CN113549101A

CN113549101A - Preparation method of eribulin and intermediate thereof

Info

Publication number: CN113549101A
Application number: CN202010338097.2A
Authority: CN
Inventors: 袁建栋; 林清泉; 杭文明
Original assignee: Brightgene Bio Medical Technology Co Ltd
Current assignee: Brightgene Bio Medical Technology Co Ltd
Priority date: 2020-04-26
Filing date: 2020-04-26
Publication date: 2021-10-26
Also published as: WO2021218041A1

Abstract

The invention provides eribulin and a preparation method thereof; particularly, the compound P1 is prepared by splicing the eribulin fragment A synthesized by diethyl naphthylsulfonyl methyl phosphonate with the fragment ERB, the yield is obviously improved and is far higher than that of the prior art, and the stereospecificity is high; in addition, the invention adopts improved NHK reaction when synthesizing the intermediate compound P1, greatly reduces the dosage of chromium reagent, not only reduces the cost, but also reduces the pollution to the environment.

Description

Preparation method of eribulin and intermediate thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to eribulin and a preparation method of an intermediate thereof.

Background

Eribulin mesylate was developed by japan wei material pharmaceuticals and was marketed under the trade name HALAVEN by FDA approval of the injection at 11 months 2010. As a tubulin polymerization inhibitor with a brand new action mechanism, eribulin mesylate is the 1 st single-drug chemotherapeutic drug for improving the overall survival time of patients with metastatic breast cancer, provides a new treatment means for improving the survival rate and the life quality of patients with locally advanced breast cancer or metastatic breast cancer, and is a drug with great application value. The chemical structure is as follows:

from the structure of eribulin, the molecule contains 19 chiral centers, and the synthesis is very difficult, and the eribulin is usually prepared by splicing the following three fragments, namely A (C27-C35), B (C14-C26) and C (C1-C13): segment A is spliced with segment B first and then with segment C. When the fragments are spliced, the leaving groups have different routes.

Chinese patent CN1216051C discloses splicing fragment A protected by MPM (methoxyphenylthio methyl) at the 35-position carbon with fragment B and then with fragment C.

In the above process, after the fragments A and B are joined together, a diastereomer mixture of C27 is obtained in a ratio of about 3:1, and the mixture is purified by multiple separations in such a way that the yield of the joining reaction of A with B, based on the fragment B, is only 33.6%. MPM group is spliced with the fragment C after leaving, and the MPM group needs to be converted for many times after leaving, so that the steps are complicated, and the yield is low.

Chinese patent CN104876896A discloses splicing fragment A with phenylsulfonyl-protected carbon at 35 position with fragment B and then with fragment C.

In the method, when the fragments A and B are spliced, the chiral ligand is required to be added, the yield of the splicing reaction is 59.2% based on the fragment B, and then the fragment B is spliced, so that the total yield of the preparation of eribulin is still low, the purification method is complicated, and column chromatography is required.

CN105713031A discloses the use of protecting groups prepared from diethyltosyl methylphosphonate for the A fragment andb, splicing the fragments:

the reaction has the characteristics of low raw material price and contribution to subsequent cyclization reaction, but the yield of the patent is 45.8 percent, column chromatography is required, and the industrial production requirement cannot be met.

In production and research and development, the splicing product stability of the eribulin fragments A and B is not high, the condition that a silica gel column is gradually changed from light yellow to black brown can be obviously seen during column chromatography, and the fact that the splicing product is decomposed in the acidic environment of the silica gel column is prompted, the overall splicing reaction yield of the fragments A and B is reduced, and the splicing reaction yield is low in the prior art, and the raw material medicine is generally large in batch size in industrial production, the time consumed in the purification process of the silica gel column is long, and the splicing product is easy to decompose.

In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing eribulin, which does not require column purification, has high yield and strong stereoselectivity, and is suitable for industrial mass production.

Disclosure of Invention

In order to solve the technical problem that the yield is not high due to easy decomposition of the splicing reaction column chromatography of the fragment A and the fragment B, the invention provides a novel intermediate fragment A for preparing eribulin and a preparation method of the intermediate fragment A; the invention also provides a method for preparing eribulin from the fragment A.

