CN113387850A - Preparation method of eribulin intermediate - Google Patents

Preparation method of eribulin intermediate Download PDF

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CN113387850A
CN113387850A CN202010171298.8A CN202010171298A CN113387850A CN 113387850 A CN113387850 A CN 113387850A CN 202010171298 A CN202010171298 A CN 202010171298A CN 113387850 A CN113387850 A CN 113387850A
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张富尧
毕万福
神小明
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Selection Bioscience LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C315/00—Preparation of sulfones; Preparation of sulfoxides
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    • 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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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4075—Esters with hydroxyalkyl compounds
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4084—Esters with hydroxyaryl compounds

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Abstract

The invention relates to a preparation method of an eribulin intermediate. In particular, the invention relates to a preparation method of compounds shown as formula II and formula III, wherein R is1Is hydrogen or C1‑6Alkyl or C2‑6Alkenyl radical, R2Is C1‑6Alkyl or substituted or unsubstituted phenyl. The method has the advantages of mild and safe reaction conditions, simple and convenient operation and purification, high product purity and the like, and is suitable for large-scale production.

Description

Preparation method of eribulin intermediate
Technical Field
The invention relates to a preparation method of an eribulin intermediate.
Background
Eribulin (shown as formula I) is a derivative for optimizing the structure of macrolide compound halichondrin B extracted from marine natural product Halichondria okadai, and is a halichondrin microtubule dynamics inhibitor. Eribulin mesylate injection (Halaven) was first approved by the FDA for treatment of metastatic breast cancer patients who received at least two chemotherapy regimens 11/15 2010 and was approved for marketing in china 7/17 2019.
Figure BDA0002409276150000011
Eribulin has a complex molecular structure containing 40 carbon atoms, wherein 19 carbon atoms have a chiral center, and the current market drug supply can only be realized through a total synthesis route. An eribulin intermediate shown in formula IIIa is disclosed in patent CN 108659031.
Figure BDA0002409276150000012
For the compound shown as formula IIIa, five synthetic routes are mainly reported in the literature.
The synthetic route of the literature Tetrahedron Letters 2018,59, 524-: at 110 ℃, di-tert-butyl ether peroxide and sodium p-ethylphenylsulfinate react in an aqueous solution to obtain the compound shown in the formula IIIa, and the yield is 87%. The reaction raw materials are not easy to obtain, and a relatively dangerous peroxidation reagent is adopted at high temperature, so that great potential safety hazard exists.
Figure BDA0002409276150000013
The synthetic route of the document Chemical Communications,2012,48,7513-7515 is: and (2) at 120 ℃, adding ethyl bromobenzene or ethyl iodobenzene into the mixture for 20 hours under the action of cuprous oxide, acetylacetone, potassium tert-butoxide and oxygen by taking DMSO as a solvent to obtain the compound shown in the formula IIIa, wherein the yield is 65%. The reaction involves oxygen and strong base at high temperature, and has great potential safety hazard.
Figure BDA0002409276150000021
The literature Tetrahedron,2001,57, 1369-; canadian Journal of Chemistry,1987,65, 2421-; inorganic, Physical, thermal and Analytical,1986,25, 678-680; the synthetic route for Indian Journal of Chemistry-Section B Organic and Medicinal Chemistry,2002,41, 1523-: the compound shown in the formula IIIa is obtained by the p-ethyl phenyl methyl sulfoxide under the action of an oxidant or ultraviolet irradiation. The reaction raw materials are not easy to obtain, and relate to a peroxidation reagent, so that great potential safety hazards exist.
Figure BDA0002409276150000022
The synthetic route of the document Recueil des Travaux Chimiques des Pays-Bas,1952,71, 361-: heating the hydrazone compound in ethanol to 200 ℃ to obtain the compound shown in the formula IIIa. The reaction raw materials are not easy to obtain, and the reaction temperature is extremely high, so that the method is not beneficial to industrial production.
Figure BDA0002409276150000023
The synthetic route of the Organic and Biomolecular Chemistry,2004,2,3150 and 3154 documents is: ethylbenzene reacts with methane sulfonic anhydride in toluene under the action of a zeolite molecular sieve catalyst to obtain a compound shown as a formula IIIa. The total yield of the reaction is 53%, the selectivity of ortho-para position is not ideal, and the difficulty of purifying the product is increased.
Figure BDA0002409276150000024
In summary, the existing methods for synthesizing the compound shown in formula IIIa have great potential safety hazard and poor yield and selectivity, and therefore, a reaction condition which is milder, safer and more suitable for amplification is urgently needed to prepare the compound shown in formula III.
Disclosure of Invention
Aiming at the defects of the existing preparation method of the compound shown as the formula IIIa, the invention provides a new synthesis method of the compound shown as the formula III, and the method has the advantages of mild and safe reaction conditions, simple and convenient operation and purification, high product purity and low cost, and is suitable for large-scale production.
The invention provides a preparation method of a compound shown in a formula III, which is characterized in that the compound is prepared by coupling reaction of a compound shown in a formula IV and sodium methylsulfinate,
Figure BDA0002409276150000031
wherein R is1Is hydrogen or C1-6Alkyl or C2-6An alkenyl group;
x is halogen or a leaving group, preferably chlorine, bromine, iodine, triflate.
The invention further provides a preparation method of the compound shown in the formula IIIa, which is characterized in that the compound is prepared by the coupling reaction of the compound shown in the formula IVA and sodium methylsulfinate,
Figure BDA0002409276150000032
wherein, X is halogen or leaving group, preferably chlorine, bromine, iodine, triflate.
In a preferred embodiment of the present invention, the method comprises the following steps:
adding a compound IV and sodium methanesulfinate into a reaction bottle, adding an organic solvent or an organic solvent/water mixed solvent for dissolving, adding a copper reagent, a ligand and an alkali, and continuously stirring for 1-24 h at 40-120 ℃ for reaction. TLC showed complete conversion of starting material. And (3) after the reaction solution is returned to the room temperature, adding water to quench the reaction, extracting with ethyl acetate, concentrating an organic phase, and then recrystallizing and purifying to obtain the compound shown in the formula III.
In the preparation method of the compound shown in the formula III, the copper reagent is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, cuprous trifluoromethanesulfonate, cuprous oxide, cupric chloride, cupric acetate, cupric oxide and cupric sulfate.
In the preparation method of the compound shown in the formula III, the molar ratio of the copper reagent to the compound shown in the formula IV is (0.01-2): 1.
In the preparation method of the compound shown in the formula III, the ligand is selected from one or more of L-proline, D-proline, DL-proline and L-hydroxyproline.
In the preparation method of the compound shown in the formula III, the structure of the ligand is selected from any one of the following structures:
Figure BDA0002409276150000033
in the preparation method of the compound shown in the formula III, the alkali is selected from one or more of potassium carbonate, potassium phosphate, sodium phosphate, cesium carbonate, sodium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, pyridine and triethylamine.
In the preparation method of the compound shown in the formula III, the solvent is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane and water.
The invention also provides a preparation method of the compound shown in the formula II, which is characterized in that the compound shown in the formula III and the compound shown in the formula VI which are prepared by the coupling reaction under the action of a copper reagent react under the action of alkali to prepare the compound shown in the formula II,
Figure BDA0002409276150000041
wherein R is1Is hydrogen or C1-6Alkyl or C2-6An alkenyl group;
R2is C1-6Alkyl or substituted or unsubstituted phenyl.
In a preferred embodiment of the present invention, the method comprises the following steps:
adding the compound III into a reaction bottle, and adding an organic solvent for dissolving. Adding alkali at the temperature of minus 20-20 ℃, and continuously stirring for 30 min-2 h at the temperature for reaction. Continuously adding the compound VI at the temperature of minus 20-20 ℃, and continuously stirring for 30 min-4 h at the temperature for reaction. TLC shows that the raw material is completely converted, saturated ammonium chloride aqueous solution is added to quench reaction, ethyl acetate is used for extraction, and after organic phase is concentrated, column chromatography purification is carried out to obtain a compound II.
In the preparation method of the compound shown in the formula II, the base is selected from one or more of n-butyllithium, sec-butyllithium, LDA, LiHMDS, NaHMDS, KHMDS and sodium hydride.
In the preparation method of the compound shown in the formula II, the organic solvent is selected from one or more of tetrahydrofuran, toluene and 2-methyltetrahydrofuran.
In another aspect, the present invention also provides a method for preparing eribulin, comprising preparing a compound of formula II or formula III according to the methods provided herein, and then preparing eribulin from a compound of formula II or formula III according to known methods, wherein reference is made to the following references: CN 108659031; CN 108948064; synlett.2013,24,333.
Abbreviation table:
abbreviations Full scale
KHMDS Hexamethyldisilazane-based amino potassium salt
LiHMDS Hexamethyldisilazane-based aminolithium salt
NaHMDS Hexamethyldisilazane-based amino sodium salt
LDA Lithium diisopropylamide
Me Methyl radical
Et Ethyl radical
Ph Phenyl radical
TLC Thin layer chromatography
DMSO Dimethyl sulfoxide
The following table shows the structural formulae of the compounds mentioned in the examples
Figure BDA0002409276150000051
Detailed Description
The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical scheme of the present invention and do not limit the present invention in any way.
Example 1: preparation of Compound IIIa
Compound IVAa (100g) and sodium methanesulfinate (88g) were added to the flask, and dimethyl sulfoxide (500mL) was added thereto to dissolve it, followed by sequentially adding cuprous bromide (0.62g), L-proline (0.5g) and sodium hydroxide (35g), and the reaction was stirred at 120 ℃ for 24 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate, concentration of the organic phase and purification by recrystallization gave 45g of compound IIIa.
MS(ESI)m/z:185(M+H+).
1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.06(s,3H),2.76(q,J＝8.0Hz,2H),1.29(t,J＝8.0Hz,3H).
Example 2: preparation of Compound IIIa
To a flask, compound IVAb (100g) and sodium methanesulfinate (71g) were added, N-dimethylformamide (500mL) was added to dissolve, and then cuprous oxide (38g), DL-proline (71g) and potassium carbonate (149g) were added in this order, and the reaction was stirred at 100 ℃ for 12 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate, concentration of the organic phase and purification by recrystallization gave 72g of compound IIIa.
MS(ESI)m/z:185(M+H+).
1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.06(s,3H),2.76(q,J＝8.0Hz,2H),1.29(t,J＝8.0Hz,3H).
Example 3: preparation of Compound IIIa
To a flask, compound IVAb (100g) and sodium methanesulfinate (82.5g) were added, dimethyl sulfoxide (500mL) was added to dissolve, and then cuprous iodide (103g), L-hydroxyproline (71g) and potassium phosphate (172g) were added in this order, and the reaction was stirred at 70 ℃ for 6 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate, concentration of the organic phase and purification by recrystallization gave 82g of compound IIIa.
MS(ESI)m/z:185(M+H+).
1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.06(s,3H),2.76(q,J＝8.0Hz,2H),1.29(t,J＝8.0Hz,3H).
Example 4: preparation of Compound IIIa
To a flask, compound IVAb (100g) and sodium methanesulfinate (110g) were added, dimethyl sulfoxide (500mL) was added to dissolve, and then cuprous chloride (107g), L-hydroxyproline (142g) and cesium carbonate (528g) were added in this order, and the reaction was stirred at 40 ℃ for 24 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate, concentration of the organic phase and purification by recrystallization gave 91g of compound IIIa.
MS(ESI)m/z:185(M+H+).
1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),3.06(s,3H),2.76(q,J＝8.0Hz,2H),1.29(t,J＝8.0Hz,3H).
Example 5: preparation of Compound IIIb
Compound IVb (10g) and sodium methanesulfinate (9g) were added to the flask, and dimethyl sulfoxide (50mL) was added to dissolve it, followed by sequentially adding cuprous iodide (6.1g), L-hydroxyproline (4.2g) and potassium phosphate (27g), and the reaction was stirred at 120 ℃ for 3 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate and purification by recrystallization after concentration of the organic phase gave 7.9g of compound IIIb.
MS(ESI)m/z:157(M+H+).
Example 6: preparation of Compound IIIc
To a flask were added compound IVc (10g) and sodium methanesulfinate (20g), dissolved by adding N-methylpyrrolidone (50mL), and then cuprous iodide (6.7g), D-proline (4.2g) and potassium hydroxide (9g) were added in this order, and the reaction was stirred at 80 ℃ for 9 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate and purification by recrystallization after concentration of the organic phase gave 7.6g of compound IIIc.
MS(ESI)m/z:171(M+H+).
Example 7: preparation of Compound IIId
To a flask were added compound IVd (10g) and sodium methanesulfinate (15g), dissolved by adding sulfolane (50mL), and then sequentially added cuprous iodide (2.0g), L-hydroxyproline (1.4g) and potassium phosphate (14.7g), and the reaction was stirred at 100 ℃ for 24 h. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate and purification by recrystallization after concentration of the organic phase gave 7.1g of compound IIId.
MS(ESI)m/z:241(M+H+).
Example 8: preparation of Compound IIIe
Compound IVe (10g) and sodium methanesulfinate (11g) were added to the flask, dimethyl sulfoxide (50mL) was added to dissolve, and then cuprous iodide (10.4g), L-hydroxyproline (7.16g) and potassium phosphate (23.2g) were added in this order, and the reaction was stirred at 70 ℃ for 4 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate and purification by recrystallization after concentration of the organic phase gives 8.3g of compound IIIe.
MS(ESI)m/z:183(M+H+).
Example 9: preparation of Compound IIIf
Compound IVf (10g) and sodium methanesulfinate (15g) were added to a flask, dimethyl sulfoxide (50mL) was added to dissolve, and then cuprous iodide (19.6g), L-hydroxyproline (13.5g) and cesium carbonate (66.9g) were added in this order, and the reaction was stirred at 120 ℃ for 24 hours. TLC showed complete conversion of starting material and after cooling the reaction to room temperature, the reaction was quenched by addition of water. Extraction with ethyl acetate and purification by recrystallisation after concentration of the organic phase gave 8.2g of compound IIIf.
MS(ESI)m/z:239(M+H+).
Example 10: preparation of Compound IIa
Compound IIIa (3.1g, 16.8mmol, 1eq.) was added to the flask, dissolved in tetrahydrofuran (15mL), 2.5M n-hexane solution of n-butyllithium (9.2mL) was added dropwise at 0 ℃, after stirring for 30min, diethyl chlorophosphonate (3.3mL) was added and the reaction continued to stir at 0 ℃ for 1h, TLC showed complete conversion of the starting material. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give 4.8g of Compound IIa.
MS(ESI)m/z:321(M+H+).
1H NMR(400MHz,Chloroform-d)δ7.90(d,J＝8.1Hz,2H),7.40(d,J＝8.1Hz,2H),4.45–3.94(m,4H),3.76(d,J＝16.8Hz,2H),2.75(q,J＝7.6Hz,2H),1.51–1.11(m,9H).
Example 11: preparation of Compound IIb
Compound IIIb (5g, 32mmol, 1eq.) was added to the flask, dissolved in toluene (25mL), LiHMDS (1.0M, 32mL) was added dropwise at 20 ℃, after stirring for 30min, dimethyl chlorophosphonate (5.1g) was added and the reaction continued to stir at 20 ℃ for 30min, TLC showed complete conversion of the starting material. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give 7.5g of compound IIb.
MS(ESI)m/z:265(M+H+).
Example 12: preparation of Compound IIc
Compound IIIc (5g, 29.4mmol, 1eq.) was added to the flask and dissolved in 2-methyltetrahydrofuran (25mL), KHMDS (1.0M, 30mL) was added dropwise at-20 ℃, after stirring for 2h, diphenyl chlorophosphonate (9.5g) was added and the reaction continued to stir at-20 ℃ for 2h, TLC showed complete conversion of starting material. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give 7.0g of compound IIb.
MS(ESI)m/z:403(M+H+).
Since the present invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those of ordinary skill in the art and are intended to be included within the scope of the present invention.

Claims (12)

1. A preparation method of a compound shown in a formula III is characterized in that the compound is prepared by coupling reaction of a compound shown in a formula IV and sodium methylsulfinate,
Figure FDA0002409276140000011
wherein R is1Is hydrogen or C1-6Alkyl or C2-6An alkenyl group;
x is halogen or a leaving group, preferably chlorine, bromine, iodine, triflate.
2. A preparation method of a compound shown in formula IIIa is characterized in that the compound is prepared by coupling reaction of a compound shown in formula IVA and sodium methylsulfinate,
Figure FDA0002409276140000012
wherein, X is halogen or leaving group, preferably chlorine, bromine, iodine, triflate.
3. The method according to claim 1 or 2, wherein the coupling reaction is carried out under the action of a copper reagent, a ligand and a base.
4. The method of claim 3, wherein the copper reagent is selected from the group consisting of cuprous iodide, cuprous bromide, cuprous chloride, cuprous trifluoromethanesulfonate, cuprous oxide, cupric chloride, cupric oxide, cupric acetate, and cupric sulfate.
5. The preparation method according to claim 3, wherein the molar ratio of the copper reagent to the compound represented by formula IV or formula IVA is (0.01-2): 1.
6. The method according to claim 3, wherein the ligand is selected from one or more of L-proline, D-proline, DL-proline and L-hydroxyproline.
7. The method according to claim 3, wherein the base is one or more selected from the group consisting of potassium carbonate, potassium phosphate, sodium phosphate, cesium carbonate, sodium carbonate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, pyridine, and triethylamine.
8. The method according to claim 1 or 2, wherein the solvent for the coupling reaction is one or more selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, sulfolane and water.
9. The method according to claim 1 or 2, wherein the temperature of the coupling reaction is 40 to 120 ℃.
10. A method for preparing a compound shown in a formula II, which is characterized in that the compound shown in the formula III is prepared by any one method of claims 1 to 9 and then reacts with a compound shown in the formula VI under the action of alkali to prepare the compound shown in the formula II,
Figure FDA0002409276140000021
wherein R is1Is hydrogen or C1-6Alkyl or C2-6An alkenyl group;
R2is C1-6Alkyl or substituted or unsubstituted phenyl.
11. The method of claim 10, wherein the base is selected from the group consisting of n-butyllithium, sec-butyllithium, LDA, LiHMDS, NaHMDS, KHMDS, and sodium hydride.
12. A process for the preparation of eribulin comprising the process for the preparation of a compound of formula III as claimed in any one of claims 1 to 9, or the process for the preparation of a compound of formula II as claimed in any one of claims 10 to 11.
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竺伟: "氨基酸促进的铜催化的芳基卤化物与叠氮化钠、亚磺酸钠及频哪醇硼烷的交叉偶联反应研究", 复旦大学博士学位论文, 25 April 2006 (2006-04-25), pages 33 - 39 *

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