CN113214307A - Intermediate for preparing eribulin and preparation method thereof - Google Patents
Intermediate for preparing eribulin and preparation method thereof Download PDFInfo
- Publication number
- CN113214307A CN113214307A CN202010090205.9A CN202010090205A CN113214307A CN 113214307 A CN113214307 A CN 113214307A CN 202010090205 A CN202010090205 A CN 202010090205A CN 113214307 A CN113214307 A CN 113214307A
- Authority
- CN
- China
- Prior art keywords
- configuration
- compound shown
- formula
- compound
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229960003649 eribulin Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 title claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 14
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 5
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 4
- JMVOCSLPMGHXPG-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium Chemical compound [K+].[K+].[O-][Os]([O-])(=O)=O JMVOCSLPMGHXPG-UHFFFAOYSA-N 0.000 claims description 4
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims description 4
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 36
- 238000000746 purification Methods 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000006385 ozonation reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 238000010791 quenching Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 241000353756 Halichondria okadai Species 0.000 description 1
- 229930195695 Halichondrin Natural products 0.000 description 1
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960000439 eribulin mesylate Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000008880 microtubule cytoskeleton organization Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to an eribulin intermediate and a preparation method thereof. Specifically, the invention relates to a compound shown as a formula III. The invention also particularly relates to a preparation method of the compound shown in the formula III, and a method for preparing the compound shown in the formula II by using the compound shown in the formula III. 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
Technical Field
The invention relates to an intermediate for preparing eribulin and a preparation method thereof.
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.
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. Patent CN108659031 discloses an eribulin intermediate shown in formula II, which is prepared from a compound shown in formula IV through an ozonization reaction. However, the ozonization reaction needs special ozonization generation equipment and extremely low reaction temperature, so that the complexity and energy consumption of the reaction equipment are increased, and the eribulin intermediate prepared by the ozonization reaction and shown as the formula II is low in purity and difficult in purification process, so that the quality of the eribulin final product is influenced. In addition, the ozone has extremely strong oxidizing ability, and the leakage of the gas easily causes great damage to human bodies and plastic equipment. Therefore, a milder and safer reaction condition is needed to prepare the compound shown in formula II for the synthesis of eribulin.
Disclosure of Invention
Aiming at the defects of harsh reaction conditions, large reagent hazard, difficult purification process, low purity and the like of the existing synthesis method of the eribulin key intermediate shown in the formula II, the invention provides a new synthesis method of the eribulin intermediate shown in the formula II.
The invention provides a novel method for preparing eribulin intermediate shown in formula II,
specifically, the synthesis method comprises the following steps:
1) carrying out dihydroxylation reaction on the compound shown as the formula IV to obtain a compound shown as a formula III;
2) carrying out oxidation reaction on the compound shown in the formula III to obtain a compound shown in a formula II;
wherein, in the compound shown in the formula III, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
Wherein, the compound IV can be prepared according to the patent (CN 108659031).
In a preferred embodiment of the present invention, the method comprises the following steps:
1) adding a dihydroxylation reaction catalyst and a dihydroxylation reaction equivalent oxidant into an organic solvent or an organic solvent/water mixed solvent of a compound IV at 0-40 ℃, reacting, and continuously stirring for 30 min-6 h at 0-40 ℃. TLC showed complete conversion of starting material. Adding sodium thiosulfate aqueous solution to carry out quenching reaction, extracting with ethyl acetate, concentrating an organic phase, and purifying by column chromatography to obtain the compound shown in the formula III.
2) Adding an oxidizing reagent into an organic solvent or an organic solvent/water mixed solvent of the compound III at 0-40 ℃, and continuously stirring for 30 min-6 h at 0-40 ℃ for reaction. TLC showed complete conversion of starting material. And (3) filtering the reaction liquid by using kieselguhr, washing a filter cake by using ethyl acetate, concentrating the filtrate, and purifying by column chromatography to obtain the compound shown as the formula II.
Compared with the existing ozonization scheme (CN108659031), the scheme for preparing the compound shown in the formula II has the advantages of mild reaction conditions, safe reaction reagents, low energy consumption, simple equipment operation and the like. On the other hand, the obtained compound shown as the formula II has higher purity due to the addition of an intermediate (the compound shown as the formula III) and column chromatography purification operation, and is more suitable for preparing eribulin.
In a preferred embodiment of the present invention, the dihydroxylation reaction catalyst in step 1) is selected from one or more of osmium tetraoxide, potassium osmate and potassium permanganate.
