Synthetic method of drug intermediate 4, 6-dihydrothieno [2, 3-c] furan-2-carboxylic ester

Abstract

The invention relates to the field of compound synthesis, in particular to a synthetic method of a drug intermediate 4, 6-dihydrothieno [2, 3-c] furan-2-carboxylic ester, which has the advantages of cheap and easily available starting materials, low toxicity, environmental friendliness, no need of expensive metal ligand catalysis, suitability for large-scale production, high yield, high yield and the like, and can be used for preparing a drug intermediate 4, 6-dihydrothieno [2, 3-c] furan-2-carboxylic ester. And the obtained final product has relatively high yield and purity.

Description

Technical Field

[0001] The present invention relates to the field of compound synthesis, and particularly to a method for synthesizing a pharmaceutical intermediate 4,6-dihydrothieno[2,3-c]furan-2-carboxylate. Background Art

[0002] In the pharmaceutical field, WRN inhibitors have shown extremely broad application prospects due to their excellent potential in combating MSI-H tumors. 4,6-Dihydrothieno[2,3-c]furan-2-carboxylate (shown in Formula I) is a key intermediate for preparing such drugs, and its importance is self-evident. In particular, ethyl 4,6-dihydrothieno[2,3-c]furan-2-carboxylate, a WRN inhibitor synthesized using it as a key intermediate, has attracted much attention.

[0003] , wherein R is selected from an alkyl group of C 1-6 an alkyl group of C 3-8 a cycloalkyl group of or a benzyl group.

[0004] Currently, Example 37 of WO2015012210 discloses a milligram-scale synthesis method of ethyl 4,6-dihydrothieno[2,3-c]furan-2-carboxylate, which has exposed a series of serious problems in practical applications. This method requires the use of oxydimethylenebis(tributylstannane), ethyl 4,5-dibromo-2-thiophenecarboxylate, tris(dibenzylideneacetone)dipalladium, and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and is completed by microwave heating in a 1,4-dioxane system. The product separation and purification yield is only 28%. [[ID=2I]]

[0005]

[0006] From the perspective of starting materials, the selected raw materials are not only difficult to purchase in the market, but their own synthesis process is also extremely complex, which undoubtedly greatly increases the production difficulty and significantly increases the production cost. In terms of toxicity and environmental impact, oxydimethylenebis(tributylstannane) has high toxicity and will cause serious harm to the environment during the production process. In terms of the catalytic system, the use of a palladium metal catalyst with a corresponding ligand not only results in high costs, but also the problem of metal residue is inevitable, which not only affects the product quality, but also greatly increases the subsequent treatment cost. In addition, the conditions required for microwave reaction are extremely harsh, and the supporting instrument equipment is expensive. It is generally applicable to laboratory-scale research and is difficult to be directly applied to large-scale industrial production.

[0007] In summary, existing synthetic methods for ethyl 4,6-dihydrothieno[2,3-c]furan-2-carboxylate suffer from numerous shortcomings, far from meeting the demands of practical production. Therefore, developing a synthetic route that utilizes inexpensive, readily available, and low-toxic starting materials, eliminates the need for palladium metal and phosphine ligand catalysis, is suitable for large-scale production, and simultaneously ensures high yield and high purity has become a critical challenge. Summary of the Invention

[0008] The present invention provides a method for synthesizing 4,6-dihydrothieno[2,3-c]furan-2-carboxylate. The method not only has cheap and readily available starting materials, low toxicity and is environmentally friendly, does not require expensive metal ligand catalysis, is suitable for scaled-up production, but also has high yield and purity of the obtained final product.

