WO2021218041A1

WO2021218041A1 - Eribulin and preparation method for intermediate thereof

Info

Publication number: WO2021218041A1
Application number: PCT/CN2020/120762
Authority: WO
Inventors: 袁建栋; 黄仰青; 池建文; 顾家宁; 杭文明; 张清泉
Original assignee: 博瑞生物医药（苏州）股份有限公司
Priority date: 2020-04-26
Filing date: 2020-10-14
Publication date: 2021-11-04
Also published as: CN113549101A

Abstract

Provided is eribulin and a preparation method for an intermediate thereof. In particular, a compound P1 is prepared by splicing an eribulin fragment A synthesized with diethyl [(naphthylsulfonyl)methyl]phosphonite and a fragment ERB. The yield is significantly improved and is much higher than that in the prior art. In addition, the stereospecificity is high. Furthermore, an improved NHK reaction is used when synthesizing an intermediate compound P, so that the amount of chromium reagents is greatly reduced, which not only reduces the cost, but also reduces environmental pollution.

Description

Preparation method of Eribulin and its intermediates

Technical field

The invention belongs to the technical field of medicine, and specifically relates to a method for preparing eribulin and its intermediates.

Background technique

Eribulin mesylate was developed by Eisai Pharmaceutical Co., Ltd., and the injection was approved by the US FDA in November 2010, under the trade name HALAVEN. As a tubulin polymerization inhibitor with a new mechanism of action, eribulin mesylate is the first single-agent chemotherapeutic agent used to improve the overall survival of patients with metastatic breast cancer. It is locally advanced breast cancer or metastatic breast cancer. Breast cancer patients have provided a new treatment method to improve the survival rate and quality of life, and it is a drug with great application value. Its chemical structure is:

From the structure of Eribulin, there are 19 chiral centers in the molecule, which is very difficult to synthesize, usually through the following three fragments A (C27-C35), B (C14-C26) and C (C1-C13) splicing Formed: Fragment A is spliced with Fragment B first, and then spliced with Fragment C. When each fragment is spliced, there are different routes due to different leaving groups.

Chinese patent CN1216051C discloses that fragment A and fragment B protected by MPM (methoxyphenylthiomethyl) at the 35-position carbon are spliced, and then spliced with fragment C.

In the above method, after fragments A and B are spliced, a mixture of C27 diastereomers is obtained with a ratio of about 3:1. The mixture is separated and purified several times. Based on fragment B, the yield of the splicing reaction of A and B is only 33.6%. After the MPM group is removed, it is spliced with fragment C, while the removal of the MPM group requires multiple transformations, the steps are cumbersome, and the yield is low.

Chinese patent CN104876896A discloses that fragment A and fragment B protected by a benzenesulfonyl group at carbon 35 are spliced together with fragment C.

In the above method, when fragments A and B are spliced, a chiral ligand needs to be added. Based on fragment B, the yield of the splicing reaction is 59.2%, and then spliced with fragment C, the total yield of preparing Eribulin is still low. And the purification method is cumbersome and requires column chromatography.

CN105713031A discloses the splicing of A fragment and B fragment with a protective group prepared by tolyl sulfonyl methyl diethyl phosphate:

This reaction has the characteristics of low price of raw materials and favorable for subsequent cyclization reactions, but the yield of the patent is 45.8%, and column chromatography is required, which still cannot meet the requirements of industrial production.

During production and R&D, we found that the stability of the spliced products of Eribulin fragments A and B was not high. During column chromatography, it was obvious that the silica gel column gradually changed from light yellow to dark brown, indicating that the splicing product was in The silica gel column decomposes under the acidic environment, resulting in a decrease in the overall splicing reaction yield of A and B. This is also one of the reasons why the splicing reaction yield of fragments A and B in the prior art is not high, and the raw materials are generally fed in the industrial production of raw materials. The amount is very large, and the purification process of the chromatographic column takes a long time, making the splicing product easier to decompose.

In view of this, the technical problem to be solved by the present invention is to provide a preparation method of Eribulin that does not require chromatographic column purification, has high yield, strong stereoselectivity, and is suitable for industrialized mass production.

Summary of the invention

In order to solve the above-mentioned technical problem of fragment A and fragment B splicing reaction column chromatography that is easy to decompose and lead to low yield, the present invention provides a new intermediate fragment A for preparing eribulin, and the intermediate fragment A Preparation method; the present invention also provides a method for preparing Eribulin from the fragment A.

