Preparation method of acyl ethyl ester polycyclic compound

Abstract

The invention relates to a preparation method of an acyl ethyl ester polycyclic compound, which comprises the following steps: reacting a compound shown as a formula (III) with a compound shown as a formula (II) to obtain a compound shown as a formula (I); definitions of substituent groups in the formula (I), the formula (II) and the formula (III) are shown in the specification. According to the preparation method, the obtained product is high in purity and low in cost, and the process is more suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing a pharmaceutical raw material, in particular to a method for preparing an acylated ethyl ester polycyclic compound. Background Art

[0002] Influenza, also known as flu, is an acute respiratory infectious disease caused by influenza virus. Influenza virus is the pathogen that causes influenza, belongs to the Orthomyxoviridae family, and is an RNA virus.

[0003] Currently known small molecule anti-influenza virus drugs include the neuraminidase inhibitor oseltamivir, the viral polymerase inhibitor mabaloxavir, and the M2 ion channel blocker amantadine.

[0004] Patents WO2016175224A1 and WO2017221869A1 disclose methods for docking dibenzothiol rings and oxazine pyridine triazine rings. In the presence of solvents such as ethyl acetate, cyclohexane, isopropyl acetate, propyl acetate, toluene, 1,4-dioxane, DMA, DMF, toluene, heptane, cyclopentyl methyl ether, or a mixed solvent of these solvents, T3P (propyl phosphoric anhydride), methanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid monohydrate, 10-camphorsulfonic acid, concentrated sulfuric acid, dichloroacetic acid, tetramethylammonium hydrogen sulfate, and other condensation agents are added to compound A5 and compound A6. These can be used alone or in combination, preferably a mixture of T3P and methanesulfonic acid, and reacted at 0 to 120° C. for 1 to 10 hours, thereby obtaining compound A7:

[0005]

[0006] Patent CN109504721A discloses a method for docking a dibenzothiol ring and an oxazine pyridine triazine ring by Mitsubobu reaction, wherein the condensation agent is selected from triphenylphosphine / DIAD or triphenylphosphine / DEAD; the reaction solvent is selected from dichlorohexane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene or xylene, and the reaction temperature is generally between -10°C and 110°C:

[0007]

[0008] Patent CN112940009A discloses a method of preparing a mesylate from the hydroxyl group of a dibenzothiol ring and then docking it with an oxazine pyridine triazine ring:

[0009] Summary of the invention

[0010] Although the above three patent applications disclose corresponding preparation methods, the applicant has repeated the above three methods but still failed to synthesize the acylated ester polycyclic compound (Formula (I'), Formula (I'-1) or Formula (I'-2)) of the present invention.

[0011] The present application provides a novel method for preparing an acylated ethyl ester polycyclic compound, wherein the acylated ethyl ester polycyclic compound is as shown in formula (I'), formula (I'-1), and formula (I'-2):

[0012]

[0013] The preparation method of the present invention not only obtains a product with high purity and low cost, but also has a process that is more suitable for industrial production.

[0014] The present invention provides a novel method for preparing an acylated ethyl ester polycyclic compound, wherein the acylated ethyl ester polycyclic compound is as shown in formula (I):

[0015]

[0016] In formula (I), R1, R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen and deuterium;

[0017] The preparation method comprises the following steps:

[0018] The compound of formula (III) reacts with the compound of formula (II) to obtain the compound of formula (I)

[0019]

[0020] Wherein, R1, R2, R3, R4, R5, R6 and R7 in formula (III) are defined the same as in formula (I); and X in formula (II) is chlorine, bromine or iodine.

[0021] In an embodiment of the present invention, the preparation method further comprises the following steps: the compound of formula (III) is obtained by removing the amino protecting group of the compound of formula (IV);

[0022]

[0023] In formula (IV), R1, R2, R3, R4, R5, R6 and R7 are defined the same as in formula (III); in formula (IV), Pr is an amino protecting group, optionally selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

[0024] In an embodiment of the present invention, the preparation method further comprises the following steps: the compound of formula (IV) is obtained by coupling reaction of the compound of formula (V) and the compound of formula (VI);

[0025]

[0026] In formula (VI), R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (III); in formula (VI), Y is bromine, chlorine or iodine.

