Synthetic methods for nitrogen-containing heterocyclic compounds

Abstract

This invention discloses a method for synthesizing nitrogen-containing heterocyclic compounds. Specifically, this invention discloses a method for preparing a compound of formula I, the method comprising the following steps: under a CO atmosphere, in an organic base, an organophosphorus ligand, a palladium catalyst, and SiH-(R z In the presence of 3, in an organic solvent, compound II is prepared into compound I via a carbonylation reaction. The method for synthesizing compound I provided by this invention has one or more of the following advantages: it uses a conventional reactor, is simple to operate, avoids the use of highly toxic reagents, is easy to post-process, has high product purity, good reproducibility, is easy to scale up, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a method for synthesizing nitrogen-containing heterocyclic compounds. Background Technology

[0002] 5-Hydroxymethylcytosine, known as the "sixth base," can regulate gene expression shutdown and is an important epigenetic modification. Deoxyribonucleotides containing 5-hydroxymethylcytosine are widely used in life science research; therefore, optimizing the synthetic routes of 5-hydroxymethylcytosine deoxyribonucleotides and their precursors has significant economic and scientific value.

[0003] Compound 2, as a precursor of 5-hydroxymethylcytosine deoxyribonucleotide, has been reported in existing technologies for synthesis. A method for synthesizing intermediate 1 is reported in *Efficient Synthesis of 5-Hydroxymethylcytosine Containing DNA* (ORGANIC LETTERS. 2010. Vol. 12, No. 24, 5671-5673) (see Supporting Information, page 7 for details). This synthetic method has at least the following drawbacks: the reaction is carried out in an unconventional, constant-pressure reactor with externally added reagents; the feed rate is slow and the operation is inconvenient (adding Bu3SnH takes approximately 7 hours when only 6 mmol of starting material 9 is available); the highly toxic reagent tributyltin hydride is used; post-processing is complex (requiring multiple purifications by column chromatography, resulting in low product purity); reaction reproducibility is poor (due to the complex operation, dehalogenation impurities are easily generated); the reaction is difficult to scale up (the yield decreases significantly with large-scale production); and it is not suitable for industrial production.

[0004]

[0005] To overcome the above shortcomings, there is an urgent need to develop a synthesis method for compound 2 that uses conventional reactors, is easy to operate, avoids the use of highly toxic reagents, is easy to post-process, has high product purity, good reproducibility, is easy to scale up, and is suitable for industrial production. Summary of the Invention

[0006] To address the shortcomings of existing methods for synthesizing 5-hydroxymethylcytosine deoxyribonucleotide precursors, such as the use of unconventional reactors, slow feed rates, inconvenient operation, use of highly toxic reagents, complex post-processing, poor reaction reproducibility, difficulty in scale-up, and unsuitability for industrial production, this invention provides a method for synthesizing compound I, which has one or more of the following advantages: using conventional reactors, simple operation, avoidance of highly toxic reagents, easy post-processing, high product purity, good reproducibility, easy scale-up, and suitability for industrial production.

[0007] This invention provides a method for preparing a compound of formula I, comprising the following steps: under a CO atmosphere, in an organic base, an organophosphorus ligand, a palladium catalyst, and SiH-(R z In the presence of 3, in an organic solvent, compound II is prepared by a carbonylation reaction;

[0008]

[0009] Where X is a halogen;

[0010] R 1 For H, -OC 1-4 Alkyl, -OTBS (TBS is tert-butyldimethylsilyl), -OTOM (TOM is (triisopropylsilyl)methyl), halogen or -O-MOE (MOE is methoxyethyl);

[0011] The organophosphorus ligand is Or XANT PHOS (4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene);

[0012] Each R y Independently for C 6-10 Aryl; n is an integer between 1 and 5;

[0013] Each R z Independently for C 1-6 alkyl.

[0014] In certain preferred embodiments of the present invention, certain conditions, operations, or materials in the preparation method of the compound of Formula I have the following definitions, and conditions, operations, or materials not mentioned are the same as those described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention"). Other aspects of the present invention are referred to using the same abbreviations as this invention and will not be described in detail hereafter.

