A method of synthesis of a serd intermediate

Abstract

The application discloses a synthesis method of a SERD intermediate. The application provides a synthesis method of compound 06, which comprises the following steps: performing an elimination reaction of compound 05 with a dehydration reagent in an organic solvent to obtain compound 06, wherein the dehydration reagent is di-tert-butyl dicarbonate, R is tert-butoxycarbonyl, or the dehydration reagent is bis(2,6-dimethylphenyl) chlorophosphate or acetyl chloride, and R is H. The method reduces the process cost, constructs a core E formula olefin skeleton through a selective elimination reaction, greatly improves the overall process yield, and can better meet the needs of scale-up production.

Description

[0001] This application claims priority to Chinese patent application 2022103345234, filed on March 30, 2022. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a method for synthesizing SERD intermediates. Background Technology

[0003] SERDs are small molecules that bind to estrogen receptors on the surface of cancer cells, reducing the stability of these receptors and inducing their degradation by normal cellular protein degradation mechanisms. This reduces estrogen receptor levels and inhibits cancer cell growth. Unlike regulators that inhibit estrogen activity, SERDs theoretically inhibit estrogen receptor function more comprehensively by mediating estrogen receptor degradation and may potentially overcome drug resistance caused by estrogen receptor mutations.

[0004] Patent CN108884035B, published by Luoxin Pharmaceutical (Shanghai) Co., Ltd., first reported a compound as a SERD inhibitor, including a method for preparing such compounds, pharmaceutical compositions, and their use as estrogen receptor downregulators in the preparation of drugs for treating estrogen receptor-positive breast cancer. This patent achieved milligram-scale preparation of this compound. Patent WO2019057201A1 reported its free acid form and its preparation method; patent WO2020108154A1 reported its salt-forming form with choline and its preparation method. The following are the synthetic routes from the aforementioned patents:

[0005] (1) Synthesis of Fragment 1

[0006]

[0007] (2) Synthesis of Fragment 2

[0008]

[0009] (3) Synthesis of compound 09

[0010]

[0011] The main challenge of this route lies in the preparation of fragment 2. This route uses indole as a substrate, deriving it into a 2-bromosubstituted indole, which undergoes a Sonogashira coupling reaction with an alkyne. Further, under the catalysis of tetraphenylphosphine platinum, the alkyne-indole undergoes a 1,2-insertion reaction to yield a near-disubstituted borate ester. This reaction can be further carried out without post-treatment, undergoing a Suzuki coupling reaction with ethyl 4-iodophenylacrylate under palladium catalysis. The resulting system, without post-treatment, reacts with 2-chloro-4-fluoroiodobenzene under palladium catalysis to obtain an intermediate, which is then hydrolyzed and chlorinated to yield fragment 2. Fragment 2 is then reacted with choline to form a salt to prepare the target molecule compound 09.

[0012] However, the existing routes have low yields, which cannot be scaled up to meet clinical needs; moreover, the existing routes involve four metal catalysis steps, including one-step sonogashira coupling, two-step Suzuki coupling, and one-step platinum catalysis. Given the current high cost of palladium and platinum catalysts, the scale-up process is prohibitively expensive and unsuitable for large-scale production. Summary of the Invention

[0013] The technical problem to be solved by the present invention is that existing routes have low yields and high costs, and are not suitable for large-scale production. To this end, the present invention provides a method for synthesizing SERD intermediates, which has lower costs, higher yields and does not involve metal catalysis.

[0014] This invention provides a method for synthesizing compound 06, comprising the following steps: in an organic solvent, compound 05 undergoes an elimination reaction with a dehydrating agent as shown below to obtain compound 06; wherein the dehydrating agent is di-tert-butyl dicarbonate, and R is tert-butyloxycarbonyl; or, the dehydrating agent is bis(2,6-dimethylphenyl)chlorophosphate or acetyl chloride, and R is H;

[0015]

[0016] In some embodiments, the organic solvent is one or more of ether solvents, haloalkane solvents, and nitrile solvents, preferably nitrile solvents.

[0017] In some embodiments, the ether solvent is one or more of tetrahydrofuran, 1,4-dioxane, and methyl tert-butyl ether, preferably tetrahydrofuran or 1,4-dioxane.

[0018] In some embodiments, the haloalkane solvent is dichloromethane.

[0019] In some embodiments, the nitrile solvent is acetonitrile.

[0020] In some embodiments, the dehydrating agent is di-tert-butyl dicarbonate, where R is tert-butyloxycarbonyl.

[0021] In some embodiments, the synthesis of compound 06 further includes the use of a base.

[0022] In some embodiments, the base is an alkali metal hydride (e.g., sodium hydride and / or potassium hydride), an organic base (e.g., 4-dimethylaminopyridine or bis(trimethylsilyl)aminopotassium); preferably 4-dimethylaminopyridine.