[0027] In an embodiment of the present invention, the present invention provides a method for preparing an acylated ester polycyclic compound as shown in formula (I), the preparation method comprising the following steps:

[0028] (a) coupling reaction of a compound of formula (V) with a compound of formula (VI) to obtain a compound of formula (IV);

[0029]

[0030] (b) removing the amino protecting group of the compound of formula (IV) to obtain a compound of formula (III);

[0031]

[0032] (c) reacting a compound of formula (III) with a compound of formula (II) to obtain a compound of formula (I);

[0033]

[0034] Wherein, in formula (I), formula (III), formula (IV) and formula (VI), R1, R2, R3, R4, R5, R6 and R7 are hydrogen or deuterium; in formula (II), X is chlorine, bromine or iodine; in formula (IV), Pr is an amino protecting group, optionally selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz); in formula (VI), Y is bromine, chlorine or iodine.

[0035] In an embodiment of the present invention, the preparation method of the present application further comprises: reacting the compound of formula (C-0) with an amino protecting group to obtain a compound of formula (VII); and debenzylating the compound of formula (VII) to obtain a compound of formula (V);

[0036]

[0037] In formula (C-0) and formula (VII), Bn is benzyl; in formula (VII) and formula (V), Pr is an amino protecting group, optionally selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

[0038] In some embodiments of the present invention, R1, R2, R3, R4, R5, R6 and R7 in Formula (I), Formula (III), Formula (IV) and Formula (VI) are all hydrogen.

[0039] In some embodiments of the present invention, in the formula (I), formula (III), formula (IV) and formula (VI), R1, R2 and R3 are all deuterium, and R4, R5, R6 and R7 are all hydrogen.

[0040] In some embodiments of the present invention, X in formula (II) is chlorine or bromine; in one embodiment of the present invention, X in formula (II) is chlorine.

[0041] In some embodiments of the present invention, Pr in formula (IV), formula (V) and formula (VII) is tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) or benzyloxycarbonyl (Cbz); in one embodiment of the present invention, Pr in formula (IV) and formula (V) is tert-butyloxycarbonyl (Boc).

[0042] In some embodiments of the present invention, Y in formula (VI) is bromine or chlorine; in one embodiment of the present invention, Y in formula (VI) is bromine.

[0043] In one embodiment of the present invention, R1, R2, R3, R4, R5, R6 and R7 in formula (I) are all hydrogen, that is, the compound of formula (I) is a compound of formula (I').

[0044] In one embodiment of the present invention, the compound of formula (I) is a compound of formula (I'-1).

[0045] In one embodiment of the present invention, the compound of formula (I) is a compound of formula (I'-2).

[0046] In one embodiment of the present invention, the present invention provides a method for preparing an acylated ester polycyclic compound as shown in formula (I'), the preparation method comprising the following steps:

[0047] (1) reacting the compound of formula (C-0) with di-tert-butyl dicarbonate to obtain a compound of formula (C-1);

[0048]

[0049] (2) the compound of formula (C-1) is subjected to a debenzylation reaction to obtain a compound of formula (C-2);

[0050]

[0051] (3) reacting the compound of formula (C-2) with 1-bromoethyl acetate to obtain a compound of formula (C-3);

[0052]

[0053] (4) removing the Boc protecting group from the compound of formula (C-3) under acidic conditions to obtain a compound of formula (C-4);

[0054]

[0055] (5) The compound of formula (C-4) is subjected to coupling reaction with the compound of formula (M2-C2) to obtain a compound of formula (I')

[0056]

[0057] In some embodiments, the step (1) is: putting the compound of formula (C-0), the reaction solvent, triethylamine and DMAP into a reactor, adding di-tert-butyl dicarbonate at a temperature of 0 to 10°C, and reacting at room temperature for 2 to 10 hours after the addition. After the reaction is completed, the compound of formula (C-1) is obtained by concentrating under reduced pressure. In some embodiments, the reaction solvent in the step (1) can be selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, water, etc., preferably tetrahydrofuran; the molar ratio of the compound of formula (C-0), triethylamine and di-tert-butyl dicarbonate is 1:1.5-2.5:1.5-2.5, preferably 1:2.0:2.0.

[0058] In some embodiments, the step (2) is: putting the compound of formula (C-1) obtained in step (1), the reaction solvent, palladium carbon, and ammonium formate into a reactor, and keeping the reaction at room temperature for 1 to 10 hours. After the reaction is completed, suction filtration, the filtrate is concentrated under reduced pressure, dichloromethane / water is added to the residue for extraction, phase separation, the aqueous phase is discarded, anhydrous sodium sulfate is added to the organic phase for drying for 1 hour, suction filtration, the filtrate is concentrated under reduced pressure, and a dichloromethane / n-hexane mixed solution is added to the residue for recrystallization, cooling and crystallization, centrifugation, and the wet product is dried to constant weight to obtain a compound of formula (C-2). In some embodiments, the reaction solvent in the step (2) can be selected from methanol, ethanol, isopropanol, water, etc., preferably methanol; the molar ratio of the compound of formula (C-2) to ammonium formate is 1:4-6, preferably 1:5; the amount of palladium carbon is 0.05 to 0.2 times, preferably 0.1 times.

[0059] In some embodiments, the step (3) is: the compound of formula (C-2) obtained in step (2), the reaction solvent, 1-bromoethyl acetate, and the base are sequentially added to the reaction bottle, and the reaction is stirred for 15 to 20 hours. After the reaction is completed, the filtrate is filtered, and the filtrate is washed with water twice, the phases are separated, and the aqueous phase is discarded. Anhydrous sodium sulfate is added to the organic phase and dried for 1 hour, filtered, and the filtrate is concentrated under reduced pressure to obtain the compound of formula (C-3). In some embodiments, the reaction solvent in step (3) can be selected from acetonitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, etc., preferably dichloromethane; the base can be selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium tert-butoxide, etc., preferably sodium bicarbonate; the molar ratio of the compound of formula (C-2), 1-bromoethyl acetate, and the base is 1:2-3:2-3, preferably 1:2.5:2.5; the reaction temperature is selected from 20°C to 50°C, preferably 40°C to 50°C.

[0060] In some embodiments, the step (4) is: the compound of formula (C-3) obtained in step (3), the acid, and the reaction solvent are sequentially added to the reaction bottle, and the reaction is stirred for 3 to 20 hours. After the reaction is completed, dichloromethane / saturated sodium bicarbonate aqueous solution is added to the reaction solution for extraction, phase separation, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, anhydrous sodium sulfate is added to the organic phase and dried for 1 hour, filtered, the filtrate is concentrated under reduced pressure, tetrahydrofuran / methyl tert-butyl ether mixed solution is added to the concentrate for recrystallization, suction filtration, and the wet product is dried to constant weight to obtain the compound of formula (C-4). In some embodiments, the reaction solvent used in step (4) can be selected from water, acetonitrile, methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrofuran, etc., preferably water; the acid can be selected from formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc., preferably formic acid; the molar ratio of the compound of formula (C-3) to formic acid is 1:1-3, preferably 1:1.5; the reaction temperature is selected from 20°C to 70°C, preferably 20°C to 30°C.

[0061] In some embodiments, the step (5) is: adding the compound of formula (C-4), the compound of formula (M2-C2), and acetonitrile obtained in step (4) to a reaction bottle, adding potassium carbonate at about 0°C, and stirring for 12 hours. Add dichloromethane and stir for 1 hour. Filter by suction, concentrate the filtrate, add a solvent and stir to crystallize. Filter by suction, and dry the wet product to constant weight to obtain a compound of formula (I'). In one embodiment, the compound of formula (I') is recrystallized from acetonitrile multiple times to obtain a compound of formula (I'-1), and the mother liquor of the recrystallization is slurried with MTBE after column chromatography to obtain a compound of formula (I'-2). In some embodiments, the solvent for the condensation reaction in step (5) is acetonitrile, DMF, preferably acetonitrile; the base can be an inorganic base or an organic base, the inorganic base can be selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, and the organic base can be selected from DBU, N-methylmorpholine, sodium bistrimethylsilylamide, preferably potassium carbonate and sodium bistrimethylsilylamide, more preferably potassium carbonate. The reaction temperature is selected from -10°C to 90°C, preferably -5°C to 35°C, more preferably -5°C to 5°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 is the mass spectrum of C-1;

