CN106946906A - A kind of compound and its preparation method and application - Google Patents
A kind of compound and its preparation method and application Download PDFInfo
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- CN106946906A CN106946906A CN201710315199.0A CN201710315199A CN106946906A CN 106946906 A CN106946906 A CN 106946906A CN 201710315199 A CN201710315199 A CN 201710315199A CN 106946906 A CN106946906 A CN 106946906A
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- eribulin
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 229960003649 eribulin Drugs 0.000 claims abstract description 39
- 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 claims abstract 7
- -1 p-methoxybenzyl Chemical group 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 35
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 11
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical compound OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 7
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 claims description 7
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 7
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- BFGKITSFLPAWGI-UHFFFAOYSA-N chromium(3+) Chemical compound [Cr+3] BFGKITSFLPAWGI-UHFFFAOYSA-N 0.000 claims description 6
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 23
- 238000003786 synthesis reaction Methods 0.000 abstract description 23
- 238000011084 recovery Methods 0.000 abstract 1
- 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 37
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 239000012634 fragment Substances 0.000 description 16
- 125000005103 alkyl silyl group Chemical group 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 0 *C=C([C@](CC=C)*C1CC(COC(c2ccccc2)=O)OC(c2ccccc2)=O)[C@]1O Chemical compound *C=C([C@](CC=C)*C1CC(COC(c2ccccc2)=O)OC(c2ccccc2)=O)[C@]1O 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000010410 layer Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229960000439 eribulin mesylate Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 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 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a kind of compound and its preparation method and application, wherein, the present invention converts the intermediate an of accepted way of doing sth (II) structure by that will have the compound of formula (III) structure first, formula (II) scaffold intermediate is converted into the compound of formula (IV) structure again, then formula (IV) is converted into eribulin again, each portion's reaction yield is high in the synthetic route, and then there is provided the total recovery of synthesis eribulin.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a compound, and a preparation method and application thereof.
Background
Eribulin (Eribulin) is a potent anticancer agent and has the structure shown in formula (I). It is a fully synthetic macrocyclic analogue of the natural product halichondrin B of the formula (I-halichondrin B). Halichondrin B is a very complex marine natural product. Eribulin mesylate (formula (I-1. MsOH)), developed by wei corp (Eisai co., Ltd.), was approved by the FDA in 2010 for the treatment of metastatic breast cancer, which had received at least two chemical treatments, under the trade name Halaven. It is also known as E7389, ER-086526, US NCI name NSC-707389. Eribulin mesylate was approved by the FDA in 2016 for the treatment of advanced liposarcoma.
Eribulin is one of the most complex synthetic drugs that have been prepared on a commercial scale. There are many documents reported to date about eribulin and methods for its synthesis, such as: kishi, y.et al.pureeappl.chem.2003, 75, 1-17; yu, m.j., et al, bioorg, med, chem, lett, 2004, 14, 5551-; kishi, et al.J.am.chem.Soc.2005, 127, 15382-15383; kishi, et al tetrahedron Lett.2007, 48, 8967-8971; philips, a.j., et al, angelw.chem.int.ed.2009, 48, 2346-; philips, a.j., et al, chem.rev.2009, 109, 3044-3079; kishi, et al, organic Lett.2009, 11, 4516-4519; kishi, et al, organic lett.2012, 14, 2262-; kishi, equivalent. organic lett.2012, 14, 660-; fang, f.g., et al.sylett 2013, 24, 333-; chase, c.e., et al. sylett2013, 24, 327-; lewis, b.m., et al. sylett 2013, 24, 323-. Patents include US6214865B1, US6365759B1, US6469182B1, US7982060B2, US8093410B2, US8097648B2, US8148554B2, US8203010B2, US8350067B2, US8445701B2, US8598373B2, US8618313B2, US8884031B2, US8927597B2, US2009198074a1, US2009203771a1, US2011054194a1, US2011172446a1, US2011184190a1, US2007244187a1, US2012029213a1, US2012095242A, US2012289718a1, US2012309988a1, US2013123519a1, US2013237711A, US2014163244a1, US2014221635a1, etc.; among them, the reported large-scale synthesis method has 10 steps, starting from the combination of 3 complex precursors (reaction scheme 1), defined as fragments a, B and C, respectively.