In one aspect, the present invention provides compound P1, which has the following structure:

Among them, R ₁ is H, C _1-6 alkyl or halogen, preferably R ₁ is H, methyl, ethyl, or Cl, and R ₂ is Cl or OMs.

On the other hand, the present invention provides a method for preparing compound P1, which includes: reacting compound ERA with compound ERB through NHK reaction to convert compound P1:

Wherein, R ₁ is H, C _1-6 alkyl or halogen, and R ₂ is Cl or OMs.

In the above method, it is preferable to add NiX ₂ , CrCl ₂ , aluminum scraps and trimethylchlorosilane _{to the reaction system, where NiX 2} is NiBr ₂ or NiCl ₂ . More preferably, the reaction is based on 1 molar equivalent of compound ERA, the amount of NiBr ₂ is 0.02-0.08 molar equivalent, _{the amount of CrCl 2} is 0.1-0.3 molar equivalent, and the amount of ERB is 1.1-2 molar equivalent. The amount of 1-bromo-2-trimethylsilylethylene is 2 to 3 molar equivalents, the amount of aluminum shavings is 2.0 to 4.0 molar equivalents, and the amount of trimethylchlorosilane is 2.5 to 4.5 molar equivalents.

On the other hand, the present invention also provides a preparation method of compound ERA including:

(1) The compound ERA2 is converted into compound ERA3 by wittig reaction with diethyl naphthylsulfonyl methylphosphonate:

Among them, the amount of diethyl naphthyl sulfonyl methylphosphonate is 1 to 2 molar equivalents; a base needs to be added to the reaction system, the base is preferably NaHMDS, KHMDS, NaH, etc., and the amount of base is 3 to 5 equivalents; The temperature is 0～15℃;

(2) Compound ERA3 is selectively deprotected from benzyl and converted into ERA4:

Preferably, the compound ERA3 is deprotected by the benzyl group under the action of trimethylsilimidazole and converted into ERA4;

(3) The double bond of compound ERA4 is converted into compound ERA5 by selective reduction:

Preferably, in the above reaction, NaBH(OAc) ₃ is used as a reducing agent to selectively reduce the double bond of compound ERA4;

(4) The ester bond of compound ERA5 is converted into ERA6 by hydrolysis reaction:

(5) The vicinal diol of compound ERA6 is converted into compound ERA7 through ketal reaction:

(6) Convert compound ERA7 into compound ERA8 through methylation reaction:

(7) Hydrolyze the ketal in the structure of compound ERA8 to convert it into compound ERA9:

(8) The hydroxyl group of compound ERA9 is protected by TBS to obtain ERA10:

(9) The double bond of ERA10 is oxidized to obtain compound ERA:

Among them, R ₁ is H, C _1-6 alkyl or halogen; preferably R ₁ is H.

On the other hand, the present invention also provides a preparation method of Eribulin intermediate P6, which is characterized in that it comprises:

(1) Make compound P1 form an ether in the molecule under the action of a base, and convert it into compound P2:

(2) The compound P2 is converted into compound P3 through a reduction reaction:

(3) Make compound P3 react with compound ERC under the action of a base to transform into compound P4

(4) Compound P4 is converted into compound P5 by Dess-Martin oxidation reaction

(5) The naphthylsulfonyl group is removed from compound P5 and converted into compound P6:

Wherein, R ₁ is H, C _1-6 alkyl or halogen.

In the above method, in step (1), compound P1 is converted into compound P2 by intramolecular ether under the action of a base;

Step (2) The reducing agent used in the reduction reaction is DIBALH;

The base in step (3) is preferably butyl lithium;

Step (5) Preferably, the naphthyl sulfonyl group of compound P5 is removed under the action of samarium diiodide to convert it into compound P6.

On the other hand, the present invention also provides a compound having the following structure:

Among them, R ₁ is H, C _1-6 alkyl or halogen, preferably R ₁ is H.

The C _1-6 alkyl group in the present invention refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, or a cycloalkyl group, including but not limited to methyl, ethyl, propyl, butyl, Isopropyl, tert-butyl, 2-methylpropyl, n-hexyl, cyclohexyl; the halogen refers to F, Cl, Br and I. In the present invention, "TBS" refers to tert-butyldimethylsilyl, "Pv" refers to pivaloyl, "Ms" refers to methylsulfonyl, and "DIBALH" refers to diisobutylaluminum hydride.