[0015] In one embodiment of the present invention, X is F, Cl, Br or I, preferably Br or I, and more preferably I.

[0016] In one aspect of the present invention, R 1 In this context, the halogen is F, Cl, Br, or I, preferably F.

[0017] In one aspect of the present invention, R 1 It can be H, -O-CH3, -OTBS, -OTOM, F, or -O-MOE.

[0018] In one embodiment of the present invention, the compound of formula II is Accordingly, the compound of formula I is .

[0019] In one aspect of the present invention, the pressure of the CO atmosphere is 0.08-3 MPa, preferably 0.08-1.5 MPa, for example 0.1 MPa or 1.2 MPa.

[0020] In one embodiment of the present invention, the pressure of the CO atmosphere is 0.8-1.5 MPa, for example 1.2 MPa.

[0021] In one aspect of the present invention, the organic base, organophosphorus ligand, palladium catalyst, and SiH-(R) are... z 3. After the organic solvent and the compound of formula II are added to the reactor, a CO atmosphere is then introduced;

[0022] The CO atmosphere is preferably introduced by charging the CO atmosphere to the target pressure in one go.

[0023] In one embodiment of the present invention, the organic base is N(R) x )3; Each R x It is independently a C1-6 alkyl group, preferably a C1-3 alkyl group, such as isopropyl or ethyl.

[0024] In one aspect of the present invention, the N(R) x )3 is N,N-diisopropylethylamine.

[0025] In one embodiment of the present invention, the molar ratio of the organic base to the compound of formula II is 1.5-2.5, for example 2.0.

[0026] In one embodiment of the present invention, each R y All are phenyl.

[0027] In one embodiment of this invention, n is 3.

[0028] In one aspect of the present invention, the... It is 1,4-bis(diphenylphosphine)butane.

[0029] In one embodiment of the present invention, the organophosphorus ligand is ;

[0030] The The preferred formulation is 1,4-bis(diphenylphosphine)butane.

[0031] In one aspect of the present invention, the molar ratio of the organophosphorus ligand to the compound of formula II is 0.08-1.0, for example 0.1 or 0.6.

[0032] In one aspect of the present invention, when the organophosphorus ligand is At that time, the pressure of the CO atmosphere is 0.08-3 MPa, preferably 0.8-1.5 MPa, for example 1.2 MPa.

[0033] In one embodiment of the present invention, when the organophosphorus ligand is XANT PHOS, the pressure of the CO atmosphere is 0.8-1.5 MPa, for example 1.2 MPa.

[0034] In one embodiment of the present invention, the palladium catalyst is a zero-valent palladium catalyst, such as tris(dibenzylacetone)dipalladium.

[0035] In one aspect of the present invention, the molar ratio of the palladium catalyst to the compound of formula II is 0.03-0.15, for example 0.05 or 0.10.

[0036] In one embodiment of the present invention, the molar ratio of the palladium catalyst to the compound of formula II is 0.03-0.07, for example, 0.05.

[0037] In one embodiment of the present invention, each R z Independently, it is a C1-3 alkyl group, such as an ethyl group.

[0038] In one embodiment of the present invention, the SiH-(R) z )3 is triethylsilane.

[0039] In one embodiment of the present invention, the SiH-(R) z The molar ratio of 3 to the compound of formula II is 1.8-2.2, for example 2.0.

[0040] In one embodiment of the present invention, the SiH-(R) z )3. The reaction system is added in a one-time introduction manner; the meaning of "one-time introduction into the reaction system" is that all SiH-(R) required for the carbonylation reaction is added. z )3. The carbonyl insertion reaction is carried out in a single pour or addition, and is added to the reaction system before the carbonyl insertion reaction begins or at the initial stage of the reaction, instead of using dropwise addition or batch addition.

[0041] In one embodiment of the present invention, the organic solvent is an amide solvent;

[0042] The amide solvent is preferably... R u and R v Independently for C 1-6 Alkyl groups, such as methyl groups;

[0043] The N,N-dimethylformamide is preferred.

[0044] In one embodiment of the present invention, the concentration of compound II in the organic solvent is 0.05-0.15 g / mL, for example 0.1 g / mL.

