CN113683572A

CN113683572A - Intermediate of oxadegril and preparation method and application thereof

Info

Publication number: CN113683572A
Application number: CN202010421962.XA
Authority: CN
Inventors: 陈晓雯; 梅倩
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-05-18
Filing date: 2020-05-18
Publication date: 2021-11-23

Abstract

The invention provides a novel method for preparing a key intermediate 1 of oxa-goril and simultaneously provides several novel intermediate compounds. Through the new intermediate and the preparation method, not only are the raw material and the synthesis cost greatly reduced, but also the yield is greatly improved. Meanwhile, the method has the advantages of low reaction energy consumption, less three wastes and mild reaction conditions, and is easy for industrial scale-up production.

Description

Intermediate of oxadegril and preparation method and application thereof

Technical Field

The invention relates to the technical field of intermediates of novel oral GnRH antagonist oxadegril and a synthesis method thereof.

Background

Endometriosis (EMs) refers to a common gynecological disease in women with intimal cells planted in abnormal locations. The endometrial cells should grow in the uterine cavity, but because the uterine cavity is communicated with the ovary and the pelvic cavity through the oviduct, the endometrial cells can enter the ovary, the pelvic cavity and the adjacent area of the uterus to grow ectopically through the oviduct. EMs are common clinical benign diseases of women in the childbearing age, the incidence rate of the diseases reaches 10.0%, and the diseases are in a remarkable rising trend, are mainly characterized by dysmenorrhea, pelvic pain and infertility, and seriously affect the reproductive health and the life quality of the women.

On 23/7/2018, the important product of erbavil, elagolix (loragol), was approved by the U.S. food and drug administration, which would be useful in treating pain due to EMs and became the first new oral drug for over 10 years for this indication, with a projected sale of $ 12.1 billion in 2022.

The chemical name of the oxa-rogle is as follows: 4- [ [ (1R) -2- [5- (2-fluoro-3-methoxyphenyl) -3- [ [ 2-fluoro-6- (trifluoromethyl) phenyl ] methyl ] -3, 6-dihydro-4-methyl-2, 6-dioxo-1 (2H) -pyrimidinyl ] -1-phenylethyl ] amino ] butanoic acid. WO2005007165A reports a synthesis method of oxa-rogue, in the route, 2-fluoro-6-trifluoromethyl benzonitrile is taken as a starting material, the 2-fluoro-6-trifluoromethyl benzonitrile is subjected to borane reduction, condensation with urea, cyclization with diethylenone and other steps in sequence to obtain an intermediate 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4(1H,3H) -diketone, the intermediate is subjected to bromination, amine alkylation and other steps, then subjected to Suzuki coupling reaction with 2-fluoro-3-methoxyphenylboronic acid, finally subjected to Boc protecting group removal to obtain a key intermediate compound 1, and subjected to condensation and hydrolysis reaction with 4-bromobutyric acid methyl ester to obtain the oxa-rogue. The synthetic route is as follows:

the synthetic route has the disadvantages of overlong steps, more complicated process, lower total yield, expensive starting materials, high risk of liquid bromine amplification production and high equipment requirement.

In the new synthesis method of the oxarogue, disclosed in the US patent 8765948B, o-fluoro anisole is used as a raw material, condensation with diethyl oxalate, reduction with sodium borohydride, bromination with lithium bromide and condensation with acetonitrile under the action of zinc powder are sequentially carried out to obtain an enamine intermediate, then amino is protected by phenyl chloroformate and undergoes cyclization reaction with (R) -tert-butyl (2-amino-1-phenylethyl) amino carbonate under the action of alkali to obtain a mother ring molecule, then the mother ring molecule and benzyl bromide intermediate complete N-alkylation reaction and undergo deprotection to obtain an oxarogue key intermediate 1, and the intermediate is subjected to condensation and hydrolysis reaction with 4-ethyl bromobutyrate to obtain the oxarogue. The synthetic route is as follows:

although the starting materials are simple and easy to obtain in the synthetic route, the reaction steps are long, a large amount of debrominated products are generated in the condensation process of bromide intermediates and acetonitrile, the yield is greatly reduced and is only 29.68%, and the scale-up production is severely limited.

Therefore, a method for synthesizing the loragoid, which has the advantages of improving the yield, reducing the cost and being suitable for industrial production, is still needed.

Disclosure of Invention

The invention aims to overcome the defects in the prior art and provide a novel method for preparing the loragolide in an industrial production mode.

Based on the new intermediate compound, the invention also provides a new intermediate compound for preparing the oxadegril and a preparation method of the new intermediate compound. Meanwhile, a novel preparation method of the existing key intermediate compound 1 is provided.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

novel compound 5 of the formula:

and R is selected from H and C1-C6 alkyl. Wherein alkyl is preferably methyl, ethyl, propyl, allyl, isopropyl, isobutyl or tert-butyl; further preferred is methyl, allyl, isopropyl, isobutyl or tert-butyl.

Novel compound 6 of the formula:

Novel compound 7 of the formula:

r is selected from H and alkyl of C1-C6, and X is selected from chlorine, bromine and iodine. Wherein alkyl is preferably methyl, ethyl, propyl, allyl, isopropyl, isobutyl or tert-butyl; further preferred is methyl, allyl, isopropyl, isobutyl or tert-butyl.

Novel compound 8 of the formula:

and R is selected from H or C1-C6 alkyl. Wherein alkyl is preferably methyl, ethyl, propyl, allyl, isopropyl, isobutyl or tert-butyl; further preferred is methyl, allyl, isopropyl, isobutyl or tert-butyl.

The preparation method of the new compound 5 comprises the following steps of carrying out condensation reaction on a compound 3 with a formula shown in the specification and R-alpha- (amido) phenylethylamine to obtain an intermediate compound 4, and carrying out cyclization reaction to obtain the new compound 5:

said R₁Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, and the like; and R is selected from H or C1-C6 alkyl. Said R₁Preferably C1-C6 alkyl, more preferably ethyl or methyl; r is preferably methyl, ethyl, propyl, allyl, isopropyl, isobutyl or tert-butyl; further preferred is methyl, allyl, isopropyl, isobutyl or tert-butyl.

According to the method for preparing the compound 5, the compound 4 is obtained through condensation reaction, the compound 5 is obtained through cyclization reaction, the product 4 does not need to be separated in the middle, and the compound 5 can be obtained through direct heating and cyclization reaction in a one-pot method.

The above condensation reaction for preparing compound 5, wherein the base may be an inorganic base or an organic base, preferably an inorganic base. The inorganic base comprises sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like, and preferably potassium carbonate; the organic base comprises triethylamine, N-diisopropylethylamine, pyridine, DBU and the like.

The condensation reaction for preparing the compound 5 as described above, wherein the reaction solvent is selected from the group consisting of toluene, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone and the like, and N, N-dimethylformamide is preferred.

In the above method for preparing the compound 5, the compound 4 can be subjected to the cyclization reaction to obtain the compound 5 under room temperature conditions or under heating conditions, preferably at 20 to 150 ℃, and more preferably at 60 to 100 ℃.

The compound 3 adopted in the preparation method of the novel compound 5 is preferably obtained by using the preparation method provided by the invention, and the method is obtained by condensation reaction of a compound 2 with chloroformate:

said R₁Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl and the like, wherein R is₂Selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl and the like selected from C1-C12. Said R₁Preferably C1-C6 alkyl, more preferably ethyl or methyl; said R₂The alkyl group is preferably a C1-C6 alkyl group, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, an allyl group, a vinyl group, an aryl group or the like, and still more preferably a phenyl group.