[0023] In some embodiments, the reaction temperature of the elimination reaction may be a conventional reaction temperature for such reactions in the art, for example 10-40°C, preferably 20-30°C.

[0024] In some embodiments, the volume-to-mass ratio of the organic solvent to the compound 05 is (6-9) mL:1 g, for example, 8 mL:1 g.

[0025] In some embodiments, the molar ratio of the dehydrating agent to the compound 05 is a conventional molar ratio in the art, for example (5-7):1, preferably 6.6:1.

[0026] In some embodiments, the amount of base used is a catalytic amount, for example, the molar ratio of the base to the compound O5 is (2-4):1, preferably 3:1.

[0027] In some embodiments, when the dehydrating agent is di-tert-butyl dicarbonate, the di-tert-butyl dicarbonate is added to a mixed solution of compound 05 and the base.

[0028] In some embodiments, the elimination reaction may also include a post-processing step, such as one or more of extraction, concentration, stirring, crystallization, drying, and filtration.

[0029] In some embodiments, the method for synthesizing compound 06 may further include, in an organic solvent, compound 04 undergoing a reducing desulfonation reaction with a reducing agent as shown below to obtain compound 05;

[0030]

[0031] In some embodiments, the organic solvent is an alcohol solvent, such as methanol.

[0032] In some embodiments, the reducing agent is metallic magnesium.

[0033] In some embodiments, the molar ratio of the reducing agent to the compound O4 is (3-5):1, preferably 4:1.

[0034] In some embodiments, the volume-to-mass ratio of the organic solvent to the compound O4 is (3-7) mL:1 g, for example, 5 mL:1 g.

[0035] In some embodiments, the reductive desulfonation reaction further includes an acidification step, such as acidification with hydrochloric acid.

[0036] In some embodiments, the reaction temperature of the reducing desulfonation reaction can be a conventional reaction temperature for such reactions in the art, for example, 10-40°C, preferably 20-30°C.

[0037] In some embodiments, the reductive desulfonation reaction may further include one or more of the following post-processing steps: extraction, neutralization, concentration, agitation crystallization, filtration, and drying.

[0038] In some embodiments, the method for synthesizing compound 06 may further include, in an organic solvent and in the presence of a base, compound 03 undergoes an addition reaction with 4-acetal bromobenzene as shown below to obtain compound 04;

[0039]

[0040] In some embodiments, the organic solvent is an ether solvent, such as tetrahydrofuran.

[0041] In some embodiments, the base is an alkali metal alkylate, such as n-butyllithium.

[0042] In some embodiments, the addition reaction is carried out under an inert gas, such as nitrogen.

[0043] In some embodiments, the volume-to-mass ratio of the organic solvent to the compound O3 is (15-20) mL:1 g, for example, 18.6 mL:1 g.

[0044] In some embodiments, the molar ratio of the base to the compound O3 is (2-3):1, for example 2.8:1.

[0045] In some embodiments, the molar ratio of the 4-acetal bromide to the compound O3 is (2-4):1, for example, 3:1.

[0046] In some embodiments, the addition reaction is quenched using a saturated aqueous solution of sodium bicarbonate.

[0047] In some embodiments, the reaction temperature of the addition reaction is -80°C to room temperature.

[0048] In some embodiments, the addition reaction further includes a post-processing step, such as one or more of extraction, concentration, crystallization, filtration, washing, and drying.

[0049] In some embodiments, the method for synthesizing compound 06 may further include, in an organic solvent, compound 02 reacting with an oxidant in an oxidation reaction as shown below, to obtain compound 03;

[0050]

[0051] In some embodiments, the organic solvent is a haloalkane solvent, such as dichloromethane.

[0052] In some embodiments, the oxidant is a Des Martin oxidant.

[0053] In some embodiments, the volume-to-mass ratio of the organic solvent to the compound O2 is (10-8) mL:1 g, for example, 8 mL:1 g.

[0054] In some embodiments, the molar ratio of the oxidant to the compound O2 is (2-3):1, for example 2.5:1.

[0055] In some embodiments, the oxidation reaction is quenched using a saturated sodium thiosulfate solution.

[0056] In some embodiments, the oxidation reaction is carried out at room temperature.

[0057] In some embodiments, the oxidation reaction further includes post-processing steps, such as one or more of extraction, concentration, crystallization, washing, filtration, and drying.

[0058] In some embodiments, the method for synthesizing compound 06 may further include, in an organic solvent and in the presence of a base, compound 01 undergoes an addition reaction with phenylsulfonylindole as shown below to obtain compound 02;

[0059]

[0060] In some embodiments, the organic solvent is an ether solvent, such as tetrahydrofuran.