In one aspect, the present invention provides compound P1, having the structure:

wherein R is₁Is H, C_1～6Alkyl or halogen of (2), preferably R₁Is H, methyl, ethyl, or Cl, R₂Cl or OMs.

In another aspect, the present invention provides a method for preparing compound P1, comprising: compound ERA was reacted with compound ERB via NHK to convert to compound P1:

wherein R is₁Is H, C_1～6Alkyl or halogen of, R₂Cl or OMs.

In the above method, it is preferable to add NiX to the reaction system₂，CrCl₂Aluminum chips and trimethylchlorosilane, where NiX₂Is NiBr₂Or NiCl₂. More preferably, the reaction is carried out by taking the charge of the compound ERA as 1 molar equivalent, and NiBr₂The amount of the compound is 0.02-0.08 molar equivalent and CrCl₂The dosage of the aluminum scrap is 0.1-0.3 molar equivalent, the dosage of the ERB is 1.1-2 molar equivalent, the dosage of the 1-bromo-2-trimethylsilylethylene is 2-3 molar equivalent, the dosage of the aluminum scrap is 2.0-4.0 molar equivalent, and the dosage of the trimethylchlorosilane is 2.5-4.5 molar equivalent.

In another aspect, the present invention also provides a method for preparing compound ERA comprising:

(1) compound ERA2 is converted by wittig reaction with diethyl naphthalenesulfonylmethylphosphonate into compound ERA 3:

wherein the dosage of the diethyl naphthalenesulfonylmethylphosphonate is 1-2 molar equivalents; adding alkali into a reaction system, wherein the alkali is preferably selected from NaHMDS, KHMDS, NaH and the like, and the using amount of the alkali is 3-5 equivalents; the reaction temperature is 0-15 ℃;

(2) compound ERA3 was selectively debenzylated and converted to ERA 4:

preferably, the compound ERA3 is subjected to debenzylation protection under the action of trimethylsilylimidazole and converted into ERA 4;

(3) converting the double bond of compound ERA4 to compound ERA5 by selective reduction:

preferably, in the above reaction, NaBH (OAc) is used₃Selective reduction of the double bond of compound ERA4 as a reducing agent;

(4) the compound ERA5 ester bond is converted into ERA 6:

(5) the vicinal diol of compound ERA6 was converted to compound ERA 7:

(6) compound ERA7 is converted by methylation to compound ERA 8:

(7) the ketal in the structure of the compound ERA8 is hydrolyzed and converted into the compound ERA 9:

(8) the compound ERA9 hydroxyl group was protected with TBS to obtain ERA 10:

(9) subjecting the double bond of ERA10 to oxidation to give compound ERA:

wherein R is₁Is H, C_1～6Alkyl or halogen of (a); preferably R₁Is H.

On the other hand, the invention also provides a preparation method of eribulin intermediate P6, which is characterized by comprising the following steps:

(1) intramolecular etherification of compound P1 with a base to compound P2:

(2) compound P2 is converted to compound P3 by reduction:

(3) reacting compound P3 with compound ERC under the action of alkali to convert into compound P4

(4) The compound P4 is converted into a compound P5 through Dess-Martin oxidation reaction

(5) Compound P5 was converted to compound P6:

wherein，R₁Is H, C_1～6Alkyl or halogen of (a).

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

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

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

step (5) preferably, compound P5 is converted to compound P6 by removing the naphthylsulfonyl group by the action of samarium diiodide.

In another aspect, the invention also provides compounds having the structure:

wherein R is₁Is H, C_1～6Alkyl or halogen of (2), preferably R₁Is H.

C according to the invention_1～6Alkyl 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. As used herein, "TBS" means t-butyldimethylsilyl group, "Pv" means pivaloyl group, "Ms" means methanesulfonyl group, and "DIBALH" means diisobutylaluminum hydride.

The compound P1 is prepared by splicing the fragment ERA synthesized by diethyl naphthalene sulfone methylphosphonate and the fragment ERB, the yield is obviously improved, and the presumed mechanism is that 1) the naphthalene sulfone phosphonate is more electron-rich than phenyl and tolyl in the prior art as a protective group, and the stability of a neutralization product in the splicing reaction process is higher; (2) the naphthyl sulfone phosphonate is used as a protective group, and can still react well under the condition of low dosage of a chromium reagent by combining with an improved NHKL reaction developed by an applicant, so that the side reaction caused by excessive catalyst is reduced, and the generation of impurities is reduced. 3) The product has high stability without column chromatography, but still contains certain impurities, which results in high yield.