In another preferred embodiment of the present invention, the dihydroxylation equivalent oxidant of step 1) is selected from NMO, K3Fe(CN)6One or more of (a).
In a preferred embodiment of the present invention, the organic solvent in step 1) is selected from one or more of tert-butanol, acetone, tetrahydrofuran, isopropanol, ethanol, ethyl acetate and dichloromethane.
In another preferred embodiment of the present invention, the oxidation reagent in step 2) is selected from one or more of sodium periodate and lead tetraacetate.
In a preferred embodiment of the present invention, the organic solvent in step 2) is selected from one or more of tert-butanol, acetone, tetrahydrofuran, isopropanol, ethanol, methanol, dichloromethane, ethyl acetate, and toluene.
The invention also provides a compound shown as the formula III,
wherein, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
The invention also provides a preparation method of the compound shown in the formula III, which is characterized in that the compound is prepared by carrying out dihydroxylation reaction on the compound shown in the formula IV,
wherein, in the compound shown in the formula III, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
In a preferred embodiment of the present invention, the method comprises the following steps:
adding a dihydroxylation reaction catalyst and a dihydroxylation reaction equivalent oxidant into an organic solvent or an organic solvent/water mixed solvent of a compound IV at 0-40 ℃, reacting, and continuously stirring for 30 min-6 h at 0-40 ℃. TLC showed complete conversion of starting material. Adding sodium thiosulfate aqueous solution to carry out quenching reaction, extracting with ethyl acetate, concentrating an organic phase, and purifying by column chromatography to obtain the compound shown in the formula III.
In a preferred embodiment of the present invention, the dihydroxylation catalyst is selected from one or more of osmium tetraoxide, potassium osmate and potassium permanganate.
In another preferred embodiment of the present invention, the dihydroxylation equivalent oxidant is selected from NMO, K3Fe(CN)6One or more of (a).
In another preferred embodiment of the present invention, the organic solvent is selected from one or more of tert-butanol, acetone, tetrahydrofuran, isopropanol, ethanol, ethyl acetate, and dichloromethane.
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 is prepared by oxidation reaction,
wherein, in the compound shown in the formula III, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
In a preferred embodiment of the present invention, the method comprises the following steps:
adding an oxidizing reagent into an organic solvent or an organic solvent/water mixed solvent of the compound III at 0-40 ℃, and continuously stirring for 30 min-6 h at 0-40 ℃ for reaction. TLC showed complete conversion of starting material. And (3) filtering the reaction liquid by using kieselguhr, washing a filter cake by using ethyl acetate, concentrating the filtrate, and purifying by column chromatography to obtain the compound shown as the formula II.
In a preferred embodiment of the present invention, the oxidation reagent is selected from one or more of sodium periodate and lead tetraacetate.
In another preferred embodiment of the present invention, the organic solvent is selected from one or more of tert-butanol, acetone, tetrahydrofuran, isopropanol, ethanol, methanol, dichloromethane, ethyl acetate, and toluene.
In another aspect, the present invention also provides a method for preparing eribulin, comprising preparing a compound of formula II according to the methods provided herein, and then preparing eribulin from the compound of formula II according to known methods, wherein reference is made to the following references: org.lett.2002, 4, 4435; org.lett.2009, 11, 4520; j.am.chem.soc.2009, 131, 15636; angew.chem.intl.ed.2009, 48, 2346; synlett.2013, 24, 323; synlett.2013, 24, 327; synlett.2013, 24, 333.
Abbreviation table:
the following table shows the structural formulae of the compounds mentioned in the examples
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 III
Compound IV (20g, 31.90mmol, 1eq.) was dissolved in a mixed solvent of acetone (200mL) and water (50mL) at 0 deg.C, potassium osmate (117mg) and NMO (4.93g) were added sequentially, the reaction was stirred at 20 deg.C for 6h, TLC showed complete conversion of the starting material, and the reaction was quenched by addition of aqueous sodium thiosulfate. Extraction with ethyl acetate, concentration of the organic phase and purification by column chromatography gave 19.95g of compound III.
MS(ESI)m/z：661(M+H+).