[0061] In some embodiments, the addition reaction is carried out under an inert gas, such as nitrogen.

[0062] In some embodiments, the base is an alkali metal alkylate, such as n-butyllithium.

[0063] In some embodiments, the volume-to-mass ratio of the organic solvent to the compound O1 is (10-15) mL:1 g, for example, 13 mL:1 g.

[0064] In some embodiments, the molar ratio of the base to the compound O1 is (1-2):1, for example, 1.4:1.

[0065] In some embodiments, the molar ratio of the phenylsulfonyl indole to the compound O1 is (1-3):1, for example 2:1.

[0066] In some embodiments, compound 01 is added to a mixed solution of phenylsulfonylindole and a base.

[0067] In some embodiments, the reaction temperature of the addition reaction is -80°C to room temperature.

[0068] In some embodiments, the addition reaction is quenched using an aqueous sodium bicarbonate solution.

[0069] In some embodiments, the addition reaction further includes a post-processing step, such as one or more of extraction, concentration, and vacuum distillation.

[0070] The present invention also provides a method for synthesizing fragment 1', which includes the following steps:

[0071] (1) Compound 06 was synthesized according to the synthesis method described above;

[0072] (2) In an organic solvent, compound 06 was subjected to the following hydrolysis reaction with a base, followed by acidification, to obtain fragment 1';

[0073]

[0074] In some embodiments, in step (2), the organic solvent is an alcohol solvent (e.g., ethanol) and / or water.

[0075] In some embodiments, in step (2), the base is an inorganic base, such as sodium hydroxide.

[0076] In some embodiments, in step (2), the acid in the acidification step is an inorganic acid, such as concentrated hydrochloric acid.

[0077] In some embodiments, in step (2), the volume-to-mass ratio of the organic solvent to the compound 06 is (7-10) mL:1g, for example, 9 mL:1g.

[0078] In some embodiments, in step (2), the molar ratio of the base to the compound O6 is (5-8):1, for example 6.9:1.

[0079] In some embodiments, step (2) of the hydrolysis reaction further includes a post-processing step, such as one or more of neutralization, filtration, washing, drying and crystallization.

[0080] The present invention provides a method for synthesizing compound 05, which includes the following steps: in an organic solvent, compound 04 undergoes a reducing desulfonation reaction with a reducing agent as shown below to obtain compound 05;

[0081]

[0082] In some embodiments, the reaction conditions for the reducing desulfonation reaction are the same as described above.

[0083] The present invention also provides a method for synthesizing compound 04, which includes the following steps: in an organic solvent, in the presence of a base, compound 03 undergoes an addition reaction with 4-acetal bromobenzene as shown below to obtain compound 04;

[0084]

[0085] In some embodiments, the reaction conditions for the addition reaction are the same as described above.

[0086] The present invention also provides a method for synthesizing compound 03, which includes the following steps: in an organic solvent, compound 02 undergoes an oxidation reaction with an oxidant as shown below to obtain compound 03;

[0087]

[0088] In some embodiments, the reaction conditions for the oxidation reaction are the same as described above.

[0089] The present invention also provides a method for synthesizing compound 02, which includes the following steps: in an organic solvent, in the presence of a base, compound 01 undergoes an addition reaction with phenylsulfonylindole as shown below to obtain compound 02;

[0090]

[0091] In some embodiments, the reaction conditions for the addition reaction are the same as described above.

[0092] The present invention also provides the following compounds:

[0093]

[0094] This invention also provides compounds 01, 02, 03, 04, 05, or 06 in the preparation of Applications in [the context of the text].

[0095] In some implementations, the application may take all or part of the following routes:

[0096] For example, the application of compound 01 in the preparation of compound 09 follows all of the following routes;

[0097] For example, the application of compound 03 in the preparation of compound 08 is via the steps of compounds 03 to 08 in the following route;

[0098]

[0099] 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.

[0100] The reagents and raw materials used in this invention are all commercially available.

[0101] The positive and progressive effects of the present invention are: (1) No metal catalysis is used in the entire process of synthesizing the target molecule. Compared with the previously reported process, the use of precious metal catalysts is greatly reduced, and the process cost is greatly reduced.

[0102] (2) This process uses selective elimination reaction to construct the core E-type olefin skeleton;

[0103] (3) This process has been fully optimized, and the overall yield has been greatly improved, which can better meet the needs of scale-up production. Attached Figure Description

[0104] Figure 1 The NMR spectrum of the product obtained in step five of Example 1. Detailed Implementation

[0105] 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.

