CN113024589A - Preparation method of eribulin and intermediate thereof - Google Patents

Preparation method of eribulin and intermediate thereof Download PDF

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Publication number
CN113024589A
CN113024589A CN201911247774.3A CN201911247774A CN113024589A CN 113024589 A CN113024589 A CN 113024589A CN 201911247774 A CN201911247774 A CN 201911247774A CN 113024589 A CN113024589 A CN 113024589A
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compound
reaction
added
preparation
eribulin
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徐安佗
周宁
张晓光
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Shandong Yilite Biomedical Technology Co ltd
Nantong Nuotai Biological Pharmaceutical Co ltd
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Shandong Yilite Biomedical Technology Co ltd
Nantong Nuotai Biological Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a preparation method of eribulin and an intermediate thereof, which is characterized in that methyl cyclopentanone is used for replacing cyclohexanone to protect the hydroxyl of a raw material D-gulonolactone for the first time, Lewis acid is used for catalysis, and compared with the prior art, the use of a chromium reagent is omitted, and the chromium pollution in the environment is reduced; the invention also provides a hydroxyl protecting group using cyclopentanone as a plurality of intermediates of eribulin and a preparation method of the intermediates. Compared with the prior art, the preparation method of the eribulin intermediate provided by the invention has the advantages of high yield, low production cost and reduced environmental pollution.

Description

Preparation method of eribulin and intermediate thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of eribulin and an intermediate thereof.
Background
Eribulin mesylate, as a tubulin polymerization inhibitor with a brand-new mechanism of action, is the 1 st single-drug chemotherapeutic drug for metastatic breast cancer patients to obtain overall improvement in survival, developed by the japan medicinal and health products company, and the injection was approved by the U.S. FDA and marketed at 11 months 2010 under the trade name HALAVEN. The eribulin mesylate provides a new treatment means for improving survival rate and life quality of patients with locally advanced breast cancer or metastatic breast cancer, and is a medicament with high application value. The structure is as follows:
Figure BDA0002308173990000011
kishi et al reported a preparation method of eribulin key intermediate C (formula C below), specifically as follows:
Figure BDA0002308173990000012
in the preparation method, the hydroxyl group of the raw material D-gulonolactone is protected by cyclohexanone until the total yield of the synthesized compound B is 19.2 percent, and the dosage of a chromium reagent in NHK reaction for synthesizing the compound B is usually 400-1600 mol percent, so the cost is high, the environment is polluted by heavy metal, and the application in large-scale production is difficult.
Disclosure of Invention
The invention provides a novel preparation method of eribulin and intermediates C and C01a thereof, and the method is high in yield, simple to operate, controllable in quality, high in purity, environment-friendly and suitable for large-scale production and application.
First, the present invention provides a process for producing compound C, which comprises deprotecting a hydroxyl group from compound C01a to convert into compound C:
Figure BDA0002308173990000021
preferably, compound C01a is suspended in a 20% to 50% aqueous solution of acetic acid and heated to remove the hydroxyl protecting group, thereby yielding compound C.
