to obtain a crude product, recrystallizing the crude product, and drying to obtain the compound represented by formula I.

4. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) In method 1, the solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol and tert-butanol; (2) In method 1, the alkali metal alkoxide is potassium tert-butoxide; (3) In method 1, the molar volume ratio of the compound 1 to the solvent is (0.7-1.5) mol / L; (4) In method 1, the molar ratio of compound 1 to compound 2 is 1:(0.7-1.5); (5) In method 1, the molar ratio of the compound 1 to the alkali metal alkoxide is 1:(2-5); (6) In method 1, the reaction temperature is 20 o C~80 o C; (7) In method 1, when the pH of the reaction solution is adjusted by acid, the acid is a dilute hydrochloric acid solution; (8) In method 1, the pH is 6-7; (9) In method 1, when an ester solvent is used for extraction, the ester solvent is ethyl acetate; (10) In method 1, the solvent used for the recrystallization is an ether solvent or an ester solvent.

5. The preparation method according to claim 4, characterized in that: It meets one or more of the following conditions: (1) In method 1, the solvent is acetonitrile; (2) In method 1, the molar volume ratio of the compound 1 to the solvent is 1 mol / L; (3) In method 1, the molar ratio of compound 1 to compound 2 is 1:1; (4) In method 1, the molar ratio of the compound 1 to the alkali metal alkoxide is 1:3; (5) In method 1, the reaction temperature is 25 o C or 65 o C; (6) In method 1, the solvent used for the recrystallization is methyl tert-butyl ether or ethyl acetate.

6. The preparation method according to claim 1, characterized in that: It meets one or both of the following conditions: (1) In method 1, under nitrogen protection, the compound 2, the alkali metal alkoxide, the compound 1 and the solvent are mixed at room temperature, and the temperature is raised to 65 o C reacts; (2) In method 1, after the reaction is completed, the following post-treatment steps are included: adding the reaction solution to a dilute hydrochloric acid solution, adjusting the pH to 6-7, extracting with ethyl acetate, concentrating the organic phase to obtain a crude product, recrystallizing the crude product with methyl tert-butyl ether or ethyl acetate, and drying to obtain the compound represented by formula I.

7. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In method 2, the solvent is selected from one or more of sulfone solvents, amide solvents, pyrrolidone solvents, aromatic hydrocarbon solvents, ether solvents, nitrile solvents and alcohol solvents; (2) In method 2, the copper salt catalyst is a monovalent copper salt; (3) In method 2, the alkaline reagent is an organic base or an inorganic base, (4) In method 2, the ligand is selected from one or more of alcohol ligands, 1,2-diamine ligands, amino acid ligands, bipyridine ligands and oxalamide ligands; (5) In method 2, the molar volume ratio of the compound 1 to the solvent is (0.2-3) mol / L; (6) In method 2, the molar ratio of compound 1 to compound 2 is 1:(0.5-2); (7) In method 2, the molar ratio of the compound 1 to the alkaline agent is 1:(0.5-6); (8) In method 2, the molar ratio of the compound 1 to the ligand is 1:(0.05-0.6); (9) In method 2, the reaction temperature is 50 o C~120 o C; (10) In method 2, the materials of the reaction are the compound 2, the copper salt catalyst, the ligand, the alkaline reagent, the compound 1 and the solvent; (11) In method 2, after the reaction is completed, the following post-treatment steps are included: adding an acid to the reaction solution to adjust the pH, extracting with an ester solvent, washing the resulting organic phase with a disodium ethylenediaminetetraacetic acid aqueous solution and a saturated sodium chloride solution, respectively, concentrating the organic phase to obtain a crude product, recrystallizing the crude product, and drying to obtain the compound represented by formula I.

8. The preparation method according to claim 7, characterized in that: It meets one or more of the following conditions: (1) In method 2, the solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, toluene, 1,4-dioxane, tetrahydrofuran, acetonitrile, ethanol, methanol, isopropanol and tert-butanol; (2) In method 2, the copper salt catalyst is cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide; (3) In method 2, the alkaline agent is selected from one or more of alkali metal hydroxides, alkali metal carbonates, alkali metal phosphates, alkali metal tertiary alcohol salts, alkali metal hydrides, alkali metal organic acid salts, heterocyclic organic bases and pyridine organic bases; (4) In method 2, the ligand is selected from one or more of ethylene glycol, cyclohexanediamine, proline, 2,2'-bipyridine and BPPO; (5) In method 2, the molar volume ratio of the compound 1 to the solvent is (0.7-1.5) mol / L; (6) In method 2, the molar ratio of compound 1 to compound 2 is 1:(0.7-1.5); (7) In method 2, the molar ratio of the compound 1 to the alkaline reagent is 1:(1-3); (8) In method 2, the molar ratio of the compound 1 to the ligand is 1:(0.1-0.4); (9) In method 2, the reaction temperature is 70 o C~100 o C; (10) In method 2, when the pH of the reaction solution is adjusted by acid, the acid is a dilute hydrochloric acid solution; (11) In method 2, the pH is 6-7; (12) In method 2, when an ester solvent is used for extraction, the ester solvent is ethyl acetate; (13) In method 2, the concentration of the disodium ethylenediaminetetraacetic acid aqueous solution is 2-10 wt%; wt% represents the ratio of the mass of disodium ethylenediaminetetraacetic acid to the total mass of the disodium ethylenediaminetetraacetic acid aqueous solution; (14) In method 2, the solvent used for the recrystallization is an ether solvent.

9. The preparation method according to claim 8, characterized in that: It meets one or more of the following conditions: (1) In method 2, the solvent is dimethyl sulfoxide; (2) In method 2, the copper salt catalyst is cuprous iodide; (3) In method 2, the alkaline agent is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium hydride, potassium acetate, 1,8-diazacyclo[5,4,0]undecene-7 and pyridine; for example, cesium carbonate; (4) In method 2, the molar volume ratio of the compound 1 to the solvent is 1 mol / L; (5) In method 2, the molar ratio of compound 1 to compound 2 is 1:1; (6) In method 2, the molar ratio of the compound 1 to the alkaline agent is 1:2; (7) In method 2, the molar ratio of the compound 1 to the ligand is 1:0.12 or 1:0.2; (8) In method 2, the reaction temperature is 80 o C; (9) In method 2, the concentration of the disodium ethylenediaminetetraacetic acid aqueous solution is 5wt%; (10) In method 2, the solvent used for the recrystallization is methyl tert-butyl ether.

10. The preparation method according to claim 1, characterized in that: It meets one or both of the following conditions: (1) In method 2, the compound 2, the copper salt catalyst, the ligand, the alkaline reagent, the compound 1 and the solvent are mixed at 80°C under nitrogen protection. o C reacts; (2) In method 2, after the reaction is completed, the following post-treatment steps are included: adding the reaction solution to a dilute hydrochloric acid solution, adjusting the pH to 6-7, extracting with ethyl acetate, washing the obtained organic phase with a 5 wt% aqueous solution of disodium ethylenediaminetetraacetate and saturated sodium chloride, respectively, concentrating the organic phase to obtain a crude product, recrystallizing the crude product with methyl tert-butyl ether, and drying to obtain the compound shown in Formula I.

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