[0045] In one aspect of the present invention, in the method for preparing the compound of formula I, the carbonyl insertion reaction is carried out in a conventional closed reactor, preferably a reaction vessel, such as a high-pressure reaction vessel.

[0046] In one aspect of this invention, the progress of the carbonylation reaction is monitored using conventional detection methods in the art (e.g., HPLC, LCMS), and the reaction endpoint is generally defined as the disappearance or cessation of reaction of one of the raw materials in the reaction solution. The preferred reaction time for the carbonylation reaction is 10-20 h, for example, 16 h.

[0047] In one embodiment of the present invention, the temperature of the carbonyl insertion reaction is 60-100 °C, preferably 75-85 °C.

[0048] In one aspect of the present invention, the materials used in the carbonyl insertion reaction are only those mentioned in the various technical solutions in the specification, and do not involve other materials.

[0049] In one aspect of the present invention, the carbonyl insertion reaction further includes one or more of the following post-processing steps:

[0050] Dilution, washing, concentration, pulping, and filtration;

[0051] The dilution is preferably performed using an ester solvent (e.g., ethyl acetate); the volume ratio of the ester solvent used for dilution to the volume of the organic solvent used in the reaction system is preferably 1-3, for example, 2.

[0052] The washing is preferably performed using water or saturated saline solution; the volume ratio of the water or saturated saline solution to the organic solvent used in the reaction system is preferably 0.5-1.5, for example, 1.

[0053] The washing is preferably performed 1-3 times, for example, 2 times;

[0054] The concentration is preferably a concentration of the organic phase to remove the solvent;

[0055] The pulping process preferably uses C. 3-10 The solvent is a straight-chain or branched alkane (e.g., n-hexane) for pulping; the C 3-10 The ratio of the volume of the straight-chain or branched-chain alkane solvent to the mass of the compound of formula II used in the reaction system is 1-4 mL / g, for example, 2.5 mL / g; "mass of the compound of formula II used in the reaction system" refers to the amount of compound of formula II used when the reaction is initiated.

[0056] In one embodiment of the present invention, the post-processing step is performed through the following steps:

[0057] After the reaction was detected by LCMS, ethyl acetate was added to the system, followed by washing twice with water. The organic phase was concentrated to remove the solvent, and then n-hexane was added. The mixture was stirred for 0.5 hours and filtered to obtain a white solid, yielding compound I.

[0058] In one embodiment of the present invention, the pressure of the CO atmosphere is 1.2 MPa, the organic base is DIPEA, the organophosphorus ligand is 1,4-bis(diphenylphosphine)butane, the palladium catalyst is tris(dibenzylacetone)dipalladium, and the SiH-(R z )3 is triethylsilane, and the organic solvent is DMF;

[0059] Preferably, the II compound is Accordingly, the compound of formula I is ;

[0060] Preferably, the temperature of the carbonyl insertion reaction is 75-85°C.

[0061] In one aspect of the present invention, the carbonyl insertion reaction is carried out via the following steps:

[0062] In an autoclave, 1,4-bis(diphenylphosphine)butane, N,N-dimethylformamide, tris(dibenzylacetone)dipalladium, diisopropylethylamine, triethylsilane and compound II were mixed, and the CO atmosphere was replaced to a pressure of 1.2 MPa. At 75-85 °C, compound II was subjected to a carbonylation reaction to prepare compound I.

[0063] Preferably, the carbonyl insertion reaction further includes the aforementioned post-processing steps.

[0064] In one aspect of the present invention, the carbonyl insertion reaction is carried out via the following steps:

[0065] 1,4-bis(diphenylphosphine)butane was added to a high-pressure reactor, and N,N-dimethylformamide, tris(dibenzylacetone)dipalladium, diisopropylethylamine, triethylsilane and compound II were added sequentially. The reaction was carried out at a carbon monoxide pressure of 1.2 MPa and a temperature of 75-85 °C until the reaction was complete as detected by LCMS. Ethyl acetate was added to the system, and the mixture was washed with water. After concentrating the organic phase to remove the solvent, n-hexane was added, and the mixture was stirred for 0.5 hours. The mixture was then filtered to obtain compound I.