Compared with the prior art, the invention provides a brand-new synthesis method and intermediate for preparing eribulin, particularly the compound P1 is prepared by splicing the fragment ERA synthesized by diethyl naphthalenesulfonylmethylphosphonate and the fragment ERB, the yield is obviously improved, for example, the yield can be as high as 81.9 percent, the yield is improved by 150 to 260 percent compared with the prior art, the stereospecificity is far higher than that of the prior art; and because the yield is high, column chromatography is not needed, and the crude product spliced by the fragments A and B can be obtained only by a conventional crystallization and precipitation process and directly used for the next step of cyclic synthesis ether reaction.

The compound P6 is prepared by taking the compound P1 as an intermediate, and the total reaction yield is greatly improved by using the compound P6 to prepare eribulin. In addition, the invention adopts improved NHK reaction when synthesizing the compound P1, greatly reduces the dosage of chromium reagent which is only 0.2 mol%, not only reduces the cost, but also reduces the pollution to the environment. The whole route is simple to operate, has high yield and purity, and is very suitable for industrial production for preparing raw material medicaments.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The technical solutions and preferred embodiments of the present invention are further explained and illustrated below with reference to specific examples.

EXAMPLE 1 preparation of the Compound ERA3a

7.6g of diethyl naphthylsulfonyl methylphosphonate is dissolved in 20ml of tetrahydrofuran at the temperature of 10 ℃, 36.04g of tetrahydrofuran solution of 25 percent NaHMDS is dropwise added, the temperature is controlled to be not more than 15 ℃, the stirring is carried out for 30 minutes, the solution is added into 38ml of tetrahydrofuran solution dissolved with 7.6g of ERA2, the temperature is controlled to be not more than 20 ℃, and the stirring is carried out for 1 hour. 49ml of 1N hydrochloric acid was added, the temperature was controlled not to exceed 20 ℃, tetrahydrofuran was removed by concentration under reduced pressure, 30ml of methylene chloride was added and extraction was carried out three times with stirring, the organic phases were combined, washed twice with 30ml of sodium bicarbonate solution and twice with 30ml of brine solution in this order, dried, filtered and concentrated to give 9.4g of ERA3 a.

EXAMPLE 2 preparation of the Compounds ERA4a and ERA5a

(1) Preparation of compound ERA4 a: 9.4g of ERA3a were dissolved in 50ml of ethyl acetate at room temperature, 11.8g of TMSI was added, the reaction was heated to 50 ℃ and stirred for 2 hours. Cooling the reaction liquid to-10 ℃, quenching the reaction liquid by using an ammonia water solution, and controlling the temperature to be lower than 30 ℃. Stirring and layering. The organic phase is washed successively with 50ml of 10% aqueous sodium sulfite, 50ml of 1N hydrochloric acid, 50ml of 5% aqueous sodium bicarbonate and 50ml of brine, dried over magnesium sulfate, filtered and concentrated to give 7.8g of ERA4 a.

(2) Preparation of compound ERA5 a: 7.8g NaBH (OAc)3, 80ml acetonitrile were added to the reaction flask, heated to 65 ℃ and 14g of 50% ERA4a solution in acetonitrile was added, the reaction temperature was raised to 80 ℃ and stirred for 3 hours. Cooled to 10 ℃ and quenched by dropwise addition of 25ml of water, maintaining the internal temperature below 20 ℃. The layers were separated by stirring and the organic layer was washed twice with 40ml of aqueous sodium bicarbonate solution and twice with 40ml of water. Drying and concentration gave 7.3g of ERA5 a.