[0009] A process for synthesizing 4,6-dihydrothieno[2,3-c]furan-2-carboxylate, comprising: Step (1): Compound 1 is subjected to a substitution reaction with thioglycolate in a base, a catalyst and a solvent to obtain compound 2. ; Step (2): removing the tert-butyl group from compound 2 in an acid and a solvent to obtain compound 3. ; Step (3): Compound 3 is subjected to a reduction reaction in the presence of a reducing agent, a base, a catalyst, a solvent and a temperature to obtain compound 4. ; Step (4): Compound 4 undergoes a ring-closure reaction in the presence of a base, a solvent, and a reaction temperature to obtain a compound of formula I. , Wherein, R is selected from C 1-6 Alkyl, C 3-8 a cycloalkyl or benzyl group; The base in step (1) is selected from one or more of triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane; the solvent in step (1) is selected from one or more of dichloromethane, ethylene glycol monomethyl ether, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetone, and toluene; the reaction temperature in step (1) is 0-50°C; The acid described in step (2) is selected from one or more of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, p-toluenesulfonic acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, and hydroiodic acid; the solvent described in step (2) is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, diethyl ether, toluene, ethylene glycol dimethyl ether, 1,4-dioxane, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, methyltetrahydrofuran, dimethyl sulfoxide, and N-methylpyrrolidone; the reaction temperature in step (2) is 0 to 60 °C; The reducing agent described in step (3) is selected from one or more of borane solution, sodium bis(2-methoxyethoxy)aluminum hydride, triethylsilane, sodium borohydride, lithium borohydride, lithium aluminum hydride, and pinacol borane; the base described in step (3) is selected from one or more of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1-pyridin-4-ylpiperidine, 4-pyrrolidinylpyridine, and 4-(pyridin-4-yl)morpholine; the catalyst described in step (3) is selected from one or more of triethylamine trifluoromethanesulfonate, diisopropylethylamine trifluoromethanesulfonate, 4-dimethylaminopyridinium trifluoromethanesulfonate, 1-pyridin-4-ylpiperidinium trifluoromethanesulfonate, 4-pyrrolidinylpyridinium trifluoromethanesulfonate, and 4-(pyridin-4-yl)morpholinium trifluoromethanesulfonate; the solvent described in step (3) is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, methyltetrahydrofuran, acetone, toluene, ethylene glycol dimethyl ether, and 1,4-dioxane; the reaction temperature in step (3) is -10 to 50 °C.

[0010] The base described in step (4) is selected from one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, and potassium trimethylsilanolate; the solvent described in step (4) is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, methyltetrahydrofuran, acetone, toluene, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone; the reaction temperature in step (4) is 0 to 40 °C.

[0011] In some embodiments, the base in step (1) is preferably triethylamine, diisopropylethylamine, or pyridine, more preferably triethylamine; the solvent is preferably acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, or methyltetrahydrofuran, more preferably acetonitrile; the reaction temperature is 20 to 30 °C, such as 20 °C or 25 °C.

[0012] In some embodiments, the acid in step (2) is preferably hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, more preferably trifluoroacetic acid; the solvent is preferably dichloromethane, ethylene glycol dimethyl ether, acetonitrile, more preferably dichloromethane; the reaction temperature is preferably 20~30°C, such as 25°C, 30°C.

[0013] In some embodiments, the reducing agent in step (3) is pinacol borane; the base is 4-dimethylaminopyridine; the catalyst is 4-diaminopyridinium trifluoromethanesulfonate; the solvent is preferably dichloromethane, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, more preferably dichloromethane; the reaction temperature is preferably -10~10°C, such as -5°C, 0°C, 5°C.

[0014] In some embodiments, the base in step (4) is preferably 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, potassium trimethylsilanolate, more preferably 1,8-diazabicyclo[5.4.0]undec-7-ene; the solvent is preferably dichloromethane, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, more preferably dichloromethane; the reaction temperature is preferably 20~30°C, more preferably 20~35°C, such as 25°C, 30°C.

[0015] In some embodiments, the yield of step (4) is greater than 80%, or the total yield of steps (3) and (4) is more than 40%.

[0016] In some embodiments, the purity of the compound of formula I obtained in step (4) is more than 95%.

[0017] In some embodiments, R is ethyl. Detailed Description of the Invention

[0018] The following further illustrates the content of the present invention through specific examples, but it should not be understood that the scope of the present invention is limited to the following examples. All the methods, steps, reagents, temperatures and other features disclosed in this specification can be combined or reasonably replaced in any way, except for obvious contradictions or mutually exclusive situations, and these all belong to the scope of protection of the present invention.