[0066] Preferably, the carbonyl insertion reaction further satisfies one or more of the following conditions:

[0067] (1) The molar ratio of the 1,4-bis(diphenylphosphine)butane to the compound of formula II is 0.1;

[0068] (2) The molar ratio of the tris(dibenzylacetone)palladium to the compound of formula II is 0.05;

[0069] (3) The molar ratio of the diisopropylethylamine to the compound of formula II is 2.0;

[0070] (4) The molar ratio of the triethylsilane to the compound of formula II is 2.0;

[0071] (5) The concentration of compound II in the N,N-dimethylformamide is 0.1 g / mL;

[0072] (6) The reaction time at 75-85℃ is 16 hours.

[0073] This invention also provides a method for preparing a compound of formula TM, comprising the following steps:

[0074] (1) In the presence of nitrogen-containing heterocyclic aromatic hydrocarbons, in an ether solvent, compound 1 and trialkylchlorosilane were reacted via a substitution reaction to prepare compound 2;

[0075] The nitrogen-containing heterocyclic aromatic hydrocarbon is preferably an imidazole;

[0076] The preferred ether solvent is tetrahydrofuran;

[0077] The trialkylchlorosilane is preferably tert-butyldimethylchlorosilane;

[0078] (2) Compound I was prepared by the aforementioned method for preparing compound I; the structure of compound I is shown in compound 3;

[0079] (3) In the presence of Lewis acid and reducing agent, in an alcohol solvent, compound 3 is reduced to prepare compound 4;

[0080] The Lewis acid is preferably cerium trichloride;

[0081] The reducing agent is preferably sodium borohydride;

[0082] The preferred alcohol solvent is methanol;

[0083] (4) In the presence of a trialkyl tertiary amine, in an ether solvent, compound 4 and p-nitrobenzene chloroformate were reacted via a cyclization reaction to prepare compound 5;

[0084] The trialkyl tertiary amine is preferably N,N-diisopropylethylamine;

[0085] The preferred ether solvent is tetrahydrofuran;

[0086] (5) Compound 5 was prepared by deprotection reaction in an ester solvent in the presence of a hydrofluoric acid complexing agent to obtain compound 6;

[0087] The hydrofluoric acid complexing agent is preferably pyridine hydrofluoric acid;

[0088] The preferred ester solvent is ethyl acetate;

[0089] (6) Compound 6 and 4,4-dimethoxytriphenylmethyl chloride were substituted in an alkaline solvent to prepare compound 7;

[0090] The alkaline solvent is preferably pyridine;

[0091] (7) In the presence of one or more nitrogen-containing heterocyclic aromatic hydrocarbons substituted with cyano groups, compound 7 and bis(diisopropylamino)(2-cyanoethoxy)phosphine are substituted in a halocarbon solvent to prepare compound TM.

[0092] The nitrogen-containing heterocyclic aromatic hydrocarbon substituted with one or more cyano groups is preferably 4,5-dicyanimidazole;

[0093] The preferred halogenated hydrocarbon solvent is dichloromethane;

[0094] .

[0095] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0096] The reagents and raw materials used in this invention are all commercially available.

[0097] The positive and progressive effects of this invention are as follows: This invention provides a method for synthesizing a compound of formula I, which has one or more of the following advantages: it uses a conventional reactor, is easy to operate, avoids the use of highly toxic reagents, is easy to post-process, has high product purity, good reproducibility, is easy to scale up, and is suitable for industrial production. Detailed Implementation

[0098] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0099] Example 1

[0100]

[0101] Raw material: 5-iodo-2-deoxycytidine

[0102] Step 1:

[0103] Under nitrogen protection, compound 1 (5-iodo-2-deoxycytidine) (200 g, 566.3 mmol, 1.00 eq) was suspended in anhydrous tetrahydrofuran (2000 mL) solution. Imidazole (174 g, 2.55 mol, 4.5 eq) was then added to the system. Tert-butyldimethylchlorosilane (256 g, 1.70 mol, 3.00 eq) was added to the suspension at 20-30 °C, and the mixture was stirred for 16 hours at room temperature (20-30 °C). After the reaction was confirmed by LCMS, the reaction solution was concentrated under reduced pressure below 40 °C to remove tetrahydrofuran. The residue was dissolved in ethyl acetate (2 L), washed with sodium bicarbonate aqueous solution (500 mL x 3), and the organic phase was concentrated. Add 500 mL of tetrahydrofuran to the crude product, stir at room temperature for 30 minutes, and then filter to obtain 291 g of yellow solid, which is the pure compound 2 (purity 96.7%, yield 88.3%).

