Intermediates for the production of halichondrin compounds and their production method

Abstract

The present invention relates to intermediates used in the preparation of halichondrin compounds, and methods for their preparation and use, particularly to intermediates used in the preparation of halichondrin, eribulin, or analogs thereof, and methods for their preparation and use. The intermediates, their preparation, and use are used to construct the C20-C26 structural fragment of halichondrin compounds. The starting materials for the synthetic pathway of the present invention are inexpensive and readily available, of stable origin and of reliable quality. The selection of chiral center construction methods utilizes the structural features of the reactants themselves, ensuring improved synthetic efficiency, reducing the difficulties and risks involved in product quality control, and avoiding the use of highly toxic and expensive organotin catalysts, resulting in significant improvements in cost and environmental friendliness.

Description

Detailed Description of the Invention

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on December 10, 2018, bearing application number 2018115084811 and entitled "Intermediates for the preparation of halichondrin compounds and preparation method thereof," the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present invention relates to intermediate compounds used in the preparation of halichondrins or analogs thereof, particularly eribulin, and methods for preparing these intermediate compounds, which belong to the field of organic synthesis.

[0003] [Background technology] Halichondrin (hereinafter referred to as HB) is a natural product with a polyether macrolide structure present in sponges, which has strong antitumor effects and broad medical prospects. Based on their structural differences, these natural products are classified into norhalichondrin, halichondrin, homohalichondrin, etc., and each class has a series of representative subtypes, the subtypes and their specific structures are known in the art and are disclosed in detail in WO2016003975A1, which is incorporated by reference in its entirety. Eribulin (hereinafter referred to as EB) is a structurally simplified analogue of halichondrin, which is currently used clinically to treat late-stage breast cancer and liposarcoma.

[0004] [ka]

[0005] Both HB and EB cannot be obtained in large quantities from natural sources, and can only be obtained by artificial synthesis. These compounds have similar structures, particularly the C1-C29 portions have the same structure, so intermediate compounds suitable for synthesizing these compounds can be used. For example, the intermediates shown in the following formula 1a and formula 4 can be used to construct the C20-C35 fragment of eribulin.

[0006] [ka]

[0007] Moreover, the intermediates shown in the following formula 1b and formula 6 are used for constructing the C20-C35 fragment portion of eribulin.

[0008] [ka]

[0009] However, the prior art methods for preparing the compounds of formula 4 or formula 6 have many shortcomings, such as the lengthy synthesis route, the difficulty in controlling the optical purity of the starting material, and the high toxicity and expensive n-Bu3S. n It involves the use of H reagents and has defects such as low stereoselectivity. These defects bring about a series of production problems in terms of cost control, environmental and labor protection, product quality, etc. Therefore, in order to improve the production method of halichondrin drug compounds, it is urgent to develop intermediates or synthesis methods that improve synthesis efficiency, improve production costs, facilitate industrial mass production, improve selectivity, yield and purity, and are environmentally friendly.

[0010] Detailed Description of the Invention In order to solve the above-mentioned problems, the present invention provides the following halichondrin and its analogues, in particular intermediates for constructing the C20-C26 structural fragment of eribulin and a method for producing the same.

[0011] The first aspect of the present invention is A method for producing a compound represented by the following formula (8):

[0012] [ka]

[0013] (wherein R1 is a hydroxyl protecting group, R2 and R3 are the same or different and independently represent H and OR a are selected from R a are independently H, C 1-10 Alkyl, R b Selected from SO2, R b is C 1-10 alkyl, or R2 and R3 are both OR a And two R a Combined to form C 1-6 or R2 and R3 together with the carbon bonded thereto form a carbonyl group; X is selected from halogen and sulfonyloxy groups; Illustratively, R1 is selected from monosilane-based hydroxyl protecting groups, such as TMS, TES, TBDMS, TBDPS, DIPS, DPS, TIPDS, and the like.

[0014] As an example, one of R2 and R3 is selected from H, and the other is OR a and R a is H or i-PrSO2, or R2 and R3 are both OR a And two R a are bonded to form n-propylene, or R2 and R3 are bonded to the carbon to form a carbonyl group, Illustratively, X is selected from chlorine, bromine, iodine, etc. The method comprises the steps of:

[0015] [ka]

[0016] (wherein, R5 in formula (2) is a silyl group, for example, selected from TMS, TES, TBDMS, TBDPS, DIPS, DPS, TIPDS, etc.; the oxazolidinone structure portion in formulas (1)-(2) is an oxazolidinone-based chiral auxiliary, for example, R4 is C 1-10 R4 is an alkyl, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted benzyl group. Preferably, R4 is an isopropyl group, an unsubstituted or mono- or multiply substituted phenyl group or a benzyl group with a hydroxy group, a nitro group, or a dimethylamino group. Preferably, the method for producing the compound represented by formula (8) further comprises a step of recrystallizing formula (2) once, twice or a plurality of times.

[0017] According to the present invention, the formula (2) is produced by reacting the formula (1) with a Grignard reagent R6MgX or R6Li, and R6 is

[0018] [ka]

[0019] It is.

[0020] According to the present invention, the reaction is carried out in the presence of a cuprous salt, such as cuprous chloride, cuprous bromide, cuprous iodide (CuI), or cuprous cyanide, in an inert atmosphere in a solvent at −50° C. to 0° C. The solvent may be tetrahydrofuran or anhydrous diethyl ether, and the amount (mass) of the cuprous salt used is about 10-25% of the reactant, formula (1), and preferably 15-20%.

[0021] According to the present invention, after producing formula (2) from formula (1), the content of its optical isomers can be reduced by recrystallizing formula (2). The solvent for the recrystallization may be any solvent that dissolves formula (2) at room temperature or a slightly higher temperature and crystallizes it at a lower temperature (e.g., −10 to −30° C.), and examples of the solvent include non-polar organic solvents, preferably alkanes such as n-pentane, n-hexane, n-heptane, isooctane, or mixtures thereof such as petroleum ether.

[0022] Preferably, the recrystallization may be repeated multiple times. By performing recrystallization once, the content of the isomer represented by formula (2) of the present invention can be controlled to 1% or less, by performing recrystallization twice, the content of the isomer can be controlled to 1‰ or less, and by performing recrystallization multiple times, the content of the isomer can be controlled to a lower range. It will be understood by those skilled in the art that the configuration of the chiral carbon atom bonded to the β-methyl group of formula (2) of the present invention does not change even in the subsequent conversion process, so that the purity related to the configuration of the chiral carbon is maintained.

[0023] According to the present invention, the method for producing a Grignard reagent comprises the steps of: Vinylsilane

[0024] [ka]

[0025] and a halogenating reagent at a relatively low temperature (e.g., −30 to −10° C.), add an acid binder at room temperature, and reflux to obtain a halogenated vinylsilane. Examples of the acid binder include organic or inorganic weak bases such as diethylamine, ethylenediamine, triethylamine, diisopropylamine, pyridine, potassium carbonate, sodium carbonate, and cesium carbonate.

[0026] The vinylsilane halide is reacted with metallic magnesium or metallic lithium in an aprotic solvent to produce the corresponding Grignard or lithium reagent. The aprotic solvent may be an ether solvent such as diethyl ether, diisopropyl ether, t-butyl methyl ether, cyclohexyl methyl ether, tetrahydrofuran, or dioxane, or a hydrocarbon solvent such as n-pentane, n-hexane, n-heptane, benzene, toluene, or xylene.