[0019] Example 1

[0020] Step 1: Add compound 1 (80 kg, 429.6 mol) and acetonitrile (640 kg) into the reaction kettle, stir, then add triethylamine (144 kg, 1425.7 mol). Cool the reaction solution to 5 - 10 °C, and dropwise add diphenyl chlorophosphate (128 kg, 476.5 mol). Control the temperature below 25 °C. After the addition is complete, stir at 20 - 25 °C for 1 - 2 hours. Cool the reaction solution to 0 - 10 °C, and slowly add ethyl mercaptoacetate (68.8 kg, 572.5 mol) while controlling the temperature below 25 °C. Stir at 20 - 25 °C for 1 - 2 hours. Detect by high-performance liquid chromatography that all the raw materials are converted. Add ethyl acetate (720 kg) and water (800 kg), extract and separate the liquid. Extract the aqueous phase again with ethyl acetate (320 kg). Combine the organic phases and concentrate under reduced pressure at 45 °C until no obvious liquid flows out to obtain a crude product of compound 2 (160 kg) as a yellow oil. The crude product is directly used for the next reaction without further purification. LC-MS (ESI): m / z 289.1 [M + H] + 。

[0021]

[0022] Step 2: Add compound 2 (160 kg) and dichloromethane (640 kg) into the reaction kettle, stir, and add trifluoroacetic acid (368 kg). Stir at 20 - 30 °C for 12 - 16 hours. Detect by high-performance liquid chromatography that all the raw materials are converted. Add dichloromethane (2080 kg) and water (1600 kg) to the reaction solution, extract and separate the liquid. Concentrate the organic phase under reduced pressure at 45 °C until no obvious liquid flows out. Add ethyl acetate (320 L), stir, and slowly add n-heptane (1600 L). Stir for 2 - 3 hours, filter, and dry the filter cake at 40 - 50 °C to obtain compound 3 (88 kg, total yield of steps (1) and (2): 88.1%) as a white solid. LC-MS (ESI): m / z 231.0 [M - H] + 。

[0023] 1 H NMR (400 MHz, DMSO) δ4.95 - 4.85 (m, 2H), 4.75 - 4.68 (m, 2H), 4.13(q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H).

[0024] Step 3: Add compound 3 (44 kg, 189.7 mol), 4-dimethylaminopyridine (32.6 kg, 266.5 mol) and dichloromethane (1760 kg) into the reaction kettle, stir until dissolved and clear, cool down to -10 - 0 °C, add 4-diaminopyridinium trifluoromethanesulfonate (97.6 kg, 294.0 mol) in batches, dropwise add pinacol borane (36.5 kg, 285.3 mol) at -10 - 0 °C, stir for 0.5 - 1 hour, detect by high performance liquid chromatography that all raw materials are converted, add 3M hydrochloric acid aqueous solution (450 kg) to the reaction solution at 0 - 5 °C, add water (1000 kg) again, stir, extract and separate the liquid, extract the aqueous phase with dichloromethane (800 kg) again, combine the organic phases and wash with water (1000 kg), concentrate the organic phase under reduced pressure at 45 °C until no obvious liquid flows out to obtain crude compound 4 (41 kg), a brown oil.

[0025] 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 5.00 – 4.94 (m, 2H), 4.92 – 4.86 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0026]

[0027] Step 4: Add compound 4 (40 kg, 185.1 mol) and dichloromethane (1600 kg) into the reaction kettle, stir until dissolved and clear, add 1,8-diazabicyclo[5.4.0]undec-7-ene (20.3 kg, 133.6 mol) at 20 - 25 °C, stir at 20 - 25 °C for 1 - 2 hours, detect by high performance liquid chromatography that all raw materials are converted, add 3M hydrochloric acid aqueous solution (400 kg) to the reaction solution at 20 - 25 °C, stir, extract and separate the liquid, extract the aqueous phase with dichloromethane (800 kg) again, combine the organic phases and wash with water (1000 kg), separate the liquid, concentrate the organic phase under reduced pressure at 45 °C until no obvious liquid flows out to obtain the crude product, and purify the crude product by silica gel column chromatography (eluted with 1% - 5% ethyl acetate - n - heptane) to obtain compound I (16.8 kg, purity: 98.8%, total yield of steps (3) and (4): 44.8%). LC - MS (ESI): m / z 199.0 [M + H] + 。 1 HNMR(400MHz,DMSO)δ7.60(s,1H),5.00(t, J =4Hz,2H),4.86(t, J =4Hz,2H),4.28(q,J = 8 Hz, 2H), 1.28 (t, J = 8 Hz, 3H).