EXAMPLE 3 preparation of the Compounds ERA6a and ERA7a

(1) Preparation of compound ERA6 a: 7.3g of ERA5a were dissolved in 16ml of methanol, 1.6g of potassium carbonate was added, and the mixture was stirred at 50 ℃ for 1 hour. The reaction solution was cooled to 15 ℃ and 24ml of 1N hydrochloric acid was added dropwise thereto while controlling the internal temperature to be lower than 30 ℃. 29ml of water and 23ml of toluene were added, the layers were separated by stirring, and the aqueous layer was back-extracted with 13ml of toluene again. The aqueous phase was concentrated under reduced pressure, methanol was removed, 2.1g of sodium hydrogencarbonate and 4.4g of sodium chloride were added thereto, and the mixture was extracted three times with 25ml of ethyl acetate. The organic phases were combined and concentrated to give crude ERA 15. The crude ERA6 was dissolved in 7:1 toluene/nBuOH at 80 deg.C, filtered hot and then recrystallized to give 4.6g ERA6 a.

(2) Preparation of compound ERA7 a: 4.6g of ERA6a were dispersed in 10ml of acetone at 25 ℃, 5ml of 2, 2-dimethoxypropane and 0.04g of concentrated sulfuric acid were added, and the reaction mixture was stirred until homogeneous. The reaction mixture was quenched by adding 23ml of toluene and 9ml of 5% potassium carbonate solution. The layers were separated by stirring and the organic layer was washed with 10% brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4.7g of ERA7 a.

EXAMPLE 4 preparation of the Compounds ERA8a and ERA9a

(1) Preparation of compound ERA8 a: 0.67g of sodium hydride (60%) was dissolved in 12ml of tetrahydrofuran and cooled to below 10 ℃. To the sodium hydride solution was added dropwise a solution of 4.7g of ERA7a in 12ml of tetrahydrofuran, maintaining the internal temperature below 15 ℃. Stirring was carried out for 30 minutes, maintaining the temperature below 15 ℃ and 1.94g of methyl iodide were added. After the completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. 23ml of water and 33ml of toluene were added to the reaction mixture, and the layers were separated by stirring, and the organic layer was washed twice with 25ml of brine, dried, filtered and concentrated under reduced pressure to obtain 4.5g of ERA8 a.

(2) Preparation of compound ERA9 a: 4.5g of ERA8a was dissolved in 5ml of methanol and 5ml of 2N hydrochloric acid, and the reaction was stirred at room temperature. The reaction mixture was added to 6.0ml of 2M NaOH solution at 10 ℃ and 10ml of water was added. 23ml of ethyl acetate was added to the reaction system, and the mixture was stirred to separate layers, and the aqueous layer was re-extracted with 23ml of ethyl acetate, and the organic layers were combined, dried, filtered, and concentrated under reduced pressure to give 3.9g of ERA9 a.

EXAMPLE 5 preparation of the Compounds ERA10a and ERAA

(1) Preparation of compound ERA10 a: 3.9g of ERA9 were dissolved in 15ml of DMF, 3.6g of triethylamine were added, and 4.0g of TBSCl were added while controlling the internal temperature to below 30 ℃. The reaction was stirred at room temperature for 2 hours. 40ml of n-heptane and 15ml of water were added to the reaction mixture, and the mixture was stirred to separate layers. The organic layer was washed successively with 12ml of 1M hydrochloric acid, 12ml of water, 12ml of aqueous sodium bicarbonate solution and 12ml of brine, and the organic layer was dried, filtered and concentrated under reduced pressure to give 5.7g of ERA10 a.

(2) Preparation of compound ERAa: 5.7g of ERA10a were dissolved in 57ml of n-heptane at-60 ℃ and ozone was passed through the solution until the solution remained blue. Nitrogen was introduced into the solution for 30 minutes to raise the temperature of the reaction solution to 5 ℃. 0.6g of 10% Lindlar catalyst was added. After hydrogen was introduced into the solution for 30 minutes, the reaction solution was allowed to warm to room temperature and stirred for 2 hours. The solution was filtered and washed with 10ml of methyl tert-butyl ether. The filtrate was concentrated to dryness and the crude ERAa product was recrystallized from heptane to give 5.1g of ERAa.

