CN113024576B - Preparation method of eribulin and intermediate thereof - Google Patents

Preparation method of eribulin and intermediate thereof Download PDF

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CN113024576B
CN113024576B CN201911247758.4A CN201911247758A CN113024576B CN 113024576 B CN113024576 B CN 113024576B CN 201911247758 A CN201911247758 A CN 201911247758A CN 113024576 B CN113024576 B CN 113024576B
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compound
reaction
eribulin
preparation
nicl
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CN113024576A (en
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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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • 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
    • C07F7/081—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
    • 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 an eribulin intermediate and a preparation method thereof, in particular provides a hydroxyl protecting group taking cyclopentanone as a plurality of eribulin intermediates, and further provides a novel intermediate and a preparation method of the intermediate. Compared with the prior art, the preparation method of the eribulin intermediate provided by the invention has high yield, the use of chromium reagent is reduced in a plurality of steps, the production cost is greatly reduced, and the environmental pollution is reduced; in addition, the invention also provides a method for preparing eribulin from the intermediates, and the method provided by the invention can obviously improve the total yield of eribulin.

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, a tubulin polymerization inhibitor with a brand-new mechanism of action, is the 1 st single-drug chemotherapeutic agent for patients with metastatic breast cancer to obtain an improvement in total survival, and is developed by the japanese guard pharmaceutical company, and injection is approved by the FDA in the united states for marketing in 11 2010 under the trade name of 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 great application value. The structure is as follows:
kishi et al report a preparation method of eribulin key intermediate C (formula C below), specifically as follows:
in the preparation method, the hydroxyl of the raw material D-gulonolactone is protected by cyclohexanone until the total yield of the synthesized compound B is 19.2%, and the dosage of a chromium reagent in the NHK reaction of the synthesized compound B is usually 400-1600 mol percent, so that the cost is high, the heavy metal pollutes the environment and the heavy metal is difficult to apply in the scale-up production.
Disclosure of Invention
The invention provides a novel preparation method of eribulin and intermediates C and C01a thereof, which has the advantages of high yield, simple operation, controllable quality, higher purity and environmental friendliness, and is suitable for large-scale production and application.
First, the present invention provides a method for preparing compound C01, comprising: condensation reaction is carried out on D-gulonolactone and cyclopentanone to obtain a compound C01:
preferably, the condensation reaction is carried out under the catalysis of Lewis acid, wherein the feeding amount of D-gulonolactone is 1 molar equivalent, and the using amount of Lewis acid is 0.01-0.05 molar equivalent; further preferably, the lewis acid is anhydrous zinc chloride.
In a second aspect of the present invention, there is also provided a process for the preparation of compound C comprising the steps of:
(1) Condensation reaction is carried out on D-gulonolactone and cyclopentanone to obtain a compound C01:
the condensation reaction is carried out under the catalysis of Lewis acid, wherein the feeding amount of D-gulonolactone is 1 molar equivalent, and the using amount of the Lewis acid is 0.01-0.05 molar equivalent;
(2) Reacting compound C01 with DIBALH to convert to compound C02:
(3) Subjecting compound C02 to ring opening reaction under NaHMDS condition, and then reacting with (methoxymethyl) triphenylphosphine chloride to convert into compound C03
(4) Adding compound C03 to the reaction solution, and adding the mixture to the reaction solution at OsO 4 Catalytically, ring closure, conversion to compound C04:
wherein the reaction solvent is 5-7:1 (v/v) of isopropanol and water;
(5) Acetic acid and acetic anhydride are used as reaction solvents, anhydrous zinc chloride is added, so that the hydroxyl of the compound C04 is selectively protected by acetyl, and the compound C05 is converted into the compound C04:
(6) Acetonitrile is used as a reaction solution to lead a compound C05, 3-trimethylsilyl-4-methyl acrylate and BF 3 ·Et 2 O reaction, conversion to compound C06:
(7) Tetrahydrofuran is used as a reaction solvent, and the compound C06 is reacted with benzyltrimethylammonium hydroxide, and the acetyl protecting agent is removed to be converted into the compound C07:
(8) With acetic acidEthyl ester and water are used as reaction solvents, naIO is used 4 As an oxidizing agent, the compound C07 is converted into a compound C08 by an oxidation reaction
(9) Adding a compound C08, niCl into a reaction system by using DMF as a solvent 2 ，CrCl 2 Aluminum chip and trimethylchlorosilane and manganese powder, converting compound C08 to compound C01a:
(10) Suspending the compound C01a in 20% -50% acetic acid aqueous solution, heating to remove hydroxyl protecting groups, and converting into a compound C:
in the above method, preferably, step (1) uses anhydrous zinc chloride as a catalyst; more preferably, D-gulonolactone is condensed with cyclopentanone in a suitable solvent (such as toluene solution) under the catalysis of anhydrous zinc chloride to obtain compound C01; wherein, the feeding amount of the D-gulonolactone is 1 to 1.5 molar equivalents, the consumption of cyclopentanone is 2 to 4 molar equivalents, the consumption of anhydrous zinc chloride is 0.01 to 0.05 molar equivalents, and the reaction temperature is heating reflux;
step (2) adding compound C01 into a proper solvent (such as toluene), then slowly adding DIBALH under cooling, and converting into compound C02 through reduction reaction, wherein the molar ratio of compound C01 to DIBALH is 1:1-2, preferably 1:1.5;
the alkali used in the alkaline condition of the step (3) is NaHMDS; still more preferably, step (3) is to dissolve compound C02 in tetrahydrofuran, add (methoxymethyl) triphenylphosphine chloride, drop-wise add tetrahydrofuran solution of NaHMDS, react, get compound C03, wherein the preferable molar ratio of compound C02 to NaHMDS is 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); osO (o) 4 The dosage of the catalyst is 0.03-0.05 molar equivalent, and the reaction temperature is 0-5 ℃;
step (5) acetic acid and acetic anhydride are used as reaction solvents, anhydrous zinc chloride is added for reaction, and the molar ratio of the compound C04 to the anhydrous zinc chloride is preferably 1:0.5-1;
step (6) using acetonitrile as a reaction solution, adding 3-trimethylsilyl-pent-4-enoic acid methyl ester and BF 3 ·Et 2 O reacts;
step (7) using tetrahydrofuran as a reaction solvent to enable the compound C06 to react with benzyl trimethyl ammonium hydroxide to be converted into a compound C07;
step (8) using ethyl acetate and water as reaction solvents and NaIO 4 Is an oxidizing agent, wherein the compound C07 and NaIO 4 The mol ratio of (2) is 1:08-1.2;
the step (9) is to add NiCl into the reaction system 2 ，CrCl 2 Aluminum scraps, trimethylchlorosilane and manganese powder; more preferably, in the step (9), DMF is taken as a solvent, and the compound C08, niCl is added into the reaction system 2 ，CrCl 2 Stirring aluminum scraps, trimethylchlorosilane, manganese powder and 1-bromo-2-trimethylsilylethylene for reaction to obtain a compound C, wherein NiCl 2 The dosage is 0.01 to 0.05 molar equivalent, crCl 2 The manganese powder is used in an amount of 0.05 to 0.1 molar equivalent, the 1-bromo-2-trimethylsilyl ethylene is used in an amount of 2 to 3 molar equivalents, the aluminum skimmings are used in an amount of 2 to 3 molar equivalents, and the trimethylchlorosilane is used in an amount of 2 to 4 molar equivalents.
On the other hand, the invention also provides a preparation method of eribulin, which comprises the steps of preparing a compound C01 by adopting the method, preparing an intermediate C by taking the compound C01 as an intermediate, and preparing eribulin or mesylate thereof by taking the intermediate C.
Unless otherwise specified, "equivalent" as used herein refers to molar equivalent.
Compared with the prior art, the invention firstly proposes that methyl cyclopentanone is used for replacing cyclohexanone to protect the hydroxyl of raw material D-gulonolactone, lewis acid is used for catalysis, compared with the prior art, the use of chromium reagent is omitted, chromium pollution in the environment is reduced, and the reaction yield of the step of the invention is obviously improved, for example, the yield of the synthetic 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, and particularly when the compound C03 is used for preparing the compound C04, 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) adopts the improved NHK reaction, the assimilating agent manganese powder is added into the reaction system, and NiCl is adopted 2 、CrCl 2 Reducing compound C09 to compound C, aluminum chips and trimethylchlorosilane can significantly improve the reaction yield, and can reduce the chromium reagent amount to 0.1mol% or less.
Fourth, the route provided by the invention is calculated from D-gulonolactone as a starting material, and the total yield of the whole route for preparing the compound C can be improved by about 20% compared with the prior art.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The technical scheme and the preferred embodiments of the present invention are further explained and illustrated below with reference to specific examples.