[0028] Example 2

[0029] Step 1: Add compound 1 (10 g, 53.8 mmol) and tetrahydrofuran (100 ml) into a 250 ml three-necked flask, stir to dissolve, add triethylamine (19.0 g, 188.3 mmol), cool down to 5 - 10 °C in an ice-water bath, dropwise add diphenyl phosphorochloridate (17.2 g, 64.1 mmol). After the addition, stir at room temperature for 1 - 2 hours. Cool the reaction solution to 0 - 10 °C in an ice-water bath, slowly add ethyl mercaptoacetate (9.4 g, 78.7 mmol), stir at room temperature for 1 - 2 hours. Detect by thin-layer chromatography that all the raw materials are converted. Add ethyl acetate (200 ml) and water (200 ml), extract and separate the layers. Extract the aqueous phase with ethyl acetate (100 ml) again. Combine the organic phases, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to remove the solvent to obtain a crude yellow oil. Purify the crude product by silica gel column chromatography (gradient elution with 3% - 10% ethyl acetate - petroleum ether solution) to obtain compound 2 (13.1 g, yield: 85%). LC-MS (ESI): m / z 289.1 [M + H] + .

[0030] Step 2: Add compound 2 (15 g, 52.1 mmol), tetrahydrofuran (100 ml) and water (100 ml) into a 250 ml three-necked flask, stir to dissolve, cool down to 5 - 10 °C in an ice-water bath, add concentrated hydrochloric acid (13 ml, 156.3 mmol). After the addition, stir at room temperature for 16 hours. Detect by thin-layer chromatography that all the raw materials are converted. Add ethyl acetate (300 ml) and water (200 ml), extract and separate the layers. Extract the aqueous phase with ethyl acetate (150 ml) again. Combine the organic phases, wash with water, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to remove the solvent to obtain a crude product. Purify the crude product by crystallization from ethyl acetate / n-heptane (1:5, 180 ml) to obtain compound 3 (7.3 g, yield: 61%). LC-MS (ESI): m / z 231.0 [M - H] + .

[0031] Step 3: Add compound 3 (6 g, 25.8 mmol), 4-dimethylaminopyridine (4.4 g, 36.1 mmol) and dichloromethane (200 ml) into a 500 ml three-necked flask. Stir until dissolved and clear, cool down to -10 - 0 °C, and add 4-diaminopyridinium trifluoromethanesulfonate (10.8 g, 40.0 mmol) in batches. Dropwise add pinacolborane (5.1 g, 40.0 mol) at -10 - 0 °C, stir for 0.5 - 1 hour. Detect by high-performance liquid chromatography that all the raw materials are converted. Quench by adding 3 M hydrochloric acid aqueous solution (30 ml) to the reaction solution at 0 - 5 °C, add water (100 mL), stir, extract and separate. Extract the aqueous phase with dichloromethane (50 ml) again. Combine the organic phases, wash with water (200 ml), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (gradient elution with 3% - 10% ethyl acetate - petroleum ether solution) to obtain compound 4 (3.2 g, yield: 57.3%).

[0032] Step 4: Add compound 4 (8.0 g, 37.0 mmol) and N,N-dimethylformamide (40 ml) into a 100 ml three-necked flask. Stir until dissolved and clear. Add potassium carbonate (10.2 g, 74 mmol) at 20 - 25 °C, stir at 20 - 25 °C for 1 - 2 hours. Detect by high-performance liquid chromatography that all the raw materials are converted. Add ethyl acetate (160 ml) and water (160 ml) to the reaction solution at 20 - 25 °C, stir, extract and separate. Extract the aqueous phase with ethyl acetate (80 ml) again. Combine the organic phases, wash with 0.5 N hydrochloric acid aqueous solution (200 ml) and water (200 ml) respectively. Dry the organic phase over anhydrous sodium sulfate and rotary evaporate under reduced pressure to obtain the crude product. Purify the crude product by silica gel column chromatography (elution with 1% - 5% ethyl acetate - n-heptane) to obtain compound I (6.0 g, yield: 81.8%), LC-MS (ESI): m / z 199.0 [M + H] + 。