The above condensation reaction for preparing compound 3, the base may be an inorganic base or an organic base, preferably an organic base. The inorganic base comprises sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like, and the organic base comprises triethylamine, N-diisopropylethylamine, pyridine, DBU and the like; pyridine is preferred.

In the condensation reaction for preparing the compound 3, when water is generated in the reaction process, a drying agent is required to be added, and the drying agent is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, calcium oxide, a 4A molecular sieve and the like, and is preferably a 4A molecular sieve.

In the condensation reaction for producing the compound 3, the reaction solvent is selected from toluene, 1, 4-dioxane, acetonitrile, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, etc., and toluene is preferred.

The condensation reaction of the prepared compound 3 is carried out at the reaction temperature of 20-150 ℃, preferably 60-90 ℃.

The new compound 6 is obtained by condensation reaction of a compound 5 and 2-fluoro-6-trifluoromethyl benzyl bromide under the action of alkali:

and R is selected from H or C1-C6 alkyl. Preferably methyl, ethyl, propyl, allyl, isopropyl, isobutyl or tert-butyl; further preferred is methyl, allyl, isopropyl, isobutyl or tert-butyl.

The above condensation reaction for preparing compound 6, wherein the base may be an inorganic base or an organic base, preferably an inorganic base. The inorganic base comprises sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like, and the organic base comprises triethylamine, N-diisopropylethylamine, pyridine, DBU and the like; further preferred is sodium carbonate. The reaction solvent is selected from toluene, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, etc., and preferably N, N-dimethylformamide. The reaction temperature is between room temperature and 150 ℃, and preferably between 60 and 100 ℃.

The new compound 7 is obtained by the halogenation reaction of the compound 6 by N-halogenated succinimide:

In the halogenation reaction of the compound 6, the reaction solvent is selected from acetonitrile, dichloromethane, chloroform, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetone, 1, 4-dioxane, toluene, etc., and preferably acetonitrile. The reaction temperature is-50 to 50 ℃, and preferably 0 to 20 ℃.

The new compound 8 is obtained by carrying out Suzuki coupling reaction on the compound 7 and 2-fluoro-3-methoxyphenylboronic acid in the presence of a catalyst:

The coupling reaction of the compound 7 is carried out by using a catalyst selected from tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, dibenzylideneacetone dipalladium, Pd-XPhos-G4 and the like, and preferably Pd-XPhos-G4. The alkali includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc., preferably potassium phosphate. The reaction solvent is selected from mixed solvents of water and acetonitrile, dichloromethane, trichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, acetone, 1, 4-dioxane, toluene and the like, and is preferably a mixed solvent of water and 1, 4-dioxane. The reaction temperature is 50-100 ℃, and preferably 70-80 ℃.

Hydrolyzing the compound 8 with acid to obtain a key intermediate compound 1:

The above compound 8 is hydrolyzed with an organic acid or an inorganic acid, preferably an inorganic acid. The inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, and the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and the like; further preferred is hydrochloric acid. The solvent is selected from methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, acetone, 1, 4-dioxane, etc., preferably methanol, ethanol or isopropanol. The reaction temperature is selected from 50-100 ℃, and preferably 60-90 ℃.

The invention has the beneficial effects that:

1. the preparation steps of the key intermediate compound 1 are shortened, the yield is greatly improved (from 29.68% to 51.88% in the prior art), the reaction energy consumption is low, the three wastes are less, the preparation period is short, and the industrial amplification production is easier.

2. 3-aminocrotonic acid ester which is cheap and easy to obtain can be further selected as a starting material, so that the cost of the raw material is greatly reduced, and reagents or intermediates used in each step of reaction can be purchased commercially.

3. Amino protecting group changed from Boc to cheap

Not only the cost is reduced, but also the atom economy is improved and the cost is reduced.

4. The method avoids the use of high and strong irritative and explosive reagents such as borane tetrahydrofuran, butyl lithium, diketene and the like in the prior method, and also does not need to use a large amount of strong corrosive reagents such as concentrated hydrochloric acid, bromine and the like in the prior method, thereby greatly reducing the equipment requirement in the actual amplification production.

Detailed Description

The present invention is illustrated by the following examples, which should be construed as merely illustrative and not a limitation of the scope of the invention.

In the synthesis method of the key intermediate (compound 1) of oxalagril provided in this embodiment, the synthetic route is exemplified as follows:

example 1:

ethyl 3-aminocrotonate (10g, 77.42mmol) was dissolved in dry toluene (100mL), pyridine (9.18g, 116.14mmol), phenyl chloroformate (11.64mL, 92.91mmol) were added at room temperature, the suspension was raised to 75 deg.C and the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and after 4h the conversion of the starting material was complete. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness to give 19.35g of a yellow-brown oil, 90% purity, 100% yield, ms (esi): [ M + H ]]⁺250, directly put into the next step without purification.

Example 2:

methyl 3-aminocrotonate (10g, 86.96mmol) was dissolved in dry 1, 4-dioxane (100mL), triethylamine (18.16mL, 130.29mmol) and phenyl chloroformate (16.32g, 104.23mmol) were added at room temperature, the suspension was raised to 70 deg.C and the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and after 6h the conversion of the starting material was complete. Mixing the reaction mixtureFiltration through celite and evaporation of the filtrate to dryness gave 18.88g of a yellow-brown oil, 89% purity, 92.40% yield, ms (esi): [ M + H ]]⁺＝236。

Example 3:

ethyl 3-aminocrotonate (10g, 77.42mmol) was dissolved in dry toluene (100mL), anhydrous potassium carbonate (16.05g, 116.14mmol), 4A molecular sieve (325 mesh, 10g) and ethyl chloroformate (10.08g, 92.91mmol) were added at room temperature, the suspension was raised to 75 deg.C, the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and the conversion of the starting material was complete after 4.5 h. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness to give 15.60g of a yellow-brown oil, 95% purity, 100% yield, ms (esi): [ M + H ]]⁺＝202。

Example 4:

ethyl 3-aminocrotonate (10g, 77.42mmol) was dissolved in dry acetonitrile (100mL), anhydrous potassium carbonate (16.05g, 116.14mmol), 4A molecular sieve (325 mesh, 10g) and methyl chloroformate (8.78g, 92.91mmol) were added at room temperature, the suspension was raised to 75 deg.C, the reaction was stirred rapidly, LC-MS monitored the progress of the reaction, and the conversion of the starting material was complete after 4.5 h. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness to give 14.67g of a yellow-brown oil, 94.69% purity, 101.22% yield, ms (esi): [ M + H ]]⁺＝188。

Example 5:

dissolving a compound 3-1 (crude product, 19.3g, 77.43mmol) in anhydrous DMF (100mL), adding R-alpha- (formamido) phenethylamine acetate (19.19g, 85.17mmol) and anhydrous potassium carbonate (16.05g, 116.14mmol), stirring at room temperature for reaction, monitoring the reaction process by LC-MS, completely converting the raw materials after 3h, and directly heating the product without separation for the second-stage reaction.

And (3) heating the reaction liquid to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate compound into the compound 5-1 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Isopropyl ether (100mL) was added, and the mixture was slurried at room temperature for 12 hours, filtered to give an off-white cake, and vacuum-dried to give an off-white powder (13.6 g), purity of LC-MS (LC-MS) of 99.78%, yield 64.26% (based on compound 2-1), MS (ESI): [ M + H ]]⁺＝274。¹HNMR:δ2.23(3H，s)，3.91-4.02(1H，d)，4.05-4.13(1H，d)，5.44-5.53(1H，m)，5.67(1H，s)，6.98-7.37(5H，m)，7.93(1H，s)。

Example 6:

compound 5-1(5g, 18.3mmol) was dissolved in anhydrous DMF (50mL), anhydrous sodium carbonate (6.59g, 62.20mmol) was added, 2-fluoro-6-trifluoromethylbromobenzyl (7.05g, 27.44mmol) was added, the reaction was stirred at 80 ℃ and the progress of the reaction was monitored by LC-MS, and after 15h the starting material was completely converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.6g of yellow oil, 98.22% purity by LC-MS, 92.43% yield, MS (esi): [ M + H ]]⁺＝450。¹HNMR:δ2.25(3H，s)，3.93-4.07(1H，d)，4.09-4.18(1H，d)，4.56(2H，s)，5.46-5.55(1H，m)，5.65(1H，s)，6.90-7.35(7H，m)，7.40-7.45(1H，m)，7.99(1H，s)。

Example 7:

compound 5-1(5g, 18.3mmol) was dissolved in anhydrous DMF (50mL), anhydrous sodium carbonate (6.59g, 62.20mmol) was added, 2-fluoro-6-trifluoromethylbromobenzyl (7.05g, 27.44mmol) was added, the reaction was stirred at 50 ℃ and the progress of the reaction was monitored by LC-MS, and after 60h the starting material was substantially converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 5.9g of a yellow oil, purity by LC-MS 94.65%, yield 71.16%.

Example 8:

compound 5(5g, 18.3mmol) was dissolved in dry toluene (50mL), triethylamine (6.29g, 49.22mmol) was added, 2-fluoro-6-trifluoromethylbromobenzyl (7.05g, 27.44mmol) was added and the reaction stirred at 80 deg.C, LC-MS monitored the progress of the reaction, and after 40h the starting material had been essentially converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 6.08g of a yellow oil, 93.55% purity LC-MS and 73.95% yield.

Example 9:

compound 6-1(5g, 11.13mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-bromosuccinimide (1.98g, 11.13mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reactionIn the process, the conversion of the raw materials is complete after 12 hours. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.35g of a pale yellow foamy solid, purity of LC-MS 96.55%, yield 91.02%, MS (esi): [ M + H ]]⁺＝528。¹HNMR:δ2.13(3H，s)，3.82-4.03(1H，d)，4.05-4.14(1H，d)，4.45(2H，s)，5.33-5.63(1H，m)，6.86-7.30(7H，m)，7.42-7.51(1H，m)，8.05(1H，s)。

Example 10:

compound 6-1(5g, 11.13mmol) was dissolved in dichloromethane (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-chlorosuccinimide (1.49g, 11.13mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase is washed with water, dried by anhydrous sodium sulfate and evaporated to dryness to obtain 4.86g of light yellow foamy solid, the purity of LC-MS is 95.33%, the yield is 90.28%, and MS (ESI): [ M + H ]]⁺＝484。δ2.19(3H，s)，3.86-4.09(1H，d)，4.11-4.18(1H，d)，4.49(2H，s)，5.31-5.60(1H，m)，6.83-7.22(7H，m)，7.39-7.46(1H，m)，7.98(1H，s)。

Example 11:

compound 6-1(5g, 11.13mmol) was dissolved in ethyl acetate (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-iodosuccinimide (2.5g, 11.13mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.54g of a pale yellow foamy solid, LC-MS purity 93.66%, yield 86.55%, MS (esi): [ M + H ]]⁺＝576。δ2.28(3H，s)，3.88-4.12(1H，d)，4.17-4.23(1H，d)，4.55(2H，s)，5.36-5.67(1H，m)，6.86-7.29(7H，m)，7.41-7.52(1H，m)，8.00(1H，s)。

Example 12:

compound 7-1-Br (5g, 9.46mmol), 2-fluoro-3-methoxyphenylboronic acid (2.09g, 12.3mmol) and potassium phosphate (6.03g, 28.39mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged with nitrogen gas and oxygen purged for 10min, and a catalyst (8.14mg, 0.009mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 2h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with pure water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.21g of a pale yellow foamy solid, purity LC-MS 95.85%, yield 95.98%, MS (esi): [ M + H ]]⁺＝574。¹HNMR:δ2.23(3H，s)，3.59-3.62(1H，d)，3.80-3.88(1H，d)，3.91(3H，s)，4.51(2H，s)，5.48-5.57(1H，m)，6.81-7.30(10H，m)，7.52-7.59(1H，m)，7.97(1H，s)。

Example 13:

compound 7-1-Cl (4g, 8.27mmol), 2-fluoro-3-methoxyphenylboronic acid (1.83g, 10.75mmol), potassium phosphate (3.42g, 24.80mmol) were added to a mixed solvent of acetonitrile (48mL,12eqV) and pure water (12mL, 3eqV), the solution was stirred, purged by bubbling with nitrogen gas for deoxygenation for 10min, and catalyst (95.6mg, 0.083mmol) was added. The temperature is raised to 70 ℃ and the reaction is stirred. TLC and LC-MS monitor the reaction progress, and after 6h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 12mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.23g of a pale yellow foamy solid with a purity of 92.89% by LC-MS and a yield of 89.22%.

Example 14:

compound 7-1-I (5g, 8.69mmol), 2-fluoro-3-methoxyphenylboronic acid (1.92g, 11.3mmol), sodium carbonate (2.76g, 26.07mmol) were added to a mixed solvent of toluene (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and catalyst (7.48mg, 0.009mmol) was added. The temperature is raised to 80 ℃ and the reaction is stirred. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.16g of a pale yellow foamy solid with a purity of 93.73% by LC-MS and a yield of 83.46%.

Example 15:

compound 8-1(5g, 8.72mmol) was added to a mixed solvent of ethanol (25mL) and 6N hydrochloric acid (25mL), and the mixture was stirred to dissolve, heated to 80 ℃ and stirred for reaction. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH of the system to 7-8 with a saturated sodium bicarbonate solution under stirring, separating, washing the organic phase with saturated saline, and evaporating to dryness to obtain a white foamy solid 4.38g, wherein the purity of LC-MS is 96.88%, and the yield is 92.1%. Ms (esi): [ M + H ] + ═ 546.

Example 16:

compound 8-1(5g, 8.72mmol) was added to a mixed solvent of isopropyl alcohol (25mL) and pure water (25mL), and stirred to dissolve, methanesulfonic acid (1.68g, 17.44mmol) was added, and the reaction was stirred at 80 ℃. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH of the system to 7-8 with a saturated sodium bicarbonate solution under stirring, separating, washing the organic phase with saturated saline, and evaporating to dryness to obtain a white foamy solid 4.29g, wherein the purity of LC-MS is 96.2%, and the yield is 90.21%.

Example 17:

dissolving a compound 3-1 (crude product, 18g, 72.21mmol) in anhydrous DMAc (100mL), adding R-alpha- (acetamido) phenethylamine acetate (19.01g, 79.43mmol) and anhydrous potassium carbonate (14.97g, 108.32mmol), stirring at room temperature for reaction, monitoring the reaction process by LC-MS, completely converting the raw materials after 3h, and directly heating the product without separation for the second-stage reaction.

And (3) heating the reaction liquid to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate state into the compound 5-2 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Adding isopropyl ether (100mL), pulping at room temperature for 12h, filtering to obtain white-like filter cake, vacuum drying to obtain white-like powder 14.63g,LC-MS purity 99.33%, yield 70.53% (based on compound 2-1), MS (esi): [ M + H ]]⁺＝288。¹HNMR:δ1.80(3H，s)，δ2.29(3H，s)，3.60-3.66(1H，d)，3.82-3.88(1H，d)，5.42-5.47(1H，m)，5.55(1H，s)，7.18-7.31(5H，m)。

Example 18:

compound 5-2(5g, 17.4mmol) was dissolved in anhydrous DMF (50mL), anhydrous sodium carbonate (6.27g, 59.17mmol) was added, 2-fluoro-6-trifluoromethylbromobenzyl (6.71g, 26.1mmol) was added, the reaction was stirred at 80 ℃ and the progress of the reaction was monitored by LC-MS, and after 15h the starting material was completely converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.44g of yellow oil, 97.98% purity LC-MS, 92.25% yield, MS (esi): [ M + H ]]⁺＝464。¹HNMR:δ1.83(3H，s)，δ2.27(3H，s)，3.58-3.63(1H，d)，3.79-3.85(1H，d)，4.49(2H，s)，5.46(1H，s)，5.50-5.56(1H，m)，7.20-7.33(7H，m)。7.60-7.65(1H，m)。

Example 19:

compound 6-2(5g, 10.79mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-bromosuccinimide (1.92g, 10.79mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase is washed with water, dried by anhydrous sodium sulfate and evaporated to dryness to obtain 5.28g of light yellow foamy solid, the purity of LC-MS is 96.98%, the yield is 90.24%, and MS (ESI): [ M + H ]]⁺＝542。¹HNMR:δ1.80(3H，s)，δ2.23(3H，s)，3.55-3.60(1H，d)，3.77-3.84(1H，d)，4.45(2H，s)，5.46-5.53(1H，m)，7.16-7.30(7H，m)。7.56-7.62(1H，m)。

Example 20:

compound 6-2(5g, 10.79mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-chlorosuccinimide (1.44g, 10.79mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.76g of a pale yellow foamy solid, LC-MS purity 93.77%, yield 88.61%, MS (esi): [ M + H ]]⁺＝498。¹HNMR:δ1.81(3H，s)，δ2.22(3H，s)，3.53-3.61(1H，d)，3.75-3.81(1H，d)，4.52(2H，s)，5.49-5.54(1H，m)，7.18-7.32(7H，m)。7.57-7.63(1H，m)。

Example 21:

compound 6-2(5g, 10.79mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature was reduced to 10 ℃ and N-iodosuccinimide (2.43g, 10.79mmol) was added and the reaction was stirred at 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.33g of a pale yellow foamy solid, purity of LC-MS 92.24%, yield 83.83%, MS (esi): [ M + H ]]⁺＝590。¹HNMR:δ1.83(3H，s)，δ2.25(3H，s)，3.52-3.63(1H，d)，3.76-3.83(1H，d)，4.56(2H，s)，5.50-5.57(1H，m)，7.19-7.34(7H，m)。7.59-7.65(1H，m)。

Example 22:

compound 7-2-Br (5g, 9.22mmol), 2-fluoro-3-methoxyphenylboronic acid (2.04g, 11.99mmol) and potassium phosphate (5.87g, 27.66mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged with nitrogen gas and purged for 10min, and a catalyst (7.93mg, 0.009mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 2h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with pure water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.11g of a pale yellow foamy solid, purity of LC-MS 96.71%, yield 94.33%, MS (esi): [ M + H ]]⁺＝588。¹HNMR:δ1.87(3H，s)，δ2.25(3H，s)，3.56-3.64(1H，d)，3.77-3.85(1H，d)，3.96(3H，s)，4.53(2H，s)，5.49-5.59(1H，m)，6.80-7.28(10H，m)，7.58-7.62(1H，m)。

Example 23:

the compound 7-2-Cl (4g, 8.03mmol), 2-fluoro-3-methoxyphenylboronic acid (1.77g, 10.44mmol) and potassium phosphate (5.12g, 24.10mmol) were added to a mixed solvent of 1, 4-dioxane (48mL,12eqV) and pure water (12mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and the catalyst (6.91mg, 0.008mmol) was added. Heating to 75-80 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 6h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 12mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.12g of a pale yellow foamy solid with a purity of 93.55% by LC-MS and a yield of 87.28%.

Example 24:

compound 7-2-I (5g, 8.48mmol), 2-fluoro-3-methoxyphenylboronic acid (1.87g, 11.03mmol) and potassium phosphate (5.40g, 25.45mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged by bubbling with nitrogen gas for deoxygenation for 10min, and a catalyst (7.3mg, 0.008mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.09g of a pale yellow foamy solid with an LC-MS purity of 92.18% and a yield of 82.05%.

Example 25:

compound 8-2(5g, 8.51mmol) was added to a mixed solvent of ethanol (25mL) and 6N hydrochloric acid (25mL), and the mixture was stirred to dissolve and clear, and the reaction was stirred at 80 ℃. TLC and LC-MS monitor the reaction progress, and after 24h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH value of the system to 7-8 by using a saturated sodium bicarbonate solution under stirring, separating, washing an organic phase by using saturated saline solution, and evaporating to dryness to obtain 4.09g of a white foamy solid, wherein the purity of LC-MS is 95.13%, and the yield is 88.1%. Ms (esi): [ M + H ] + ═ 546.

Example 26:

dissolving a compound 3-1 (crude product, 18g, 72.21mmol) in anhydrous DMF (100mL), adding R-alpha- (isobutyramido) phenethylamine acetate (21.16g, 79.43mmol) and anhydrous potassium carbonate (14.97g, 108.32mmol), stirring at room temperature for reaction, monitoring the reaction process by LC-MS, completely converting the raw material after 3h, and directly heating the product without separation for the second-stage reaction.

And (3) heating the reaction solution to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate state into a compound 5-3 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Isopropyl ether (100mL) was added, and the mixture was slurried at room temperature for 12 hours, filtered to give an off-white cake, and vacuum-dried to give an off-white powder (15.81 g), purity of LC-MS (99.57%) and yield (69.42%) based on Compound 2-1, MS (ESI): [ M + H ]]⁺＝316。¹HNMR:δ1.21-1.23(6H，s)，2.23(3H，s),2.70(1H，m)，3.61-3.67(1H，d)，3.89-3.86(1H，d)，5.46(1H，s)，5.49-5.54(1H，m)，7.15-7.48(5H，m)。

Example 27:

dissolve compound 5-3(5g, 15.85mmol) in anhydrous DMF (50mL), add anhydrous sodium carbonate (5.71g, 53.90mmol), add 2-fluoro-6-trifluoromethyl benzyl bromide (6.11g, 23.78mmol), raise to 80 deg.C and stir the reaction, LC-MS monitors the progress of the reaction, after 15h the starting material is completely converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.12g of yellow oil, 98.1% purity by LC-MS, 91.37% yield, MS (esi): [ M + H ]]⁺＝492。¹HNMR:δ1.22-1.26(6H，s)，2.25(3H，s),2.71(1H，m)，3.64-3.70(1H，d)，3.92-3.95(1H，d)，4.50(2H，s)，5.48(1H，s)，5.52-5.60(1H，m)，7.12-7.46(7H，m)，7.59-7.63(1H，m)。

Example 28:

compound 6-3(5g, 10.17mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-bromosuccinimide (1.81g, 10.17mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.33g of a pale yellow foamy solid, purity of LC-MS 96.75%, yield 91.85%, MS (esi): [ M + H ]]⁺＝570。¹HNMR:δ1.19-1.23(6H，s)，2.21(3H，s),2.69(1H，m)，3.61-3.68(1H，d)，3.88-3.93(1H，d)，4.52(2H，s)，5.50-5.59(1H，m)，7.13-7.44(7H，m)，7.57-7.61(1H，m)。

Example 29:

compound 6-3(5g, 10.17mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-chlorosuccinimide (1.36g, 10.17mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase is washed with water, dried by anhydrous sodium sulfate and evaporated to dryness to obtain 4.86g of light yellow foamy solid, the purity of LC-MS is 92.99%, the yield is 90.83%, and MS (ESI): [ M + H ]]⁺＝526。¹HNMR:δ1.20-1.26(6H，s)，2.24(3H，s),2.71(1H，m)，3.63-3.69(1H，d)，3.86-3.92(1H，d)，4.50(2H，s)，5.53-5.62(1H，m)，7.11-7.47(7H，m)，7.55-7.65(1H，m)。

Example 30:

compound 6-3(5g, 10.17mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-iodosuccinimide (2.29g, 10.17mmol) is added, and the reaction is stirred at 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.50g of a pale yellow foamy solid, LC-MS purity 93.03%, yield 87.57%, MS (esi): [ M + H ]]⁺＝618。¹HNMR:δ1.22-1.29(6H，s)，2.27(3H，s),2.72(1H，m)，3.62-3.71(1H，d)，3.87-3.95(1H，d)，4.53(2H，s)，5.54-5.66(1H，m)，7.15-7.55(7H，m)，7.60-7.68(1H，m)。

Example 31:

compound 7-3-Br (5g, 8.77mmol), 2-fluoro-3-methoxyphenylboronic acid (1.94g, 11.40mmol) and potassium phosphate (5.58g, 26.30mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged by bubbling with nitrogen gas for 10min, and a catalyst (7.54mg, 0.009mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 2h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with pure water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.07g of a pale yellow foamy solid, purity of LC-MS 95.89%, yield 93.95%, MS (esi): [ M + H ]]⁺＝616。¹HNMR:δ1.18-1.26(6H，s)，2.25(3H，s),2.69(1H，m)，3.50-3.62(1H，d)，3.76-3.83(1H，d)，3.94(3H，s)，4.55(2H，s)，5.51-5.63(1H，m)，6.81-7.29(10H，m)，7.56-7.61(1H，m)。

Example 32:

the compound 7-3-Cl (4g, 7.61mmol), 2-fluoro-3-methoxyphenylboronic acid (1.68g, 9.89mmol) and potassium phosphate (4.84g, 22.82mmol) were added to a mixed solvent of 1, 4-dioxane (48mL,12eqV) and pure water (12mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and the catalyst (6.54mg, 0.008mmol) was added. Heating to 75-80 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 6h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 12mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.14g of a pale yellow foamy solid with a purity of 92.96% by LC-MS and a yield of 88.42%.

Example 33:

compound 7-3-I (5g, 8.10mmol), 2-fluoro-3-methoxyphenylboronic acid (1.79g, 10.53mmol) and potassium phosphate (5.16g, 24.30mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and a catalyst (6.97mg, 0.008mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.22g of a pale yellow foamy solid with a purity of 93.01% by LC-MS and a yield of 84.64%.

Example 34:

the compound 8-3(5g, 8.12mmol) was added to a mixed solvent of ethanol (25mL) and 6N hydrochloric acid (25mL), and the mixture was stirred to dissolve and clear, and heated to 80 ℃ to stir the reaction. TLC and LC-MS monitor the reaction progress, and after 24h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH value of the system to 7-8 with a saturated sodium bicarbonate solution under stirring, separating, washing the organic phase with saturated saline solution, and evaporating to dryness to obtain 4.01g of white foamy solid, wherein the purity of LC-MS is 94.69%, and the yield is 90.50%. Ms (esi): [ M + H ] + ═ 546.

Example 35:

dissolving a compound 3-1 (crude product, 18g, 72.21mmol) in anhydrous DMSO (100mL), adding R-alpha- (isovaleryl amino) phenethylamine acetate (22.35g, 79.43mmol) and anhydrous potassium carbonate (14.97g, 108.32mmol), stirring at room temperature for reaction, monitoring the reaction process by LC-MS, completely converting the raw materials after 3h, and directly heating the product without separation for the second-stage reaction.

And (3) heating the reaction liquid to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate state into a compound 5-4 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Isopropyl ether (100mL) was added, and the mixture was slurried at room temperature for 12 hours, filtered to give an off-white cake, and vacuum-dried to give an off-white powder (16.33 g), purity of LC-MS (LC-MS) of 99.30%, yield 68.66% (based on compound 2-1), MS (ESI): [ M + H ]]⁺＝330。¹HNMR:δ0.95-0.98(6H，d)，2.06-2.11(1H，m)，2.15-2.20(2H，d)，2.32(3H，s)，3.65-3.71(1H，d)，3.89-3.98(1H，d)，5.47-5.52(1H，m)，5.68(1H，s)，7.17-7.43(5H，m)。

Example 36:

dissolve compound 5-4(5g, 15.18mmol) in anhydrous DMF (50mL), add anhydrous sodium carbonate (5.47g, 51.61mmol), add 2-fluoro-6-trifluoromethyl benzyl bromide (5.85g, 22.77mmol), raise to 80 deg.C and stir the reaction, LC-MS monitors the progress of the reaction, after 15h the starting material is completely converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.05g of yellow oil, 97.76% purity LC-MS, 91.88% yield, MS (esi): [ M + H ]]⁺＝506。¹HNMR:δ1.01-1.06(6H，d)，2.09-2.13(1H，m)，2.18-2.22(2H，d)，2.33(3H，s)，3.62-3.68(1H，d)，3.85-4.00(1H，d)，4.56(2H，s)，5.44-5.50(1H，m)，5.66(1H，s)，7.20-7.49(7H，m),7.66-7.70(1H，m)。

Example 37:

compound 6-4(5g, 9.89mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-bromosuccinimide (1.76g, 9.89mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.23g of a pale yellow foamy solid, purity of LC-MS 95.81%, yield 90.48%, MS (esi): [ M + H ]]⁺＝585。¹HNMR:δ0.99-1.04(6H，d)，2.11-2.15(1H，m)，2.17-2.21(2H，d)，2.30(3H，s)，3.65-3.72(1H，d)，3.83-4.02(1H，d)，4.58(2H，s)，5.41-5.48(1H，m)，7.18-7.47(7H，m),7.65-7.69(1H，m)。

Example 38:

compound 6-4(5g, 10.17mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-chlorosuccinimide (1.32g, 10.17mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow foamy solid (4.80 g), LC-MS purity 93.23%, yield 89.88%, MS (esi): [ M + H ]]⁺＝540。¹HNMR:δ1.00-1.06(6H，d)，2.12-2.16(1H，m)，2.18-2.23(2H，d)，2.34(3H，s)，3.64-3.70(1H，d)，3.81-3.98(1H，d)，4.55(2H，s)，5.39-5.45(1H，m)，7.16-7.44(7H，m),7.63-7.66(1H，m)。