Example 1 preparation of compound C01:
0.11mol of D-gulonolactone, 0.35mol of p-methylcyclohexanone, 100ml of toluene and 0.03mol of anhydrous zinc chloride are reacted under stirring and refluxing, and after the reaction, the reaction mixture is cooled and washed with 60ml of aqueous sodium bicarbonate solution and 60ml of saturated aqueous sodium chloride solution in sequence. The organic phase is concentrated to remove part of toluene, 200ml of n-heptane is added, heated and refluxed for 2 to 4 hours, cooled to 40 to 50 ℃ and stirred for 2 hours. Filtration and drying gave 34.14g of compound C01.
EXAMPLE 2 preparation of Compound C02
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, the temperature was controlled to not exceed-10℃and stirred for 30 minutes, the reaction solution was added to a potassium sodium tartrate solution, and the mixture was warmed to room temperature and stirred for 4 hours. The layers were separated by filtration, extracted twice with 60ml of ethyl acetate, the organic layers were combined, dried, filtered, and concentrated to give 31g of compound C02.
EXAMPLE 3 preparation of Compound C03
0.1mol of Compound C02 was dissolved in 80ml of tetrahydrofuran, 65g of (methoxymethyl) triphenylphosphine chloride was added thereto, and a solution of 36.5g of NaHMDS in 80ml of tetrahydrofuran was slowly added dropwise thereto at room temperature. After the completion of the dropwise addition, stirring was continued at room temperature, and after the completion of the reaction, 100ml of brine, 100ml of water and 160ml of ethyl acetate were added. The layers were separated by stirring and 100g of 20% sodium hydroxide solution were slowly added to the organic phase under stirring. The organic layer was separated and concentrated to give a crude compound of formula (C03). The crude product was stirred with 160ml of n-heptane and 20g of celite for 1 hour. The mixture was filtered and the filter cake was washed with 180g of n-heptane. The filtrate was concentrated to a solution of 25% methanol 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
0.1mol of compound C03 was dissolved in 80ml of isopropanol and 15ml of water, 20-g N-methylmorpholine N-oxide was added, and the mixture was cooled to 0 to 5 ℃. 1.5ml of OsO was added 4 (0.3M aqueous solution) at 0-5 DEG CThe reaction was stirred down, filtered after the reaction was completed, and the solid was washed with 23ml of acetone/water (1/1, v/v) pre-chilled (0-5 ℃) and dried to give 23.3g of compound C04, d.r. =25:1.
EXAMPLE 5 preparation of Compound C05
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, the reaction was stirred at room temperature, after the completion of the reaction, the reaction solution was added to 250g of ice water, 150ml of ethyl acetate was added under stirring, and the layers were separated. The aqueous layer was re-extracted with 100ml of ethyl acetate. The combined organic layers were washed sequentially with brine, 1% aqueous sodium hydroxide solution and brine. The organic layer was concentrated, the crude concentrate was dissolved with 20% ethyl acetate/n-heptane, filtered through silica gel, the silica gel 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
0.05mol of Compound C05 was dissolved in 300ml of acetonitrile at 0-5℃and 20ml of methyl 3-trimethylsilyl-pent-4-enoate was added, 12ml of BF was added 3 ·Et 2 O, maintaining the temperature at 0-5 ℃, stirring and reacting, 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
0.05mol of Compound C06 was dissolved in 2010ml of tetrahydrofuran at room temperature, 75ml of benzyltrimethylammonium hydroxide was added thereto, and the mixture was stirred until the reaction was completed. The filtrate was filtered, concentrated, the concentrate was dissolved with 50% ethyl acetate/n-heptane, then purified by short silica gel column chromatography (ethyl acetate elution) and the filtrate washed with brine, and the organic phase was concentrated to give 16.8g of compound C07.
EXAMPLE 8 preparation of Compound C08
0.05mol of Compound C07 was dissolved in 100ml of ethyl acetate and 100ml of water at 0-5℃and then 10.7g of NaIO was added in portions 4 The reaction was stirred until the reaction was completed. The mixture was then filtered, the filter cake was washed with ethyl acetate, the layers separated and the aqueous phase extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride, dried and concentrated to give 16.6g of compound C08.