[0063] Figure 2 is the mass spectrum of C-2;

[0064] Figure 3 is the mass spectrum of C-3;

[0065] Figure 4 is the mass spectrum of C-4;

[0066] Figure 5 is the mass spectrum of formula (I').

[0067] Figure 6 It is a related substance diagram of formula (I'-2). DETAILED DESCRIPTION

[0068] The embodiments of the present invention are described below by specific examples. For those skilled in the art, these specific examples do not constitute a limitation on the scope of the present invention. Under the guidance of the present invention, obvious substitutions using techniques known in the art still fall within the scope of protection of the present invention.

[0069] LC-MS detection method:

[0070] In an embodiment of the present invention, the mass spectrometer is: Agilent 6120 liquid spectrometer-mass spectrometer.

[0071] Chromatographic column: KROMASIL-C18 (150×4.6mm, 5μm) Mobile phase: 0.1% formic acid-acetonitrile (60:40)

[0072] UV detection wavelength: 254nm

[0073] Flow rate: 1.0ml / min

[0074] Mass spectrometry: ESI

[0075] Related substance detection methods:

[0076] Chromatographic column: Innertsil TM ODS-3V (250×4.6mm, 5μm)

[0077] Mobile phase A: 0.1% phosphoric acid water; Mobile phase B: methanol-acetonitrile (50:50)

[0078] T(min)0 5 30 30.1 40

[0079] B(%)50 50 85 50 50

[0080] UV detection wavelength: 210nm

[0081] Column temperature: 35°C

[0082] Flow rate: 1.0ml / min

[0083] The technical solution of the present invention is further specifically described below through specific embodiments; however, the present invention is not limited to these embodiments.

[0084] Example 1

[0085] Add 30g C-0, 18.5g triethylamine, 1.1g DMAP and 300mL tetrahydrofuran to the reaction bottle in sequence, cool to 0-10°C, add 40g di-tert-butyl dicarbonate dropwise, and stir at room temperature for 3h. Concentrate under reduced pressure to obtain a semi-oil and semi-solid C-1, which is directly used in the next step. The yield is calculated as 100%. Take 2g of C-1 concentrate, pass it through a column with ethyl acetate / n-hexane = 1 / 30, concentrate the eluent and slurry it with 10mL n-hexane to obtain 1.5g of C-1 solid for mass spectrometry detection.

[0086] ESI:[M+H] + 428.3 (see Figure 1 ).

[0087] Example 2

[0088] Add 10g C-0, 4g triethylamine, 0.2g DMAP and 300mL dichloromethane to the reaction bottle in sequence, cool to 0-10°C, add 8.8g di-tert-butyl dicarbonate dropwise, and stir at room temperature for 10h. Concentrate under reduced pressure to obtain a semi-oil and semi-solid C-1, which is directly used in the next step. The yield is calculated as 100%.

[0089] Example 3

[0090] 39g C-1, 28.9g ammonium formate, and 390mL methanol were added to the reaction bottle in sequence, replaced with nitrogen, and 3.9g palladium carbon was added, and the mixture was stirred at room temperature for 2h. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. 390mL of dichloromethane and 195mL of saturated brine were added to the residue, stirred, separated, the aqueous phase was discarded, the organic phase was dried over anhydrous sodium sulfate for 1h, filtered, the filtrate was concentrated to dryness under reduced pressure, 117mL of dichloromethane / 312mL of n-hexane mixture was added to the residue for recrystallization, the temperature was lowered to 0-5℃ for crystallization for 2 hours, filtered, and the wet product was dried to constant weight to obtain 28g of off-white solid of formula C-2, with a yield of 91%.