In another aspect, the present invention also provides a method for preparing compound C01a, comprising the steps of:
(1) the condensation reaction of D-gulonolactone with cyclopentanone is converted to the compound C01:
Figure BDA0002308173990000022
(2) reduction of compound C01 to compound C02:
Figure BDA0002308173990000023
(3) compound C02 is opened under basic condition, then reacts with (methoxymethyl) triphenyl phosphine chloride to convert into compound C03
Figure BDA0002308173990000024
(4) Compound C03 was added to the reaction solution at OsO4Catalytically, ring closure, conversion to compound C04:
Figure BDA0002308173990000031
(5) the hydroxyl group of compound C04 was selectively protected with acetyl group and converted to compound C05:
Figure BDA0002308173990000032
(6) reacting compound C05 with methyl 3-trimethylsilylpent-4-enoate and BF3·Et2O reaction, conversion to compound C06:
Figure BDA0002308173990000033
(7) compound C06 is cyclized under basic conditions and the acetyl protecting agent is deacetylated to compound C07:
Figure BDA0002308173990000034
(8) converting compound C07 into compound C08 by oxidation reaction
Figure BDA0002308173990000035
(9) Compound C08 was reacted with 1-bromo-2-trimethylsilylethylene to convert to compound C01 a:
Figure BDA0002308173990000041
in the above method, preferably, step (1) uses anhydrous zinc chloride as a catalyst; more preferably, the D-gulonolactone is condensed with cyclopentanone in a suitable solvent (such as toluene solution) under the catalysis of anhydrous zinc chloride to obtain a compound C01; wherein the feeding amount of D-gulonolactone is 1-1.5 molar equivalent, the dosage of cyclopentanone is 2-4 molar equivalent, the dosage of anhydrous zinc chloride is 0.01-0.05 molar equivalent, and the reaction temperature is 120-150 ℃;
adding a compound C01 into a suitable solvent (such as toluene), then slowly adding DIBALH under cooling, and converting into a compound C02 through reduction reaction, wherein the molar ratio of the compound C01 to the DIBALH is 1: 1-2, preferably 1: 1.5;
the alkali used in the alkaline condition in the step (3) is NaHMDS; more preferably, in the step (3), the compound C02 is dissolved in tetrahydrofuran, (methoxymethyl) triphenylphosphine chloride is added, and a tetrahydrofuran solution of NaHMDS is dropwise added to react to obtain the compound C03, wherein the molar ratio of the compound C02 to the NaHMDS is preferably 1: 2-2.5;
the reaction solvent in the step (4) is isopropanol and water, wherein the dosage ratio of the isopropanol to the water is 5-7: 1 (v/v); OsO4The dosage of the catalyst is 0.03-0.05 molar equivalent, and the reaction temperature is 0-5 ℃;
adding anhydrous zinc chloride into acetic acid and acetic anhydride serving as reaction solvents to perform reaction, wherein the preferable molar ratio of the compound C04 to the anhydrous zinc chloride is 1: 0.5-1;
step (6) acetonitrile is taken as reaction liquid, 3-trimethylsilyl amyl-4-methyl enoate and BF are added3·Et2O is reacted;
step (7) using tetrahydrofuran as a reaction solvent, reacting compound C06 with benzyltrimethylammonium hydroxide to convert into compound C07;
step (8) using ethyl acetate and water as reaction solvent, and NaIO4Is an oxidant, wherein the compound C07 is reacted with NaIO4The molar ratio of (A) to (B) is 1: 08-1.2;
adding NiCl into the reaction system in the step (9)2，CrCl2Aluminum chips and trimethylchlorosilane and manganese powder; more preferably, in the step (9), DMF is used as a solvent, and the compound C08 and NiCl are added into the reaction system2，CrCl2Aluminum chips, trimethylchlorosilane, manganese powder and 1-bromo-2-trimethylsilylethylene are stirred to react to obtain a compound C, wherein NiCl2The dosage of the compound is 0.01-0.05 mol equivalent and CrCl2The amount of the manganese powder is 0.05-0.1 molar equivalent, the amount of the manganese powder is 0.5-2 molar equivalent, the amount of the 1-bromo-2-trimethylsilylethylene is 2-3 molar equivalent, the amount of the aluminum chips is 2-3 molar equivalent, and the amount of the trimethylchlorosilane is 2-4 molar equivalent.
On the other hand, the invention also provides a preparation method of eribulin, which comprises the steps of preparing the compound C01 by adopting the method, preparing the intermediate C by taking the compound C01 as an intermediate, and preparing the eribulin or the mesylate thereof by taking the intermediate C.
Unless otherwise specified, "equivalent" in the present invention means molar equivalent.
Compared with the prior art, the invention firstly proposes that methyl cyclopentanone replaces cyclohexanone to protect the hydroxyl of the raw material D-gulonolactone, and Lewis acid is adopted for catalysis, so that the use of a chromium reagent is omitted, the chromium pollution in the environment is reduced, and the reaction yield of the step is obviously improved, for example, the yield of the synthesized compound C01 can be improved to more than 85 percent.
Secondly, the method for preparing the compound C provided by the invention has mild reaction conditions and is easy to purify, particularly when the compound C04 is prepared from the compound C03, the reaction chiral selectivity is high, and the isomer of the prepared compound C04 can be obviously improved to more than 10: 1.
Thirdly, the step (9) of the invention adopts improved NHK reaction, adds assimilation agent manganese powder into the reaction system and adopts NiCl2、CrCl2Aluminum scraps and trimethylchlorosilane, the compound C09 is reduced into the compound C, the reaction yield can be obviously improved, and the dosage of a chromium reagent can be reduced to 0.1 mol% or less.