EXAMPLE 9 preparation of Compound C01a
Under the protection of argon, 0.05mol of compound C08 and 0.02mol of Ni Cl are added into a reaction vessel 2 ，0.05molCrCl 2 0.1mol of aluminum scraps, 0.15mol of trimethylchlorosilane and 100ml of DMF, cooling to 0-5 ℃ and stirring for about 30 minutes. 0.15mol of 1-bromo-2-trimethylsilylethylene was added dropwise at room temperature, and after completion of the dropwise addition, 40ml of methanol/water (1/1, v/v) was added and stirred at room temperature until the reaction was completed, followed by stirring for 10 to 20 minutes. 350ml of methyl tert-butyl ether are added and stirring is continued for 10 to 20 minutes, and the reaction mixture is transferred to 500ml of 1N hydrochloric acid and 200ml of water. The layers were separated with stirring, the aqueous layer was back extracted twice with methyl tert-butyl ether, the combined organic layers were washed sequentially with 1% sodium chloride solution and brine, and then the organic layers were dried and concentrated to give 18.7g of compound C01a.
EXAMPLE 10 preparation of Compound C
18.7g of Compound C01a are suspended in 100g of 40% aqueous acetic acid, heated to 80℃and the reaction is stirred until it is over, cooled to room temperature, washed twice with n-heptane and the aqueous layer is collected. Dropwise adding 10% KHCO to the water layer 3 The solution was adjusted to pH 7-7.5, extracted twice with methyl tert-butyl ether, the organic phases were combined, washed with saturated brine, then concentrated, and the residue was dissolved in methyl tert-butyl ether, heated to dissolve, and then 160g of n-heptane was added, dissolved and crystallized, and filtered and dried to give 13g of Compound C.
Methods for preparing eribulin or its mesylate salt from compound C refer to the prior art, including but not limited to the methods disclosed in WO 9965894.
Example 11 influence of different reaction substrates on the preparation of Compound C01a
Referring to the procedure of example 9, compound C01a was prepared according to the following feed ratio:
examples CrCl 2 NiCl 2 Al Me 3 SiCl 2 Mn powder Yield (%)
1 0.1 0.01 0 0 0 0
2 0.2 0.02 2.0 4.5 0 72％
3 0.2 0.04 3.0 3.0 1 87％
4 0.3 0.05 2.3 3.0 3 91％
From the above, it can be seen that when CrCl 2 The feeding amount is 0.05 to 0.1 equivalent, niCl 2 When the feeding amount is 0.01-0.05 equivalent, al and Me 3 SiCl 2 All are necessary for the reaction, and the addition of the manganese powder can obviously improve the reaction yield.

Claims (3)

1. A process for the preparation of compound C comprising the steps of:
(9) Adding a compound C08, niCl into a reaction system by using DMF as a solvent 2 ，CrCl 2 Aluminum turnings and trimethylchlorosilane, converting compound C08 to compound C01a:
wherein NiCl 2 The dosage is 0.02 to 0.05 molar equivalent, crCl 2 0.05 to 0.1 molar equivalent, the aluminum skimmings are 2 to 3 molar equivalents, and the trimethylchlorosilane is 2 to 4 molar equivalents;
(10) Suspending the compound C01a in 20% -50% acetic acid aqueous solution, heating to remove hydroxyl protecting groups, and converting into a compound C:
2. the process according to claim 1, wherein in step (9), 0.05mol of compound C08,0.02mol of NiCl are charged into the reaction vessel under the protection of argon 2 ，0.05molCrCl 2 0.1mol of aluminum scraps, 0.15mol of trimethylchlorosilane, 100ml of DMF, cooling to 0-5 ℃, and stirring for 30 minutes; 0.15mol of 1-bromo-2-trimethylsilylethylene was added dropwise at room temperature, and after the completion of the addition, the mixture was stirred at room temperature until the reaction was completed.
3. A process for the preparation of eribulin or its mesylate salt, characterized in that (1) compound C is prepared using the process of any one of claims 1 to 2 and (2) compound C is used as an intermediate to prepare eribulin or its mesylate salt.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5386019A (en) * 1992-01-15 1995-01-31 Yale University Synthesis of inhibitors of calmodulin-mediated enzymes including KS-501, KS-502 and their enantiomers
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5386019A (en) * 1992-01-15 1995-01-31 Yale University Synthesis of inhibitors of calmodulin-mediated enzymes including KS-501, KS-502 and their enantiomers
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
路易斯酸盐ZnCl_2催化合成缩醛(酮)的研究;梁学正等;《化工时刊》;实验部分 *

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