[0106] The following abbreviations have the following meanings: THF: Tetrahydrofuran; MTBE: Methyl tert-butyl ether; DCM: Dichloromethane; DMP: Dysmart reagent; DMAP: 4-Dimethylaminopyridine; DBU: 1,8-diazabicyclo-bicyclo(5,4,0)-7-undecene; NCS: N-chlorosuccinimide; KHMDS: Potassium bis(trimethylsilyl)amino; TEA: Triethylamine;

[0107] Example 1

[0108] Synthesis of fragment 1':

[0109]

[0110] Steps one and two:

[0111] In a 5L reactor, phenylsulfonylindole (141g, 1.0eq) and THF (1800ml) were added and stirred until dissolved. The mixture was then purged with nitrogen three times. The temperature was lowered, and 2.5M n-butyllithium (280ml) solution was added dropwise at -60 to -80℃. After the addition was complete, the mixture was stirred for 1 hour. 2-Chloro-4-fluorophenylethylacetaldehyde (100g) was added to the system, and the reaction was maintained at this temperature for 2 hours. After the reaction was complete, an aqueous solution of sodium bicarbonate (3eq) was added to quench the reaction. The mixture was then separated into two phases. The organic phase was retained, and the aqueous phase was extracted using MTBE (1L*2). The combined organic phases were concentrated and distilled under reduced pressure to obtain 248g of a brown oily substance.

[0112] The oily substance was dissolved in DCM (1200 ml), transferred to a 5 L reactor, stirred, and DMP solid (260 g) was added at room temperature. After the addition was complete, the reaction was maintained at this temperature for 2 h. Upon completion of the reaction, saturated sodium thiosulfate solution was added to quench the reaction. The mixture was separated, and the aqueous phase was extracted with DCM (1 L). The combined organic phases were concentrated to 200–300 mL, replaced with methanol (500 ml * 2), and concentrated to dryness. 500 mL of methanol was added, and the mixture was heated to dissolve the solid. Crystallization was then precipitated by cooling and filtered. The filter cake was washed with a small amount of methanol and dried under vacuum at 40 °C to obtain 118 g of intermediate O3 product, with an overall yield of 52% for both steps. MS (ESI) m / r: 456 [M+H + ].

[0113] Step 3:

[0114] Add intermediate 03 (118g), 4-acetal bromobenzene (178g), and THF (2200ml) to a 5L reactor and stir until dissolved. Purge with nitrogen three times, lower the temperature to -60 to -80°C, and add 2.5M n-butyllithium (288ml) solution dropwise. After addition, maintain the temperature for 2 hours. After the reaction is complete, quench with saturated sodium bicarbonate aqueous solution (1500mL), separate the phases, extract the aqueous phase using DCM (500mL*2), combine the organic phases, concentrate to 250-400mL, add methyl tert-butyl ether (3000mL), and stir to induce crystallization. After crystallization, filter. Wash the filter cake with a small amount of DCM and dry under vacuum at 40°C to obtain intermediate 04 125g, yield 80%, purity 99.5%. MS (ESI) m / r: 606 [M+H + ].

[0115] Step Four:

[0116] Add 125g of O4 and 625ml of methanol to a 5L reactor and stir until dissolved. Add 20g of magnesium powder at 20-30℃ and stir at room temperature for 15 hours. After the reaction is complete, add 2M hydrochloric acid to the system and stir until dissolved. Add DCM (1L*2) for extraction, combine the organic phases, and adjust the pH to 8-9 with saturated sodium bicarbonate. Separate the liquid and concentrate the organic phase to 200-300mL at 35-45℃. Add 3L of n-heptane dropwise and stir to crystallize for 3 hours. Filter. Dry the filter cake under vacuum at 35-45℃ to obtain 85g of intermediate O5, yield 88%. MS (ESI) m / r: 466 [M+H + ].

[0117] Step 5:

[0118] Add 05 (85g, 0.18mol) and acetonitrile (680ml) to a 5L reactor, stir until dissolved, and add a catalytic amount of DMAP. Add di-tert-butyl dicarbonate (260g) dropwise at 20-30℃, and stir for 15 hours after the addition is complete. After the reaction is complete, concentrate the solution, add methanol (1L*2) to replace the solvent, concentrate to 500-600mL, add water (1L), and a white solid precipitates. Stir for 2 hours, filter, and vacuum dry the filter cake at 35-45℃ to obtain 88g of intermediate 06, yield 88%. MS (ESI) m / r: 548 [M+H + Nuclear magnetic resonance (NMR) analysis revealed that the product peak and the characteristic peak of the isomer appeared in the δ range of 5.5–6.0, with an integrated area ratio of 0.9:0.1. Therefore, the ratio of the target product to the isomer was 9:1. Figure 1 ).

[0119] Step Six:

[0120] Add intermediate O6 (88g), NaOH (44g), ethanol (704ml), and water (88g) to a 5L reactor, and stir under reflux for 36 hours until the reaction is complete. After the reaction is complete, cool to room temperature, filter to remove the solid, and transfer the filtrate back to the reactor.