Fourthly, the total yield of the whole route for preparing the compound C can be improved by about 20 percent compared with the prior art by calculating the route from D-gulonolactone as a starting material.
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 compound C01:
Figure BDA0002308173990000051
0.11mol of D-gulonolactone, 0.35mol of p-methylcyclohexanone, 100ml of toluene and 0.03mol of anhydrous zinc chloride are stirred for reflux reaction, and after the reaction is finished, the reaction mixture is cooled and washed with 60ml of an aqueous sodium bicarbonate solution and 60ml of an aqueous saturated sodium chloride solution in this order. Concentrating the organic phase to remove partial toluene, adding 200ml of n-heptane, heating and refluxing for 2-4 hours, cooling to 40-50 ℃, and stirring for 2 hours. Filtration and drying gave 34.14g of Compound C01.
EXAMPLE 2 preparation of Compound C02
Figure BDA0002308173990000052
0.1mol of compound C01 was dissolved in 250ml of toluene, cooled to-10 ℃ and 80ml of DIBALH (1.5M toluene solution) was slowly added thereto while controlling the temperature not to exceed-10 ℃, stirred for 30 minutes, the reaction solution was added to a potassium sodium tartrate solution, the mixture was warmed to room temperature and stirred for 4 hours. The layers were separated by filtration, extracted twice with 60ml ethyl acetate, the organic layers were combined, dried, filtered and concentrated to give 31g of compound C02.
EXAMPLE 3 preparation of Compound C03
Figure BDA0002308173990000061
0.1mol of Compound C02 is dissolved in 80ml of tetrahydrofuran, 65g of (methoxymethyl) triphenylphosphine chloride are added and, at room temperature, a solution of 36.5g of NaHMDS in 80ml of tetrahydrofuran is slowly added dropwise. After the addition, the mixture was stirred at room temperature, and 100ml of brine, 100ml of water and 160ml of ethyl acetate were added after the reaction. The layers were separated by stirring and the organic phase was slowly added to 100g of 20% sodium hydroxide solution with stirring. The organic layer was separated and concentrated to give a crude compound represented by the formula (C03). The crude product is stirred for 1 hour with 160ml of n-heptane and 20g of kieselguhr. Filtration and washing of the filter cake with 180g of n-heptane. The filtrate was concentrated to then 25% methanol solution was added and extracted three times with 200g of n-heptane. The organic layers were combined and concentrated to give 33.5g of Compound C03.
EXAMPLE 4 preparation of Compound C04
Figure BDA0002308173990000062
0.1mol of compound C03 is dissolved in 80ml of isopropanol and 15ml of water, 20g N-methylmorpholine N-oxide is added, and the mixture is cooled to 0-5 ℃. 1.5ml of OsO was added4(0.3M aqueous solution), stirring at 0-5 ℃ for reaction, after completion of the reaction, filtering, washing the solid with 23ml of acetone/water (1/1, v/v) pre-cooled (0-5 ℃) and drying to give 23.3g of compound C04, d.r. ═ 25: 1.
EXAMPLE 5 preparation of Compound C05
Figure BDA0002308173990000063
0.08mol of Compound C05 was suspended in 15ml of acetic acid and 60g of acetic anhydride, 6.0g of anhydrous zinc chloride was added, and the mixture was stirred at room temperature to react, and after the reaction, the reaction mixture was added to 250g of ice water, and 150ml of ethyl acetate was added with stirring to separate layers. The aqueous layer was re-extracted with 100ml ethyl acetate. The combined organic layers were washed sequentially with brine, 1% aqueous sodium hydroxide solution and brine. The organic layer was concentrated and the crude concentrate was dissolved in 20% ethyl acetate/n-heptane, filtered through silica gel, which was washed with 20% ethyl acetate/n-heptane and the organic layer was concentrated to give 33.8g of compound C05.
EXAMPLE 6 preparation of Compound C06
Figure BDA0002308173990000071
0.05mol of Compound C05 are dissolved in 300ml of acetonitrile at 0-5 ℃, 20ml of methyl 3-trimethylsilylpent-4-enoate are added and 12ml of BF are added3·Et2O, keeping the temperature at 0-5 ℃, stirring for reaction, adding the reaction solution into 500ml of saturated sodium bicarbonate after the reaction is finished, and extracting with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated to give 22.7g of compound C06.