Example 39:

compound 6-4(5g, 9.89mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-iodosuccinimide (2.23g, 9.89mmol) is added, and the reaction is stirred at 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow foamy solid 5.31g, LC-MS purity 91.89%, yield 85.02%, MS (esi): [ M + H ]]⁺＝632。¹HNMR:δ1.02-1.09(6H，d)，2.14-2.19(1H，m)，2.18-2.25(2H，d)，2.37(3H，s)，3.65-3.74(1H，d)，3.85-4.05(1H，d)，4.60(2H，s)，5.40-5.47(1H，m)，7.18-7.49(7H，m),7.69-7.71(1H，m)。

Example 40:

compound 7-4-Br (5g, 8.56mmol), 2-fluoro-3-methoxyphenylboronic acid (1.89g, 11.12mmol) and potassium phosphate (5.45g, 25.67mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged with nitrogen gas and oxygen purged for 10min, and a catalyst (7.36mg, 0.009mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 2h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with pure water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.00g of a pale yellow foamy solid, purity of LC-MS 95.11%, yield 92.82%, MS (esi): [ M + H ]]⁺＝630。¹HNMR:δ0.96-1.02(6H，d)，2.13-2.16(1H，m)，2.16-2.24(2H，d)，2.35(3H，s)，3.63-3.71(1H，d)，3.81(3H，s)，3.89-4.07(1H，d)，4.62(2H，s)，5.39-5.45(1H，m)，7.22-7.53(10H，m),7.70-7.72(1H，m)。

Example 41:

the compound 7-4-Cl (4g, 7.41mmol), 2-fluoro-3-methoxyphenylboronic acid (1.64g, 9.63mmol) and potassium phosphate (4.72g, 22.22mmol) were added to a mixed solvent of 1, 4-dioxane (48mL,12eqV) and pure water (12mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and the catalyst (6.37mg, 0.007mmol) was added. Heating to 75-80 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 6h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 12mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.09g of a pale yellow foamy solid with a purity of LC-MS of 92.10% and a yield of 87.69%.

Example 42:

compound 7-4-I (5g, 7.92mmol), 2-fluoro-3-methoxyphenylboronic acid (1.75g, 10.29mmol) and potassium phosphate (5.04g, 23.76mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged by bubbling with nitrogen gas for deoxygenation for 10min, and a catalyst (6.81mg, 0.008mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.19g of a pale yellow foamy solid with a purity of 92.16% by LC-MS and a yield of 84.04%.

Example 43:

the compound 8-4(5g, 7.94mmol) was added to a mixed solvent of ethanol (25mL) and 6N hydrochloric acid (25mL), and the mixture was stirred to dissolve and clear, heated to 80 ℃ and stirred for reaction. TLC and LC-MS monitor the reaction progress, and after 24h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH of the system to 7-8 with a saturated sodium bicarbonate solution under stirring, separating, washing the organic phase with saturated saline, and evaporating to dryness to obtain a white foamy solid 3.87g, wherein the purity of LC-MS is 95.25%, and the yield is 89.34%. Ms (esi): [ M + H ] + ═ 546.

Example 44:

dissolving the compound 3-1 (crude product, 18g, 72.21mmol) in anhydrous DMF (100mL), adding R-alpha- (tert-amyl amido) phenethylamine acetate (22.35g, 79.43mmol) and anhydrous potassium carbonate (14.97g, 108.32mmol), stirring at room temperature for reaction, monitoring the reaction progress by LC-MS, completely converting the raw material after 3h, and directly heating the product without separation for the second-stage reaction.

And (3) heating the reaction liquid to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate state into a compound 5-5 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Isopropyl ether (100mL) was added, and the mixture was slurried at room temperature for 12 hours, filtered to give an off-white cake, and vacuum-dried to give an off-white powder (16.77 g), purity of LC-MS (LC-MS) of 99.60%, yield 70.51% (based on compound 2-1), MS (ESI): [ M + H ]]⁺＝330。¹HNMR:δ1.25(9H，s)，2.30(3H，s)，3.51-3.60(1H，d)，3.87-3.93(1H，d)，5.50-5.62(1H，m)，5.80(1H，s)，7.14-7.43(5H，m)。

Example 45:

dissolve compound 5-5(5g, 15.18mmol) in anhydrous DMF (50mL), add anhydrous sodium carbonate (5.47g, 51.61mmol), add 2-fluoro-6-trifluoromethyl benzyl bromide (5.85g, 22.77mmol), raise to 80 deg.C and stir the reaction, LC-MS monitors the progress of the reaction, after 15h the starting material is completely converted. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.06g of yellow oil, 97.79% purity LC-MS, 92.01% yield, MS (esi): [ M + H ]]⁺＝506。¹HNMR:δ1.22(9H，s)，2.28(3H，s)，3.50-3.58(1H，d)，3.86-3.95(1H，d)，4.50(2H，s)，5.49-5.60(1H，m)，5.82(1H，s)，7.15-7.51(7H，m)，7.66-7.70(1H，m)。

Example 46:

compound 6-5(5g, 9.89mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-bromosuccinimide (1.76g, 9.89mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.04g of a pale yellow foamy solid, purity of LC-MS 95.51%, yield 87.19%, MS (esi): [ M + H ]]⁺＝584。¹HNMR:δ1.24(9H，s)，2.31(3H，s)，3.49-3.56(1H，d)，3.85-3.94(1H，d)，4.52(2H，s)，5.51-5.59(1H，m)，7.13-7.48(7H，m)，7.62-7.66(1H，m)。

Example 47:

compound 6-5(5g, 9.89mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-chlorosuccinimide (1.32g, 9.89mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow foamy solid (4.76 g), LC-MS purity 91.83%, yield 89.13%, MS (esi): [ M + H ]]⁺＝540。¹HNMR:δ1.22(9H，s)，2.32(3H，s)，3.47-3.54(1H，d)，3.83-3.91(1H，d)，4.49(2H，s)，5.50-5.59(1H，m)，7.11-7.46(7H，m)，7.60-7.63(1H，m)。

Example 48:

compound 6-5(5g, 9.89mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-iodosuccinimide (2.23g, 9.89mmol) is added, and the reaction is stirred at 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.46g of a pale yellow foamy solid, purity of LC-MS 91.98%, yield 87.43%, MS (esi): [ M + H ]]⁺＝632。¹HNMR:δ1.21(9H，s)，2.33(3H，s)，3.45-3.54(1H，d)，3.81(3H，s)，3.86-3.97(1H，d)，4.58(2H，s)，5.50-5.59(1H，m)，7.01-7.53(10H，m)，7.61-7.67(1H，m)。

Example 49:

compound 7-5-Br (5g, 8.56mmol), 2-fluoro-3-methoxyphenylboronic acid (1.89g, 11.12mmol) and potassium phosphate (5.45g, 25.67mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged with nitrogen gas and oxygen purged for 10min, and a catalyst (7.36mg, 0.009mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 2h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with pure water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.97g of a pale yellow foamy solid, with a purity of LC-MS of 96.06%, yield of 92.26%, MS (esi): [ M + H ]]⁺＝630。¹HNMR:δ1.26(9H，s)，2.34(3H，s)，3.49-3.56(1H，d)，3.84-3.93(1H，d)，4.55(2H，s)，5.52-5.61(1H，m)，7.13-7.50(7H，m)，7.63-7.71(1H，m)。

Example 50:

the compound 7-5-Cl (4g, 7.41mmol), 2-fluoro-3-methoxyphenylboronic acid (1.64g, 9.63mmol) and potassium phosphate (4.72g, 22.22mmol) were added to a mixed solvent of 1, 4-dioxane (48mL,12eqV) and pure water (12mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and the catalyst (6.37mg, 0.007mmol) was added. Heating to 75-80 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 6h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 12mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.10g of a pale yellow foamy solid with a purity of 93.31% by LC-MS and a yield of 87.90%.