[0121] At room temperature, concentrated hydrochloric acid (200g) was added dropwise to the above solution, and the reaction was maintained for 3 hours. After the reaction was complete, sodium carbonate aqueous solution was added dropwise to adjust the pH to 7-8. The solution was filtered, washed with water, and dried to obtain 66g of crude fragment 1'. The crude product was added to toluene (300mL), heated to 75-85℃ to dissolve, and then cooled to crystallize. The cooling rate was controlled. The mixture was stirred at 0-5℃ for 2 hours, filtered, and the filter cake was vacuum dried at 35-45℃ to obtain 35.7g of product, with a total yield of 55% and a purity greater than 99%. MS (ESI) m / r: 404 [M+H + ]. 1H NMR (CDCl3): δ9.89 (s, 1H, CO-H), 7.65 (t, 4H, Ar-H), 7.23-7.06 (m, 4H, Ar-H), 7.05-6.75 (m, 4H, Ar-H), 2.94-2.75 (m, 2H, -CH2CH3), 1.14 (t, 3H, -CH2CH3).

[0122] Example 2

[0123] Synthesis of Fragment 2'

[0124]

[0125] Step Seven:

[0126] Add compound fragment 1' (48.5 kg, 1.0 eq), LiCl (10.2 kg, 2.0 eq), triethyl phosphonoacetate (32.3 kg, 1.10 eq), and 100 L of DCM to the reactor. Purge with nitrogen, stir until dissolved, and cool to -5 to 5°C. Stir in an ice bath, and add 100 L of DCM solution containing DBU (23.8 kg, 1.30 eq) while maintaining the temperature. After addition, restore the temperature to 20 to 25°C and stir for 2 hours. The reaction is complete. Add 2 M HCl to the reaction system to adjust the pH of the aqueous phase to 3 to 4. Separate the liquids, retaining the organic phase. Wash the organic phase once with saturated sodium bicarbonate. Concentrate the solution, maintaining the temperature below 45°C, until the volume is 150 to 200 L. Add 250 L of n-heptane and concentrate to 150 to 200 L. Add n-heptane (1000 L) dropwise, precipitating a large amount of solid. Stir and crystallize for 5 hours. Cool to 0–5°C and stir for 1 hour. Filter by suction, and wash the filter cake with a small amount of a mixture of dichloromethane and n-heptane. Dry the filter cake under vacuum to obtain 45.3 kg of a yellow solid, with a yield of 80% and a purity greater than 99%.

[0127] Step 8:

[0128] Add intermediate 7 (37.2 kg, 1.0 eq) and dichloromethane (250 kg) to the reactor, and stir until dissolved. Transfer to a container. Add NCS (10.4 kg, 1.1 eq) and dichloromethane (250 kg) to the reactor, and stir until dissolved. Purge with nitrogen three times and cool to -5 to 5°C. Add the prepared intermediate 7 solution dropwise to the reactor. React at -5 to 5°C until detection is complete. Quench the reaction with 5% sodium sulfite solution until the starch-potassium iodide test shows no color change. Separate the solutions. Wash the organic phase with purified water (100 kg * 2). Retain the organic phase and concentrate it to 300–400 L. Add n-heptane (280 kg) and concentrate to 300–400 L. Add n-heptane (280 kg) and stir at 20–30°C for 2 hours. Cool to 0–10°C and stir for 2 hours. Centrifugal filtration was performed, and the filter cake was washed with a small amount of a mixture of dichloro and n-heptane. Vacuum drying yielded 33.25 kg of product, with a yield of 91% and a purity of 99.7%.

[0129] Step Nine:

[0130] Add intermediate 8 (33.1 kg, 1.0 eq) and ethanol (18 kg) to the reactor. Heat the reactor to 35–45°C and stir. Add 30% NaOH solution (17 kg) and stir for 6–16 hours until the reaction is complete. Add 13.2% phosphoric acid solution (194 kg) dropwise to quench the reaction. Stir for 2–6 hours while maintaining the temperature. Cool to 25–35°C and stir for 5 hours. Centrifuge and filter. Wash the filter cake with purified water (50 L). Dissolve the filter cake in isopropanol (250 L) by heating, filter, concentrate to 100–120 L while maintaining the temperature at 35–45°C, add purified water (320 kg), stir for 4–5 hours while maintaining the temperature at 35–45°C, cool to 25–35°C and stir for 4–5 hours. Centrifuge and filter. Wash the filter cake with a small amount of isopropanol-water mixture and vacuum dry to obtain 30.6 kg of product, yield 88%. Purity 99.5%.

[0131] Example 3: Construction of the E-double bond backbone:

[0132] 1. Protection and Elimination

[0133]

[0134] The reaction conditions for substrates with protecting groups of indole were screened according to the method in step five of Example 1, as shown in the table below.