Wherein,
reaction scheme 1
The reported synthesis of fragment A, part 1, is shown in reaction scheme 2,
reaction scheme 2
The reported synthesis of fragment A, part 2, see reaction scheme 3,
in the reaction scheme 3, the reaction is carried out,
the reported synthesis of fragment A, part 3, see reaction scheme 4,
reaction scheme 4
Synthesis of reported fragment A, part 4 of reaction scheme 5
Reaction scheme 5
Synthesis of reported fragment B, part 1 see reaction scheme 6
Reaction scheme 6
The reported synthesis of fragment B, part 2, see reaction scheme 7,
reaction scheme 7
The reported synthesis of fragment B, part 3, see reaction scheme 8,
reaction scheme 8
The reported synthesis of fragment B, part 4, see reaction scheme 9,
reaction scheme 9
Synthesis of reported fragment B, see reaction scheme 10 in section 5
Reaction scheme 10
Synthesis of reported fragment C, part 1 of reaction scheme 11
Reaction scheme 11
The reported synthesis of fragment C, part 2, see reaction scheme 12,
reaction scheme 12
The reported eribulin synthesis, part 1, is shown in reaction scheme 13,
reaction scheme 13
The reported eribulin synthesis, part 2, is shown in reaction scheme 14
Reaction scheme 14
The reported eribulin synthesis, part 3 of which is shown in reaction scheme 15,
reaction scheme 15
The reported eribulin synthesis, part 4 of the reaction scheme 16
Reaction scheme 16
The reported eribulin synthesis, part 5 of which is shown in reaction scheme 17
Reaction scheme 17
From the above synthesis steps, the synthesis of the fragment A, the fragment B and the fragment C itself requires many steps (see reaction schemes 2-12), and the synthesis of eribulin from the fragments A, B and C is also relatively long (see reaction schemes 13-17). And the reported synthesis of eribulin (reaction scheme 14-16), which involves the coupling of sulfone and aldehyde, the oxidation of sulfone/alcohol compounds to form sulfone/ketone/aldehyde compounds (2), and the reduction of compounds (2) to remove the sulfone to give ketone/aldehyde compounds (3), is now disclosed. The ketone/aldehyde compound (3) is cyclized in the presence of NiCl2 and CrCl2 to form a ketone/alcohol compound (4), and then the ketone/alcohol compound (4) is oxidized to a diketone compound (5), as shown in reaction scheme 18,
the total reaction yield of the currently disclosed synthetic routes of the compounds 2 to 5 is low, and further more reaction raw materials are needed, so that the synthetic efficiency of eribulin is seriously influenced, and therefore, the development of a new eribulin synthetic method and the improvement of the synthetic efficiency and the total yield of eribulin are of great significance.
Disclosure of Invention
In view of this, the technical problem to be solved by the present invention is to provide a compound, a preparation method and an application thereof, wherein the compound provided by the present invention is used for preparing eribulin, and the total yield of eribulin is increased.
The invention provides a compound, which has a structure shown in a formula (II),
wherein, R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
ar is selected from aryl of C6-C30.
Preferably, said R is1、R2、R3、R4、R5Independently selected from TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl or 2-ethoxyethyl;
ar is 2-methylphenyl, 4-methoxyphenyl, 2-ethylphenyl, 4-ethoxyphenyl, 4-trifluoromethylphenyl or 4-fluorophenyl. Preferably, the compound is of formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5),
the invention also provides a preparation method of the compound with the structure of the formula (II), which comprises the following steps:
converting the compound with the structure of the formula (III) into a compound with the structure of the formula (II),
wherein, R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
ar is selected from aryl of C6-C30.
Preferably, the catalyst for the conversion reaction is CrCl2/NiCl2、Cp2Cr/NiCl2、CpCrCl/NiCl2、Cr(II)/Mg(0)/TMS-X/NiCl2、Cr(II)/Zn(0)/TMS-X/NiCl2、Cr(III)/Mg(0)/TMS-X/NiCl2、Cr(III)/Zn(0)/TMS-X/NiCl2Wherein Cp is cyclopentadienyl; x is halogen. Preferably, the base of the conversion reaction is one or two of triethylamine and diisopropylethylamine.
Preferably, the solvent for the transformation reaction is one or more of tetrahydrofuran, acetonitrile, DMF, DMSO, dimethylacetamide, NMP, HMPA, DMPU and dioxane.
The invention also provides a preparation method of the eribulin intermediate with the structure of formula (IV), which comprises the following steps:
converting a compound of the invention into a compound having the structure of formula (IV),
the R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25.