[0027] Alternatively, the vinyl halide silane can undergo a metal-halogen exchange reaction in the solvent with other readily available Grignard reagents, such as methyl, ethyl, n-propyl, isopropyl Grignard reagents, or readily available alkyllithium reagents, such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, to produce the corresponding Grignard or lithium reagent.

[0028] The method for producing the compound represented by the formula (8) in the present invention further includes a step of producing the compound represented by the formula (3) from the following formula (2).

[0029] [ka]

[0030] (In the formula (3), X is halogen or sulfonyloxy.) According to the present invention, the reaction is a halogenation reaction known to those skilled in the art, and is carried out in a suitable solvent at a mild reaction temperature, for example, from 0° C. to room temperature. The halogenation reagents used are X2, RCO2X, R n Six 4-n wherein X is a halogen selected from chlorine, bromine, and iodine, and the two Xs in X2 may be different; R is C 1-10 Alkyl or Fluorine Substituted C 1-10alkyl, and n is an integer of 1 to 3. Examples of the halogenating reagent include chlorine, bromine, and iodine, BrCl, ICl, TMSCl, TMSI, and CF3CO2I.

[0031] Alternatively, the process of the present invention further comprises the step of converting a compound of formula (3) where X is a halogen to a compound of formula (3) where X is a sulfonyloxy by substitution reactions known in the art.

[0032] The method for producing the compound represented by formula (8) of the present invention further comprises the step of producing the compound represented by formula (1) from an oxazolidinone-based chiral auxiliary and a corresponding acyl compound.

[0033] [ka]

[0034] According to the present invention, the reaction is carried out under basic, low temperature conditions (-80°C to -20°C), and the reaction may optionally use catalytic amounts of lithium chloride and a solvent. The base is one or more selected from organic bases, inorganic bases or mixtures thereof, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, triethylamine, pyridine, piperidine, and n-butyl lithium (n-BuLi). The solvent is, for example, tetrahydrofuran, N,N-dimethylformamide (DMF), dichloroethane, diethyl ether, carbon tetrachloride, toluene, etc., and the acyl compound may be an ester, a carboxylic acid, an acid halide, or an acid anhydride. According to one embodiment of the present invention, the oxazolidinone chiral auxiliary is reacted with an acid halide at -80 to -60°C in tetrahydrofuran under argon protection and in the presence of n-butyllithium, the amount of n-butyllithium used being about 30-50% by mass of the oxazolidinone; or the oxazolidinone chiral auxiliary is reacted with an acid anhydride at -30 to -20°C in tetrahydrofuran in the presence of lithium chloride and triethylamine, the amount of lithium chloride used being about 35%-55% by mass of the oxazolidinone.

[0035] The method for producing the compound represented by the formula (8) of the present invention further includes a step of producing the compound represented by the formula (4) from the following formula (3).

[0036] [ka]

[0037] The reaction is carried out under conditions that allow the oxazolidinone chiral auxiliary to be eliminated and separated, preferably by hydrolysis under basic conditions.

[0038] According to the present invention, the reaction can be carried out at -15 to 5°C under basic conditions, in a solvent medium and optionally in the presence of hydrogen peroxide. The reaction temperature is -10 to 0°C, preferably -5 to 0°C. The base is one or more selected from an organic base, an inorganic base or a mixture thereof, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium hydroxide, potassium hydroxide, calcium hydroxide, aqueous ammonia, sodium acetate, triethylamine, pyridine, and piperidine. The solvent is a mixed solvent consisting of water and one or more selected from an alcoholic or etheric solvent, such as tetrahydrofuran (THF) or dioxane, and acetone, and the ratio (volume ratio) of water to the organic solvent in the mixed solvent may be about 1:1 to about 1:6, and is preferably about 1:2 to 1:3. According to one embodiment of the present invention, the reaction is carried out in a mixed solvent of tetrahydrofuran and water at −5 to 0° C. in the presence of lithium hydroxide monohydrate and hydrogen peroxide, and the mass ratio of the compound represented by formula (3), hydrogen peroxide, and lithium hydroxide monohydrate is 12-20:3-9:1-6.

[0039] The method for producing the compound represented by the formula (8) of the present invention further comprises the step of producing the compound represented by the formula (5) from the compound represented by the formula (4).

[0040] [ka]

[0041] According to the present invention, the reaction is carried out in the presence of a coupling agent, which may be EDCI / DMAP, EDC / DMAP, EDC / NHS, DCC / NHS system, and the reaction is carried out at 15-40° C., preferably at room temperature (20-25° C.), and the reaction solvent may be dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF), etc.

[0042] The method for producing the compound represented by the formula (8) of the present invention further comprises the step of producing the compound represented by the formula (6) from the compound represented by the formula (5) and an aldehyde.

[0043] [ka]

[0044] According to the present invention, the reaction is carried out in the presence of titanium tetrachloride (TiCl4) and triethylamine (TEA) under the protection of an inert atmosphere at a relatively low temperature of -10 to 10°C, preferably 0°C, and the reaction solvent may be dichloromethane (DCM) or the like.

[0045] According to the present invention, the method for producing an aldehyde comprises the steps of: Butanediol and R n Six 4-n in the presence of a coupling agent to obtain a monohydroxy protected product, X is a halogen selected from chlorine, bromine, and iodine, and R is C 1-10 Alkyl or Fluorine Substituted C 1-10 alkyl, and n is an integer from 1 to 3. n Six 4-n Examples of the above may be TMSCl, TMSI, TBDPSCl, TBDPSI, etc. The coupling agent may be EDCI / DMAP, EDC / DMAP, EDC / NHS, DCC / NHS system, and the reaction is carried out at 15-40° C., preferably at room temperature (20-25° C.). The reaction solvent may be dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF), etc. Step (I); A step (II) of oxidizing the product of step (I), The oxidation includes a step (II) which is any process for oxidizing an alcohol to an aldehyde or ketone as described below.

[0046] The method for producing the compound represented by the formula (8) of the present invention further comprises the step of producing the compound represented by the formula (7) from the compound represented by the formula (6).

[0047] [ka]

[0048] According to the present invention, the oxidation can be any method known to those skilled in the art that can oxidize alcohol to an aldehyde or ketone, such as Swern oxidation, Pfitzner-Moffatt oxidation, and Albright-Goldman oxidation. According to one embodiment of the present invention, the oxidation employs the Parikh-Doering oxidation method in which dimethylsulfoxide (DMSO) and sulfur trioxide-pyridine complex (SO3·py) are reacted with alcohol under basic conditions at -15 to 25°C. The base can be triethylamine or N,N-diisopropylethylamine (DIPEA), the reaction temperature is preferably 0°C to room temperature (room temperature is 20-25°C), and the reaction can be performed by adding a solvent according to the amount of DMSO added. A small amount of DMSO requires the use of a large amount of solvent, and a large amount of DMSO requires the use of less or no solvent. The solvent can be, for example, dichloromethane, tetrahydrofuran, chloroform, etc.

[0049] The method for producing the compound represented by the formula (8) in the present invention further includes a step of hydrolyzing the compound represented by the formula (7) to obtain the compound represented by the formula (8) in which "R2 and R3 form a carbonyl together with the carbon to which they are bonded."