[0135]

[0136] Screening reaction conditions using indole-protected substrates failed to yield the product. Therefore, screening reaction conditions using unsubstituted substrates was considered.

[0137] 2. Unprotected elimination

[0138] (1) Screening of various reaction conditions

[0139]

[0140] The reaction conditions for substrates without protecting groups of indole were screened according to the method in step five of Example 1, as shown in the table below.

[0141]

[0142] a) Using the Boc2O system, the substituent R in the product is Boc, and the R in the rest of the system is H.

[0143] Dehydration with phosphoryl chloride resulted in good conversion, but the cis-trans ratio after dehydration was non-selective. Using the acetyl chloride-KH system, the main product was the Z-product. Further optimization using Boc₂O resulted in selectivity in the reaction; further optimization of selectivity was performed using the Boc₂O system.

[0144] (2) Screening of reaction conditions when the dehydrating agent is Boc2O

[0145]

[0146]

[0147]

[0148] a) The ratio of E-type to Z-type was determined by NMR; b) The reaction temperature was reduced from 20–25 °C to 0–5 °C.

[0149] The process was optimized in the Boc2O reaction system. After screening reaction solvents, acetonitrile was found to be the optimal solvent, achieving an E-type to Z-type selectivity of 8:2 and a reaction conversion rate of 70%. Further optimization of the reaction alkali revealed that using DMAP further increased the yield to 90%. Lowering the reaction system temperature to 0–5°C further improved the E-type to Z-type selectivity to 9:1.

[0150] In summary, we selected the optimal process conditions: the reaction uses Boc2O-DMAP as the dehydration system and acetonitrile as the solvent.

Claims

1. A method for synthesizing compound 06, comprising the following steps: in an organic solvent, reacting compound 05 with a dehydrating agent as shown in the following elimination reaction to obtain compound 06; wherein the dehydrating agent is di-tert-butyl dicarbonate, and R is tert-butyloxycarbonyl; or, the dehydrating agent is bis(2,6-dimethylphenyl)chlorophosphate or acetyl chloride, and R is H; 。 2. The synthesis method according to claim 1, characterized in that, The reaction conditions in the elimination reaction satisfy one of the following conditions: (1) The organic solvent is one or more of ether solvents, haloalkane solvents and nitrile solvents; (2) The dehydrating agent is di-tert-butyl dicarbonate, where R is tert-butyloxycarbonyl; (3) The method for synthesizing compound 06 also includes the use of a base; (4) The reaction temperature of the elimination reaction is 10-40℃; (5) The volume-to-mass ratio of the organic solvent to compound 05 is (6-9) mL:1 g; (6) The molar ratio of the dehydrating agent to compound 05 is (5-7):1; (7) The elimination reaction also includes a post-treatment step.

3. The synthesis method as described in claim 2, characterized in that, The organic solvent is a nitrile solvent; or, The post-processing steps include one or more of the following: extraction, concentration, stirring, crystallization, drying, and filtration.

4. The synthesis method according to claim 2, characterized in that, The reaction conditions in the elimination reaction satisfy one of the following conditions: (1) The ether solvent is one or more of tetrahydrofuran, 1,4-dioxane and methyl tert-butyl ether; (2) The haloalkane solvent is dichloromethane; (3) The nitrile solvent is acetonitrile; (4) The alkali is an alkali metal hydride or an organic base; (5) The reaction temperature of the elimination reaction is 20-30℃; (6) The volume-to-mass ratio of the organic solvent to compound 05 is 8 mL: 1 g; (7) The molar ratio of the dehydrating agent to compound 05 is 6.6:1; (8) The molar ratio of the base to the compound 05 is (2-4):1; (9) When the dehydrating agent is di-tert-butyl dicarbonate, the di-tert-butyl dicarbonate is added to the mixed solution of compound 05 and the base.

5. The synthesis method as described in claim 4, characterized in that, The reaction conditions in the elimination reaction satisfy one of the following conditions: (1) The ether solvent is tetrahydrofuran or 1,4-dioxane; (2) The hydride of the alkali metal is sodium hydride and / or potassium hydride; (3) The organic base is 4-dimethylaminopyridine or bis(trimethylsilyl)aminopotassium). (4) The molar ratio of the base to the compound 05 is 3:

1.

6. The synthesis method according to claim 4, characterized in that, The base is 4-dimethylaminopyridine.

7. The synthesis method according to claim 1, characterized in that, It further includes the following steps: in an organic solvent, compound 04 undergoes a reducing desulfonation reaction with a reducing agent as shown below to obtain compound 05; 。 8. The synthesis method according to claim 7, characterized in that, The reaction conditions for the reduction desulfonation reaction satisfy one of the following conditions: (1) The organic solvent is an alcohol solvent; (2) The reducing agent is metallic magnesium; (3) The molar ratio of the reducing agent to the compound O4 is (3-5):1; (4) The volume-to-mass ratio of the organic solvent to the compound O4 is (3-7) mL:1 g; (5) The reducing desulfonation reaction further includes an acidification step; (6) The reaction temperature of the reducing desulfonation reaction is 10-40℃; (7) The reducing desulfonation reaction also includes a post-treatment step.