[0091] ESI:[M+H] + 338.2 (see Figure 2 ).

[0092] Example 4

[0093] Add 40g C-2, 49.2g 1-bromoethyl acetate, 24.9g sodium bicarbonate, 400mL dichloromethane to the reaction bottle, stir and control the temperature at 40-50°C for 15h. Cool to room temperature, filter, wash the filtrate with water twice, and dry the obtained organic phase with anhydrous sodium sulfate for 1h. Filter by suction, and concentrate the filtrate under reduced pressure to obtain a semi-oil and semi-solid C-3, which is directly put into the next step, and the yield is calculated as 100%. Take 1g of C-3 concentrate, dichloromethane / methanol = 1 / 50 column, concentrate the eluent and slurry it with 10mL of n-hexane to obtain 0.8g of formula C-3 solid for mass spectrometry detection.

[0094] ESI:[M+H] + 424.2 (see Figure 3 ).

[0095] Example 5

[0096] Add 20g C-2, 36.9g 1-bromoethyl acetate, 24.6g potassium carbonate, and 400mL dichloromethane to the reaction flask in sequence, stir and control the temperature at 40-50°C for 15h. Cool to room temperature, filter, wash the filtrate with water twice, and dry the obtained organic phase with anhydrous sodium sulfate for 1h. Filter by suction, and concentrate the filtrate under reduced pressure to obtain a semi-oil and semi-solid C-3, which is directly used in the next step. The yield is calculated as 100%.

[0097] Example 6

[0098] Add 50g C-3, 8g formic acid, and 250mL water to the reaction bottle, stir and control the temperature at 40-50°C for 5h. Add 300mL dichloromethane / 100mL saturated sodium bicarbonate aqueous solution to the reaction solution for extraction, phase separation, extract the aqueous phase twice with 300mL dichloromethane, combine the organic phases, add anhydrous sodium sulfate to the organic phase and dry for 1h, filter, and concentrate the filtrate under reduced pressure. Add 200mL tetrahydrofuran / 800mL methyl tert-butyl ether mixed solution to the concentrate for recrystallization, cool to 0-5°C for crystallization for 2 hours, filter, and dry the wet product to constant weight to obtain 29g off-white solid of formula C-4, with a yield of 77%.

[0099] ESI: [MH]-322.1 (see Figure 4 ).

[0100] Example 7

[0101] Add 10g C-3, 40mL acetic acid, and 60mL acetonitrile to the reaction bottle, stir and control the temperature at 60-70℃ for 5h. Adjust the pH value of the reaction solution to 7-8 with saturated sodium bicarbonate aqueous solution, add 60mL dichloromethane, extract and separate the phases, extract the aqueous phase twice with 60mL dichloromethane, combine the organic phases, add anhydrous sodium sulfate to the organic phase and dry for 1h, filter, and concentrate the filtrate under reduced pressure. Add 40mL tetrahydrofuran / 160mL methyl tert-butyl ether mixed solution to the concentrate for recrystallization, cool to 0-5℃ for crystallization for 2 hours, filter, and dry the wet product to constant weight to obtain 4.4g off-white solid of formula C-4, with a yield of 58%.

[0102] Example 8

[0103] Add C-4 (2 g), M2-C2 (2.6 g), 30 mL of acetonitrile to the reaction flask, cool to 0°C, add potassium carbonate (1.7 g), and stir for 12 h. Add 20 ml of dichloromethane and stir for 1 hour. Filter with suction, concentrate the filtrate under reduced pressure, add 10 ml of acetonitrile, stir for 2 hours, filter with suction, and obtain 1.44 g of off-white solid (I') of filter cake drying, with a yield of 41%.

[0104] ESI:[M+H] + 570.2 (see Figure 5 ).

[0105] 1.4 g of the compound of formula (I) was added to 7 ml of acetonitrile and recrystallized twice under the same conditions to obtain 0.5 g of the compound of formula (I'-1).