[0050] According to the present invention, the hydrolysis reaction is carried out in a solvent medium under basic conditions at 15-40°C. The reaction temperature may be room temperature (20-25°C), and the base is one or more selected from an organic base, an inorganic base, or a mixture thereof, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium hydroxide, lithium hydroxide hydrate, sodium hydroxide, potassium hydroxide, calcium hydroxide, aqueous ammonia, sodium acetate, triethylamine, pyridine, and piperidine. The solvent is a mixed solvent consisting of water and one or more selected from an alcoholic or etheric solvent, such as tetrahydrofuran (THF) or dioxane, and acetone, and the ratio (volume ratio) of water to organic solvent in the mixed solvent may be about 1:1 to about 1:6, and is preferably about 1:4. According to one embodiment of the present invention, the hydrolysis reaction is carried out at room temperature in a mixed solvent of tetrahydrofuran and water in the presence of lithium hydroxide monohydrate.

[0051] According to the method for producing the compound represented by the formula (8) of the present invention, there is provided a process for obtaining the compound represented by the formula (8) from the compound represented by the formula (6), in which "R2 and R3 are the same or different and independently represent H and OR a are selected from R a are independently H, C 1-10 Alkyl, R b Selected from SO2, R b is C 1-10 The reaction may be a hydroxyalkylation or sulfonylation reaction known in the art.

[0052] According to the method for producing the compound represented by the formula (8) of the present invention, it is possible to arbitrarily select "R2 and R3 from the formula (8) in which R2 and R3 form a carbonyl group with the carbon bonded thereto, and R2 and R3 are both OR a And two R a Combined to form C 1-6The reaction includes a step of preparing a ketal of formula (8) in which a ketone is reacted with a corresponding glycol such as ethylene glycol or propylene glycol in the presence of p-toluenesulfonic acid as a catalyst and benzene, toluene, or the like as a water-carrying agent to obtain the ketal.

[0053] According to the present invention, the formula (8) is a C of halichondrin, particularly eribulin or a pharma- ceutically acceptable salt thereof. 20 -C 26 It is an intermediate for constructing structural fragments.

[0054] A second aspect of the present invention provides a compound represented by the following formula (2) and a method for producing the same.

[0055] [ka]

[0056] (wherein R4 and R5 are as defined above.) The method for producing the compound represented by formula (2) includes a step of producing the compound represented by formula (2) from the compound represented by formula (1).

[0057] According to the present invention, the process for preparing the compound represented by formula (2) further comprises the step of recrystallizing once, twice or multiple times.

[0058] According to the present invention, the method for producing the compound represented by the formula (2) further comprises the step of producing the compound represented by the formula (1) from an oxazolidinone-based chiral auxiliary and a corresponding acyl compound.

[0059] A third aspect of the present invention provides a compound represented by the following formula (3) and a method for producing the same.

[0060] [ka]

[0061] (wherein, R4 and X are as defined above.) The method for producing the compound represented by formula (3) includes the step of producing the compound represented by formula (3) from the compound represented by formula (2) described above.

[0062] According to the present invention, the method further comprises a method for producing the compound represented by formula (2), preferably further comprising a step of recrystallizing the compound represented by formula (2) once, twice or multiple times.

[0063] Preferably, the method further comprises the step of preparing the compound of formula (1) from an oxazolidinone-based chiral auxiliary and a corresponding acyl compound.

[0064] A fourth aspect of the present invention provides a compound represented by the following formula (7) and a method for producing the same.

[0065] [ka]

[0066] (wherein R1 is a hydroxy protecting group.

[0067] R2 and R3 are the same or different and independently represent H and OR a are selected from R a are independently H, C 1-10 Alkyl, R b Selected from SO2, R b is C 1-10 alkyl, or R2 and R3 are both OR a And two R a Combined to form C 1-6 or R2 and R3 together with the carbon bonded thereto form a carbonyl group; X is selected from the group consisting of halogen and sulfonyloxy. Preferably, R1 is a monosilane based hydroxy protecting group, such as TMS, TES, TBDMS, TBDPS, DIPS, DPS, TIPDS, and the like.

[0068] One of R2 and R3 is selected from H, and the other is OR a and R a is H or i-PrSO2, or R2 and R3 are both OR a And two R a are bonded to form n-propylene, or R2 and R3 form a carbonyl group with the carbon to which they are bonded, X is selected from chlorine, bromine, iodine, and the like.

[0069] The method for producing the compound represented by the formula (7) includes the following steps:

[0070] Method 1: Formula (7) in which R2 and R3 form a carbonyl group with the carbon to which they are attached can be oxidized from formula (7) in which R2 and R3 are H and OH, respectively.

[0071] [ka]

[0072] According to the present invention, the oxidation is any method known to those skilled in the art that can oxidize an alcohol to an aldehyde or ketone, such as Swern oxidation, Pfitzner-Moffatt oxidation, and Albright-Goldman oxidation. According to one embodiment of the present invention, the oxidation employs the Parikh-Doering oxidation method in which dimethylsulfoxide (DMSO) and sulfur trioxide-pyridine complex (SO3·py) are reacted with an alcohol under basic conditions at -15 to 25°C. The base may be triethylamine or N,N-diisopropylethylamine (DIPEA), the reaction temperature is preferably 0°C to room temperature (20-25°C), and the reaction may optionally include a solvent depending on the amount of DMSO added, but a small amount of DMSO requires the use of a large amount of solvent, and a large amount of DMSO requires the use of less or no solvent, and the solvent may be, for example, dichloromethane, tetrahydrofuran, chloroform, etc.

[0073] Method 2: The compound (7) in which R2 and R3 are H and OH, respectively, can be prepared from the compound (5) of the following formula:

[0074] [ka]

[0075] According to the present invention, the reaction is carried out in the presence of titanium tetrachloride (TiCl4) and triethylamine (TEA) under the protection of an inert atmosphere at a relatively low temperature of -10 to 10°C, preferably 0°C, and the reaction solvent may be dichloromethane (DCM) or the like.

[0076] Compounds in which R2 and R3 in formula (7) are otherwise defined can be prepared by any method known in the art, such as substitution or condensation, in which R2 and R3 form a carbonyl together with the carbon to which they are attached, or ... 2 , R 3 can be prepared from a compound of formula (7) in which

[0077] The fifth aspect of the present invention further provides the use of the compounds of formula (2), (3) and (7) for preparing halichondrins, particularly eribulin, pharma- ceutically acceptable salts and analogs thereof. Specifically, the compounds of formula (2), (3) and (7) are used for preparing the compounds of formula (8), which are intermediates for constructing the C20-C26 structural fragment of halichondrins, particularly eribulin.

[0078] A sixth aspect of the present invention provides a method for producing a compound of formula (8) comprising the following steps:

[0079] [ka]

[0080] The method for producing the compound represented by formula (8) in the present invention is as follows: Preferably, the method further includes a step of producing a compound of formula (7) below, in which R2 and R3 are H and OH, respectively, by oxidation reaction, in which R2 and R3 form a carbonyl group with the carbon bonded thereto.

[0081] [ka]

[0082] Preferably, the method further includes a step of producing a compound represented by formula (7) in which R2 and R3 are H and OH, respectively, from the compounds represented by formulas (5) and (6).

[0083] [ka]

[0084] Preferably, the method further comprises the step of producing the compound represented by formula (5) from formula (4).

[0085] Preferably, the method further comprises the step of producing the compounds represented by the above-mentioned formula (3) to formula (4).

[0086] Preferably, the method further comprises the step of producing the compounds represented by the above-mentioned formula (2) to formula (3).