The compound P1 was prepared by splicing the fragment ERA synthesized with the diethyl naphthylsulfonyl methylphosphonate and the fragment ERB, and the yield was significantly improved. The speculated mechanism: 1) the naphthylsulfonyl phosphonate as the protective group is better than the prior art Phenyl and tolyl groups are more electron-rich, and the stability of the product during the splicing reaction is higher; (2) naphthylsulfone phosphonate as a protective group, combined with the improved NHKL reaction developed by the applicant, is used in the low-volume chromium reagent Under the circumstances, it can still react well, reducing the side reactions caused by excessive catalyst and reducing the generation of impurities. 3) The high stability of the product does not require column chromatography, but it still contains certain impurities, resulting in an overall high yield.

Compared with the prior art, the present invention provides a new synthetic method and intermediate for preparing Eribulin, in particular, the compound is prepared by splicing fragment ERA synthesized with diethyl naphthylsulfonyl methylphosphonate and fragment ERB. P1, the yield is significantly improved, for example, it can be as high as 81.9%, which is 150%-260% higher than the prior art, which is much higher than the prior art, and the three-dimensional specificity is high; and because of the higher yield, no column layer is required After precipitation, the crude product of the splicing of fragments A and B can be obtained directly through the conventional crystallization process and used in the next step of the cyclic ether synthesis reaction.

Using compound P1 as an intermediate to prepare compound P6, and to prepare eribulin based on this, the overall reaction yield is greatly improved. In addition, the present invention adopts an improved NHK reaction when synthesizing compound P1, which greatly reduces the amount of chromium reagent to only 0.2 mol%, which not only reduces cost, but also reduces environmental pollution. The overall route is simple to operate, with high yield and purity, and is very suitable for industrial production for the preparation of bulk drugs.

Specific embodiment

The technical solutions and preferred embodiments of the present invention will be further explained and illustrated below in conjunction with specific examples.

Example 1 Preparation of compound ERA3a

At 10°C, 7.6g of diethyl naphthylsulfonyl methylphosphonate was dissolved in 20ml of tetrahydrofuran, and 36.04g of 25% NaHMDS tetrahydrofuran solution was added dropwise. The temperature was controlled not to exceed 15°C. Stir for 30 minutes, then add the solution to the solution. 7.6g ERA2 in 38ml tetrahydrofuran solution, control the temperature not to exceed 20℃, and stir for 1 hour. Add 49ml 1N hydrochloric acid, control the temperature not to exceed 20℃, concentrate under reduced pressure to remove tetrahydrofuran, add 30ml dichloromethane and stir and extract three times, combine the organic phases, wash with 30ml sodium bicarbonate solution twice, 30ml brine solution twice, and dry and filter , Concentrated to obtain 9.4g ERA3a.

Example 2 Preparation of compounds ERA4a and ERA5a

(1) Preparation of compound ERA4a: At room temperature, 9.4g ERA3a was dissolved in 50ml ethyl acetate, 11.8g TMSI was added, and the reaction was heated to 50°C and stirred for 2 hours. The reaction solution was reduced to -10°C, and quenched with an aqueous ammonia solution, and the temperature was controlled to be lower than 30°C. Stir to separate layers. The organic phase was washed successively with 50ml 10% sodium sulfite aqueous solution, 50ml 1N hydrochloric acid, 50ml 5% sodium bicarbonate aqueous solution and 50ml brine, dried over magnesium sulfate, filtered and concentrated to obtain 7.8g ERA4a.

(2) Preparation of compound ERA5a: Add 7.8g NaBH(OAc)3 and 80ml acetonitrile to a reaction flask, heat to 65°C, add 14g 50% ERA4a acetonitrile solution, increase the reaction temperature to 80°C, and stir for 3 hours. Cool to 10°C, add 25ml of water dropwise for quenching, and keep the internal temperature below 20°C. Stir and separate the layers, and the organic layer was washed with 40 ml of sodium bicarbonate aqueous solution twice and 40 ml of water twice in sequence. Dry and concentrate to obtain 7.3g ERA5a.