[0033] Example 3

[0034] Step 1: Add compound 1 (10 g, 53.8 mmol) and acetonitrile (100 ml) into a 250 ml three-necked flask, stir to dissolve, add diisopropylethylamine (24.3 g, 188.3 mmol), cool down to 5 - 10 °C in an ice-water bath, dropwise add diphenyl phosphorochloridate (17.2 g, 64.1 mmol). After the addition, stir at room temperature for 1 - 2 hours. Cool the reaction solution to 0 - 10 °C in an ice-water bath, slowly add ethyl mercaptoacetate (9.4 g, 78.7 mmol), stir at room temperature for 1 - 2 hours. Detect by thin-layer chromatography that all the raw materials are converted. Add ethyl acetate (200 ml) and water (200 ml), extract and separate the layers. Extract the aqueous phase again with ethyl acetate (100 ml). Combine the organic phases, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to remove the solvent to obtain a crude yellow oil. Purify the crude product by silica gel column chromatography (gradient elution with 3% - 10% ethyl acetate - petroleum ether solution) to obtain compound 2 (14.1 g, yield: 91.50%). LC-MS (ESI): m / z 289.1 [M + H] + 。

[0035] Step 2: Add compound 2 (20 g, 69.4 mmol) and dichloromethane (200 ml) into a 250 ml three-necked flask, stir to dissolve, cool down to 5 - 10 °C in an ice-water bath, add trifluoroacetic acid (30 ml), stir at room temperature for 16 hours. Detect by thin-layer chromatography that all the raw materials are converted. Add dichloromethane (100 ml) and water (300 ml), extract and separate the layers. Extract the aqueous phase again with dichloromethane (100 ml). Combine the organic phases, wash with water, dry over anhydrous sodium sulfate, and rotary evaporate under reduced pressure to remove the solvent to obtain a crude product. Purify the crude product by crystallization from ethyl acetate / n-heptane (1:5, 240 ml) to obtain compound 3 (14.7 g, yield: 91%). LC-MS (ESI): m / z 231.0 [M - H] + 。

[0036] Step 3: Add compound 3 (10 g, 25.8 mmol), 1-pyridin-4-ylpiperidine (9.7 g, 60.3 mmol) and dichloromethane (300 ml) into a 500 ml three-necked flask, stir until dissolved and clear, cool down to -10 - 0 °C, add 1-pyridin-4-ylpiperidinium trifluoromethanesulfonate (29.7 g, 66.8 mmol) portionwise, add pinacolborane (8.5 g, 66.8 mmol) dropwise under the condition of -10 - 0 °C, stir for 0.5 - 1 hour, detect by high performance liquid chromatography that all the raw materials are converted, add 3 M hydrochloric acid aqueous solution (50 ml) to quench the reaction solution under the condition of 0 - 5 °C, add water (200 mL), stir, extract and separate the layers, extract the aqueous phase with dichloromethane (100 ml) again, combine the organic phases, wash with water (300 ml), dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography (gradient elution with 3% - 10% ethyl acetate - petroleum ether solution) to obtain compound 4 (4.8 g, yield: 51.6%).

[0037] Step 4: Add compound 4 (10.0 g, 46.3 mmol) and acetonitrile (100 ml) into a 250 ml three-necked flask, stir until dissolved and clear, add 1,8-diazabicyclo[5.4.0]undec-7-ene (35.2 g, 92.6 mmol) at 20 - 25 °C, stir at 20 - 25 °C for 4 hours, detect by high performance liquid chromatography that all the raw materials are converted, add ethyl acetate (100 ml) and water (200 ml) to the reaction solution at 20 - 25 °C, stir, extract and separate the layers, extract the aqueous phase with ethyl acetate (100 ml) again, combine the organic phases, wash with water (100 ml), dry the organic phase with anhydrous sodium sulfate, rotary evaporate under reduced pressure to obtain the crude product, and purify the crude product by silica gel column chromatography (elution with 1% - 5% ethyl acetate - n-heptane) to obtain compound I (7.6 g, yield: 83.2%). LC-MS (ESI): m / z 199.0 [M + H] + 。

