CN110498770A - A kind of method for preparing Elagoli intermediate - Google Patents

Abstract

The present invention relates to a method for preparing an intermediate of Elagoli. Specifically, the present invention discloses a preparation method for preparing the key intermediate compound E8 of Elagoli, and compounds such as compound C for preparing the intermediate compound E8. The method is easy to operate, mild in conditions, and very suitable for industrial production. .

Description

A kind of method for preparing Elagoli intermediate

technical field

The invention belongs to the field of pharmaceutical synthesis, and specifically, the invention provides an intermediate and a method for preparing elagolix.

Background technique

Elagolix is a novel oral gonadotropin-releasing hormone antagonist jointly developed by Neurocrine Biosciences and AbbVie for the treatment of endometriosis and uterine fibroids. AbbVie has submitted a New Drug Application for Elagoli to the FDA in 2017 for endometriosis.

Elagolix has the following structural formula:

The existing Elagoli synthesis routes mainly include the following three:

1) Patent WO2005007165 reported that 2-fluoro-6-(trifluoromethyl) benzonitrile was used as raw material, reduced by BH, and condensed with urea in aqueous hydrochloric acid to obtain compound I- ₃ , I-3 and diketene ring The pyrimidinedione ring compound I-4 is synthesized, and I-4 is brominated at the 5th position, and reacts with the side chain of N-tert-butoxy-D-phenylglycinol to obtain compound I-6, and I-6 is sealed in a tube. Suzuki coupling occurs with 2-fluoro-3-methoxyphenylboronic acid, and I-7 is obtained by column chromatography. I-7 was de-Boc protected, substituted with ethyl 4-bromobutyrate, and the compound I-9 was obtained by column chromatography. I-9 was then hydrolyzed with sodium hydroxide, adjusted to pH 3 with citric acid, extracted and concentrated, and passed through a large pore A cation exchange column yields elagolix sodium salt. There are some defects in this route: the preparation of I-6 by Mitsunobu reaction is not suitable for industrial scale-up, and it needs to be purified by column chromatography. 9 all need to be purified by column chromatography, and the yield is low.

2) Patent WO2009062087 uses o-fluoroanisole as raw material, reacts with tert-butyl acetoacetate to obtain compound II-3, which is then reduced, mesylated, and brominated to obtain II-6, and II-6 uses zinc as a catalyst, Reaction with acetonitrile to obtain enamine II-7 (Bryce reaction), and then protected by phenoxyacyl to obtain II-8, II-8 and II-10 are cyclized to obtain pyrimidinedione II-9, II-9 is successively combined with 2 -Fluoro-6-(trifluoromethyl)benzyl bromide, substituted with ethyl bromobutyrate to give I-9, and then hydrolyzed to give Elagoli. The steps of this route are long and the yield is not high. The first step reaction requires low temperature reaction, and the yield of Bryce reaction is relatively low.

3) Patent WO2009062087 also reported that urea I-3 was used as a raw material, cyclized with tert-butyl acetoacetate to obtain pyrimidinedione I-4, and I-4 was iodized with 2-fluoro-3-methoxyphenyl group. Boronic acid is coupled to obtain III-2, and III-2 undergoes two-step substitution and one-step hydrolysis to obtain Elagoli. This route uses highly toxic iodine chloride, which is expensive and unsafe to operate, and is not suitable for industrial production.

Therefore, there is still a need in the art to develop a method for preparing Elagoli suitable for large-scale industrial production.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a mild reaction, easy to operate Elagoli preparation method suitable for large-scale industrial production.

The present invention provides a method for preparing an intermediate compound E8, the method comprising the steps of: in an inert solvent, compound C and compound E7 are reacted to form compound E8;

Wherein, R ₁ is C1-C6 alkyl or benzyl.

In another preferred embodiment, water removal treatment is required during the reaction; preferably, water removal is performed with a water separator.

In another preferred embodiment, the method includes the steps of: reacting compound C and compound E7 in an inert solvent, and after the reaction until compound C is consumed, adding a dehydrating agent to continue the reaction, thereby forming compound E8.

In another preferred example, the dehydrating agent is p-toluenesulfonic acid monohydrate.

In another preferred embodiment, the inert solvent is selected from the group consisting of toluene, xylene, or a combination thereof.

In another preferred embodiment, the reaction is carried out at the reflux temperature of the solvent.

In another preferred example, R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.

In another preferred embodiment, the preparation method of compound C comprises the steps of: in a solvent, under the catalysis of a ligand and a catalyst, compound B and The reaction is carried out to form compound C;

Wherein, R ₁ is as defined above.