Example 3 Preparation of compounds ERA6a and ERA7a

(1) Preparation of compound ERA6a: Dissolve 7.3g ERA5a in 16ml methanol, add 1.6g potassium carbonate, and stir at 50°C for 1 hour. Cool the reaction solution to 15°C, add 24ml 1N hydrochloric acid dropwise, and control the internal temperature below 30°C. Add 29ml of water and 23ml of toluene, stir to separate the layers, and back-extract the water layer with 13ml of toluene again. The aqueous phase was concentrated under reduced pressure, methanol was removed, 2.1 g of sodium bicarbonate and 4.4 g of sodium chloride were added, and the mixture was extracted three times with 25 ml of ethyl acetate. The organic phases were combined and concentrated to obtain crude ERA15. Dissolve the crude ERA6 in 7:1 toluene/nBuOH at 80°C, recrystallize after hot filtration, and filter to obtain 4.6g ERA6a.

(2) Preparation of compound ERA7a: Disperse 4.6g ERA6a in 10ml acetone at 25°C, add 5ml 2,2-dimethoxypropane, 0.04g concentrated sulfuric acid, and stir the reaction solution until uniform. Add 23ml of toluene and 9ml of 5% potassium carbonate solution to the reaction solution for quenching. Stir and separate the layers, the organic layer was washed with 10% brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4.7 g of ERA7a.

Example 4 Preparation of compounds ERA8a and ERA9a

(1) Preparation of compound ERA8a: Dissolve 0.67 g of sodium hydride (60%) in 12 ml of tetrahydrofuran, and cool to below 10°C. Add 4.7 g of ERA7a dissolved in 12 ml of tetrahydrofuran to the above sodium hydride solution, and keep the internal temperature below 15°C. Stir for 30 minutes, keep the temperature below 15°C, and add 1.94 g of methyl iodide. After the addition was completed, the reaction solution was raised to room temperature and stirred for 2 hours. Add 23ml of water and 33ml of toluene to the reaction solution, stir and separate the layers. The organic layer was washed twice with 25ml of brine, dried and filtered, and concentrated under reduced pressure to obtain 4.5g of ERA8a.

(2) Preparation of compound ERA9a: Dissolve 4.5g ERA8a in 5ml methanol and 5ml 2N hydrochloric acid, and stir the reaction at room temperature. At 10°C, add the reaction solution to 6.0ml 2M NaOH solution and add 10ml water. Add 23ml of ethyl acetate to the reaction system, stir to separate the layers, extract the aqueous layer again with 23ml of ethyl acetate, combine the organic layers, dry and filter, and concentrate under reduced pressure to obtain 3.9g of ERA9a.

Example 5 Preparation of compounds ERA10a and ERAa

(1) Preparation of compound ERA10a: Dissolve 3.9g ERA9 in 15ml DMF, add 3.6g triethylamine, control the internal temperature below 30°C, add 4.0g TBSCl. The reaction was stirred at room temperature for 2 hours. Add 40ml of n-heptane and 15ml of water to the reaction solution, stir and separate into layers. The organic layer was washed successively with 12ml 1M hydrochloric acid, 12ml water, 12ml sodium bicarbonate aqueous solution and 12ml brine. The organic layer was dried, filtered, and concentrated under reduced pressure to obtain 5.7g ERA10a.

(2) Preparation of compound ERAa: Dissolve 5.7g ERA10a in 57ml n-heptane at -60°C, and pass ozone in the solution until the solution remains blue. Nitrogen gas was passed through the solution for 30 minutes, and the temperature of the reaction solution was raised to 5°C. Add 0.6g 10% Lindlar catalyst. Hydrogen gas was blown into the solution for 30 minutes, and then the reaction solution was allowed to rise to room temperature and stirred for 2 hours. The solution was filtered and rinsed with 10ml of methyl tert-butyl ether. The filtrate was concentrated to dryness, and the crude ERAa was recrystallized from heptane to obtain 5.1 g of ERAa.

Example 6 Preparation of compound P1a

Under argon protection, strictly ensure that the reaction vessel is anhydrous and oxygen-free, add 5.8g ERAa, 59mg NiBr2, 1.78g CrCl2, 0.56g aluminum chips, 3.39ml trimethylchlorosilane, 30ml DMF, cool to 0-3℃, stir 30 minutes. Add 5.94g ERB dropwise to keep the temperature below 30°C. After dripping, the reaction was stirred at room temperature for 24 hours. Add 20ml methanol/water (1/1, volume ratio) and stir for 10 minutes. Add 320ml methyl tert-butyl ether, stir for 10 minutes, and transfer the reaction mixture to 250ml 1N hydrochloric acid and 100ml water. Stir and separate the layers, the aqueous layer was back-extracted twice with 100 ml of methyl tert-butyl ether, and the combined organic layer was washed with 150 ml of 1% sodium chloride solution twice and 150 ml of brine successively. Dry and concentrate the organic layer, dissolve the crude product in a small amount of ethyl acetate, add 4 times the amount of ethyl acetate to n-hexane to crystallize the product, and dry to obtain 6.0 g of P1a, e.e. >96%, with a yield of 62.1%.