[0106] The mother liquor of recrystallization was collected and passed through a column with ethyl acetate / n-hexane = 2 / 1. The eluate was concentrated to dryness and then slurried with 3 ml of methyl tert-butyl ether to obtain 0.4 g of formula (I'-2) with a purity of 99.8% (see Figure 6 ).

[0107] Example 9

[0108] Add C-4 (2g), M2-C2 (2.6g), THF (30mL) to the reaction flask, cool to 0°C, add 2M sodium bistrimethylsilylamide (4.7ml) dropwise, and stir for 12h. Add 10ml of water to quench, add 20ml of dichloromethane, and stir to separate the phases. After the organic phase is concentrated, column chromatography is performed, and the eluent is ethyl acetate / n-hexane = 2 / 1. After the eluent is concentrated to dryness, 2ml of methyl tert-butyl ether is used for pulping, and suction filtration is performed. The filter cake is dried to obtain 0.68g of off-white solid formula (I'), with a yield of 19.2%.

[0109] Comparative Example 1:

[0110] C-4 (0.2 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.25 g), T3P (0.2 g), methanesulfonic acid (0.12 g), and ethyl acetate (6 ml) were added to the reaction bottle. The mixture was stirred and heated to 70-75°C for 12 hours. No target product was produced according to TLC detection.

[0111] Comparative Example 2:

[0112] C-4 (60 mg), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (60 mg), T3P (0.5 ml), and isopropyl acetate (6 ml) were added to the reaction bottle. The mixture was stirred and heated to 80-90°C for 8 hours. No target product was produced according to TLC detection.

[0113] Comparative Example 3:

[0114] C-4 (0.2 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.2 g), T3P (0.59 g), methanesulfonic acid (0.09 g), ethyl acetate (2 ml), and cyclohexane (0.5 ml) were added to the reaction bottle. The mixture was stirred and heated to 70-75°C for overnight reaction. No target product was produced according to TLC detection.

[0115] Comparative Example 4:

[0116] C-4 (0.1 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.09 g), p-toluenesulfonic acid (53 mg) and toluene (2 ml) were added to the reaction bottle. The mixture was stirred and heated to 50-55°C for overnight reaction. No target product was produced according to TLC detection. The mixture was heated to 110-115°C for 5 hours. No target product was produced according to TLC detection.

[0117] Comparative Example 5:

[0118] C-4 (0.1 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.09 g), camphorsulfonic acid (0.14 g) and ethyl acetate (2 ml) were added to the reaction bottle and reacted at room temperature overnight. No target product was produced according to TLC detection. The temperature was raised to reflux for 4 hours. No target product was produced according to TLC detection.

[0119] Comparative Example 6:

[0120] C-4 (0.2 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.33 g), triphenylphosphine (0.24 g), and dichloromethane (4 ml) were added to the reaction bottle, the temperature was lowered to 0-5°C, DIAD (0.19 g) was added, the temperature was raised to room temperature and the reaction was carried out for 10 hours. No target product was produced according to TLC detection.

[0121] Comparative Example 7:

[0122] C-4 (0.1 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.09 g), triphenylphosphine (0.12 g), and tetrahydrofuran (4 ml) were added to the reaction bottle. Under nitrogen protection, the temperature was lowered to 0-5°C, DIAD (0.1 g) was added, and the temperature was raised to room temperature for reaction for 6 hours. TLC detection showed that no target product was produced.

[0123] Comparative Example 8:

[0124] Triphenylphosphine (0.16 g) and dichloromethane (4 ml) were added to the reaction bottle, and the temperature was lowered to 0-5°C under nitrogen protection. DEAD (0.156 g) was added and stirred for 10 minutes. C-4 (0.1 g) and 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol (0.09 g) were added and the temperature was raised to room temperature for reaction for 7 hours. No target product was produced according to TLC detection.

[0125] Comparative Example 9:

[0126] C-4 (0.1 g), 7,8-difluoro-6,11-dihydro-dibenzo[B,E]thieno-11-ol methanesulfonate (0.15 g), pyridine (0.05 g), and 1,4-dioxane (1.5 ml) were added to the reaction bottle. Under nitrogen protection, the temperature was raised to 70-75°C and the reaction was stirred for 6 hours. No target product was produced according to TLC detection.