[0104] Step 2:

[0105] 1,4-Bis(diphenylphosphine)butane (14.7 g, 34.4 mmol, 0.1 eq) was added to an autoclave, followed by the sequential addition of N,N-dimethylformamide (2 L) solution and tris(dibenzylacetone)palladium (15.7 g, 17.1 mmol, 0.05 eq), diisopropylethylamine (89 g, 688.6 mmol, 2.00 eq), triethylsilane (80 g, 688.6 mmol, 2.00 eq), and compound 2 (200 g, 343.8 mmol, 1.00 eq). The reaction was carried out at 1.2 MPa carbon monoxide pressure and 75–85 °C for 16 hours. After the reaction was detected by LCMS, ethyl acetate (4 L) was added to the system, and the mixture was washed with water (2 L x 2). The organic phase was concentrated to remove the solvent, and then n-hexane (1000 ml) was added and stirred for 0.5 hours. The mixture was filtered to obtain a white solid, which was pure intermediate 1 (purity 94%, yield 72.4%).

[0106] Step 3:

[0107] Intermediate 1 (158 g, 326.6 mmol, 1.00 eq) and cerium trichloride (242 g, 979.8 mmol, 3.00 eq) were added to a reaction vessel containing methanol (1.7 L). Under nitrogen protection, sodium borohydride (13 g, 342.9 mol, 1.05 eq) was added in portions to the reaction vessel at a controlled temperature of 15-20 °C. The reaction was stirred at 15-20 °C for 2-3 hours. After the reaction was confirmed by LCMS, ethyl acetate (2 L) was added to the reaction vessel to dissolve the product. The mixture was washed three times with saturated ammonium chloride aqueous solution (1 L). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Methyl tert-butyl ether (300 mL) was added to the crude product, and the mixture was stirred at room temperature for 0.5 hours. The mixture was then filtered, and the filter cake was collected to obtain a white solid, which was compound 4 (137 g, purity: 89%, yield: 86.3%).

[0108] Step 4:

[0109] Compound 4 (130 g, 267.6 mmol, 1.00 eq) was added to a flask containing anhydrous tetrahydrofuran (950 mL). Under nitrogen protection, p-nitrobenzene chloroformate (59 g, 294.4 mmol, 1.10 eq) and N,N-diisopropylethylamine (69.2 g, 535.2 mmol, 2.00 eq) were added sequentially. The reaction was stirred at 15–25 °C for 16 hours. After the reaction was complete as determined by LC-MS, ethyl acetate (1 L) was added to the reaction vessel to dissolve the organic phase. The organic phase was washed three times with saturated ammonium chloride aqueous solution (800 mL), three times with saturated sodium bicarbonate solution (800 mL), and three times with saturated sodium chloride solution (800 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was eluted by column chromatography (ethyl acetate: n-hexane = 1:10 to 1:1) to give a yellow solid compound 5 (110 g, purity: 64%, yield: 80.3%).

[0110] Step 5:

[0111] Compound 5 (93 g, 181.7 mmol, 1.00 eq) and pyridine (94 g, 181 mol, 6.50 eq) were added to a flask containing ethyl acetate (1.0 L). Under nitrogen protection, pyridine hydrofluoric acid (90 g, 909 mmol, 5.00 eq) was added dropwise. The reaction was stirred at 15–25 °C for 12 hours. After the reaction was completed by LCMS, the mixture was filtered, and the filter cake was washed with methanol (100 mL). The filter cake was then homogenized with methanol:dichloromethane = 2:1 (300 mL) for 0.5 hours, filtered, and washed twice with ethyl acetate (100 mL) to obtain a white solid compound 6 (46 g, purity: 88.5%, yield: 89.4%).