In another preferred embodiment, the solvent is selected from the group consisting of DMSO, DMF or a combination thereof.

In another preferred embodiment, the ligand is selected from the following group: trans-4-hydroxy-L-proline, 1,3-benzoxazole, 1,10-phenanthroline, L-proline .

In another preferred embodiment, the catalyst is selected from the group consisting of cuprous bromide, cuprous iodide, cuprous chloride or a combination thereof.

In another preferred example, the reaction requires a base, and the base is selected from the group consisting of potassium carbonate, sodium hydroxide, cesium carbonate, potassium phosphate, triethylamine, diisopropylethylamine or a combination thereof.

The present invention also provides an intermediate compound C,

Wherein, R1 is C1-C6 alkyl or benzyl.

The present invention also provides a method for preparing the intermediate compound C, comprising the steps of: in a solvent, under the catalysis of a ligand and a catalyst, compound B and The reaction is carried out to form compound C;

Wherein, R ₁ is as defined above.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

Through extensive and in-depth research, the inventors have found a new method for preparing Elagoli, which breaks through the existing technical barriers, reduces the number of reaction steps, has mild reaction conditions and is easy to operate, and is suitable for both Small-scale preparation in the laboratory is also suitable for large-scale industrial production. The present invention has been completed on this basis.

the term

As used herein, an "inert solvent" refers to a solvent that does not react with the reaction starting materials in the reaction in which the solvent participates.

"C1-C6 alkyl" as used herein refers to a straight or branched chain alkyl group having 1-6 carbon atoms, eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl butyl, tert-butyl or similar groups.

Intermediate

The present invention provides novel intermediate compounds for the preparation of Elagoli, the structures of which are as follows:

Wherein, R1 is C1-C6 alkyl or benzyl.

Preparation

The present invention also provides methods for the preparation of various intermediate compounds for the preparation of elagolix. E.g,

The invention provides a preparation method for preparing a key intermediate E8 of Elagoli, comprising the steps of: in an inert solvent, compound C and compound E7 are reacted to form compound E8;

Wherein, R ₁ is C1-C6 alkyl or benzyl.

In another preferred embodiment, water removal treatment is required during the reaction; preferably, water removal is performed with a water separator.

Specifically, the method includes the steps of: reacting compound C and compound E7 in an inert solvent, and after the reaction until compound C is consumed, adding a dehydrating agent to continue the reaction, thereby forming compound E8.

In another preferred example, the dehydrating agent is p-toluenesulfonic acid monohydrate.

In another preferred embodiment, the inert solvent is selected from the group consisting of toluene, xylene, or a combination thereof.

In another preferred embodiment, the reaction is carried out at the reflux temperature of the solvent.

In another preferred embodiment, the reaction time is within 4-8 hours; preferably, it is 6 hours.

In another preferred embodiment, the preparation method of compound C comprises the steps of: in a solvent, under the catalysis of a ligand and a catalyst, compound B and The reaction is carried out to form compound C;

Wherein, R ₁ is as defined above.

The reaction is carried out at 40-80°C.

The solvent is selected from the group consisting of DMSO, DMF or a combination thereof.

The ligand is selected from the group consisting of trans-4-hydroxy-L-proline, 1,3-benzoxazole, 1,10-phenanthroline, L-proline.

The catalyst is selected from the group consisting of cuprous bromide, cuprous iodide, cuprous chloride, or combinations thereof.

The reaction requires a base selected from the group consisting of potassium carbonate, sodium hydroxide, cesium carbonate, potassium phosphate, triethylamine, diisopropylethylamine, or combinations thereof.

In another preferred embodiment, the preparation method of compound B comprises the steps of: in a solvent, compound A is subjected to an iodination reaction to form compound B;

The present invention also provides a method for preparing elagolix, which uses intermediate compound E8 as a raw material to prepare elagolix. For specific steps, please refer to the preparation steps of compound III-2 to elagolix in patent WO2009062087.

In addition, the preparation method of compound E7 can refer to the methods familiar to those skilled in the art, and can also adopt the experimental procedures disclosed in this application.

The main advantages of the present invention are:

The present invention provides a new method for preparing Elagoli.

The method simplifies the preparation steps, has mild conditions, does not need special equipment, and does not need highly toxic and harmful reagents. Therefore, the operation is simpler, safer and lower in cost.

The method is suitable for both small-scale laboratory preparation and large-scale industrial production.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.