The invention also provides a preparation method of eribulin, which comprises the following steps:
converting the compound of the invention into eribulin.
The invention also provides a preparation method of eribulin, which comprises the following steps:
1) converting a compound of the invention into a compound having the structure of formula (IV),
the R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
2) converting the compound with the structure of the formula (IV) into eribulin.
Preferably, the reactant of the conversion reaction in the step 1) is SmI2CrCl2、NiCl2And Hg (0).
Compared with the prior art, the invention provides a compound and a preparation method and application thereof, wherein the compound with the structure of formula (III) is firstly converted into the intermediate with the structure of formula (II), then the intermediate with the structure of formula (II) is converted into the compound with the structure of formula (IV), and then the compound with the structure of formula (IV) is converted into eribulin, and experimental results show that the total yield from the compound with the structure of formula (III) to the compound with the structure of formula (IV) is up to 69%, and compared with the prior art, the yield is improved by nearly 1 time.
Detailed Description
The invention provides a compound, which has a structure shown in a formula (II),
wherein, R is1、R2、R3、R4、R5Independently selected from alkyl silicon base of C3-C30, benzyl, alkyl of C1-C5 or alkoxy of C1-C8;
ar is selected from aryl of C6-C30.
According to the invention, said R1Preferably C3-C30 alkylsilyl, benzyl, C1-C5 alkyl or C1-C8 alkoxy; more preferably an alkylsilyl group of C6-C15, a benzyl group of C8-C15, or an alkyl group of C6-C20, and more preferably TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl, or 2-ethoxyethyl; the R is2Preferably C3-C30 alkylsilyl, benzyl, C1-C5 alkyl or C1-C8 alkoxy; more preferably an alkylsilyl group of C6-C15, a benzyl group of C8-C15, or an alkyl group of C6-C20, and more preferably TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl, or 2-ethoxyethyl; the R3 is preferably C3-C30 alkylsilyl, benzyl, C1-C5 alkyl or C1-C8 alkoxy; more preferably an alkylsilyl group of C6-C15, a benzyl group of C8-C15, or an alkyl group of C6-C20, and more preferably TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl, or 2-ethoxyethyl; the R is4Preferably C3-C30 alkylsilyl, benzyl, C1-C5 alkyl or C1-C8 alkoxy; more preferably an alkylsilyl group of C6-C15, a benzyl group of C8-C15, or an alkyl group of C6-C20, and more preferably TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl, or 2-ethoxyethyl; the R is5Preferably C3-C30 alkylsilyl, benzyl, C1-C5 alkyl or C1-C8 alkoxy; more preferably an alkylsilyl group of C6-C15, a benzyl group of C8-C15, or an alkyl group of C6-C20, and still more preferably TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl, or 2-ethoxyethyl.
According to the invention, Ar is preferably an aryl group having from C7 to C20, more preferably an aryl group having from C9 to C15, and most preferably a 2-methylphenyl, 4-methoxyphenyl, 2-ethylphenyl, 4-ethoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-trifluoromethylphenyl or 4-fluorophenyl group.
More specifically, the compound of the present invention is a compound of formula (II-1), formula (II-2), formula (II-3), formula (II-4) or formula (II-5),
the invention also provides a preparation method of the compound with the structure of the formula (II), which comprises the following steps:
converting the compound with the structure of the formula (III) into a compound with the structure of the formula (II),
wherein, R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
ar is selected from aryl of C6-C30.
According to the invention, the compound with the structure of the formula (III) is converted into the compound with the structure of the formula (II), wherein R in the compound with the structure of the formula (III)1、R2、R3、R4、R5And Ar is as defined for the substituents in the intermediate; in the invention, the catalyst for the conversion reaction is CrCl2/NiCl2、Cp2Cr/NiCl2、CpCrCl/NiCl2、Cr(II)/Mg(0)/TMS-X/NiCl2、Cr(II)/Zn(0)/TMS-X/NiCl2、Cr(III)/Mg(0)/TMS-X/NiCl2、Cr(III)/Zn(0)/TMS-X/NiCl2Wherein Cp is cyclopentadienyl; x is halogen; is more excellentIs selected as CrCl2/NiCl2. The chiral ligand of the conversion reaction preferably has a structure shown in a formula (V); the solvent for the reaction is preferably one or more of tetrahydrofuran, acetonitrile, DMF, DMSO, dimethylacetamide, NMP, HMPA, DMPU and dioxane, more preferably tetrahydrofuran, acetonitrile, DMF, DMSO, dimethylacetamide, NMP or HMPA, and most preferably tetrahydrofuran and acetonitrile; the alkali of the conversion reaction is one or two of triethylamine and diisopropylethylamine. The temperature of the conversion reaction is preferably room temperature reaction, the time of the conversion reaction is preferably 1-2 hours,
in addition, it is noted that the catalyst is CrCl2/NiCl2The catalyst is represented by CrCl2And NiCl2A mixture of (a).