Example 7 Preparation of compound P1b

The dosage of ERAa and the molar ratio of ERB to ERAa are the same as in Example 6. Using the same experimental conditions as in Example 6, the crude product is dissolved in a small amount of ethyl acetate, and 4 times the amount of ethyl acetate is added to crystallize the product. Precipitated and dried to obtain 7.9g P1a, ee>96%, and the yield was 81.9%.

Example 8 Preparation of Compound P2a and Compound P3a

(1) Preparation of compound P2: Dissolve 6.0g P1a in 500ml tetrahydrofuran, cool to -20°C, add 75.4g 0.5M NaHMDS toluene solution dropwise, control the temperature not to exceed -12°C, stir and react for 4 hours. The reaction solution was added to 200ml 50% ammonium chloride solution, 500ml n-heptane was added, and the layers were separated by stirring. The organic layer was separated, and the aqueous layer was back-extracted with 400 ml of n-heptane. The combined organic layer was washed with 400 ml of saturated sodium chloride solution. The organic layer was dried and concentrated, the crude P2a was dissolved in 200ml n-heptane, and purified by silica gel column to obtain 4.9g P2a.

(2) Preparation of compound P3a: Dissolve 4.2g P2 in 30ml dichloromethane, cool to -78°C, add 12.6g 1M DIBALH dichloromethane solution dropwise, control the temperature not to exceed -60°C, and add 0.5ml methanol dropwise. After the dripping is completed, the reaction is stirred for 10 minutes, the temperature is raised to room temperature, and 45ml of 1N hydrochloric acid and 120ml of methyl tert-butyl ether are added. Stir and separate the layers, and the aqueous layer was back-extracted with 70 ml of methyl tert-butyl ether. The organic layers were combined, washed successively with 20 ml of water, 20 ml of saturated sodium bicarbonate and 30 ml of saturated sodium chloride solution, and then dried and concentrated. The crude concentrate was purified by silica gel column to obtain 3.6 g of P3a.

Example 9 Preparation of Compound P2a and Compound P3a 2

The feeding amount of P1a and the molar ratio of P2a to P1a are the same as in Example 8. The same experimental conditions as in Example 8 are used, and the crude concentrate is purified by a silica gel column to obtain 3.5 g of P3a.

Example 10 Preparation of Compound P4a and Compound P5a

(1) Preparation of compound P4a: Dissolve 3.6g P3a in 20ml tetrahydrofuran solution at 0°C, add 5.4ml n-butyllithium (1.6M hexane solution) dropwise, control the temperature not to exceed 5°C, and stir and react for 10 minutes. Cool to -78°C, add dropwise a solution of 3.9g ERC dissolved in 20ml n-hexane, keep the maximum temperature not exceeding -65°C, stir and react for 40 minutes. Add 20ml saturated ammonium chloride, 40ml methyl tert-butyl ether, 20ml water, stir to separate layers, dry and concentrate. The crude P4a was prepared and purified to obtain 5.6g P4a.

(2) Preparation of compound P5a: At room temperature, 5.6g P4a is dissolved in 40ml dichloromethane, 3.8g Dess-Martin reagent is added, and the reaction is stirred for 30 minutes. Add 50ml saturated sodium bicarbonate and 50ml 10% sodium sulfite aqueous solution and stir for 30 minutes. Add 50ml saturated sodium chloride and 300ml n-heptane, stir and separate into layers. The aqueous layer was discarded, the organic layer was dried and concentrated, and separated by a silica gel column to obtain 5.0 g of compound P5a.