EXAMPLE 7 preparation of Compound C07
Figure BDA0002308173990000072
0.05mol of compound C06 are dissolved in 2010ml of tetrahydrofuran at room temperature, 75ml of benzyltrimethylammonium hydroxide are added and stirring is carried out until the reaction is complete. Filtration and concentration of the filtrate, the concentrate being dissolved in 50% ethyl acetate/n-heptane and then chromatographed on short silica gel (ethyl acetate elution), the filtrate being washed with brine and the organic phase being concentrated to give 16.8g of compound C07.
EXAMPLE 8 preparation of Compound C08
Figure BDA0002308173990000073
0.05mol of Compound C07 are dissolved in 100ml of ethyl acetate and 100ml of water at 0-5 ℃ and 10.7g of NaIO are added in portions4The reaction was stirred until the reaction was completed. Then filtered, the filter cake was washed with ethyl acetate, the layers were separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried and concentrated to give 16.6g of Compound C08.
EXAMPLE 9 preparation of Compound C01a
Figure BDA0002308173990000081
Under the protection of argon, 0.05mol of compound C08 and 0.02mol of Ni Cl are added into a reaction vessel2，0.05molCrCl20.1mol of aluminum scraps, 0.15mol of trimethylchlorosilane and 100ml of DMF, cooling to 0-5 ℃, and stirring for about 30 minutes. Dropwise adding 0.15mol of 1-bromo-2-trimethylsilylethylene at room temperature, stirring at room temperature after the dropwise adding is finished until the reaction is finished, adding 40ml of methanol/water (1/1, v/v), and stirring for 10-20 minutes. 350ml of methyl tert-butyl ether was added, stirring was continued for 10 to 20 minutes, and the reaction mixture was transferred to 500ml of 1N hydrochloric acid and 200ml of water. The layers were separated by stirring, the aqueous layer was back-extracted twice with methyl tert-butyl ether, and the combined organic layers were washed successively with 1% sodium chloride solution and brine, and then the organic layers were dried and concentrated to afford 18.7g of Compound C01a through preparative purification.
EXAMPLE 10 preparation of Compound C
Figure BDA0002308173990000082
18.7g of Compound C01a were suspended in 100g of 40% aqueous acetic acid, heated to 80 ℃, stirred until the reaction was complete, cooled to room temperature, washed twice with n-heptane and the water layer collected. Dripping 10% KHCO into the water layer3Adjusting the pH of the solution to 7-7.5, extracting twice with methyl tert-butyl ether, combining organic phases, and then usingThe residue was dissolved in methyl t-butyl ether, heated to dissolve, then 160g of n-heptane was added, dissolved and crystallized, and filtered and dried to obtain 13g of compound C.
Reference is made to the prior art for the preparation of eribulin or its mesylate salt from compound C, including but not limited to the methods disclosed in WO 9965894.
Example 11 Effect of different substrates on the preparation of Compound C01a
Compound C01a was prepared according to the following charge ratio with reference to the procedure of example 9:
Figure BDA0002308173990000083
Figure BDA0002308173990000091
from the above, it can be seen that when CrCl is used2The feed amount is 0.05-0.1 equivalent, and NiCl2When the material is fed by 0.01-0.05 equivalent, Al and Me3SiCl2The reaction is necessary, and the addition of the manganese powder can obviously improve the reaction yield.

Claims (10)

1. A process for the preparation of compound C, characterized in that the hydroxyl protection is removed from compound C01a and converted into compound C:
Figure FDA0002308173980000011
2. the method according to claim 1, wherein the hydroxyl protecting group is removed by suspending compound C01a in a 20% to 50% aqueous solution of acetic acid and heating.