Claims

1. A method for preparing an acyl ethyl ester polycyclic compound, wherein: The acylated ester polycyclic compound is shown in formula (I): In formula (I), R1, R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen and deuterium; The preparation method comprises the following steps: The compound of formula (III) reacts with the compound of formula (II) to obtain the compound of formula (I) Wherein, R1, R2, R3, R4, R5, R6 and R7 in formula (III) are defined the same as in formula (I); and X in formula (II) is chlorine, bromine or iodine.

2. The preparation method according to claim 1, further comprising the following steps: obtaining the compound of formula (III) by removing the amino protecting group of the compound of formula (IV); In formula (IV), R1, R2, R3, R4, R5, R6 and R7 are defined the same as in formula (III); in formula (IV), Pr is an amino protecting group, optionally selected from tert-butyloxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc) and benzyloxycarbonyl (Cbz).

3. The preparation method according to claim 2, further comprising the following steps: obtaining the compound of formula (IV) by coupling reaction of the compound of formula (V) and the compound of formula (VI); In formula (VI), R1, R2, R3, R4, R5, R6 and R7 are as defined in formula (III); in formula (VI), Y is bromine, chlorine or iodine.

4. The preparation method according to claim 3, wherein In the formula (I), formula (III), formula (IV) and formula (VI), R1, R2, R3, R4, R5, R6 and R7 are all hydrogen; or, in the formula (I), formula (III), formula (IV) and formula (VI), R1, R2 and R3 are all deuterium, and R4, R5, R6 and R7 are all hydrogen.

5. The preparation method according to claim 3 or 4, wherein In formula (II), X is chlorine or bromine; and / or In formula (IV), formula (V) and formula (VII), Pr is tert-butyloxycarbonyl (Boc); and / or In formula (VI), Y is bromine or chlorine.

6. The preparation method according to any one of claims 1 to 5, wherein In formula (I), R1, R2, R3, R4, R5, R6 and R7 are all hydrogen, that is, the compound of formula (I) is the compound of formula (I'); Alternatively, the compound of formula (I) is a compound of formula (I'-1); Alternatively, the compound of formula (I) is a compound of formula (I'-2); 7. A method for preparing an acyl ethyl ester polycyclic compound as shown in formula (I'), the preparation method comprising the following steps: (1) reacting the compound of formula (C-0) with di-tert-butyl dicarbonate to obtain a compound of formula (C-1); (2) the compound of formula (C-1) is subjected to a debenzylation reaction to obtain a compound of formula (C-2); (3) reacting the compound of formula (C-2) with 1-bromoethyl acetate to obtain a compound of formula (C-3); (4) removing the Boc protecting group from the compound of formula (C-3) under acidic conditions to obtain a compound of formula (C-4); (5) The compound of formula (C-4) is subjected to coupling reaction with the compound of formula (M2-C2) to obtain a compound of formula (I') 8. The preparation method according to claim 7, wherein: The step (1) comprises: putting the compound of formula (C-0), a reaction solvent, triethylamine and DMAP into a reactor, adding di-tert-butyl dicarbonate at a temperature of 0 to 10° C., and reacting at room temperature for 2 to 10 hours after the addition; after the reaction is completed, concentrating under reduced pressure to obtain the compound of formula (C-1); Optionally, the reaction solvent in step (1) can be selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, water, etc., preferably tetrahydrofuran; the molar ratio of the compound of formula (C-0), triethylamine, and di-tert-butyl dicarbonate is 1:1.5-2.5:1.5-2.5, preferably 1:2.0:2.

0.