Claims

1. A method for synthesizing 4,6-dihydrothieno[2,3-c]furan-2-carboxylate, characterized in that, The method includes the following steps: Step (1): A substitution reaction is carried out on compound 1 and mercaptoacetate in the presence of a base, a catalyst and a solvent to obtain compound 2. ； Step (2): The tert-butyl group of compound 2 is removed in an acid and a solvent to obtain compound 3. ； Step (3): A reduction reaction is carried out on compound 3 in the presence of a reducing agent, a base, a catalyst, a solvent and at a certain temperature to obtain compound 4. ； Step (4): A ring-closing reaction occurs on compound 4 in a base, a solvent and at a reaction temperature to obtain the compound of formula I. ， Among them, R is selected from an alkyl group of C 1-6 , a cycloalkyl group of C 3-8 , or benzyl; The base described in step (1) is selected from one or more of triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane; the solvent described in step (1) is selected from one or more of dichloromethane, ethylene glycol monomethyl ether, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetone, toluene; the reaction temperature in step (1) is 0-50 °C. The acid described in step (2) is selected from one or more of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, p-toluenesulfonic acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid; the solvent described in step (2) is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, diethyl ether, toluene, ethylene glycol dimethyl ether, 1,4-dioxane, methanol, ethanol, isopropanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, methyltetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone; the reaction temperature in step (2) is 0-60 °C. The reducing agent described in step (3) is selected from one or more of borane solution, sodium bis(2-methoxyethoxy)aluminum dihydride, triethylsilane, sodium borohydride, lithium borohydride, lithium aluminum hydride, pinacolborane; the base described in step (3) is selected from one or more of triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1-pyridin-4-ylpiperidine, 4-pyrrolidinylpyridine, 4-(pyridin-4-yl)morpholine; the catalyst described in step (3) is selected from one or more of triethylamine trifluoromethanesulfonate, diisopropylethylamine trifluoromethanesulfonate, 4-diaminopyridinium trifluoromethanesulfonate, 1-pyridin-4-ylpiperidinium trifluoromethanesulfonate, 4-pyrrolidinylpyridinium trifluoromethanesulfonate, 4-(pyridin-4-yl)morpholinium trifluoromethanesulfonate; the solvent described in step (3) is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, methyltetrahydrofuran, acetone, toluene, ethylene glycol dimethyl ether, 1,4-dioxane; the reaction temperature in step (3) is -10-50 °C. The base described in step (4) is selected from one or more of 1,8-diazabicyclo[5,4,0]undec-7-ene, triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydride, and potassium trimethylsilanolate; the solvent described in step (4) is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, methyltetrahydrofuran, acetone, toluene, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or N-methylpyrrolidone; the reaction temperature in step (4) is 0 to 40 °C.

2. The method according to claim 1, wherein The base in step (1) is selected from triethylamine, the solvent is selected from acetonitrile, and the reaction temperature is 20 to 30 °C.

3. The method according to claim 1, wherein The acid in step (2) is selected from trifluoroacetic acid, the solvent is selected from dichloromethane, and the reaction temperature is 20 to 30 °C.

4. The method according to claim 1, wherein The reducing agent in step (3) is pinacol borane; the base is 4-dimethylaminopyridine; the catalyst is 4-diaminopyridinium trifluoromethanesulfonate; the reaction solvent is dichloromethane; the reaction temperature is -10 to 10 °C.

5. The method according to claim 1, characterized in that The base in step (4) is 1,8-diazabicyclo[5,4,0]undec-7-ene; the solvent is dichloromethane; the reaction temperature is 20 to 30 °C.

6. The method according to claim 1, characterized in that, The yield of step (4) is greater than 80%, or the total yield of steps (3) and (4) is more than 40%.

7. The method according to claim 1, wherein The purity of the compound of formula I obtained in step (4) is more than 95%.

8. The method according to claim 1, characterized in that, R is ethyl.

Images