The invention also provides a preparation method of the eribulin intermediate with the structure of formula (IV), which comprises the following steps:
converting a compound of the invention into a compound having the structure of formula (IV),
the R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25.
According to the invention, the compound is converted into the compound with the structure of formula (IV), wherein the catalyst for the conversion reaction is preferably SmI2、CrCl2/NiCl2And Hg (0), more preferably Smi2(ii) a The solvent for the conversion reaction is preferably THF, acetonitrile, DMF, DMSO, dimethyl acetylAmine, NMP or HMPA; the temperature of the reaction is preferably-65 ℃ or lower, more preferably-68 to-75 ℃.
The invention also provides a preparation method of eribulin, which comprises the following steps:
converting the compound of the invention into eribulin. The method for converting the compound into eribulin is not particularly limited, and one skilled in the art can select a suitable synthetic route according to actual needs.
The invention also provides a preparation method of eribulin, which comprises the following steps:
1) converting a compound of the invention into a compound having the structure of formula (IV),
the R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
2) converting the compound with the structure of the formula (IV) into eribulin.
According to the invention, the compound is converted into the compound with the structure of formula (IV), wherein the catalyst for the conversion reaction is preferably SmI2、CrCl2/NiCl2And Hg (0), more preferably Smi2(ii) a The solvent for the conversion reaction is preferably THF, acetonitrile, DMF, DMSO, dimethylacetamide, NMP, or HMPA; the temperature of the reaction is preferably-65 ℃ or lower, more preferably-68 to-75 ℃.
According to the present invention, the compound having the structure of formula (IV) is converted into eribulin, and the method for converting the compound having the structure of formula (IV) into eribulin is not particularly limited, and those skilled in the art can select an appropriate reaction route according to actual conditions.
The invention provides a compound and a preparation method and application thereof, wherein the compound with the structure of formula (III) is firstly converted into an intermediate with the structure of formula (II), then the intermediate with the structure of formula (II) is converted into a compound with the structure of formula (IV), and then the compound with the structure of formula (IV) is converted into eribulin.
The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
To a 50ml three necked round bottom flask, under nitrogen, was added chiral ligand (2.96g, 10mmol) and anhydrous CrCl2(1.23g, 10mmol), and 15ml of anhydrous acetonitrile was added via syringe. The resulting suspension was heated and TEA (1.01g, 10mmol) was added dropwise with stirring to give a dark green mixture. The mixed solution was further stirred at room temperature for 40min, and NiCl 2. DMP (338mg, 1mmol) was added thereto, and the color of the reaction solution rapidly became dark. Stirring was continued for 20min, and the compound of formula (III) (1.588g, 1mmol) was dissolved in a mixed solution of 4ml of anhydrous THF and 2ml of acetonitrile and added dropwise to the reaction solution over 10min with a syringe. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour, 20ml of n-heptane was added, followed by filtration, and the filter cake was washed with n-heptane and acetonitrile. The bottom layer of the filtrate was separated, extracted with n-heptane, and the n-heptane layers combined and washed with acetonitrile. Vacuum concentrating the n-heptane layer at a temperature of less than or equal to 50 deg.C. The obtained product was purified by silica gel column chromatography to give a yellow oily compound of the formula (II) in a total amount of 1.1g, in a yield of 75%, and in a purity of 94% by high performance liquid chromatography.
In a round-bottom flask, the compound of the structure (II) (2.924g, 20mmol) is dissolved in 50ml THF, the temperature is reduced to-65 ℃, and SmI2(0.09mol/L, 560ml, 504mmol) is slowly added dropwise thereto by a syringe. The mixed reaction solution is continuously stirred for 1H at the temperature of less than or equal to-65 ℃, and then a mixed solution of K2CO 3/potassium sodium tartrate/H2O (W/W/W-1/1/10) is added to quench the reaction. The reaction was warmed to room temperature and MTBE was added. Separating organic layer, extracting water phase with MTBE, mixing organic layers, washing with saline solution, drying with anhydrous sodium sulfate, filtering, and vacuum concentrating at 50 deg.C or below. The yellow oily compound was obtained as a compound having the structure of the formula (IV) by purification by silica gel column chromatography in a total of 2.43g, in a yield of 92% and in a purity of 95% by high performance liquid chromatography.