3. A method for preparing compound C01a, comprising the steps of:
(1) the condensation reaction of D-gulonolactone with cyclopentanone is converted to the compound C01:
Figure FDA0002308173980000012
(2) compound C01 was reacted with DIBALH to convert to compound C02:
Figure FDA0002308173980000013
(3) compound C02 is opened under basic condition, then reacts with (methoxymethyl) triphenyl phosphine chloride to convert into compound C03
Figure FDA0002308173980000014
(4) Compound C03 was added to the reaction solution at OsO4Catalytically, ring closure, conversion to compound C04:
Figure FDA0002308173980000021
(5) the hydroxyl group of compound C04 was selectively protected with acetyl group and converted to compound C05:
Figure FDA0002308173980000022
(6) reacting compound C05 with methyl 3-trimethylsilylpent-4-enoate and BF3·Et2O reaction, conversion to compound C06:
Figure FDA0002308173980000023
(7) compound C06 is cyclized under basic conditions and the acetyl protecting agent is deacetylated to compound C07:
Figure FDA0002308173980000024
(8) converting compound C07 into compound C08 by oxidation reaction
Figure FDA0002308173980000025
(9) Compound C08 was reacted with 1-bromo-2-trimethylsilylethylene to convert to compound C01 a:
Figure FDA0002308173980000031
4. the method of claim 3,
in the step (1), anhydrous zinc chloride is used as a catalyst, and the dosage of the anhydrous zinc chloride is 0.01-0.05 molar equivalent;
the alkali used in the alkaline condition in the step (3) is NaHMDS;
adding NiCl into the reaction system in the step (9)2，CrCl2Aluminum chips and trimethylchlorosilane and manganese powders.
5. The method according to claim 3, wherein the compound C02 is dissolved in tetrahydrofuran in the step (3), and (methoxymethyl) triphenylphosphine chloride is added thereto, and a solution of NaHMDS in tetrahydrofuran is added dropwise to carry out the reaction, thereby obtaining the compound C03.
6. The method according to claim 3, wherein the reaction solvent in the step (4) is isopropanol and water, wherein the dosage ratio of the isopropanol to the water is 5-7: 1 (v/v); and (5) taking acetic acid and acetic anhydride as reaction solvents, and adding anhydrous zinc chloride for reaction.
7. The method according to claim 3, wherein in the step (6), acetonitrile is used as the reaction solution, and 3-trimethylsilylpent-4-enoic acid methyl ester and BF are added3·Et2O is reacted; step (7) using tetrahydrofuran as a reaction solvent, reacting compound C06 with benzyltrimethylammonium hydroxide to convert it into compound C07.
8. The method of claim 3, wherein the reaction solvent in step (8) is ethyl acetate and water, and NaIO is used4Is an oxidizing agent.
9. The method of claim 3, wherein the compound C08, NiCl is added to the reaction system in step (9) using DMF as a solvent2，CrCl2Aluminum chips, trimethylchlorosilane, manganese powder and 1-bromo-2-trimethylsilylethylene are stirred to react to obtain a compound C, wherein NiCl2The dosage of the compound is 0.02-0.05 molar equivalent and CrCl20.05-0.1 mol equivalent, and the amount of manganese powder is 0.5-2 mol equivalent.
10. A preparation method of eribulin or mesylate thereof is characterized by comprising the following steps:
(1) preparing compound C01a using the process of any one of claims 3 to 9;
(2) preparing compound C using the process of any one of claims 1-2;
(3) and (3) preparing eribulin or mesylate thereof by using the compound C obtained in the step (2) as an intermediate.
CN201911247774.3A 2019-12-09 2019-12-09 Preparation method of eribulin and intermediate thereof Pending CN113024589A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101899026A (en) * 2004-06-03 2010-12-01 卫材R&D管理有限公司 Be used to prepare the intermediate of halichondrin B
CN102421782A (en) * 2009-04-14 2012-04-18 日产化学工业株式会社 Method for producing tetrahydropyran compound and intermediate thereof
CN111689982A (en) * 2019-03-15 2020-09-22 博瑞生物医药（苏州）股份有限公司 Eribulin intermediate and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101899026A (en) * 2004-06-03 2010-12-01 卫材R&D管理有限公司 Be used to prepare the intermediate of halichondrin B
CN102421782A (en) * 2009-04-14 2012-04-18 日产化学工业株式会社 Method for producing tetrahydropyran compound and intermediate thereof
CN111689982A (en) * 2019-03-15 2020-09-22 博瑞生物医药（苏州）股份有限公司 Eribulin intermediate and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
梁学正 等: "路易斯酸盐ZnCl2催化合成缩醛（酮）的研究", 化工时刊, pages 38 - 40 *

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