1H NMR(400MHz，Chloroform-d)δ7.74(d，J＝7.9Hz，2H)，7.34(d，J＝7.9Hz，2H)，3.92-3.76(m，2H)，3.76-3.60(m，5H)，3.61-3.45(m，2H)，3.44-3.35(m，2H)，3.31(d，J＝6.5Hz，3H)，3.00(dd，J＝7.5，3.9Hz，2H)，2.68(q，J＝7.6Hz，2H)，2.50(q，J＝6.1，4.6Hz，1H)，2.02-1.84(m，2H)，1.87-1.51(m，7H)，1.20(t，J＝7.6Hz，3H)，0.80(dd，J＝3.8，1.0Hz，18H)，0.00(s，6H)，-0.04(s，6H).
Example 2: preparation of Compound III
Compound IV (20g, 31.90mmol, 1eq.) was dissolved in a mixed solvent of tert-butanol (200mL) and water (50mL) at 20 ℃ and osmium tetroxide (95mg) and K were added in that order3Fe(CN)6(15.75g), the reaction was stirred at 40 ℃ for 2h, TLC showed complete conversion of starting material, and the reaction was quenched by addition of aqueous sodium thiosulfate. Extraction with ethyl acetate, concentration of the organic phase and purification by column chromatography gave 19.02g of compound III.
MS(ESI)m/z：661(M+H+).
1H NMR(400MHz，Chloroform-d)δ7.74(d，J＝7.9Hz，2H)，7.34(d，J＝7.9Hz，2H)，3.92-3.76(m，2H)，3.76-3.60(m，5H)，3.61-3.45(m，2H)，3.44-3.35(m，2H)，3.31(d，J＝6.5Hz，3H)，3.00(dd，J＝7.5，3.9Hz，2H)，2.68(q，J＝7.6Hz，2H)，2.50(q，J＝6.1，4.6Hz，1H)，2.02-1.84(m，2H)，1.87-1.51(m，7H)，1.20(t，J＝7.6Hz，3H)，0.80(dd，J＝3.8，1.0Hz，18H)，0.00(s，6H)，-0.04(s，6H).
Example 3: preparation of Compound II
Compound III (18g, 27.23mmol, 1eq.) was dissolved in a mixed solvent of tetrahydrofuran (200mL) and water (200mL) at 0 ℃, sodium periodate (6.99g) was added, the reaction was stirred at 25 ℃ for 2h, TLC showed complete conversion of the starting material, the reaction was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to give 16.4g of compound II. HPLC purity 99.3%.
MS(ESI)m/z：629(M+H+).
1H NMR(400MHz，Chloroform-d)δ9.63(t，J＝1.4Hz，1H)，7.83-7.60(m，2H)，7.39-7.25(m，2H)，3.94-3.81(m，2H)，3.78-3.63(m，2H)，3.49(dd，J＝10.2，5.5Hz，1H)，3.38(dd，J＝10.2，5.5Hz，1H)，3.29(s，3H)，3.22(dd，J＝14.1，5.1Hz，1H)，3.00(dd，J＝14.1，8.9Hz，1H)，2.81(ddd，J＝17.5，6.5，1.8Hz，1H)，2.78(q，J＝7.6Hz，2H)，2.70(ddd，J＝17.5，5.9，1.2Hz，1H)，2.42(ddd，J＝8.9，5.0，1.2Hz，1H)，1.89(ddd，J＝13.9，6.3，5.1Hz，1H)，1.30(t，J＝7.6Hz，3H)，0.81(d，J＝3.3Hz，18H)，0.00(s，6H)，-0.03(s，3H)，-0.04(s，3H).
Example 4: preparation of Compound II
Compound III (18g, 27.23mmol, 1eq.) was dissolved in a mixed solvent of methanol (200mL) and water (200mL) at 20 ℃, sodium periodate (6.99g) was added, the reaction was stirred at 40 ℃ for 30min, TLC showed complete conversion of the starting material, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to give 16.6g of compound II. HPLC purity 99.4%.
MS(ESI)m/z：629(M+H+).
1H NMR(400MHz，Chloroform-d)δ9.63(t，J＝1.4Hz，1H)，7.83-7.60(m，2H)，7.39-7.25(m，2H)，3.94-3.81(m，2H)，3.78-3.63(m，2H)，3.49(dd，J＝10.2，5.5Hz，1H)，3.38(dd，J＝10.2，5.5Hz，1H)，3.29(s，3H)，3.22(dd，J＝14.1，5.1Hz，1H)，3.00(dd，J＝14.1，8.9Hz，1H)，2.81(ddd，J＝17.5，6.5，1.8Hz，1H)，2.78(q，J＝7.6Hz，2H)，2.70(ddd，J＝17.5，5.9，1.2Hz，1H)，2.42(ddd，J＝8.9，5.0，1.2Hz，1H)，1.89(ddd，J＝13.9，6.3，5.1Hz，1H)，1.30(t，J＝7.6Hz，3H)，0.81(d，J＝3.3Hz，18H)，0.00(s，6H)，-0.03(s，3H)，-0.04(s，3H).