The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Preparing Elagoli

Example 1 Preparation of 2-fluoro-3-methoxyiodobenzene B

In a 500ml three-necked flask, 15.56g of pentamethyl-di-(ethylene)triamine and 200ml of THF were added, and 35.2ml of n-BuLi was added dropwise at -78°C. After stirring for 40min, 10g of 2-fluoroanisole was added dropwise. After stirring at -78 °C for 1 h, 100 ml of I ₂ 22.84 g THF solution was added dropwise. After stirring at -78 °C for 2 h, the reaction solution was warmed to room temperature, quenched with 400 ml saturated ammonium chloride solution, separated, and the organic phase layer was removed by rotary evaporation. Solvent, add 200 ml of ethyl acetate to the residue, wash with saturated sodium thiosulfate solution and saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain 18.16 g of yellow liquid (yield 90.89%).

¹ H NMR(CDCl ₃ )δ3.88(s,3H), 6.83-6.85(m,1H), 6.90-6.92(m,1H), 7.28-7.30(m,1H); MS(ESI) m/z 253.12 (MH ⁺ ).

Example 2 Preparation of 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid tert-butyl ester (R1 is tert-butyl) C-1

In a 250ml reaction flask, add 15g of B, 19g of tert-butyl acetoacetate, 4.6g of cuprous iodide, 6.3g of trans-4-hydroxy-L-proline, 78g of cesium carbonate and 150ml of DMSO, stir and heat, and react at 60°C Four days. Then the reaction solution was cooled to room temperature, the solid was removed by filtration, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain a black oil, which was passed through a column 5.37 g of yellow oily liquid was obtained (yield 32%).

¹ H NMR(CDCl ₃ )δ1.38(s, 9H), 1.83(s, 1.4H), 2.21(s, 1.6H), 3.88(s, 3H), 4.96(s, 0.53H), 6.67(t , 0.44H), 6.69-7.09 (m, 2.51H), 13.33 (s, 0.47H); MS (ESI) m/z 283.31 (MH ⁺ ).

Example 3 Preparation of 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid ethyl ester (R1 is ethyl) C-2

In a 250ml reaction flask, add 15g of B, 18g of ethyl acetoacetate, 4.6g of cuprous iodide, 6.3g of trans-4-hydroxy-L-proline, 78g of cesium carbonate and 150ml of DMSO, stir and heat, and react at 60°C for four sky. Then the reaction solution was cooled to room temperature, the solid was filtered off, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain a black oil, which was passed through a column 4.38 g of yellow oily liquid were obtained (yield 29%).

¹ H NMR (CDCl ₃ ) δ 1.28(t, 3H), 1.86(s, 1.8H), 2.23(s, 1.2H), 3.89(s, 3H), 4.15(m, 2H); 5.05(s, 0.4H), 6.72 (t, 0.6H), 6.90-7.10 (m, 2.4H), 13.2 (s, 0.63H); MS (ESI) m/z 255.10 (MH ⁺ ).

Example 4 Preparation of 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid benzyl ester (R1 is benzyl) C-3

In a 250ml reaction flask, add B 15g, benzyl acetoacetate 20.2g, cuprous iodide 4.6g, trans-4-hydroxy-L-proline 6.2g, cesium carbonate 78g and DMSO 150ml, stir and heat, react at 60°C Four days. Then the reaction solution was cooled to room temperature, the solid was filtered off, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain a black oil, which was passed through a column 5.65 g of yellow oily liquid was obtained (yield 30%).

MS (ESI) m/z 317.11 (MH ⁺ ).

Example 5 Preparation of 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid methyl ester (R1 is methyl) C-4

In a 250ml reaction flask, add 15g of B, 14g of methyl acetoacetate, 4.6g of cuprous iodide, 6.2g of trans-4-hydroxy-L-proline, 78g of cesium carbonate and 150ml of DMSO, stir and heat, and react at 60°C for four sky. Then the reaction solution was cooled to room temperature, the solid was filtered off, the mother liquor was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and after suction filtration, the filtrate was concentrated to obtain a black oily substance, which was obtained by column 4.43 g of yellow oily liquid (yield 31%).

MS (ESI) m/z 241 (MH ⁺ ).

Example 6 Preparation of 2-fluoro-6-trifluoromethylbenzylamine E6

In a 100ml three-necked flask, add 5g of E5, 2.17g of hydroxylamine hydrochloride and 50ml of absolute ethanol, and after stirring at room temperature for 1 hour, add hydrochloric acid (6mol/L, 8.7ml) dropwise at room temperature, add 5.1g of zinc powder, and stir for 0.5% below 35°C. After h, filter, concentrate to remove ethanol, add water and ethyl acetate to the residue, separate the layers, adjust the pH of the aqueous phase to 11 with sodium hydroxide, extract the aqueous phase twice with dichloromethane, wash the organic phase with saturated brine, and use the Dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to obtain 2.39 g of a yellow oil (yield 47.50%).