Comparative example 1
Dissolving the compound 2a (403mg, 0.256mmol) in 10ml of anhydrous methanol and 10ml of anhydrous THF, and dropwise adding SmI at the temperature of less than or equal to-65 ℃ under the protection of argon2Solution (25.6ml, 2.56mmol, 1M in THF). After the dropwise addition, the reaction solution was kept at-65 ℃ for 1 hour or less, and monitored by TLC (supplemented with SmI when necessary)2). After the reaction is finished, 10ml of K is added at the temperature of less than or equal to minus 50 DEG C2CO3The reaction was quenched with aqueous solution. The mixture is warmed to room temperature, extracted 3 times with 100ml MTBE, the organic layers are combined, washed with 50ml brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo at 50 ℃ or below. Purifying with silica gel column chromatography using n-hexane/EA as eluent to obtain light yellow oily compound (3) 230mg with yield 60%, and detecting by high performance liquid chromatographyThe purity was 93%.
To a 100ml three necked round bottom flask, under argon protection, was added chiral ligand (1.9g, 6.42mm0l) and anhydrous CrCl2(789mg, 6.42mm0 l). At room temperature, 20ml of MeCN was added with stirring, and then TEA (661mg) was added dropwise to the mixture. After 1h of reaction, a dark green solution was obtained, to which NiCl 2. DMP (220mg, 0.642mmol) was added under argon. Stirring was continued for 30min and the reaction turned dark brown in color. Compound 3(930mg, 0.642mmol) was dissolved in 10ml of anhydrous THF, added under argon and added to the resulting dark brown solution by syringe. The reaction mixture was stirred at room temperature for 8 hours, and 50ml of n-heptane was added to quench the reaction. The reaction solution was extracted 3 times with 200ml of n-heptane, and the organic layers were combined and washed 2 times with 50ml of MeCN. Vacuum concentrating the n-heptane layer at a temperature of less than or equal to 50 deg.C. Purifying with silica gel column chromatography using n-hexane/EA as eluent to obtain yellow-green oily compound (4) 510mg with yield of 60%, and purity of 93% by high performance liquid chromatography.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (11)
1. A compound having a structure represented by formula (II),
wherein, R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
ar is selected from aryl of C6-C30.
2. A compound of claim 1, wherein R is1、R2、R3、R4R5 is independently selected from TMS, TES, TBS, TIPS, TBDPS, benzyl, p-methoxybenzyl, trityl, 2-tetrahydropyranyl, methoxymethyl or 2-ethoxyethyl;
ar is 2-methylphenyl, 4-methoxyphenyl, 2-ethylphenyl, 4-ethoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-trifluoromethylphenyl or 4-fluorophenyl.
3. The compound of claim 1, wherein the compound is of formula (II-1), formula (II-2), formula (II-3), formula (II-4), or formula (II-5),
4. a method of preparing a compound having the structure of formula (II), comprising:
converting the compound with the structure of the formula (III) into a compound with the structure of the formula (II),
wherein, R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
ar is selected from aryl of C6-C30.
5. The method according to claim 4Characterized in that the catalyst of the conversion reaction is CrCl2/NiCl2、Cp2Cr/NiCl2、CpCrCl/NiCl2、Cr(II)/Mg(0)/TMS-X/NiCl2、Cr(II)/Zn(0)/TMS-X/NiCl2、Cr(III)/Mg(0)/TMS-X/NiCl2、Cr(III)/Zn(0)/TMS-X/NiCl2Wherein Cp is cyclopentadienyl; x is halogen.
6. The method according to claim 4, wherein the base for the conversion reaction is one or both of triethylamine and diisopropylethylamine.
7. The method according to claim 4, wherein the solvent for the transformation reaction is one or more selected from tetrahydrofuran, acetonitrile, DMF, DMSO, dimethylacetamide, NMP, HMPA, DMPU and dioxane.
8. A method for preparing eribulin intermediates having the structure of formula (IV), comprising:
converting a compound according to any one of claims 1 to 3 to a compound having the structure of formula (IV),
the R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25.