EXAMPLE 6 preparation of Compound P1a

Under the protection of argon, strictly ensuring that the reaction vessel has no water and oxygen, adding 5.8g of ERAa, 59mg of NiBr2, 1.78g of CrCl2, 0.56g of aluminum chips, 3.39ml of trimethylchlorosilane and 30ml of DMF, cooling to 0-3 ℃, and stirring for 30 minutes. 5.94g of ERB were added dropwise, maintaining the temperature below 30 ℃. After completion of the dropwise addition, the reaction was stirred at room temperature for 24 hours. 20ml of methanol/water (1/1, vol.) were added and stirred for 10 minutes. 320ml of methyl tert-butyl ether were added, stirred for 10 minutes and the reaction mixture was transferred to 250ml of 1N hydrochloric acid and 100ml of water. The layers were separated by stirring, the aqueous layer was back-extracted twice with 100ml of methyl tert-butyl ether and the combined organic layers were washed twice with 150ml of 1% sodium chloride solution and 150ml of brine in that order. The concentrated organic layer was dried, the crude product was dissolved in a small amount of ethyl acetate, and 4 times the amount of ethyl acetate was added to crystallize the product, which was dried to obtain 6.0g P1a, e.e. > 96%, yield 62.1%.

EXAMPLE 7 preparation of Compound P1b

The charge amount of ERAa and the molar ratio of ERB to ERAa were the same as in example 6, and the same experimental conditions as in example 6 were used to dissolve the crude product in a small amount of ethyl acetate, and 4 times the amount of ethyl acetate was added to crystallize and precipitate the product, which was dried to obtain 7.9g P1a, e.e. > 96%, and the yield was 81.9%.

EXAMPLE 8 preparation of Compound P2a and Compound P3a

(1) Preparation of compound P2: 6.0g P1. 1a is dissolved in 500ml tetrahydrofuran, cooled to-20 ℃, 0.5M NaHMDS toluene solution 75.4g is added dropwise, the temperature is controlled not to exceed-12 ℃, and the reaction is stirred for 4 hours. The reaction solution was added to 200ml of a 50% ammonium chloride solution, and 500ml of n-heptane was added, followed by stirring and separation. The organic layer was separated and the aqueous layer was back-extracted with 400ml of n-heptane. The combined organic layers were washed with 400ml of saturated sodium chloride solution. The organic layer was dried and concentrated, and the crude P2a was dissolved in 200ml of n-heptane and purified by silica gel column to give 4.9g P2 a.

(2) Preparation of compound P3 a: 4.2g P2 was dissolved in 30ml of dichloromethane, cooled to-78 deg.C, 12.6g of 1M DIBALH in dichloromethane was added dropwise, the temperature was controlled not to exceed-60 deg.C, and 0.5ml of methanol was added dropwise. After the completion of the dropwise addition, the reaction was stirred for 10 minutes, warmed to room temperature, and added with 45ml of 1N hydrochloric acid and 120ml of methyl t-butyl ether. The layers were stirred and the aqueous layer was back extracted with 70ml of methyl tert-butyl ether. The organic layers were combined, washed successively with 20ml of water, 20ml of saturated sodium bicarbonate and 30ml of saturated sodium chloride solution, dried and concentrated. The crude concentrate was purified by silica gel column to give 3.6g P3 a.

EXAMPLE 9 preparation of Compound P2a and Compound P3a 2

The charge of P1a and the molar ratio of P2a to P1a were the same as in example 8, and the crude concentrate was purified by silica gel column using the same experimental conditions as in example 8 to give 3.5g P3 a.

EXAMPLE 10 preparation of Compound P4a and Compound P5a

(1) Preparation of compound P4 a: 3.6g P3a was dissolved in 20ml of tetrahydrofuran solution at 0 ℃ and 5.4ml of n-butyllithium (1.6M hexane solution) was added dropwise thereto, the temperature was controlled to not more than 5 ℃ and the reaction was stirred for 10 minutes. Cooling to-78 deg.C, adding dropwise a solution of 3.9g ERC in 20ml n-hexane, keeping the highest temperature not higher than-65 deg.C, and stirring for 40 min. Adding 20ml saturated ammonium chloride, 40ml methyl tert-butyl ether and 20ml water, stirring, layering, drying and concentrating. The crude P4a product is purified to obtain 5.6g P4 a.

(2) Preparation of compound P5 a: 5.6g P4a was dissolved in 40ml of methylene chloride at room temperature, and 3.8g of Dess-Martin reagent was added thereto and the reaction was stirred for 30 minutes. 50ml of saturated sodium bicarbonate and 50ml of a 10% aqueous sodium sulfite solution were added thereto, and the mixture was stirred for 30 minutes. 50ml of saturated sodium chloride and 300ml of n-heptane were added, and the layers were separated by stirring. The aqueous layer was discarded, and the organic layer was dried and concentrated, followed by silica gel column separation to obtain 5.0g of Compound P5 a.