[0112] Step 6:

[0113] Compound 6 (48 g, 169.5 mmol, 1.00 eq) and 4,4-dimethoxytriphenylmethyl chloride (57.5 g, 169.5 mol, 1.00 eq) were added to a flask containing pyridine (960 mL). The reaction was stirred at 15–25 °C for 3–4 hours. The reaction was monitored by LCMS until complete, and then quenched with methanol (500 mL). The reaction solution was concentrated under reduced pressure. The crude product was homogenized twice with ethyl acetate:methyl tert-butyl ether at a ratio of 1:3 (crude product mass 20 V) to give a white solid compound 7 (66 g, purity: 92.5%, yield: 66.5%).

[0114] Step 7:

[0115] Compound 7 (32 g, 54.6 mmol, 1.00 eq), bis(diisopropylamino)(2-cyanoethoxy)phosphine (21.4 g, 7.10 mol, 1.30 eq), and 4,5-dicyanimidazole (5.16 g, 43.72 mmol, 0.80 eq) were added to a flask containing 300 mL of dichloromethane. The reaction was stirred at 15–25 °C for 1–2 hours. After the reaction was complete as determined by LC-MS, the reaction solution was quenched with 300 mL of saturated sodium bicarbonate solution and separated. The organic phase was washed four times with 300 mL of saturated sodium bicarbonate solution and twice with 300 mL of saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was washed 10 times with N,N-dimethylformamide:water = 1:1 (160 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was then separated by column chromatography (ethyl acetate:n-hexane = 1:5 to 1:1) to give a white solid compound TM (28.9 g, purity: 98.2%, yield: 67.3%).

[0116] 1H NMR (400 MHz, CD3CN) δ = 8.94 (s, 1H), 8.03 - 8.00 (d, J = 14.0 Hz,1H), 7.35 - 7.23 (m, 2H), 7.21 - 7.18 (m, 7H), 6.79 - 6.76 (m, 4H), 6.07 -6.02 (m, 1H), 4.60 - 4.46 (m, 2H), 4.30 (t, J = 15.6 Hz 1H), 3.66 - 3.47 (m,10H), 3.32 - 3.29 (m, 2H), 2.56 - 2. 42 (m, 3H), 2.29 - 2.25 (m, 1H), 1.08 –0.95 (m, 12H)

[0117] 31 P NMR: CD3CN 400 MHz

[0118] δ: 148.23, 148.17.

[0119] LCMS (ESI) m / z: 784.4 [MH] -

[0120] Example 2

[0121] Example 2-1 was a repeat of the experimental procedure described on page 7 of the Supporting Information in ORGANIC LETTERS. 2010. Vol. 12, No. 24, 5671-5673, using compound 2 as the baseline (compound 2 was 1 equivalent); the amount of compound 2 used was 3 g (5.158 mmol).

[0122] Following the procedure in Example 1, only the type, amount, or presence of some reagents were changed to screen the reaction conditions. The results are as follows (Examples 2-2 to 2-11):

[0123] The equivalents in Examples 2-2 to 2-11 are based on compound 2 (compound 2 is 1 equivalent); the amount of compound 2 used is 3g (5.158mmol).

[0124]

[0125] Tol. is an abbreviation for toluene.

[0126] x-vol. represents the amount of solvent used (in mL); for example, when x=10, 10 vol. means that the amount of solvent used (in mL) is 10 times the weight (in g) of substrate compound 2.

[0127] In Example 2-1, the Bu3SnH was slowly added dropwise as described in the original literature, and the product was purified by column chromatography (iHex / EtOAc 4:1→2:1→1:1) as described in the original literature. After one column chromatography purification, the purity of the product was only about 80%.

[0128] In comparison, all other conditions and operations were the same as in Example 2-1, except that Bu3SnH was added dropwise within 10 minutes, resulting in a yield of less than 20%.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: Under a CO atmosphere, with organic bases, organophosphorus ligands, palladium catalysts, and SiH-(R z In the presence of 3, in an organic solvent, compound II is prepared by a carbonylation reaction; ； Where X is a halogen; R 1 For H, -OC 1-4 Alkyl, -OTBS, -OTOM, halogen, or -O-MOE; The organophosphorus ligand is Or XANT PHOS; Each R y Independently for C 6-10 Aryl; n is an integer between 1 and 5; Each R z Independently for C 1-6 alkyl.

2. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) X is F, Cl, Br or I; (2) R 1 For H, -O-CH3, -OTBS, -OTOM, F, or -O-MOE; (3) The compound of formula II is Accordingly, the compound of formula I is ; (4) The pressure of the CO atmosphere is 0.08-3 MPa; (5) In the process of adding the organic base, organophosphorus ligand, palladium catalyst, and SiH-(R) z 3. After the organic solvent and the compound of formula II are added to the reactor, a CO atmosphere is then introduced; (6) The organic base is N(R) x )3; Each R x Independently, it is a C1-6 alkyl group; (7) The molar ratio of the organic base to the compound of formula II is 1.5-2.5; (8) Each R y All are phenyl; (9) n is 3; (10) The organophosphorus ligand is ; (11) The molar ratio of the organophosphorus ligand to the compound of formula II is 0.08-1.0; (12) The palladium catalyst is a zero-valent palladium catalyst; (13) The molar ratio of the palladium catalyst to the compound of formula II is 0.03-0.15; (14) Each R z Independently, it is a C1-3 alkyl group; (15) The SiH-(R) z The molar ratio of compound 3 to compound II is 1.8-2.2; (16) The organic solvent is an amide solvent; (17) In the organic solvent, the concentration of compound of formula II is 0.05-0.15 g / mL; (18) The temperature of the carbonyl insertion reaction is 60-100 °C; (19) The SiH-(R) z )3. The reaction system is added in a one-time manner.

3. The preparation method according to claim 2, characterized in that, It meets one or more of the following conditions: (1) X is Br or I; (2) The pressure of the CO atmosphere is 0.08-1.5 MPa; (3) The CO atmosphere is introduced by charging the CO atmosphere to the target pressure in one go; (4) The organic base is N(R) x )3; Each R x Independently, it is a C1-3 alkyl group; (5) The molar ratio of the organic base to the compound of formula II is 2.0; (6) The above It is 1,4-bis(diphenylphosphine)butane; (7) The molar ratio of the organophosphorus ligand to the compound of formula II is 0.1 or 0.6; (8) The palladium catalyst is tris(dibenzylacetone)dipalladium; (9) The molar ratio of the palladium catalyst to the compound of formula II is 0.05 or 0.10; (10) Each R z Independently, it is ethyl; (11) The SiH-(R) z The molar ratio of 3 to the compound of formula II is 2.0; (12) The amide solvent is R u and R v Independently for C 1-6 alkyl; (13) The concentration of compound II in the organic solvent is 0.1 g / mL; (14) The temperature of the carbonyl insertion reaction is 75-85℃.

4. The preparation method according to claim 3, characterized in that, It meets one or more of the following conditions: (1) X is I; (2) The N(R) x )3 is N,N-diisopropylethylamine; (3) The SiH-(R) z )3 is triethylsilane; (4) The above It is N,N-dimethylformamide; (5) The pressure of the CO atmosphere is 0.1 MPa or 1.2 MPa.

5. The preparation method according to claim 1, characterized in that, The carbonyl insertion reaction further includes one or more of the following post-processing steps: Dilution, washing, concentration, pulping, and filtration.

6. The preparation method according to claim 5, characterized in that, It meets one or more of the following conditions: (1) The dilution is performed using an ester solvent; (2) The volume ratio of the ester solvent used in the dilution to the volume of the organic solvent used in the reaction system is 1-3; (3) The washing process uses water or saturated salt water; (4) The volume ratio of the water or saturated saline solution to the organic solvent used in the reaction system is 0.5-1.5; (5) The washing is performed 1-3 times; (6) The concentration is to a concentrated organic phase to remove the solvent; (7) The pulping process uses C 3-10 Slurrying is performed using straight-chain or branched alkane solvents.