Example 5: preparation of Compound II
Compound III (15g, 22.69mmol, 1eq.) was dissolved in dichloromethane at 20 ℃, lead tetraacetate (20.12g) was added, the reaction was stirred at 30 ℃ for 6h, TLC showed complete conversion of the starting material, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to give 13.98g of compound II. HPLC purity 99.2%.
MS(ESI)m/z：629(M+H+).
1H NMR(400MHz，Chloroform-d)δ9.63(t，J＝1.4Hz，1H)，7.83-7.60(m，2H)，7.39-7.25(m，2H)，3.94-3.81(m，2H)，3.78-3.63(m，2H)，3.49(dd，J＝10.2，5.5Hz，1H)，3.38(dd，J＝10.2，5.5Hz，1H)，3.29(s，3H)，3.22(dd，J＝14.1，5.1Hz，1H)，3.00(dd，J＝14.1，8.9Hz，1H)，2.81(ddd，J＝17.5，6.5，1.8Hz，1H)，2.78(q，J＝7.6Hz，2H)，2.70(ddd，J＝17.5，5.9，1.2Hz，1H)，2.42(ddd，J＝8.9，5.0，1.2Hz，1H)，1.89(ddd，J＝13.9，6.3，5.1Hz，1H)，1.30(t，J＝7.6Hz，3H)，0.81(d，J＝3.3Hz，18H)，0.00(s，6H)，-0.03(s，3H)，-0.04(s，3H).
Example 6; preparation of Compound II (comparative example, ozonization reaction)
Dissolving the compound IV (2g) in 20mL of isopropanol, cooling to-40 ℃, introducing ozone, stirring for 30min, adding triphenylphosphine (20g) to quench the reaction, stirring for 2h, directly concentrating the reaction solution, and carrying out column chromatography to obtain 1.8g of a compound II. HPLC purity 97.1%.
MS(ESI)m/z：629(M+H+).
1H NMR(400MHz，Chloroform-d)δ9.63(t，J＝1.4Hz，1H)，7.83-7.60(m，2H)，7.39-7.25(m，2H)，3.94-3.81(m，2H)，3.78-3.63(m，2H)，3.49(dd，J＝10.2，5.5Hz，1H)，3.38(dd，J＝10.2，5.5Hz，1H)，3.29(s，3H)，3.22(dd，J＝14.1，5.1Hz，1H)，3.00(dd，J＝14.1，8.9Hz，1H)，2.81(ddd，J＝17.5，6.5，1.8Hz，1H)，2.78(q，J＝7.6Hz，2H)，2.70(ddd，J＝17.5，5.9，1.2Hz，1H)，2.42(ddd，J＝8.9，5.0，1.2Hz，1H)，1.89(ddd，J＝13.9，6.3，5.1Hz，1H)，1.30(t，J＝7.6Hz，3H)，0.81(d，J＝3.3Hz，18H)，0.00(s，6H)，-0.03(s，3H)，-0.04(s，3H).
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 (8)
1. A compound shown as a formula III in the specification,
wherein, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
2. A preparation method of a compound shown in a formula III is characterized in that the compound is prepared by carrying out dihydroxylation reaction on a compound shown in a formula IV,
wherein, in the compound shown in the formula III, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
3. A preparation method of a compound shown in a formula II is characterized in that the compound is prepared by oxidation reaction of a compound shown in a formula III,
wherein, in the compound shown in the formula III, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
4. A preparation method of a compound shown as a formula II is characterized by comprising the following steps,
1) carrying out dihydroxylation reaction on the compound shown as the formula IV to obtain a compound shown as a formula III;
2) carrying out oxidation reaction on the compound shown in the formula III to obtain a compound shown in a formula II;
wherein, in the compound shown in the formula III, the configuration of the chiral center at the C27 position can be R configuration, S configuration or racemic configuration.
5. The method for preparing a compound represented by formula II according to claim 4, wherein the dihydroxylation reaction catalyst in step 1) is selected from one or more of osmium tetraoxide, potassium osmate and potassium permanganate.
6. The method of claim 4, wherein the dihydroxylation equivalent oxidant of step 1) is NMO or K3Fe(CN)6One or more of (a).