Example 7 Preparation of 2-fluoro-6-trifluoromethylbenzylamine E6

In a 250ml three-necked flask, add 2.4g of hydroxylamine hydrochloride and 50ml of water, adjust the aqueous phase to neutrality with 10% sodium hydroxide, then slowly add the ethanol solution of E5 (5g/20ml) dropwise, and after stirring for 1h, divide the 6 g of zinc powder was added in batches, hydrochloric acid (6 mol/L, 40 ml) was added dropwise, after 2 h of reaction, filtration was performed, and 50 ml of ammonia water was added to the filtrate. Then the mixture was adjusted to pH 11 with 6 ml of 33% sodium hydroxide, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain 4.78 g of yellow oil (yield 95 g). %).

Example 8 Preparation of 1-[2-Fluoro-6-(trifluoromethyl)benzyl]urea E7

In a 250ml three-necked flask, add 3.4g of E6, 20ml of water, 4.23g of urea and hydrochloric acid (12mol/L, 2ml), and after refluxing for 3h, the reaction solution was cooled to 4°C with an ice-water bath, and suction filtered to obtain 3.78g of white solid ( yield 91%).

¹ H NMR(DMSO-d ₆ )δ4.36(s,2H), 5.47(s,2H), 6.16(s,1H), 7.49-7.61(m,3H); MS(ESI) m/z 237.07( MH ⁺ ).

Example 9 5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-(trifluoromethyl-)benzyl)-6-methylpyrimidine-2,4( Preparation of 1H,3H)-diketone E8

In a 250ml there-necked flask, add 0.6g of 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid ethyl ester (C-2), E70.67g and 30ml of toluene, heat to reflux, The water was separated by a water separator, and after refluxing for 4 hours, 0.67 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove toluene to obtain a crude brown oily product, which was passed through a column to obtain 0.31 g of product E8 (yield 31%).

¹ H NMR(CDCl ₃ )δ2.04(s,3H),3.88(s,3H),5.47(s,2H),6.79(m,1H),6.95(m,1H),7.10(m,1H) , 7.26 (m, 1H), 7.39 (m, 1H), 7.55 (m, 1H), 8.46 (s, 1H); MS (ESI) m/z 427.23 (MH ⁺ ).

Example 10 5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-(trifluoromethyl-)benzyl)-6-methylpyrimidine-2,4( Preparation of 1H,3H)-diketone E8

In a 250ml three-necked flask, add 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid tert-butyl ester (C-1) 0.6g, E7 0.6g and toluene 30ml, heat to reflux , the water separator separates the water, and after refluxing for 4 hours, 0.61 g of p-toluenesulfonic acid monohydrate is added, and the mixture is refluxed for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove toluene, and ethyl acetate was added to the residue to precipitate a white solid, which was filtered off with suction, and the solid was washed with cold ethyl acetate to obtain 0.65 g of E8 (yield 72%).

Example 11 5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-(trifluoromethyl-)benzyl)-6-methylpyrimidine-2,4( Preparation of 1H,3H)-diketone E8

In a 250ml three-necked flask, add 2-(2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid benzyl ester (C-3) 0.6g, E70.54g and toluene 30ml, heat to reflux, The water was separated by a water separator, and after refluxing for 4 hours, 0.54 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove toluene to obtain a crude brown oily product, which was passed through a column to obtain 0.29 g of E8 (yield 36%).

Example 12 5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-(trifluoromethyl-)benzyl)-6-methylpyrimidine-2,4( Preparation of 1H,3H)-diketone E8

In a 250ml three-necked flask, add (2-fluoro-3-methoxyphenyl)-3-oxo-butyric acid methyl ester (C-4) 0.6g, E70.71g and 30ml of toluene, heat to reflux, separate water The water was separated from the device, and after refluxing for 4 hours, 0.71 g of p-toluenesulfonic acid monohydrate was added, and the mixture was refluxed for 2 hours. The completion of the reaction was monitored by TLC, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove toluene to obtain a crude brown oily product, which was passed through a column to obtain 0.40 g of E8 (yield 38%).

Example 13 (R)-3-(2-Amino-2-phenylethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoro Preparation of methyl-benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione E9

In a 250ml three-necked flask, add 1 g of E8, 1.1 g of (R)-2-phenyl 2-tert-butoxycarbonyl aminoethyl methanesulfonate, 2 g of potassium carbonate and 25 ml of DMF, react at 100°C for 7 hours, then add isopropyl acetate After the organic phase was dried, filtered, 0.5 g of methanesulfonic acid was added to the filtrate, stirred at 60 °C for 2 h, water was added, and the liquids were separated. After extraction, the organic phase was dried and concentrated to obtain 1 g of crude E9 (yield 78.12%).