Example 51:

compound 7-5-I (5g, 7.92mmol), 2-fluoro-3-methoxyphenylboronic acid (1.75g, 10.29mmol) and potassium phosphate (5.04g, 23.76mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged by bubbling with nitrogen gas for deoxygenation for 10min, and a catalyst (6.81mg, 0.008mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.18g of a pale yellow foamy solid with a purity of LC-MS of 93.55% and a yield of 83.84%.

Example 52:

the compound 8-5(5g, 7.94mmol) was added to a mixed solvent of ethanol (25mL) and 6N hydrochloric acid (25mL), and the mixture was stirred to dissolve and clear, heated to 80 ℃ and stirred for reaction. TLC and LC-MS monitor the reaction progress, and after 24h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH value of the system to 7-8 by using a saturated sodium bicarbonate solution under stirring, separating liquid, washing an organic phase by using saturated saline solution, and evaporating to dryness to obtain a white foamy solid 3.85g, wherein the purity of LC-MS is 95.09%, and the yield is 88.87%. Ms (esi): [ M + H ] + ═ 546.

Example 53:

dissolving the compound 3-1 (crude product, 18g, 72.21mmol) in anhydrous DMF (100mL), adding R-alpha- (acrylamido) phenethylamine acetate (19.96g, 79.43mmol) and anhydrous potassium carbonate (14.97g, 108.32mmol), stirring at room temperature for reaction, monitoring the reaction progress by LC-MS, completely converting the raw material after 3h, and directly heating the product without separation for the second-stage reaction.

And (3) heating the reaction liquid to 80 ℃, stirring for reaction, monitoring the reaction process by LC-MS, and completely converting the intermediate state into a compound 5-6 after 15 hours. The mixture was cooled to room temperature, purified water (400mL) and methylene chloride (400mL) were added, and the mixture was extracted and separated. The aqueous phase was extracted once with dichloromethane (200mL), and the organic phases were combined and washed with pure water (400 mL). The organic phase was evaporated to dryness to give a brown slurry. Isopropyl ether (100mL) was added, and the mixture was slurried at room temperature for 12 hours, filtered to give an off-white cake, and vacuum-dried to give 15.31g of an off-white powder, purity 99.38% by LC-MS, yield 70.84% (based on Compound 2-1), MS (ESI): [ M + H ]]⁺＝300。¹HNMR:δ2.28(3H，s)，3.58-3.62(1H，d)，3.86-3.93(1H，d)，5.49-5.52(1H，m)，5.56(1H，s)，5.71-5.73(1H，m)，6.01-6.04(1H，m)，6.33-6.36(1H，m)，7.22-7.35(5H，m)。

Example 54:

dissolve 5-6(5g, 16.70mmol) in anhydrous DMF (50mL), add anhydrous sodium carbonate (6.02g, 56.79mmol), add 2-fluoro-6-trifluoromethyl benzyl bromide (6.44g, 25.06mmol), raise to 80 deg.C and stir the reaction, LC-MS monitors the progress of the reaction, and after 15h complete conversion of the starting material. The reaction mixture was cooled to room temperature, filtered through celite, and isopropyl acetate (100mL) and pure water (100mL) were added to the filtrate, followed by extraction with stirring and liquid separation. The organic phase was washed with pure water (100mL) and separated. The organic phase was washed with saturated brine (100mL) and separated. The organic phase was evaporated to dryness to give 7.22g of a yellow oil, LC-MS purity 97.56%, yield 90.91%, MS (esi): [ M + H ]]⁺＝476。¹HNMR:δ2.26(3H，s)，3.55-3.61(1H，d)，3.83-3.89(1H，d)，4.49(2H，s)，5.46-5.50(1H，m)，5.55(1H，s)，5.68-5.70(1H，m)，5.99-6.01(1H，m)，6.30-6.32(1H，m)，7.20-7.42(7H，m)，7.59-7.65(1H，m)。

Example 55:

compound 6-6(5g, 10.52mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-bromosuccinimide (1.87g, 10.17mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.18g of a pale yellow foamy solid, purity of LC-MS 95.55%, yield 88.86%, MS (esi): [ M + H ]]⁺＝554。¹HNMR:δ2.24(3H，s)，3.52-3.60(1H，d)，3.81-3.88(1H，d)，4.50(2H，s)，5.44-5.48(1H，m)，5.66-5.68(1H，m)，5.97-6.00(1H，m)，6.28-6.31(1H，m)，7.19-7.44(7H，m)，7.55-7.62(1H，m)。

Example 56:

compound 6-6(5g, 10.52mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature is reduced to 10 ℃, N-chlorosuccinimide (1.40g, 10.52mmol) is added, and the reaction is stirred at the temperature of 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.78g of a pale yellow foamy solid, purity of LC-MS 92.32%, yield 89.14%, MS (esi): [ M + H ]]⁺＝510。¹HNMR:δ2.27(3H，s)，3.50-3.58(1H，d)，3.80-3.86(1H，d)，4.48(2H，s)，5.42-5.47(1H，m)，5.63-5.67(1H，m)，5.97-6.01(1H，m)，6.26-6.30(1H，m)，7.16-7.42(7H，m)，7.54-7.62(1H，m)。

Example 57:

compound 6-6(5g, 10.52mmol) was dissolved in acetonitrile (50mL) and the solution was stirred. The temperature was reduced to 10 ℃ and N-iodosuccinimide (2.37g, 10.52mmol) was added and the reaction was stirred at 10-15 ℃. TLC and LC-MS monitor the reaction progress, and after 12h the conversion of the starting material is complete. A saturated sodium bicarbonate solution (50mL) was added thereto, and the mixture was stirred for 10min and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.46g of a pale yellow foamy solid, purity of LC-MS 91.98%, yield 86.34%, MS (esi): [ M + H ]]⁺＝602。¹HNMR:δ2.25(3H，s)，3.54-3.61(1H，d)，3.85-3.89(1H，d)，4.52(2H，s)，5.46-5.51(1H，m)，5.66-5.71(1H，m)，6.00-6.04(1H，m)，6.31-6.34(1H，m)，7.23-7.47(7H，m)，7.61-7.68(1H，m)。

Example 58:

compound 7-6-Br (5g, 9.02mmol), 2-fluoro-3-methoxyphenylboronic acid (1.99g, 11.73mmol) and potassium phosphate (5.74g, 27.06mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged with nitrogen gas and purged for 10min, and a catalyst (7.76mg, 0.009mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 2h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with pure water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 5.02g of a pale yellow foamy solid, LC-MS purity 93.90%, yield 92.83%, MS (esi): [ M + H ]]⁺＝600。¹HNMR:δ2.22(3H，s)，3.51-3.58(1H，d)，3.81(3H，s)，3.86-3.91(1H，d)，4.51(2H，s)，5.44-5.50(1H，m)，5.64-5.68(1H，m)，6.01-6.04(1H，m)，6.30-6.33(1H，m)，7.00-7.47(10H，m)，7.57-7.66(1H，m)。

Example 59:

the compound 7-6-Cl (4g, 7.84mmol), 2-fluoro-3-methoxyphenylboronic acid (1.73g, 10.20mmol) and potassium phosphate (5.0g, 23.53mmol) were added to a mixed solvent of 1, 4-dioxane (48mL,12eqV) and pure water (12mL, 3eqV), the solution was stirred, nitrogen was bubbled through to remove oxygen for 10min, and the catalyst (6.75mg, 0.008mmol) was added. Heating to 75-80 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 6h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 12mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (40mL) and saturated brine (40mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.22g of a pale yellow foamy solid with a purity of 92.50% by LC-MS and a yield of 89.72%.