7. The method according to claim 4, wherein the oxidation reagent in step 2) is selected from one or more of sodium periodate and lead tetraacetate.
8. A preparation method of eribulin is characterized by comprising the step of preparing eribulin from a compound shown in formula III.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010090205.9A CN113214307A (en) | 2020-02-04 | 2020-02-04 | Intermediate for preparing eribulin and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010090205.9A CN113214307A (en) | 2020-02-04 | 2020-02-04 | Intermediate for preparing eribulin and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113214307A true CN113214307A (en) | 2021-08-06 |
Family
ID=77085557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010090205.9A Withdrawn CN113214307A (en) | 2020-02-04 | 2020-02-04 | Intermediate for preparing eribulin and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113214307A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180009825A1 (en) * | 2016-07-06 | 2018-01-11 | Apicore Us Llc | Methods of making eribulin mesylate |
| CN108659031A (en) * | 2017-03-28 | 2018-10-16 | 上海时莱生物技术有限公司 | A kind of intermediate and preparation method thereof being used to prepare eribulin |
| CN108948064A (en) * | 2017-05-17 | 2018-12-07 | 上海时莱生物技术有限公司 | A kind of eribulin intermediate and preparation method thereof |
| WO2019102490A1 (en) * | 2017-11-21 | 2019-05-31 | Natco Pharma Limited | Intermediates for the preparation of eribulin thereof |
-
2020
- 2020-02-04 CN CN202010090205.9A patent/CN113214307A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180009825A1 (en) * | 2016-07-06 | 2018-01-11 | Apicore Us Llc | Methods of making eribulin mesylate |
| CN108659031A (en) * | 2017-03-28 | 2018-10-16 | 上海时莱生物技术有限公司 | A kind of intermediate and preparation method thereof being used to prepare eribulin |
| CN108948064A (en) * | 2017-05-17 | 2018-12-07 | 上海时莱生物技术有限公司 | A kind of eribulin intermediate and preparation method thereof |
| WO2019102490A1 (en) * | 2017-11-21 | 2019-05-31 | Natco Pharma Limited | Intermediates for the preparation of eribulin thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Park et al. | Catalytic osmylation of conjugated dienes: a one-pot stereoselective synthesis of polyols | |
| CN112608296B (en) | Synthesis method of Brazilane natural product Brazilane | |
| CN114644612B (en) | Preparation method of benzodiazepine nerve inhibitor intermediate compound | |
| CN112609202B (en) | Method for synthesizing natural product Xanthoisozoline B through electrocatalysis and product thereof | |
| CN113214307A (en) | Intermediate for preparing eribulin and preparation method thereof | |
| CN106892928B (en) | A kind of synthetic method of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates | |
| CN105085463B (en) | A kind of microwave quickly prepares seven yuan of methods of lactone of biaryl | |
| CN113278021B (en) | Preparation method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate and oxalate thereof | |
| CN105646532B (en) | A kind of synthetic method of diaza spiro [5.6] dodecane of 2 tertbutyloxycarbonyl, 10 carbonyl, 8 oxo 2,11 | |
| CN113651812A (en) | Preparation method of polysubstituted indolizine derivative | |
| CN107216332A (en) | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 | |
| CN111793047A (en) | Preparation method of eribulin intermediate | |
| CN110922355A (en) | Preparation method of nicorandil | |
| CN104341428A (en) | Pentamethyl pentacarbonyl cucurbit[5]uril and preparation method thereof | |
| CN116102562B (en) | A naphtho[2,1-b]indolo[2,3-d]cyclooctanolactone derivative and preparation method thereof | |
| CN115160280B (en) | Synthesis method of flavonoid compound | |
| CN119143773B (en) | Preparation method of indolone spiro isochromanone derivative | |
| CN115872995B (en) | Pyrazolopyridine compound and preparation method of carboxylic acid derivative | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester | |
| CN111171006B (en) | Process method of 3-substituted iminodibenzyl amino compound | |
| CN115716799A (en) | Method for preparing cis-chiral-3-fluoro-4-hydroxypiperidine and derivatives thereof by reduction of organic borohydride metal reagent | |
| CN114716452A (en) | Dihydro-L-glucosone enamine derivative and preparation method thereof | |
| CN119432937A (en) | Method for preparing milabalin by chemical-enzymatic method | |
| CN118480055A (en) | Preparation method of [1,2] oxazine [2,3-b ] isoquinoline-10-ketone derivative | |
| CN116891430A (en) | Synthesis method of dimethylpyridine amine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20210806 |