9. The synthesis method as described in claim 8, characterized in that, The post-processing steps include one or more of the following: extraction, neutralization, concentration, stirring crystallization, filtration, and drying.

10. The synthesis method according to claim 8, characterized in that, The reaction conditions for the reduction desulfonation reaction satisfy one of the following conditions: (1) The organic solvent is methanol; (2) The molar ratio of the reducing agent to the compound O4 is 4:1; (3) The volume-to-mass ratio of the organic solvent to the compound O4 is 5 mL: 1 g; (4) The reducing desulfonation reaction further includes acidification with hydrochloric acid; (5) The reaction temperature of the reducing desulfonation reaction is 20-30℃.

11. The synthesis method according to claim 7, characterized in that, It further includes the following steps: in an organic solvent, in the presence of a base, compound 03 undergoes an addition reaction with 4-acetal bromobenzene as shown below to give compound 04; 。 12. The synthesis method according to claim 11, characterized in that, The reaction conditions for the addition reaction satisfy one of the following conditions: (1) The organic solvent is an ether solvent; (2) The base is an alkali metal alkylate; (3) The addition reaction is carried out under an inert gas atmosphere; (4) The volume-to-mass ratio of the organic solvent to the compound O3 is (15-20) mL:1 g; (5) The molar ratio of the base to the compound O3 is (2-3):1; (6) The molar ratio of the 4-acetal bromobenzene to the compound O3 is (2-4):1; (7) The addition reaction is quenched by using a saturated sodium bicarbonate aqueous solution; (8) The reaction temperature of the addition reaction is -80℃ to room temperature; (9) The addition reaction also includes a post-processing step.

13. The synthesis method according to claim 12, characterized in that, The post-processing steps include one or more of the following: extraction, concentration, crystallization, filtration, washing, and drying.

14. The synthesis method according to claim 12, characterized in that, The reaction conditions for the addition reaction satisfy one of the following conditions: (1) The organic solvent is tetrahydrofuran; (2) The alkali is n-butyllithium; (3) The addition reaction is carried out under nitrogen atmosphere; (4) The volume-to-mass ratio of the organic solvent to the compound O3 is 18.6 mL: 1 g; (5) The molar ratio of the base to the compound O3 is 2.8:1; (6) The molar ratio of the 4-acetal bromobenzene to the compound O3 is 3:

1.

15. The synthesis method according to claim 11, characterized in that, It further includes the following steps: in an organic solvent, compound O2 undergoes an oxidation reaction with an oxidizing agent as shown below to obtain compound O3; 。 16. The synthesis method according to claim 15, characterized in that, The oxidation reaction must satisfy one of the following conditions: (1) The organic solvent is a haloalkane solvent; (2) The oxidant is a Des Martin oxidant; (3) The volume-to-mass ratio of the organic solvent to the compound O2 is (10-8) mL:1 g; (4) The molar ratio of the oxidant to the compound O2 is (2-3):1; (5) The oxidation reaction is quenched using a saturated sodium thiosulfate solution; (6) The reaction temperature of the oxidation reaction is room temperature; (7) The oxidation reaction also includes a post-treatment step.

17. The synthesis method according to claim 16, characterized in that, The post-processing steps include one or more of the following: extraction, concentration, crystallization, washing, filtration, and drying.

18. The synthesis method according to claim 16, characterized in that, The oxidation reaction must satisfy one of the following conditions: (1) The haloalkane solvent is dichloromethane; (2) The volume-to-mass ratio of the organic solvent to the compound O2 is 8 mL: 1 g; (3) The molar ratio of the oxidant to the compound O2 is 2.5:

1.

19. The synthesis method according to claim 15, characterized in that, It further includes the following steps: in an organic solvent, in the presence of a base, compound 01 undergoes an addition reaction with phenylsulfonylindole as shown below to give compound 02; 。 20. The synthesis method according to claim 19, characterized in that, The reaction conditions for the addition reaction satisfy one of the following conditions: (1) The organic solvent is an ether solvent; (2) The addition reaction is carried out under an inert gas atmosphere; (3) The base is an alkali metal alkylate; (4) The volume-to-mass ratio of the organic solvent to compound 01 is (10-15) mL:1 g; (5) The molar ratio of the base to the compound O1 is (1-2):1; (6) The molar ratio of the phenylsulfonyl indole to the compound O1 is (1-3):1; (7) Compound 01 is added to a mixed solution of phenylsulfonyl indole and a base; (8) The reaction temperature of the addition reaction is -80℃ to room temperature; (9) The addition reaction is quenched using an aqueous solution of sodium bicarbonate; (10) The addition reaction further includes a post-processing step.