¹ H NMR(CDCl ₃ )δ2.07(s,3H),3.89(s,3H),4.12(m,1H),4.28(m,1H),4.41(dd,J=4.5,10.2Hz,1H) ,5.49(s,2H),6.78-6.84(ddd,J=1.5,6.0,7.8Hz,1H),6.95-6.98(dd,J=1.5,8.1Hz,1H),7.11(m,1H),7.21 -7.28(m, 2H), 7.33(t, J=6.9Hz, 2H), 7.37-7.46(m, 3H), 7.55(d, J=7.8Hz, 1H); MS(ESI) m/z 546.22( MH ⁺ ).

Example 14 4-((R)-2-[3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxy-phenyl)-3-(2- Fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-1-yl]-1-phenyl-ethylamino)butane Preparation of acid ethyl ester-pyrimidine-2,4(1H,3H)-dione E10

In a 250ml three-necked flask, add 1g of E9, 10ml of DMF, 0.54g of ethyl 4-bromobutyrate and 0.5g of diisopropylethylamine, stir at 60°C for 2h, add isopropyl acetate and water, the water phase is 85% Phosphoric acid aqueous solution was adjusted to pH 2, and the solution was separated. The aqueous phase was adjusted to alkaline pH with potassium carbonate aqueous solution, extracted with isopropyl acetate, and the organic phase was dried and concentrated to obtain E10 1 g (yield 85%).

¹ H NMR(CDCl ₃ )δ1.28(t, 3H), 1.91(m, 2H), 2.20-2.40(m, 2H), 2.71(m, 1H), 2.95(m, 1H), 3.84(s, 1H), 4.13(q, 2H), 4.15(m, 1H), 4.38(m, 0.5H), 4.60-4.80(m, 1.5H), 5.24(d, J=17.1Hz, 1H), 5.66(d , J=17.1Hz, 1H), 6.81-7.00(m, 2H), 7.11(t, J=5.8Hz, 1H), 7.18-7.31(m, 2H), 7.36-7.50(m, 5H), 7.52( d, J=7.8 Hz, 1H); MS (ESI) m/z 660.24 (MH ⁺ ).

Example 15 Preparation of Elagoli E11

In a 250ml three-necked flask, add 1g of E10 and 15ml of ethanol, then dropwise add 1.2ml of 2mol/L NaOH aqueous solution, react at 50°C for 2h, cool the reaction solution to 0-10°C, dropwise add 1mol/L hydrochloric acid to adjust pH to 6, and stir at room temperature After 3 hours, suction filtration to obtain 0.8 g of an off-white solid (yield 83.59%).

¹ H NMR (CD ₃ OD) δ 1.72 (m, 2H), 2.08 (s, 3H), 2.16 (t, J=6.9Hz, 2H), 2.50 (t, J=6.9Hz, 2H), 3.84 ( s,3H),4.24(m,3H),5.40(d,J=9.0Hz,1H),5.46(d,J=9.0Hz,1H),6.62-6.78(m,1H),7.12(m,2H) ), 7.34 (m, 5H), 7.41 (m, 1H), 7.56 (m, 1H), 7.61 (d, J=8.0 Hz, 1H); MS (ESI) m/z 632.21 (MH ⁺ ).

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (7)

1. a preparation method of intermediate compound E8, is characterized in that, described method comprises the step: in inert solvent, compound C and compound E7 are reacted, thereby form compound E8; Wherein, R ₁ is C1-C6 alkyl or benzyl. 2. preparation method as claimed in claim 1, is characterized in that, described method comprises the step: in inert solvent, compound C and compound E7 are reacted, react to after compound C is consumed, add dehydrating agent and continue to react, thereby Compound E8 is formed. 3. The preparation method of claim 1, wherein the inert solvent is selected from the group consisting of toluene, xylene, or a combination thereof. 4. The preparation method of claim 1, wherein R ₁ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl. 5. preparation method as claimed in claim 1 is characterized in that, the preparation method of compound C comprises the step: in solvent, under the catalysis of ligand and catalyst, compound B and The reaction is carried out to form compound C; Wherein, R ₁ is as defined above. 6. an intermediate compound C, Wherein, R1 is C1-C6 alkyl or benzyl. 7. the preparation method of intermediate compound as claimed in claim 6, is characterized in that, comprises step: in solvent, under the catalysis of part and catalyst, compound B and The reaction is carried out to form compound C; Wherein, R ₁ is as defined above.