9. The preparation method according to claim 7 or 8, wherein: The step (2) comprises: placing the compound of formula (C-1) obtained in step (1), a reaction solvent, palladium carbon, and ammonium formate into a reactor, and maintaining the reaction at room temperature for 1 to 10 hours; after the reaction is completed, filtering with suction, concentrating the filtrate under reduced pressure, adding dichloromethane / water to the residue for extraction, separating the phases, discarding the aqueous phase, adding anhydrous sodium sulfate to the organic phase for drying for 1 hour, filtering with suction, concentrating the filtrate under reduced pressure, adding dichloromethane / n-hexane mixed solution to the residue for recrystallization, cooling and crystallizing, centrifuging, and drying the wet product to constant weight to obtain the compound of formula (C-2); Optionally, the reaction solvent in step (2) can be selected from methanol, ethanol, isopropanol, water, etc., preferably methanol; the molar ratio of the compound of formula (C-2) to ammonium formate is 1:4-6, preferably 1:5; the amount of palladium carbon is 0.05 to 0.2 times, preferably 0.1 times.

10. The preparation method according to any one of claims 7 to 9, wherein The step (3) comprises: adding the compound of formula (C-2) obtained in step (2), a reaction solvent, 1-bromoethyl acetate, and a base into a reaction bottle in sequence, and stirring the reaction for 15 to 20 hours; after the reaction is completed, filtering with suction, washing the filtrate with water twice, separating the phases, and discarding the aqueous phase; adding anhydrous sodium sulfate to the organic phase and drying it for 1 hour, filtering, and concentrating the filtrate under reduced pressure to obtain a compound of formula (C-3); Optionally, in the step (3), the reaction solvent can be selected from acetonitrile, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, etc., preferably dichloromethane; the base can be selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium tert-butoxide, etc., preferably sodium bicarbonate; the molar ratio of the compound of formula (C-2), 1-bromoethyl acetate, and the base is 1:2-3:2-3, preferably 1:2.5:2.5; the reaction temperature is selected from 20°C to 50°C, preferably 40°C to 50°C.

11. The preparation method according to any one of claims 7 to 10, wherein The step (4) comprises: adding the compound of formula (C-3), acid and reaction solvent obtained in step (3) into a reaction bottle in sequence, and stirring the reaction for 3 to 20 hours; after the reaction is completed, adding dichloromethane / saturated sodium bicarbonate aqueous solution to the reaction solution for extraction, separating the phases, extracting the aqueous phase twice with dichloromethane, combining the organic phases, adding anhydrous sodium sulfate to the organic phases, drying for 1 hour, filtering, concentrating the filtrate under reduced pressure, adding tetrahydrofuran / methyl tert-butyl ether mixed solution to the concentrate for recrystallization, filtering with suction, and drying the wet product to constant weight to obtain the compound of formula (C-4); Optionally, the reaction solvent used in step (4) can be selected from water, acetonitrile, methanol, ethanol, dichloromethane, ethyl acetate, tetrahydrofuran, etc., preferably water; the acid can be selected from formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc., preferably formic acid; the molar ratio of the compound of formula (C-3) to formic acid is 1:1-3, preferably 1:1.5; the reaction temperature is selected from 20°C to 70°C, preferably 20°C to 30°C.

12. The preparation method according to any one of claims 7 to 11, wherein The step (5) is as follows: adding the compound of formula (C-4), the compound of formula (M2-C2) and acetonitrile obtained in step (4) into a reaction bottle, adding potassium carbonate at about 0°C, stirring for 12 hours; adding dichloromethane, stirring for 1 hour; filtering with suction, concentrating the filtrate, adding a solvent, stirring and crystallizing; filtering with suction, and drying the wet product to constant weight to obtain a compound of formula (I'); Optionally, the compound of formula (I') is recrystallized from acetonitrile multiple times to obtain the compound of formula (I'-1), and the mother liquor of recrystallization is slurried with MTBE after column chromatography to obtain the compound of formula (I'-2); Optionally, the solvent for the condensation reaction in step (5) is acetonitrile or DMF, preferably acetonitrile; the base can be an inorganic base or an organic base, the inorganic base can be selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, and the organic base can be selected from DBU, N-methylmorpholine, sodium bistrimethylsilylamide, preferably potassium carbonate and sodium bistrimethylsilylamide, more preferably potassium carbonate; the reaction temperature is selected from -10°C to 90°C, preferably -5°C to 35°C, more preferably -5°C to 5°C.

Images