21. The synthesis method according to claim 20, characterized in that, The post-processing steps include one or more of extraction, concentration, and vacuum distillation.

22. The synthesis method according to claim 20, characterized in that, The reaction conditions for the addition reaction satisfy one of the following conditions: (1) The organic solvent is tetrahydrofuran; (2) The addition reaction is carried out under nitrogen atmosphere; (3) The alkali is n-butyllithium; (4) The volume-to-mass ratio of the organic solvent to compound 01 is 13 mL: 1 g; (5) The molar ratio of the base to the compound O1 is 1.4:1; (6) The molar ratio of the phenylsulfonyl indole to the compound 01 is 2:

1.

23. A method for synthesizing fragment 1', comprising the following steps: (1) Compound 06 is synthesized according to the synthetic method according to any one of claims 1-22; (2) In an organic solvent, compound 06 was subjected to the following hydrolysis reaction with a base, followed by acidification, to obtain fragment 1'; 。 24. The synthesis method according to claim 23, characterized in that, The hydrolysis reaction must satisfy one of the following conditions: (1) In step (2), the organic solvent is an alcohol solvent; (2) In step (2), the base is an inorganic base; (3) In step (2), the acid in the acidification step is an inorganic acid; (4) In step (2), the volume-to-mass ratio of the organic solvent to compound 06 is (7-10) mL:1g; (5) In step (2), the molar ratio of the base to the compound O6 is (5-8):1; (6) In step (2), the hydrolysis reaction also includes a post-treatment step.

25. The synthesis method according to claim 24, characterized in that, The post-processing steps include one or more of neutralization, filtration, washing, drying, and crystallization.

26. The synthesis method according to claim 24, characterized in that, The hydrolysis reaction must satisfy one of the following conditions: (1) The alcohol solvent is ethanol; (2) The inorganic base is sodium hydroxide; (3) The inorganic acid is concentrated hydrochloric acid; (4) In step (2), the volume-to-mass ratio of the organic solvent to compound 06 is 9 mL: 1 g; (5) In step (2), the molar ratio of the base to the compound O6 is 6.9:

1.

27. A method for synthesizing compound 05, comprising the following steps: in an organic solvent, compound 04 undergoes a reducing desulfonation reaction with a reducing agent as shown below to obtain compound 05; ； The reaction conditions for the reducing desulfonation reaction are as described in any one of claims 7-10.

28. The synthesis method according to claim 27, characterized in that, The reducing desulfonation reaction further includes an addition reaction as described in any one of claims 11-14.

29. The synthesis method according to claim 27, characterized in that, The reductive desulfonation reaction further includes an addition reaction as described in any one of claims 11-14 and an oxidation reaction as described in any one of claims 15-18.

30. The synthesis method according to claim 27, characterized in that, The reducing desulfonation reaction further includes an addition reaction as described in any one of claims 11-14, an oxidation reaction as described in any one of claims 15-18, and an addition reaction as described in any one of claims 19-22.

31. A method for synthesizing compound 04, comprising the following steps: in an organic solvent, in the presence of a base, compound 03 undergoes an addition reaction with 4-acetal bromobenzene as shown below to obtain compound 04; ； The reaction conditions for the addition reaction are as described in any one of claims 11-14.

32. The synthesis method according to claim 31, characterized in that, The addition reaction further includes the oxidation reaction as described in any one of claims 15-18.

33. The synthesis method according to claim 31, characterized in that, The addition reaction further includes the oxidation reaction as described in any one of claims 15-18 and the addition reaction as described in any one of claims 19-22.

34. A method for synthesizing compound O3, comprising the following steps: in an organic solvent, compound O2 reacts with an oxidizing agent in an oxidation reaction as shown below to obtain compound O3; ； The reaction conditions for the oxidation reaction are as described in any one of claims 15-18.

35. The synthesis method according to claim 34, characterized in that, The oxidation reaction further includes an addition reaction as described in any one of claims 19-22.

36. A method for synthesizing compound 02, comprising the following steps: in an organic solvent, in the presence of a base, compound 01 undergoes an addition reaction with phenylsulfonylindole as shown below to obtain compound 02; ； The reaction conditions for the addition reaction are as described in any one of claims 19-22.

37. A compound as indicated by 01, 02, 03, 04, 05 or 06: , , , , or .

38. The compound as described in claim 37, as shown in O1, O2, O3, O4, O5, or O6, in the preparation of , , , or Applications in; The application method described is all or part of the following routes. 。

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