Example 11 Preparation of Compound P6 and Eribulin

(1) Preparation of compound P6: _{Under the protection of N 2} , 3.1 g of samarium diiodide solution was dissolved in 15 ml of tetrahydrofuran, and the temperature was lowered to an internal temperature of -78°C. Dissolve 5.0g of P5a in 20ml of tetrahydrofuran, add the P5 solution dropwise to the samarium solution, and control the temperature not to exceed -60°C. The reaction is stirred for 30 minutes, and 50 ml potassium carbonate/potassium tartrate/water (1/10/100) and 16 ml n-heptane are added, and the temperature does not exceed -65°C. Stir and raise to room temperature, add 70ml potassium carbonate/potassium tartrate/water (1/10/100) and 70ml n-heptane. Stir and separate into layers, the organic layer is dried and concentrated, and the concentrate is purified by silica gel column to obtain 2.5 g of P6.

(2) Preparation of Eribulin: Eribulin or its methanesulfonic acid can be prepared from compound P6 by referring to any method disclosed in the prior art.

Comparative example 1

With reference to the method of splicing fragment A and fragment B in CN1216051C, repeating the feeding amount and reaction conditions in the patent, the yield of fragment A and fragment B was 33.6%, and dark brown decomposition products appeared during the column chromatography.

Comparative example 2

With reference to the method of splicing fragment A and fragment B in CN104876896AC, repeating the feeding amount and reaction conditions in the patent, the yield of fragment A and fragment B was 59.2%, and light brown decomposition products appeared during the column chromatography.

Comparative example 3

With reference to the splicing method of fragment A and fragment B in CN105713031A, repeating the feeding amount and reaction conditions in the patent, the yield of fragment A and fragment B was 45.8%, and brown decomposition products appeared during the column chromatography.

Claims

Compound P1 is characterized in that it has the following structure:

Wherein, R 1 is H, C 1-6 alkyl or halogen, and R 2 is Cl or OMs.
A preparation method of compound P1 includes: reacting compound ERA with compound ERB through NHK reaction to convert compound P1:

Wherein, R 1 is H, C 1-6 alkyl or halogen, and R 2 is Cl or OMs.
The method according to claim 2, characterized in that NiX 2 , CrCl 2 , aluminum scraps and trimethylchlorosilane are added to the reaction system, wherein NiX 2 is NiBr 2 or NiCl 2 .
The method according to claim 3, characterized in that, based on 1 molar equivalent of compound ERA, the amount of NiBr 2 is 0.02-0.08 molar equivalent, the amount of CrCl 2 is 0.1-0.3 molar equivalent, and the amount of ERB is 1.1 ~ 2 molar equivalents.
The method according to claim 2, wherein the preparation method of compound ERA comprises:

(1) The compound ERA2 is converted into compound ERA3 by wittig reaction with diethyl naphthylsulfonyl methylphosphonate:

(2) Compound ERA3 is selectively deprotected from benzyl and converted into ERA4:

(3) The double bond of compound ERA4 is converted into compound ERA5 by selective reduction:

(4) The ester bond of compound ERA5 is converted into ERA6 by hydrolysis reaction:

(5) The vicinal diol of compound ERA6 is converted into compound ERA7 through ketal reaction:

(6) Convert compound ERA7 into compound ERA8 through methylation reaction:

(7) Hydrolyze the ketal in the structure of compound ERA8 to convert it into compound ERA9:

(8) The hydroxyl group of compound ERA9 is protected by TBS to obtain ERA10:

(9) The double bond of ERA10 is oxidized to obtain compound ERA:

Wherein, R 1 is H, C 1-6 alkyl or halogen.
A preparation method of Eribulin intermediate P6, which is characterized in that it comprises:

(1) Make compound P1 form an ether in the molecule under the action of a base, and convert it into compound P2:

(2) Turn compound P2 into compound P3 through reduction reaction:

(3) Make compound P3 react with compound ERC under the action of a base to transform into compound P4

(4) Compound P4 is converted into compound P5 by Dess-Martin oxidation reaction

(5) The naphthylsulfonyl group is removed from compound P5 and converted into compound P6:

Wherein, R 1 is H, C 1-6 alkyl or halogen, and R 2 is Cl or OMs.
A method for preparing Eribulin, comprising: preparing the compound P1 according to claim 1 as an intermediate; or preparing it by using the method comprising any one of claims 2-6.
The compound is characterized in that it has the following structure:

Wherein, R 1 is H, C 1-6 alkyl or halogen.
The compound or method according to claims 1-8, wherein R 1 is H and R 2 is Cl or OMs.
A compound characterized in that the structure is as follows: