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CN108341738B - Process for the preparation of eribulin and intermediates thereof - Google Patents

Process for the preparation of eribulin and intermediates thereof Download PDF

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CN108341738B
CN108341738B CN201810063859.5A CN201810063859A CN108341738B CN 108341738 B CN108341738 B CN 108341738B CN 201810063859 A CN201810063859 A CN 201810063859A CN 108341738 B CN108341738 B CN 108341738B
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compound
formula
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methylbut
eribulin
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CN108341738A (en
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黄建
祝令建
管忠俊
唐应刚
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Shengdi Pharmaceutical Co ltd
Jiangsu Hengrui Medicine Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/013—Preparation of halogenated hydrocarbons by addition of halogens
    • C07C17/04—Preparation of halogenated hydrocarbons by addition of halogens to unsaturated halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • 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
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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

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Abstract

The present invention provides a process for the preparation of eribulin and intermediates thereof. Specifically, the invention provides a preparation process of (3R) -2,4-dihalo-3-methylbut-1-ene (a compound shown in a formula I), wherein X is halogen such as iodine, bromine or chlorine. Also provided are processes for the preparation of compounds of formula I useful for the preparation of halichondrin and derivatives thereof, such as eribulin.

Description

Process for the preparation of eribulin and intermediates thereof
Technical Field
The invention relates to a preparation method of (3R) -2,4-dihalo-3-methylbut-1-ene.
Background
Halichondrin B (Halichondrin B) is a natural product with anti-tumor activity, originally isolated from marine sponge black sponges. Eribulin is the first macrocyclic ketone analog obtained by structural optimization of halichondrin B, and currently eribulin mesylate injection is marketed in a number of countries for the treatment of metastatic breast cancer.
Figure BDA0001556064190000011
US6214865 and US5436238 respectively report a method for synthesizing halichondrin and derivatives thereof using compound 2,5-disubstituted (2S, 5S) -3-methylene-tetrahydrofuran (compound of formula B-12) as an intermediate,
Figure BDA0001556064190000012
angew. Chem. Int. Ed.2009,48,2346 reports a process for obtaining a compound of formula B-12 starting from (3R) -2,4-diiodo-3-methylbut-1-ene (compound of formula 1),
Figure BDA0001556064190000013
CN104053645A discloses that 2,4-dihalo-3-methylbut-1-ene is prepared from compound 4-hydroxy protecting group-3-methylbut-1-alkyne through addition, deprotection, substitution or through addition, deprotection, esterification and substitution, but this method can generate triphenylphosphine oxide by-product which is difficult to remove and has longer steps, and at the same time, expensive B-I-9-BBN reagent is needed in the process, which is not suitable for industrial mass production. Wherein PG is a protecting group for hydroxyl group,
Figure BDA0001556064190000021
disclosure of Invention
The present invention provides a process for the preparation of a compound of formula I,
Figure BDA0001556064190000022
the method comprises the following steps: converting a compound of formula II to a compound of formula I, wherein LG is a leaving group or a hydroxy group,
Figure BDA0001556064190000023
wherein X is halogen including Cl, br, I.
The conversion of the compound of formula II to the compound of formula I according to the present invention may be a one-step or multi-step reaction, and if a multi-step reaction, the multi-step reaction may be a "one-pot multi-step" or "one-pot" process.
In some embodiments, X in the compounds of formula I may be the same or different.
The leaving group of the compound of formula II according to the present invention is a molecular fragment that can be detached in the bond breaking step, and the leaving group is not particularly limited and is known to or can be determined by a person skilled in the art. Examples of leaving group forming include, but are not limited to, halogen or sulfonic acid based leaving groups, halogen may include iodine, bromine, or chlorine, preferably iodine; the sulfonic acid group-based leaving group may include, but is not limited to, a perfluorobutylmethanesulfonate group, a trifluoromethanesulfonate group, a fluorosulfonate group, a tosylate group, a methanesulfonate group or a benzenesulfonate group, preferably a tosylate group.
In embodiments, under halide salt/halosilane conditionsThe compound of formula II is converted to a compound of formula I, and the halide salt is an alkaline earth metal halide salt, which may include but is not limited to LiI, naI, KI, csI, caI 2 ，MgI 2 ，LiBr，NaBr，KBr，CsBr，CaBr 2 ，MgBr 2 ，LiCl，NaCl，KCl，CsCl，CaCl 2 ，MgCl 2 Preferably lithium iodide (LiI), sodium iodide (NaI); the halosilane is well known or ascertainable by those skilled in the art and is selected from, but not limited to, trimethyliodosilane, triethyliodosilane, trimethylbromosilane, triethylbromosilane, trimethylchlorosilane, triethylchlorosilane, and preferably, trimethylsilicon chloride.
In some embodiments, the compound of formula II is reacted first with a halide salt to form a compound of formula II-1 and then with a halide salt/halosilane to form a compound of formula I, wherein X 1 Is halogen, including Cl, br, I,
Figure BDA0001556064190000031
in some embodiments, the compound of formula II is reacted first with a halide salt/halosilane to form a compound of formula II-2, and then with a halide salt to form a compound of formula I, wherein X is halogen,
Figure BDA0001556064190000032
in some embodiments, starting with (S) -2-methylbutyl-3-yn-1-ol (1), after conversion of the hydroxyl group into a leaving group, is reacted with a halide salt/halosilane to yield compound 3:
Figure BDA0001556064190000033
in some embodiments, starting with (S) -2-methylbutyl-3-yn-1-ol (1), compound 3 can be obtained via the following reaction scheme:
Figure BDA0001556064190000034
further, intermediate 1 or intermediate 2 may be isolated or may be subjected to the next reaction without isolation to obtain compound 3.
In some embodiments, starting with (S) -2-methylbutyl-3-yn-1-ol (1), after conversion of the hydroxyl group to halogen, is reacted with a halide salt/halosilane to give the compound of formula I:
Figure BDA0001556064190000035
wherein X is iodine, bromine or chlorine.
The use of starting materials of high enantiomeric purity may help to obtain the compound having formula 3. In some embodiments, for example and without limitation, the enantiomeric purity of a compound having any one of formulas 1 through 3 is about 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% e.e., or any value in between.
The present invention also provides a compound of formula II, wherein LG is a leaving group, preferably the leaving group is a sulfonic acid based leaving group or a halogen,
Figure BDA0001556064190000041
in embodiments, LG is a tosylate group,
Figure BDA0001556064190000042
in some embodiments, LG is halo, wherein X is 1 Is the compound of iodine, bromine and chlorine,
Figure BDA0001556064190000043
a process for preparing a compound of formula B-12 comprising the steps described above, followed by the steps shown below, wherein the reaction conditions are as in angew.chem.int.ed.2009,48,2346; org.lett.2002,4,4435; J.am.chem.Soc.2009,131,15387, etc.
Figure BDA0001556064190000044
A process for the preparation of halichondrin analogs, which may be eribulin or a pharmaceutically acceptable salt thereof, comprising the reaction steps described above, followed by a process as described in US6214865 or US5436238, and the like.
A process for the preparation of a halichondrin analog, comprising the step of synthesizing a halichondrin analog, which may be eribulin or a pharmaceutically acceptable salt thereof, using a compound of formula II as described above.
Eribulin according to the present invention may be salified with an acid known to or determinable by one skilled in the art selected from the group consisting of, but not limited to, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, maleic acid, acetic acid, trifluoroacetic acid.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are only for illustrating the technical solution of the present invention, and the spirit and scope of the present invention are not limited thereto.
Example 1: preparation of (2S) -2-methylbut-3-yne-1-p-toluenesulfonate
Figure BDA0001556064190000051
(2S) -2-Methylbut-3-ynol (27.7 g) was dissolved in 180mL dry CH 2 Cl 2 DMAP (2.0 g) and triethylamine (50.1 g) were further added to the system. Cool to-10 to-5 deg.C, and slowly add TsCl (69.2 g) in dichloromethane. After completion of the dropwise addition, the temperature was naturally raised to room temperature, the reaction mixture was stirred for 2 hours, and after completion of the reaction, water (100 mL) was added to the reaction mixture. Separating organic layer, separating water layer, and reusing CH 2 Cl 2 Extracting, and combining organic layers. The organic phase was washed successively with water, a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium hydrogencarbonate solution and brine, and dried over anhydrous sodium sulfate. Filtering, concentrating, separating and purifying by a silica gel column to obtain 72.2g of a product, wherein the yield is as follows: 92 percent.
Example 2: preparation of (3R) -2,4-diiodo-3-methylbut-1-ene
LiI (88.8 g) was weighed into a reaction flask, acetonitrile (500 mL) was added, followed by dropwise addition of TMSCl (42.6 g), the reaction solution became cloudy, and after stirring for 5 minutes, (2S) -2-methylbut-3-yne-1-p-toluenesulfonate (38.1 g) was then added. After 10 hours of reaction at room temperature, water (200 mL) was added to separate the organic layer, the aqueous layer was extracted with MTBE, and the organic layers were combined. The organic phase was washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering, concentrating, separating and purifying by a silica gel column to obtain an oily liquid product 44.8g, and obtaining the yield: 87 percent.
Example 3: preparation of (3S) -4-iodo-3-methylbut-1-yne
(2S) -2-methylbut-3-yne-1-p-toluenesulfonate (12.2 g) was weighed in a reaction flask, acetonitrile (150 mL) and LiI (11.5 g) were added, and after reacting at room temperature for 20 hours, filtration was carried out, the filter cake was washed with 50mL of acetonitrile, and the obtained filtrate was concentrated to obtain 8.7g of an oily liquid product, yield: 88 percent.
Example 4: preparation of (3R) -2,4-diiodo-3-methylbut-1-ene
NaI (19.5 g) and acetonitrile (200 mL) were weighed in a reaction flask, TMSCl (13.7 g) was added dropwise at room temperature, the reaction solution gradually became cloudy, and after stirring for 30 minutes, the compound (3S) -4-iodo-3-methylbut-1-yne (10.0 g) was added, and after 12 hours of reaction at room temperature, water (200 mL) was added. The organic layer was separated, the aqueous layer was extracted with ether, and the organic layers were combined, washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering, concentrating, separating and purifying by a silica gel column to obtain 15.1g of oily liquid product, and obtaining the yield: 91 percent.
Example 5: preparation of (3S) -4-bromo-3-methylbut-1-yne
In a reaction flask, (2S) -2-methylbut-3-yne-1-p-toluenesulfonate (12.2 g) was weighed, acetonitrile (150 mL) and NaBr (15.8 g) were added, and after reacting at room temperature for 20 hours, filtration was performed, a filter cake was washed with 50mL of acetonitrile, and the obtained filtrate was concentrated to obtain 6.5g of an oily liquid product, yield: 86 percent.
Example 6: preparation of (3R) -2,4-diiodo-3-methylbut-1-ene
LiI (9.4 g) was weighed into a reaction flask, acetonitrile (60 mL) was added, followed by dropwise addition of TMSCl (4.3 g), the reaction solution became cloudy, and after stirring for 5 minutes, (3S) -4-bromo-3-methylbut-1-yne (2.3 g) was added. After 10 hours of reaction at room temperature, water (20 mL) was added to separate the organic layer, the aqueous layer was extracted with MTBE, and the organic layers were combined. The organic phase was washed successively with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. Filtering, concentrating, separating and purifying by a silica gel column to obtain 4.1g of oily liquid product, wherein the yield is as follows: 81 percent.
Example 7: preparation of (3S) -4-iodo-3-methylbut-1-yne
Weighing (3S) -4-bromo-3-methylbut-1-yne (7.2 g) in a reaction flask, adding acetonitrile (150 mL) and LiI (29.5 g), reacting at room temperature for 20h, filtering, washing a filter cake with 50mL of acetonitrile, and concentrating the obtained filtrate to obtain 8.5g of an oily liquid product, wherein the yield is as follows: 89 percent.
Example 8: preparation of (3S) -4-iodo-3-methylbut-1-yne
A solution of dichloromethane (25 mL), triphenylphosphine (6.3 g), imidazole (1.8 g), (2S) -2-methylbut-3-ynol (1.7 g) was cooled to 5 deg.C, the temperature controlled at 5-10 deg.C, and I2 (6.1 g) was added slowly. Then, the reaction mixture was allowed to warm to room temperature naturally for 1 hour, and then quenched with a saturated sodium thiosulfate solution (100 mL). The organic layer was separated, the aqueous layer was extracted with dichloromethane (30 mL), and the organic layers were combined. The organic layer was washed twice with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. Cyclohexane (100 mL) was added to the residue, filtered, concentrated, and then separated and purified by a silica gel column to obtain 3.2g of an oily liquid product, yield: 82 percent.

Claims (4)

1. A process for the preparation of a compound of formula I,
Figure FDA0003705607870000011
the method comprises the following steps: the compound of formula II is reacted with a halide salt/halosilane "one-pot" to form the compound of formula I, wherein the compound of formula II is reacted with a halide salt to form the compound of formula II-1, which is then reacted with a halide salt/halosilane to form the compound of formula I, or the compound of formula II is reacted with a halide salt/halosilane to form the compound of formula II-2, which is then reacted with a halide salt to form the compound of formula I, LG is tosylate, X is iodine, X is 1 Is iodine, the halide salt is lithium iodide or sodium iodide, the halosilane is selected from trimethyl silicon chloride,
Figure FDA0003705607870000012
2. a process for the preparation of a B-12 compound comprising a process as claimed in claim 1 and a process for the preparation of a B-12 compound by reacting a compound of formula I,
Figure FDA0003705607870000013
3. a process for the preparation of halichondrin analogs comprising the process of claim 1 or 2 and a process for the preparation of eribulin or a pharmaceutically acceptable salt thereof from a compound of formula I.
4. The method of claim 3, wherein said halichondrin analog is eribulin or a pharmaceutically acceptable salt thereof.
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CN108689795B (en) * 2017-04-11 2022-06-28 上海时莱生物技术有限公司 Intermediate for preparing eribulin and preparation method thereof
CN111875470B (en) * 2020-08-17 2023-02-03 苏州正济药业有限公司 Preparation method of intermediate (R) -2-methyl-1-bromo-3-iodo-3-butene for preparing eribulin

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WO2016176560A1 (en) * 2015-04-30 2016-11-03 President And Fellows Of Harvard College Chromium-mediated coupling and application to the synthesis of halichondrins

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CN104053645A (en) * 2011-11-30 2014-09-17 阿方拉研究股份有限公司 Process for preparation of (3R)-2,4-di-leaving group-3-methylbut-1-ene
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