[0087] Preferably, the method further comprises the step of producing the compound represented by formula (2) from the above-mentioned formula (1).

[0088] Preferably, the method further comprises the step of recrystallizing formula (2) one, two or more times.

[0089] Preferably, the method further comprises the step of producing the compound represented by formula (1) from the above-mentioned oxazolidinone chiral auxiliary.

[0090] A seventh aspect of the present invention provides a method for producing a halichondrin, eribulin, an analogue thereof or a pharma- ceutically acceptable salt thereof, or a C20-C26 moiety thereof, comprising using an oxazolidinone chiral auxiliary, any of the compounds of Formulae (1)-(7), and / or any of the production methods of one or more of Formulae (1)-(8).

[0091] The present invention further provides the use of the oxazolidinone chiral auxiliary, any of the compounds of formula (1) to (7), for the preparation of halichondrin, eribulin, an analogue thereof or a C20-C26 moiety thereof.

[0092] The symbols, group definitions, and reaction conditions of the above compounds of the present invention have the same definitions or meanings as those described above, except as listed.

[0093] Terms and Definitions Unless otherwise defined, all technical terms in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise specified, all patents, patent applications, and disclosed materials cited in this specification are incorporated herein by reference in their entirety.

[0094] For the numerical ranges described in the specification and claims of the present invention, when the numerical range is understood as an "integer", it is understood that the two end points of the range and each integer within the range are recited. For example, "0-10 integers" is understood to describe the integers 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. When the numerical range is understood as a "number", it is understood to describe the two end points of the range, each integer within the range, and each decimal within the range. For example, "1-10 numbers" is understood to describe the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, as well as the sum of each integer and at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9.

[0095] The term "halichondrin, analogs thereof" should be understood to mean those having a polyether macrolide structure and having a C20-C26 structural fragment of eribulin, such as eribulin, norhalichondrin AC, halichondrin BC, homohalichondrin AC, or pharmaceutically acceptable salts thereof, such as salts formed with pharmaceutically acceptable acids, such as methanesulfonates, e.g., eribulin methanesulfonate.

[0096] The term “C 1~10 "Alkyl" is to be understood as denoting a linear or branched, saturated monovalent hydrocarbon radical, preferably having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Said alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or isomers thereof. Particularly preferably, said radicals are those having 1, 2, 3, 4, 5 or 6 carbon atoms ("C 1~6 alkyl), such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more preferably those groups having 1, 2 or 3 carbon atoms ("C 1~3 alkyl"), for example, methyl, ethyl, n-propyl or isopropyl.

[0097] The term “C 1~6"Alkylene" should be understood to represent a linear or branched saturated divalent hydrocarbon radical, preferably having 1, 2, 3, 4, 5 or 6 carbon atoms, for example methylene, ethylene, n-propylene, isopropylene.

[0098] The term "hydroxyl protecting group" refers to any group capable of protecting the oxygen atom to which it is attached from reacting or binding. These hydroxyl protecting groups are known in the art. Exemplary hydroxyl protecting groups include, but are not limited to, acyl, ester, carbonate, urethane, sulfonate, and ether groups.

[0099] Illustrative ether groups, as defined herein, are hydroxyl protecting groups, such as C 1~12 Alkyl (e.g., C 1~8 , C 1~6 , C 1~4 , C 2~7 , C 3~12 and C 3~6 alkyl), and silyl systems (e.g., tris(C 1-6 Alkyl)silyl, tris(C 6-10 Aryl or C 1-6 Heteroaryl)silyl, bis(C 6-10 Aryl or C 1-6 Heteroaryl)(C 1-6 Alkyl)silyl and (C 6-10 Aryl or C 1-6 Heteroaryl)bis(C 1-6 Specific examples of alkyl include methyl and tert-butyl, and specific examples of silyl include trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS) and triphenylsilyl (TPS) ethers, TBDMS, DIPS, DPS, TIPDS, and the like.

[0100] The hydroxyl protecting group as defined above may be deprotected using a removing agent. The hydroxyl protecting group removing agent is a reagent that reacts with a compound having a protected hydroxyl to provide a compound having a deprotected hydroxyl group. Hydroxyl protecting group removing agents and deprotection reaction conditions are known in the art. As a non-limiting example, a hydroxyl group masked as a silyl ether can be unmasked by reaction with a fluoride source (e.g., a fluoride salt, such as KF or TBAF). Alternatively, a hydroxyl protected as a TMS or TES ether can be deprotected by reaction with a Bronsted acid (e.g., a carboxylic acid). As another non-limiting example, a hydroxyl protected as an ester can be unmasked by reaction with a fluoride source (e.g., a fluoride salt, such as KF or TBAF). 1~6 Alkoxides (e.g., alkali metal C 1~6 Alkoxide or alkaline earth metal C 1~6 As another non-limiting example, a hydroxyl protected as an arylalkyl ether (e.g., 1-arylalkyl-1-yl ether) can be deprotected using a reduction reaction (e.g., reaction with Pd / C and H2, or reaction with Na / NH3). Alternatively, a hydroxyl protected as an alkoxy-arylalkyl ether (e.g., MPM ether) can be deprotected by reaction with 2,3-dichloro-5,6-dicyanyl-1,4-benzoquinone (DDQ). As another non-limiting example, a hydroxyl protected as an alkoxyalkyl ether (e.g., 1-alkoxyalkyl-1-yl) or THP ether can be deprotected by reaction with a Bronsted acid. Cyclically protected diols (e.g., acetals or ketals (e.g., 2-alkyl-1,3-dioxolane, 2,2-dialkyl-1,3-dioxolane, 2-alkyl-1,3-dioxane or 2,2-dialkyl-1,3-dioxane)) can be deprotected by reaction with a Bronsted acid (e.g., a carboxylic acid).

[0101] The sulfonyloxy group in the present invention is an alkylsulfonyloxy group (e.g., C 1-10 Alkyl groups), alkenylsulfonyloxy groups (e.g., C 2-10 Examples of the sulfonyloxy group include, but are not limited to, a methanesulfonyloxy group, a toluenesulfonyloxy group (e.g., a p-toluenesulfonyloxy group), a trifluoromethanesulfonyloxy group, a nitrobenzenesulfonyloxy group (o-, p-nitrobenzenesulfonyloxy group), and a bromobenzenesulfonyloxy group (o-, p-bromobenzenesulfonyloxy group).

[0102] The silyl group in the present invention is tri(C 1-6 Alkyl)silyl, tri(C 6-10 Phenyl or C 6-10 Heteroaryl)silyl, di(C 6-10 Phenyl or C 6-10 Heteroaryl)(C 1-6 Alkyl)silyl and (C 6-10 Phenyl or C 6-10 Heteroaryl)di(C 1-6 Examples of silyl include, but are not limited to, trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS) and triphenylsilyl (TPS) ethers, TBDMS, DIPS, DPS, TIPDS, etc.

[0103] Suitable phenyl or benzyl substituents in the present invention include halogen (fluorine, chlorine, bromine, iodine), C1-10 alkyl, C1-10 alkoxy, hydroxyl, nitro, amino, one or two C 1-10 Alkyl-substituted amino groups, SO3H, SO3C 1-10 Examples include, but are not limited to, alkyl.

[0104] The base in the present invention may be an organic base, an inorganic base or a mixture thereof, for example, as an alkali metal or alkaline earth metal carbonate or bicarbonate, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, as an alkali metal alkoxide, such as sodium tert-butoxide or potassium tert-butoxide, as an organolithium, such as butyllithium or phenyllithium, as an alkali metal hydride, such as sodium hydride, Examples of the ammonia compound include, for example, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or lithium diisopropylamide (LDA). Examples of the organic amine include, for example, triethylamine, N-methylmorpholine, piperidine, N-methylpiperidine, N,N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), pyridine, or 4-dimethylaminopyridine (DMAP).

[0105] The acid according to the present invention may be an organic acid, an inorganic acid or a mixture thereof, for example one or more selected from carboxylic acids such as acetic acid or trifluoroacetic acid, sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, phosphonic acids, hydrochloric acid, sulfuric acid, phosphoric acid, etc. Said acids further include Lewis acids. Examples of the Lewis acid include BF3·OEt2, MgCl2, MgBr2, ZnBr2, ZnI2, ZnCl2, ZnSO4, CuCl2, CuCl, Cu(O3SCF3)2, CoCl2, CoI2, FeI2, FeCl3, FeCl2, FeCl2, SnCl4, TiCl4, TiCl3, MnCl2, ScCl3, AlCl3, (i-C4H9)2AlCl, (C6H5)2AlCl, (C6H5)AlCl2, ReCl5, ZrCl4, NbCl5, VCl3, CrCl2, and MoCl5. , YCl3, CdCl2, LaCl3, Er(O3SCF3)3, Yb(O2CCF3)3, SmCl3, B(C6H5)3, TaCl5 or trimethylsilyl trifluoromethanesulfonate, and specific examples thereof include one or more selected from BF3·OEt2, MgCl2, ZnCl2, MgBr2, ZnBr2, AlCl3, SnCl4, TiCl4 or trimethylsilyl trifluoromethanesulfonate.

[0106] The solvents described in the present invention may comprise one or more of water, ketone solvents such as acetone and methyl ethyl ketone, ether solvents including acyclic ethers and cyclic ethers such as diethyl ether, tetrahydrofuran, dioxane, ester solvents such as ethyl acetate or butyl acetate, alkane solvents such as n-hexane or n-heptane, haloalkane solvents such as methyl chloride, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cycloalkane solvents such as cyclohexane or cycloheptane, substituted or unsubstituted aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or other solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), acetonitrile or pyridine. Preferably, the solvent is selected from inert solvents that do not react with the reaction substrate and the catalyst. Illustratively, the inert solvent may be one or more of alcohol solvents (e.g., methanol, ethanol), ether solvents (e.g., diethyl ether, tetrahydrofuran, dioxane), haloalkane solvents (e.g., dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane), and substituted or unsubstituted aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene).

[0107] Unless otherwise specified, the solvents in the present invention are anhydrous solvents.

[0108] beneficial effect The present invention provides intermediates for the synthesis of halichondrin, eribulin or analogs thereof, particularly the C20-C26 structural fragment portion thereof, as well as their preparation and use. The starting materials for the synthesis pathway of the present invention are inexpensive and easily available, and the compounds represented by formula (2) and formula (3) are both crystalline, and the purity of the product can be easily increased by recrystallization purification. In particular, after the compound represented by formula (2) is recrystallized twice, an optical purity of over 99.9% is obtained, and the configuration of the chiral carbon atom bonded to the β-methyl group of the compound does not change in the subsequent process, so that the optical purity of C20-C26 of halichondrin, eribulin or analogs thereof can be guaranteed. Therefore, the method for constructing the chiral center of the C20-26 structural fragment of the present invention has relatively high diastereomeric selectivity and yield, and by-products can be removed by a simple method such as recrystallization. In this method, all steps, especially the step of producing the compound represented by formula (8) from the compound represented by formula (7), are carried out under mild reaction conditions at relatively low temperatures, so that the loss of the product due to thermal decomposition caused by high temperature heating can be avoided. The products of the production method of the present invention, especially the products of the initial steps, are all crystalline solids, and are easy to purify and refine. Due to the above advantages, the method of the present invention is low cost, has high yield and high purity, and is easy to purify, and is therefore more suitable for industrial mass production.

[0109] Description of the drawings FIG. 1 is a diagram showing the synthesis route of Example 1 of the present invention.

[0110] [Mode for carrying out the invention] The above-mentioned features and other features and advantages of the present invention will be explained in more detail and illustrated by the description of the embodiments of the present invention. It should be understood that the following embodiments are intended to illustrate the scope of the present invention, and are not intended to limit the scope of the present invention, which is defined by the claims and their equivalents.

[0111] Unless otherwise stated, materials and reagents herein are either commercially available or can be prepared by one of skill in the art in light of the prior art.

[0112] The starting materials, reagents, intermediates, target compounds or reaction schemes in the following examples are exemplary configurations of the compounds shown in the above-mentioned general formula or their reactions, and it should be understood that one or more specific compounds or specific reaction schemes can be combined with the above-mentioned general embodiments of the present invention, and the configurations obtained by combination are the configurations described in this specification.

[0113] Unless otherwise stated, in the following examples, yields are calculated based on product purity of 99.5% or greater.

[0114] Example 1: Preparation method 1 of compound 8 (see FIG. 1) 1.1 Preparation of compound 1 Method one (s)-4-phenyl-2-oxazolidinone (15.6g) was added to a 500ml three-neck flask, and dry THF (200ml) was added to dissolve it. The mixture was replaced with argon gas and protected with argon gas. The reaction solution was then cooled to -78°C, and a THF solution of n-BuLi (2.5M, 38ml) (maintained at an internal temperature of ≦-60°C) was added dropwise. After the addition was completed, the mixture was reacted for 15min while maintaining at -78°C, and crotonic acid chloride (10g) was added dropwise. After the addition was completed, the mixture was reacted for 30min while maintaining at -78°C, and the mixture was then heated to 0°C and reacted for 1.5h. After confirming the completion of the reaction by TLC, the mixture was quenched by slowly adding a saturated ammonium chloride solution, and the mixture was stirred well until the solid disappeared, and the layers were clearly separated. The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed once with a saturated sodium chloride solution. The organic phase was dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Ethyl acetate (100 ml) was added to the concentrate obtained, and the mixture was dissolved by heating under reflux, and n-hexane (500 ml) was added, cooled, and stirred to crystallize. Filtration gave 17.7 g of a white solid product with a yield of 80%.

[0115] Method two: (s)-4-phenyl-2-oxazolidinone (60 g) was added to a 2000 ml three-neck flask, and general (reagent grade without anhydrous treatment) THF (1200 ml) was added to dissolve it. LiCl (26.4 g) and TEA (91.2 ml) were added at room temperature, and crotonic anhydride (82.2 ml) was slowly added dropwise, maintaining the internal temperature at ≦25°C. After the dropwise addition was completed, the reaction was carried out for 3 hours while maintaining room temperature. After confirming the disappearance of the raw material (s)-4-phenyl-2-oxazolidinone by TLC monitoring, water (800 ml) was added, the solid was dissolved in the reaction liquid, the liquid was separated, the aqueous layer was extracted twice with ethyl acetate, the organic phase was combined, and washed once with saturated sodium chloride solution. Anhydrous sodium sulfate was added to the organic phase to dry it, filtered, and the filtrate was concentrated. The concentrate was dissolved in ethyl acetate (400 ml) by heating under reflux, and then n-hexane (2000 ml) was added, cooled, and stirred to crystallize. After filtration, 72 g of a white solid product was obtained with a yield of 85%.

[0116] 1H NMR (400 MHz, ) δ 7.44 - 7.23 (m, 6H), 7.21 - 6.96 (m, 1H), 5.47 (dd, J = 8.7, 3.9 Hz, 1H), 4.68 (t, J = 8.8 Hz, 1H), 4.26 (dd, J = 8.9, 3.9 Hz, 1H), 1.92 (dd, J = 6.9, 1.6 Hz, 3H). 1.2 Preparation of compound 2 1) Preparation of (1-bromovinyl)trimethylsilane Vinyltrimethylsilane (100g) was added to a 2000ml three-neck flask, cooled to -35℃ to -30℃, and bromine water was slowly added dropwise. During the dropwise addition, heat was generated vigorously, and the internal temperature was kept between -30℃ to -10℃ (if the internal temperature was less than -30℃, the reaction system would become solid). After the dropwise addition was completed, the temperature was allowed to naturally rise to room temperature, and diethylamine (676ml) was slowly added dropwise. Heat was generated at the beginning of the dropwise addition, and after the dropwise addition was completed, the reaction was heated under reflux for 1.2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with diethyl ether (1000ml), washed with water 2-3 times, washed with 2N hydrochloric acid, and washed until the aqueous layer pH = 1. The organic phase was washed in turn with saturated sodium bicarbonate and saturated sodium chloride, dried by adding anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Distilled under reduced pressure, and 80g of distillate (38-42℃) was collected. The yield was 45%.

[0117] 1H NMR (400 MHz, Chloroform-d) δ 6.27 (s, 1H), 6.19 (s, 3H), 0.20 (s, 9H). 2) Preparation of Compound 2 Mg particles (8.4g) and iodine particles (1-2 particles) were added to a three-necked flask, and the flask was replaced with argon gas and protected with argon gas. (1-Bromovinyl)trimethylsilane (62.7g) was dissolved in dry THF (159ml), and a portion (20ml) was added to the three-necked flask at room temperature. The three-necked flask was heated and refluxed until a reaction occurred in the reaction flask, dropwise addition was continued, and the reflux state was maintained. After the dropwise addition was completed, the reaction flask was heated and refluxed in an oil bath for 1 hour. A Grignard reagent was produced.

[0118] CuI (6.69g) was added to a 1000ml three-neck flask, THF was added, and the reaction solution was protected by replacing with argon gas, and then the temperature of the reaction solution was lowered to -40°C, the Grignard reagent was added dropwise, and the internal temperature was maintained at ≦-30°C. After the addition was completed, the reaction was continued for 0.5 hours while maintaining the temperature at -40°C, and then a solution of compound 1 in THF (40.45g / 40ml THF) was added dropwise, and after the addition was completed, the temperature was raised to 0°C and the reaction was continued for 2 hours. After confirming the disappearance of compound 1 by TLC monitoring, a saturated ammonium chloride solution was slowly added to quench the reaction, and the mixture was stirred vigorously for 4-6 hours to obtain clear two phases, which were then separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed twice with saturated saline, dried by adding anhydrous sodium sulfate, filtered, and concentrated to obtain 57g of crude product. The crude product was dissolved in 570ml of n-hexane at room temperature, placed in a refrigerator at -20°C, and allowed to crystallize. The next day, it was filtered in cold and washed with cold n-hexane to obtain 42 g of a white solid, which was recrystallized twice to reach a purity of 99.94%.

[0119] 1H NMR (500 MHz, Chloroform-d) δ 7.63 - 7.26 (m, 5H), 5.74 (d, J = 1.9 Hz, 1H), 5.51 (dd, J = 8.7, 3.8 Hz, 1H), 5.42 (d, J = 2.2 Hz, 1H), 4.76 (t, J = 8.8 Hz, 1H), 4.35 (dd, J = 9.0, 3.8 Hz, 1H), 3.30 (q, J = 9.4 Hz, 1H), 3.08 - 2.84 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H), 0.12 (s, 9H). 1.3 Preparation of compound 3 Iodine (43.2g) was dissolved in DCM (752ml), and raw material 2 (18.8g) was added in portions at 0℃. After the addition was completed, the temperature was raised to room temperature and the reaction was continued for about 12-20h. After confirming that the raw material point had basically disappeared by TLC monitoring, the reaction was quenched by adding saturated sodium sulfite solution, and the solution was vigorously stirred until the purple color faded to colorless, and the liquid was separated. The aqueous layer was extracted once with DCM, and the organic phases were combined, dried by adding anhydrous sodium sulfate, filtered, and concentrated to obtain 20g of crude product. The product was isolated by column chromatography to obtain 15g of product. The product was dissolved in a mixed solvent of n-hexane-ethyl acetate (70ml) with heating, cooled, and stirred to crystallize. Filtration gave 9.4g of white solid with a yield of 43%.

[0120] 1H NMR (500 MHz, Chloroform-d) δ 7.41 - 7.27 (m, 5H), 6.09 (d, J = 1.6 Hz, 1H), 5.62 (d, J = 1.6 Hz, 1H), 5.43 (dd, J = 8.8, 4.0 Hz, 1H), 4.70 (t, J = 8.8 Hz, 1H), 4.27 (dd, J = 9.0, 4.0 Hz, 1H), 3.23 (dd, J = 16.9, 6.6 Hz, 1H), 2.85 (dd, J = 16.9, 7.0 Hz, 1H), 2.56 (q, J = 6.8 Hz, 1H), 1.04 (d, J = 6.7 Hz, 3H). 1.4 Preparation of compound 4 The raw material 3 (14.27g) was dissolved in a THF-H2O mixed solution (148ml-37ml), and the temperature was lowered to about -5℃. Hydrogen peroxide (35%, 15.8ml) and an aqueous solution of lithium hydroxide monohydrate (3.1g / 30ml H2O) were added in sequence, and after the addition was completed, the reaction was carried out for 2h while maintaining the temperature at 0℃. After confirming the disappearance of the raw material point by TLC monitoring, the reaction solution was warmed to room temperature, and a saturated sodium sulfite solution was slowly added until the color of the potassium starch iodide test paper did not change. THF was distilled off under reduced pressure, and the aqueous phase was washed 2-3 times with DCM so that (s)-4-phenyl-2-oxazolidinone was removed. The aqueous phase was placed in a round-bottom flask, cooled to 0℃, and the pH was adjusted to 1 with a 10% dilute hydrochloric acid solution. Then, the mixture was extracted 2-3 times with DCM, dried, filtered, and concentrated to obtain compound 4.

[0121] 1H NMR (400 MHz, Chloroform-d) δ 6.21 (s, 1H), 5.90 - 5.59 (m, 1H), 2.62 - 2.54 (m, 1H), 2.54 - 2.46 (m, 1H), 2.31 (dd, J = 15.0, 6.4 Hz, 1H), 1.11 (d, J = 6.5 Hz, 3H). 1.5 Preparation of compound 5 The obtained compound 4 was dissolved in DCM (185 ml), and thiazoline-2-thione (4.84 g), EDCI (8.86 g) and DMAP (0.7 g) were added at room temperature. The reaction was carried out for 4-6 hours while maintaining room temperature. After the disappearance of the raw material was confirmed by TLC monitoring, the reaction was quenched by adding saturated sodium hydrogen sulfate solution, stirred and separated, the aqueous phase was extracted twice with DCM, the organic phase was combined, washed with saturated sodium bicarbonate and saturated saline, and then dried by adding anhydrous sodium sulfate, filtered, concentrated, and isolated and purified by column chromatography to obtain 10.06 g of a yellow syrup-like product (solidifies when left or frozen) with a yield of 80%.