Example 60:

compound 7-6-I (5g, 8.31mmol), 2-fluoro-3-methoxyphenylboronic acid (1.84g, 10.81mmol) and potassium phosphate (5.29g, 24.94mmol) were added to a mixed solvent of 1, 4-dioxane (60mL,12eqV) and pure water (15mL, 3eqV), the solution was stirred, purged by bubbling with nitrogen gas for deoxygenation for 10min, and a catalyst (7.15mg, 0.008mmol) was added. Heating to 70-75 deg.c and stirring for reaction. TLC and LC-MS monitor the reaction progress, and after 1h the conversion of the raw material is complete. The temperature was lowered to room temperature, the insoluble matter was removed by Celite filtration, the filtrate was evaporated to 15mL, isopropyl acetate (50mL) and pure water (50mL) were added, and the extract was stirred and separated. The organic phase was washed with purified water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4.35g of a pale yellow foamy solid with a purity of 92.79% by LC-MS and a yield of 87.26%.

Example 61:

the compound 8-6(5g, 8.34mmol) was added to a mixed solvent of ethanol (25mL) and 6N hydrochloric acid (25mL), and the mixture was stirred to dissolve and clear, and the reaction was stirred at 80 ℃. TLC and LC-MS monitor the reaction progress, and after 24h the conversion of the raw material is complete. Cooling to room temperature, evaporating to dryness until the volume is 5mL, adding isopropyl acetate (50mL) and pure water (50mL), and adjusting the pH of the system to be 7-8 by sodium carbonate solid under stirring. The organic phase was added with 10% phosphoric acid (50mL), extracted with stirring, and separated. Adding the water phase into isopropyl acetate (50mL), adjusting the pH value of the system to 7-8 by using a saturated sodium bicarbonate solution under stirring, separating, washing an organic phase by using saturated saline solution, and evaporating to dryness to obtain 4.10g of a white foamy solid, wherein the purity of LC-MS is 95.04%, and the yield is 90.12%. Ms (esi): [ M + H ] + ═ 546.

Use of compound 1:

example 62:

under nitrogen protection, dissolving compound 1(5g, 9.17mmol) in anhydrous DMF (10mL), adding ethyl bromobutyrate (2.32g, 11.92mmol) and DIPEA (1.78g, 13.75mmol) in sequence, and adding sodium iodide (0.14g, 0.9 mmol); after the addition, the temperature is raised to 52 ℃, and the reaction is stirred for 20 hours. Cooling to room temperature, adding isopropyl acetate (50mL) and water (50mL), stirring, extracting, separating, washing organic phase (50mL, 10eqV) once, adding 10% phosphoric acid (75g), stirring, extracting, separating, and collecting water layer; the organic phase was extracted once with 10% phosphoric acid (10g), the aqueous layers were combined and washed once with isopropyl acetate (20 mL); separating, adding isopropyl acetate (50mL) into the acid water phase, adjusting the pH to 8-9 with potassium carbonate solid, stirring, extracting, separating, washing the organic phase with saturated saline solution, drying for 2h with anhydrous sodium sulfate, filtering, evaporating the filtrate to dryness to obtain colorless oil 4.63g, with the purity of 95.31% and the yield of 76.58%. Ms (esi): [ M + H ] + -660.

Example 63:

to a solution of compound 9(4.6g, 6.97mmol) in ethanol (23mL) was added a solution consisting of sodium hydroxide (0.58g, 14.64mmol) and water (17.6 mL); after the addition, the reaction was stirred at 25 ℃ for 4 hours. The reaction mixture was concentrated, and the residue was added to pure water (13.8mL) and evaporated to 23 mL; EA (13.8mL) and pure water (23mL) were added, the mixture was extracted with stirring, the mixture was separated, the aqueous phase was washed once more with EA (13.8mL), methyl isobutyl ketone (13.8mL) was added, and the mixture was concentrated to 46 mL; adding sodium chloride (6g, 1.3eqM) and methyl isobutyl ketone (32mL) at 25-30 ℃, stirring for 10min, separating liquid, concentrating an organic phase to 11.5mL, and filtering through diatomite; and (3) slowly dropping the filtrate into well-stirred n-heptane (46mL) at the temperature of 10 ℃, stirring for 2 hours after dropping, filtering, and drying a filter cake to obtain 3.89g of oxa-rogue sodium with the purity of 99.37 percent and the yield of 85.35 percent. Ms (esi): [ M + H ] + ═ 632(elagolix form).

Claims

1. Compound 5 of the formula:

and R is selected from H and C1-C6 alkyl.

2. Compound 6 of the formula:

and R is selected from H and C1-C6 alkyl.

3. Compound 7 of the formula:

r is selected from H and alkyl of C1-C6, and X is selected from chlorine, bromine and iodine.

4. Compound 8 of the formula:

and R is selected from H or C1-C6 alkyl.

5. The preparation method of the compound 5 comprises the following steps of carrying out condensation reaction on a compound 3 with a formula shown in the specification and R-alpha- (acylamino) phenethylamine to obtain an intermediate compound 4, and carrying out cyclization reaction to obtain a new compound 5:

said R₁Selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl; and R is selected from H or C1-C6 alkyl.

6. A process for the preparation of compound 5 according to claim 5, characterized in that: after the condensation reaction of the compound 3 is finished, directly heating by a one-pot method to carry out cyclization reaction to obtain a compound 5.

7. A process for the preparation of compound 5 according to claim 5, characterized in that: compound 3 is obtained by condensation reaction of compound 2 of the formula with chloroformate:

said R₁Selected from the group consisting of C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl groups, said R₂Is selected from C1-C12 substituted or unsubstituted alkyl, alkenyl, alkynyl and aryl.

8. A process for the preparation of compound 1 by acid hydrolysis of compound 8 of the formula:

r is selected from H and C1-C6 alkyl, and X is chlorine, bromine or iodine.

9. A process for the preparation of compound 1 according to claim 8, characterized in that: the compound 8 is obtained by carrying out Suzuki coupling reaction on a compound 7 with the following formula and 2-fluoro-3-methoxyphenylboronic acid in the presence of a catalyst:

r is selected from H and C1-C6 alkyl, and X is chlorine, bromine or iodine.

10. A process for the preparation of compound 1 according to claim 9, characterized in that: the compound 7 is obtained by halogenating a compound 6 with the following formula through N-halogenated succinimide:

r is selected from H and C1-C6 alkyl, and X is chlorine, bromine or iodine.

11. A process for the preparation of compound 1 according to claim 10, characterized in that: the compound 6 is obtained by condensation reaction of a compound 5 with a formula shown in the specification and 2-fluoro-6-trifluoromethyl benzyl bromide under the action of alkali:

and R is selected from H or C1-C6 alkyl.

12. A process for the preparation of compound 1 according to claim 11, characterized in that: the compound 5 is obtained by the preparation method of any one of claims 5 to 7.

13. The compounds 2-8 are used for preparing oxalagogrel and intermediates thereof.