7. The preparation method according to claim 1, characterized in that, The CO atmosphere pressure is 1.2 MPa, the organic base is DIPEA, the organophosphorus ligand is 1,4-bis(diphenylphosphine)butane, the palladium catalyst is tris(dibenzylacetone)dipalladium, and the SiH-(R z )3 is triethylsilane, and the organic solvent is DMF.

8. The preparation method according to claim 1, characterized in that, The carbonyl insertion reaction is carried out through the following steps: In an autoclave, 1,4-bis(diphenylphosphine)butane, N,N-dimethylformamide, tris(dibenzylacetone)dipalladium, diisopropylethylamine, triethylsilane and compound II were mixed, and the CO atmosphere was replaced to a pressure of 1.2 MPa. At 75-85 °C, compound II was subjected to a carbonylation reaction to prepare compound I.

9. The preparation method according to claim 1, characterized in that, The carbonyl insertion reaction is carried out through the following steps: 1,4-bis(diphenylphosphine)butane was added to a high-pressure reactor, and N,N-dimethylformamide, tris(dibenzylacetone)dipalladium, diisopropylethylamine, triethylsilane and compound II were added sequentially. The reaction was carried out at a carbon monoxide pressure of 1.2 MPa and a temperature of 75-85 °C until the reaction was complete as detected by LCMS. Ethyl acetate was added to the system, and the mixture was washed with water. After concentrating the organic phase to remove the solvent, n-hexane was added, and the mixture was stirred for 0.5 hours. The mixture was then filtered to obtain compound I. Preferably, the preparation method satisfies one or more of the following conditions: (1) The molar ratio of the 1,4-bis(diphenylphosphine)butane to the compound of formula II is 0.1; (2) The molar ratio of the tris(dibenzylacetone)palladium to the compound of formula II is 0.05; (3) The molar ratio of the diisopropylethylamine to the compound of formula II is 2.0; (4) The molar ratio of the triethylsilane to the compound of formula II is 2.0; (5) The concentration of compound II in the N,N-dimethylformamide is 0.1 g / mL; (6) The reaction time at 75-85℃ is 16 hours.

10. A method for preparing a compound of formula TM, comprising the following steps: (1) In the presence of nitrogen-containing heterocyclic aromatic hydrocarbons, in an ether solvent, compound 1 and trialkylchlorosilane were reacted via a substitution reaction to prepare compound 2; The nitrogen-containing heterocyclic aromatic hydrocarbon is preferably an imidazole; The preferred ether solvent is tetrahydrofuran; The trialkylchlorosilane is preferably tert-butyldimethylchlorosilane; (2) Compound I is prepared by the method for preparing compound I according to any one of claims 1-9; the structure of compound I is as shown in compound 3; (3) In the presence of Lewis acid and reducing agent, in an alcohol solvent, compound 3 is reduced to prepare compound 4; The Lewis acid is preferably cerium trichloride; The reducing agent is preferably sodium borohydride; The preferred alcohol solvent is methanol; (4) In the presence of a trialkyl tertiary amine, in an ether solvent, compound 4 and p-nitrobenzene chloroformate were reacted via a cyclization reaction to prepare compound 5; The trialkyl tertiary amine is preferably N,N-diisopropylethylamine; The preferred ether solvent is tetrahydrofuran; (5) Compound 5 was prepared by deprotection reaction in an ester solvent in the presence of a hydrofluoric acid complexing agent to obtain compound 6; The hydrofluoric acid complexing agent is preferably pyridine hydrofluoric acid; The preferred ester solvent is ethyl acetate; (6) Compound 6 and 4,4-dimethoxytriphenylmethyl chloride were substituted in an alkaline solvent to prepare compound 7; The alkaline solvent is preferably pyridine; (7) In the presence of one or more nitrogen-containing heterocyclic aromatic hydrocarbons substituted with cyano groups, compound 7 and bis(diisopropylamino)(2-cyanoethoxy)phosphine are substituted in a halocarbon solvent to prepare compound TM. The nitrogen-containing heterocyclic aromatic hydrocarbon substituted with one or more cyano groups is preferably 4,5-dicyanimidazole; The preferred halogenated hydrocarbon solvent is dichloromethane; 。

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