[0122] 1H NMR (400 MHz, Chloroform-d) δ 6.22 (dd, J = 1.6, 0.9 Hz, 1H), 5.76 (d, J = 1.7 Hz, 1H), 4.65 - 4.45 (m, 2H), 3.47 (dd, J = 17.1, 7.3 Hz, 1H), 3.35 - 3.22 (m, 2H), 1.10 (d, J = 6.7 Hz, 3H). 1.6 Preparation of compound 6 1) Preparation of 4-((tert-butyldiphenylsilyl)oxy)butyraldehyde First step: At room temperature, 1,4-butanediol (100ml) was added to a 2000ml three-neck flask, and then DCM (1300ml), triethylamine (59ml) and DMAP (4.7g) were added, followed by slow dropwise addition of TBSCl. After the dropwise addition was completed, the reaction was carried out overnight (about 17 hours) while maintaining room temperature. After confirming the disappearance of the raw material point of TBSCl by TLC monitoring, the reaction was quenched by adding a saturated ammonium chloride solution, the liquids were separated, the aqueous layer was extracted twice with DCM, the organic phases were combined, washed once with saturated saline, dried by adding anhydrous sodium sulfate, filtered and concentrated. The product was isolated and purified by column chromatography to obtain 108g of a syrup-like product in 80% yield.

[0123] 1H NMR (400 MHz, Chloroform-d) δ 7.89 - 7.56 (m, 4H), 7.53 - 7.35 (m, 6H), 3.68 (dt, J = 15.2, 5.9 Hz, 4H), 1.74 - 1.59 (m, 4H), 1.05 (s, 9H). Second step: 4-((tert-butyldiphenylsilyl)oxy)butanol (11.6g) was added to dry DCM (71ml), and the temperature was lowered to 0°C. Dry DMSO (12.6ml) and DIPEA (15.4ml) were added in sequence, and then sulfur trioxide pyridine (11.3g) was added in portions, and the internal temperature was maintained at ≦10°C. After the addition was completed, the temperature was raised to room temperature and reacted for 0.5-1 hour. After confirming the disappearance of the raw material point by TLC monitoring, water was added to quench the reaction, washed once with 1N dilute hydrochloric acid, the aqueous layer was extracted once with DCM, the organic phase was combined, washed once each with saturated sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a syrup-like product, which was used directly in the next reaction, and therefore could be prepared when used.

[0124] 1H NMR (400 MHz, Chloroform-d) δ 9.79 (s, 1H), 7.65 (t, J = 7.6 Hz, 4H), 7.52 - 7.30 (m, 6H), 3.79 - 3.49 (m, 2H), 2.55 (d, J = 6.7 Hz, 2H), 1.88 (t, J = 8.3 Hz, 2H), 1.04 (s, 9H). 2) Raw material 5 (10.1g) was placed in a 1000ml three-neck flask, dried DCM was added to dissolve, and the atmosphere was replaced with argon. The reaction solution was cooled to 0°C, titanium tetrachloride (3.4ml) was added dropwise, triethylamine (3.58ml) was quickly added, and the temperature was maintained at 0°C after the dropwise addition was completed, and the reaction was carried out for 1 hour. A DCM solution (11g / 20ml) of 4-((t-butyldiphenylsilyl)oxy)butyraldehyde was added dropwise, and the reaction was carried out for 4 to 6 hours while maintaining the temperature at 0°C after the dropwise addition was completed. The reaction was quenched by adding saturated saline, and the liquids were separated. The aqueous phase was extracted twice with DCM, and the organic phases were combined, washed twice with saturated sodium bicarbonate and once with saturated saline, dried by adding anhydrous sodium sulfate, filtered, concentrated, and purified by column separation. 13.1g of a yellow syrup-like product was obtained in a yield of 84%.

[0125] Compound 6 contains four diastereomers.

[0126] Opposite form A: 1H NMR (400 MHz, Chloroform-d) δ 7.65 (ddd, J = 7.9, 4.3, 1.8 Hz, 4H), 7.44 - 7.35 (m, 6H), 6.37 (dd, J = 1.3, 0.6 Hz, 1H), 5.84 (d, J = 1.4 Hz, 1H), 5.26 (dd, J = 10.0, 3.8 Hz, 1H), 4.56 (td, J = 7.4, 5.8 Hz, 2H), 3.69 (t, J = 6.1 Hz, 3H), 3.23 - 3.07 (m, 2H), 2.85 (d, J = 10.1 Hz, 1H), 2.67 (dd, J = 9.9, 6.6 Hz, 1H), 1.88 - 1.56 (m, 3H), 1.07 (d, J = 6.7 Hz, 3H), 1.04 (s, 9H). Abnormal body B: 1H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.63 (m, 4H), 7.45 - 7.34 (m, 6H), 6.17 (s, 1H), 5.76 - 5.73 (m, 1H), 4.74 (dd, J = 10.3, 3.4 Hz, 1H), 4.56 (ddd, J = 11.9, 7.5, 2.1 Hz, 1H), 4.38 - 4.26 (m, 1H), 3.72 - 3.62 (m, 3H), 3.41 (ddd, J = 12.3, 11.0, 7.5 Hz, 1H), 3.13 (ddd, J = 10.9, 7.3, 2.1 Hz, 1H), 2.87 (d, J = 10.9 Hz, 1H), 2.67 (dd, J = 10.3, 6.4 Hz, 1H), 2.21 - 2.06 (m, 1H), 1.97 - 1.72 (m, 2H), 1.15 (d, J = 5.7 Hz, 3H), 1.04 (s, 9H). Characteristic chromatogram of isomer C: 1H NMR (400 MHz, Chloroform-d) δ 6.22 (dt, J = 1.8, 0.9 Hz, 1H), 5.72 (d, J = 1.5 Hz, 1H), 5.38 (dd, J = 9.7, 5.3 Hz, 1H). Characteristic peaks for Isomer D: 1H NMR (400 MHz, Chloroform-d) δ 6.19 - 6.18 (m, 1H), 5.76 - 5.75 (m, 1H), 4.96 (dd, J = 10.6, 5.2 Hz, 1H). 1.7 Preparation of compound 7 Raw material 6 (13.07g) was dissolved in dry DCM (40ml), then cooled to 0°C, and dry DMSO (6.95ml) and DIPEA (8.54ml) were added in sequence, followed by sulfur trioxide pyridine (6.23g) added in portions, with the internal temperature maintained at ≦10°C. After the addition was completed, the temperature was raised to room temperature and reacted for 0.5-1 hour, and after confirming the disappearance of the raw material point by TLC monitoring, water was added to quench the reaction, washed once with 1N dilute hydrochloric acid, the aqueous layer was extracted once with DCM, the organic phase was combined, washed once each with saturated sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a syrup-like product, which was purified by column chromatography to obtain 10.4g of the product in 80% yield.

[0127] 1H NMR (400 MHz, Chloroform-d) δ 7.92 - 7.54 (m, 10H)(A / B), 7.39 (q, J = 7.8, 7.1 Hz, 10H) (A / B), 6.25 (d, J = 8.5 Hz, 1H) (A), 6.21 (s, 2H) (A / B), 5.77 (d, J = 1.7 Hz, 1H) (A), 5.75 (d, J = 1.7 Hz, 1H) (B), 5.07 (d, J = 9.4 Hz, 1H)(A), 4.61-4.08 (m, 2H) (A / B), 4.26 - 4.05 (m, 2H) (A / B), 3.69 - 3.61 (m, 4H) (A / B), 3.33 - 3.13 (m, 4H) (A / B), 3.00 - 2.86 (m, 1H)(A),2.79 (dt, J = 15.2, 7.8 Hz, 5H) (A / B), 1.81 (q, J = 6.9 Hz, 3H) (A), 1.12 (d, J = 6.7 Hz, 3H) (A), 1.09 (d, J = 6.5 Hz, 2H) (B), 1.05 (s, 18H) (A / B). 1.8 Preparation of compound 8 Raw material 7 (10.4 g) was dissolved in a mixed solvent of THF and H2O (120 ml / 30 ml), lithium hydroxide monohydrate (6.54 g) was added at room temperature, and the reaction was stirred for 6 to 8 hours while maintaining room temperature. After the reaction was completed, water was added, the liquids were separated, the aqueous phase was extracted with n-hexane, the THF layer was concentrated under reduced pressure and then dissolved in n-hexane, the organic phase was combined, washed with saturated sodium dihydrogen phosphate and saturated saline, dried by adding anhydrous sodium sulfate, filtered, and concentrated. The product was purified by column chromatography to obtain 7.08 g in a yield of 87%.

[0128] 1H NMR (400 MHz, Chloroform-d) δ 7.65 (dd, J = 7.8, 1.5 Hz, 5H), 7.54 - 7.27 (m, 5H), 6.16 (dd, J = 1.5, 0.8 Hz, 1H), 5.70 (d, J = 1.7 Hz, 1H), 3.78 - 3.55 (m, 2H), 2.63 (dd, J = 16.4, 6.5 Hz, 1H), 2.52 (td, J = 7.1, 1.5 Hz, 3H), 2.29 (dd, J = 16.3, 6.6 Hz, 1H), 1.88 - 1.75 (m, 2H), 1.05 (s, 9H), 1.02 (d, J = 6.5 Hz, 3H). [Brief description of the drawings]

[0129] [Figure 1] FIG. 1 is a synthetic route diagram of Example 1 of the present invention.

Claims

1. A method for producing a compound represented by the following formula (8): 【Chemistry 1】 (Of these, R １ is a hydroxyl protecting group, R2 and R ３ forms a carbonyl group with the carbon attached to it, X is a halogen. The method comprises the steps of: Formula (1) and Grignard reagent R ６ MgX or R ６ Li to obtain a compound of formula (2), R ６ teeth 【Chemistry 2】 wherein X is a halogen and the reaction is carried out in the presence of a cuprous salt under an inert atmosphere at −50° C. to 0° C.; 【Chemistry 3】 (Of these, R ５ is a silyl group, R ４ C １－１０ alkyl, unsubstituted or substituted phenyl or benzyl groups with hydroxy, nitro or dimethylamino groups. A step of producing a compound of formula (3) from the compound of formula (2) and a halogenating reagent by a halogenation reaction: 【Chemistry 4】 A step of producing a compound represented by the following formula (4) from the following formula (3) by a hydrolysis reaction, the reaction being carried out at −15 to 5° C. under basic conditions; 【Chemistry 5】 A step of preparing a compound represented by the following formula (4) from a compound represented by the following formula (5) and a thiazoline-2-thione, the reaction being carried out in the presence of a coupling agent, which may be a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-N,N-dimethylaminopyridine (DMAP) system, or a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 4-N,N-dimethylaminopyridine (DMAP) system, and the reaction being carried out at 15 to 40° C.; 【Chemistry 6】 The following formula (5) and aldehyde O=CH-(CH ２ ) ３ -O-R １ The reaction is carried out by reacting titanium tetrachloride (TiCl ４ ) and triethylamine (TEA) in an inert atmosphere at a temperature between −10 and 10° C.; 【Chemistry 7】 A step of producing a compound represented by the following formula (7) from the following formula (6) by an oxidation reaction of converting an alcohol into a ketone; 【Chemistry 8】 A method for producing a compound represented by formula (8), comprising: hydrolyzing formula (7) to obtain formula (8), the hydrolysis reaction being carried out in a solvent medium under basic conditions at 15 to 40° C.

2. A method for preparing the compound of formula (8) according to claim 1, further comprising the step of recrystallizing formula (2) once, twice or multiple times.

3. and a step of producing a compound represented by formula (1) from oxazolidinone represented by formula (0) and crotonic acid, crotonic acid chloride, crotonic ester, or crotonic acid anhydride, the reaction being carried out in a basic condition at a temperature of −80° C. to −20° C. using catalytic amounts of lithium chloride and a solvent. 【Chemistry 9】 A method for producing the compound represented by formula (8) according to claim 1, comprising:

4. Formula (5) and the aldehyde O=CH-(CH ２ ) ３ -O-R １ In the process for producing the compound of formula (6), 【Chemistry 10】 The method for producing an aldehyde comprises the steps of: (I) Butanediol and R ｎ Six ４－ｎ in the presence of a coupling agent to obtain a monohydroxy protected product, wherein X is a halogen selected from chlorine, bromine, and iodine, and R is C １－１０ alkyl, fluoro-substituted alkyl, n is an integer from 1 to 3; and (II) oxidizing the product of step (I); The method of claim 1 , comprising:

5. A compound represented by the following formula (2): 【Chemistry 11】 (Of these, R ４ , R ５ The definitions are as set forth in claim 1.

6. Formula (1) and Grignard reagent R ６ MgX or R ６ Li to obtain a compound of formula (2), 【Chemistry 12】 A method for producing the compound represented by formula (2) according to claim 5; R ６ teeth 【Chemistry 13】 where X is a halogen and the reaction is carried out in the presence of a cuprous salt under an inert atmosphere at -50°C to 0°C.

7. 7. A method for preparing the compound of formula (2) according to claim 6, further comprising the step of recrystallizing said compound of formula (2) once, twice or multiple times.

8. A compound represented by the following formula (3): 【Chemistry 14】 (Of these, R ４ , X is defined as in claim 1.

9. A method for producing a compound represented by formula (3) according to claim 8, comprising the step of producing a compound represented by formula (3) from the following formula (2) and a halogenating reagent by a halogenation reaction: 【Chemistry 15】 (Of these, R ４ , R ５ and X is defined as in claim 1.

10. A compound represented by the following formula (7): 【Chemistry 16】 wherein R 1 is selected from tris(C 1-6 alkyl)silyl, tris(C 6-10 aryl)silyl, bis(C 6-10 aryl)(C 1-6 alkyl)silyl, (C 6-10 aryl)bis(C 1-6 alkyl)silyl; R 2 and R 3 form a carbonyl group together with the carbon bonded thereto; X is a halogen.

11. A method for producing the compound represented by formula (7) according to claim 10, comprising the steps of: The following formula (5) and aldehyde O=CH-(CH ２ ) ３ -O-R １ to produce the compound represented by the following formula (6), ４ ) and triethylamine (TEA) in an inert atmosphere at a temperature between −10 and 10° C.; 【Chemistry 17】 A step of oxidizing the compound represented by formula (6) by an oxidation reaction converting the alcohol into a ketone to produce the compound represented by formula (7). 【Chemistry 18】

12. A method for producing eribulin or a pharma- ceutically acceptable salt thereof, comprising the method according to claim 1.

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