9. A preparation method of eribulin comprises the following steps:
converting a compound according to any one of claims 1 to 3 into eribulin.
10. A preparation method of eribulin comprises the following steps:
1) converting a compound according to any one of claims 1 to 3 to a compound having the structure of formula (IV),
the R is1、R2、R3、R4、R5Independently selected from alkyl silicon group of C3-C30, benzyl group of C7-C30 or alkyl group of C1-C25;
2) converting the compound with the structure of the formula (IV) into eribulin.
11. The method according to claim 10, wherein the reactant of the conversion reaction in step 1) is Smi2、CrCl2/NiCl2And Hg (0).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973804A (en) * | 2017-11-29 | 2018-05-01 | 戊言医药科技（上海）有限公司 | The synthetic method of Ai Ruibulin intermediates |
| CN111689982A (en) * | 2019-03-15 | 2020-09-22 | 博瑞生物医药（苏州）股份有限公司 | Eribulin intermediate and preparation method thereof |
| WO2020216034A1 (en) * | 2019-04-26 | 2020-10-29 | 北京天一绿甫医药科技有限公司 | Intermediate of eribulin, synthesis method therefor and use thereof |
| CN113549101A (en) * | 2020-04-26 | 2021-10-26 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of eribulin and intermediate thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910180A (en) * | 2007-11-16 | 2010-12-08 | 卫材R&D管理有限公司 | Novel intermediates for halichondrin B analog synthesis and novel desulfonylation reaction for the intermediates |
| JP2010285428A (en) * | 2009-05-15 | 2010-12-24 | Eisai R & D Management Co Ltd | New method for removing substituent having hetero atom at alpha position of carbonyl group |
| WO2016031796A1 (en) * | 2014-08-27 | 2016-03-03 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for producing antitumor agent using homogenizer |
-
2017
- 2017-05-05 CN CN201710315199.0A patent/CN106946906A/en active Pending
- 2017-05-27 WO PCT/CN2017/086243 patent/WO2018201543A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101910180A (en) * | 2007-11-16 | 2010-12-08 | 卫材R&D管理有限公司 | Novel intermediates for halichondrin B analog synthesis and novel desulfonylation reaction for the intermediates |
| JP2010285428A (en) * | 2009-05-15 | 2010-12-24 | Eisai R & D Management Co Ltd | New method for removing substituent having hetero atom at alpha position of carbonyl group |
| WO2016031796A1 (en) * | 2014-08-27 | 2016-03-03 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for producing antitumor agent using homogenizer |
Non-Patent Citations (2)
| Title |
|---|
| KAZATO INANAGA 等: "Novel and Efficient Chromium(II)-Mediated Desulfonylation ofα‑Sulfonyl Ketone", 《ORGANIC LETTERS》 * |
| TAKASHI FUKUYAMA 等: "Application of a Rotor−Stator High-Shear System for Cr/Mn-Mediated Reactions in Eribulin Mesylate Synthesis", 《ORG. PROCESS RES. DEV.》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973804A (en) * | 2017-11-29 | 2018-05-01 | 戊言医药科技（上海）有限公司 | The synthetic method of Ai Ruibulin intermediates |
| CN107973804B (en) * | 2017-11-29 | 2020-07-03 | 戊言医药科技（上海）有限公司 | Synthetic method of eribulin intermediate |
| CN111689982A (en) * | 2019-03-15 | 2020-09-22 | 博瑞生物医药（苏州）股份有限公司 | Eribulin intermediate and preparation method thereof |
| CN111689982B (en) * | 2019-03-15 | 2023-04-07 | 博瑞生物医药（苏州）股份有限公司 | Eribulin intermediate and preparation method thereof |
| WO2020216034A1 (en) * | 2019-04-26 | 2020-10-29 | 北京天一绿甫医药科技有限公司 | Intermediate of eribulin, synthesis method therefor and use thereof |
| JP2022530882A (en) * | 2019-04-26 | 2022-07-04 | 北京天一緑甫医葯科技有限公司 | Eribulin intermediate, its synthesis method and use |
| US11976081B2 (en) | 2019-04-26 | 2024-05-07 | Beijing Tienyi Lufu Pharmatech Co. Ltd. | Intermediate of eribulin and synthesis method and use thereof |
| CN113549101A (en) * | 2020-04-26 | 2021-10-26 | 博瑞生物医药（苏州）股份有限公司 | Preparation method of eribulin and intermediate thereof |
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