EXAMPLE 11 preparation of Compound P6 and eribulin

(1) Preparation of compound P6: n is a radical of₂Under protection, 3.1g of samarium diiodide solution was dissolved in 15ml of tetrahydrofuran and cooled to an internal temperature of-78 ℃. Dissolving 5.0g P5a in 20ml tetrahydrofuran, dripping the P5 solution into the samarium solution, and controlling the temperature not to exceed-60 ℃. The reaction was stirred for 30 minutes and 50ml of potassium carbonate/potassium tartrate/water (1/10/100), 16ml of n-heptane were added, keeping the temperature at-65 ℃ or lower. The mixture was stirred to room temperature, and 70ml of potassium carbonate/potassium tartrate/water (1/10/100) and 70ml of n-heptane were added. The layers were separated by stirring, the organic layer was dried and concentrated, and the concentrate was purified by silica gel column to give 2.5g P6.

(2) Preparing eribulin: eribulin or its methanesulfonic acid can be prepared from compound P6 by any of the methods disclosed in the prior art.

Comparative example 1

Referring to the method for splicing the fragment A and the fragment B in CN1216051C, the material feeding amount and the reaction conditions in the patent are repeated, the yield of the fragment A and the fragment B is 33.6 percent, and dark brown decomposition products appear in the process of column chromatography.

Comparative example 2

Referring to the method for splicing the fragment A and the fragment B in CN104876896AC, the charging amount and the reaction conditions in the patent are repeated, the yield of the fragment A and the fragment B is 59.2%, and light brown decomposition products appear in the process of column chromatography.

Comparative example 3

Referring to the method for splicing the fragment A and the fragment B in CN105713031A, the charging amount and the reaction conditions in the patent are repeated, the yield of the fragment A and the fragment B is 45.8%, and brown decomposition products appear in the process of column chromatography.

Claims

1. Compound P1, characterized by the following structure:

wherein R is₁Is H, C_1～6Alkyl or halogen of, R₂Cl or OMs.

2. A process for the preparation of compound P1, comprising: compound ERA was reacted with compound ERB via NHK to convert to compound P1:

wherein R is₁Is H, C_1～6Alkyl or halogen of, R₂Cl or OMs.

3. The method of claim 2, wherein the reaction system is a reaction systemAdding NiX₂，CrCl₂Aluminum chips and trimethylchlorosilane, where NiX₂Is NiBr₂Or NiCl₂。

4. The method of claim 3, wherein the amount of NiBr added is 1 molar equivalent of ERA compound₂The amount of the compound is 0.02-0.08 molar equivalent and CrCl₂The amount of ERB is 0.1-0.3 molar equivalent, and the amount of ERB is 1.1-2 molar equivalent.

5. The method of claim 2, wherein the compound ERA is prepared by a process comprising:

(2) compound ERA3 was selectively debenzylated and converted to ERA 4:

(4) the compound ERA5 ester bond is converted into ERA 6:

(5) the vicinal diol of compound ERA6 was converted to compound ERA 7:

(6) compound ERA7 is converted by methylation to compound ERA 8:

(8) the compound ERA9 hydroxyl group was protected with TBS to obtain ERA 10:

(9) subjecting the double bond of ERA10 to oxidation to give compound ERA:

wherein R is₁Is H, C_1～6Alkyl or halogen of (a).

6. A preparation method of eribulin intermediate P6 is characterized by comprising the following steps:

(1) intramolecular etherification of compound P1 with a base to compound P2:

(2) compound P2 is converted to compound P3 by reduction:

(5) Compound P5 was converted to compound P6:

wherein R is₁Is H, C_1～6Alkyl or halogen of, R₂Cl or OMs.

7. A method for preparing eribulin, comprising preparing the compound P1 of claim 1 as an intermediate; or prepared by the method of any one of claims 2 to 6.

8. A compound characterized by the structure:

wherein R is₁Is H, C_1～6Alkyl or halogen of (a).

9. The compound or method of claims 1-8, wherein R is₁Is H, R₂Cl or OMs.

10. A compound having the structure: