CN111285894B - 用于制备软海绵素类化合物的中间体及其制备方法 - Google Patents
用于制备软海绵素类化合物的中间体及其制备方法 Download PDFInfo
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- CN111285894B CN111285894B CN201811508481.1A CN201811508481A CN111285894B CN 111285894 B CN111285894 B CN 111285894B CN 201811508481 A CN201811508481 A CN 201811508481A CN 111285894 B CN111285894 B CN 111285894B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- 229930195695 Halichondrin Natural products 0.000 title claims abstract description 26
- 229960003649 eribulin Drugs 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 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 3
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 52
- -1 sulfonyloxy Chemical group 0.000 claims description 43
- 239000002904 solvent Substances 0.000 claims description 31
- 230000008569 process Effects 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 150000004795 grignard reagents Chemical class 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 239000007818 Grignard reagent Substances 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- UKRDPEFKFJNXQM-UHFFFAOYSA-N vinylsilane Chemical compound [SiH3]C=C UKRDPEFKFJNXQM-UHFFFAOYSA-N 0.000 claims description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- 150000003855 acyl compounds Chemical class 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- 239000011630 iodine Chemical group 0.000 claims description 4
- 229910052740 iodine Chemical group 0.000 claims description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 2
- 125000000020 sulfo group Chemical class O=S(=O)([*])O[H] 0.000 claims description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- 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 1
- 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 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 15
- 239000012634 fragment Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000010276 construction Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 231100000086 high toxicity Toxicity 0.000 abstract 1
- 238000003908 quality control method Methods 0.000 abstract 1
- 239000012974 tin catalyst Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 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 15
- 239000012074 organic phase Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 230000003647 oxidation Effects 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000012046 mixed solvent Substances 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 230000000171 quenching effect Effects 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 4
- 229930190448 norhalichondrin Natural products 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 150000007530 organic bases Chemical group 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 4
- 125000001831 (C6-C10) heteroaryl group Chemical group 0.000 description 3
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000007848 Bronsted acid Substances 0.000 description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明涉及用于制备软海绵素类化合物的中间体及其制备方法。尤其是涉及用于制备软海绵素、艾日布林或其类似物的中间体、制备方法和用途。所述中间体、其制备方法和用途用于构建软海绵素类化合物的C20‑C26结构片段。本发明合成路线的起始原料廉价易得,来源稳定且质量可靠;手性中心构建构方法的选择上充分利用了反应物本身的结构特点,切实提高了合成效率,降低了产品质量控制的难度和风险;并且避免使用高毒性且昂贵的有机锡催化剂,显著改善了成本和环境友好性。
Description
技术领域
本发明涉及可用于制备软海绵素或其类似物、特别是艾日布林的中间体化合物、以及这些中间体化合物的制备方法,属于有机合成技术领域。
背景技术
软海绵素(Halichondrin,以下简称HB)是一类存在于海绵体内、具有聚醚大环内酯结构的天然产物,这类物质具有强烈的抗肿瘤作用和广阔的药用前景。基于其结构差异,这类天然产物被分为以下几类:去甲软海绵素(norhalichondrin)、软海绵素(Halichondrin)、高软海绵素(homohalichondrin)等,且每一类都有一系列代表亚型,所述亚型和具体结构是本领域已知的,且详细公开于WO2016003975A1中,在此全文引入该现有技术文献;艾日布林(Eribulin,以下简称EB)是一种软海绵素的结构简化类似物,目前已在临床上用于治疗晚期乳腺癌和脂肪肉瘤。
HB和EB均无法从天然来源大量获取,只能依赖于人工合成。由于这类化合物结构类似,特别是C1-C29部分具有完全相同的结构,为此可将适宜的中间体化合物用于合成此类化合物。例如,可将下式1a和式4所示的中间体用于构建艾日布林的C20-C35的片段部分。
或者,可用下式1b和式6所示的中间体构建艾日布林的C20-C35的片段部分。
然而,现有技术中,上述式4或式6化合物的制备方法存在诸多缺陷,例如,合成路线过于冗长,起始原料光学纯度难以控制,涉及高毒性且昂贵的n-Bu3SnH试剂,立体选择性不佳等。这些缺陷会带来成本控制、环境和劳动保护、产品品质等一系列的生产问题。因此,亟需开发可改善合成效率、改善生产成本、易于工业化大规膜生产、提高选择性、产率和纯度、且环境友好的中间体或合成方法,以改善软海绵素类药物化合物的制备方法。
发明内容
为改善上述问题,本发明提供如下的用于构建软海绵素及其类似物,尤其是艾日布林的C20-C26结构片段的中间体及其制备方法。
本发明第一方面,提供式(8)化合物的制备方法,所述式(8)如下定义:
其中,R1选自羟基保护基;
R2、R3相同或不同,彼此独立地选自H和ORa,Ra独立的选自H、C1-10烷基、RbSO2,其中Rb为C1-10烷基;或者R2和R3均为ORa,且两个Ra键链形成C1-6亚烷基;或者R2和R3与其键链的碳一起形成羰基;
X选自卤素、磺酰氧基。
优选地,R1选自甲硅烷类羟基保护基,例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等。
R2、R3中的一个选自H,另一个选自ORa,且Ra为H或i-PrSO2;或者R2和R3均为ORa,且两个Ra键链形成亚正丙烷基;或者R2和R3与其键链的碳一起形成羰基;
X选自氯、溴、碘等。
所述方法包括如下步骤:
其中,式(2)中的R5选自甲硅烷基,例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等;式(1)-(2)中的噁唑烷酮结构部分为噁唑烷酮类手性辅基,例如:R4为C1-10烷基,取代或未取代的苯基,或取代或未取代的苄基的2-氧代噁唑烷酮。优选地,所述R4是异丙基,未取代或羟基、硝基、二甲氨基单取代或多取代的苯基或苄基。
优选地,还包括将式(2)重结晶一次、二次或多次的步骤。
所述反应在碘化亚铜(CuI)存在下,惰性气氛,-50℃~0℃和溶剂中进行。所述溶剂可以是四氢呋喃或无水乙醚,CuI的用量(质量)约为反应物式(1)的10-25%,优选地为15-20%。
优选地,由式(1)制备式(2)后,将式(2)重结晶即可控制降低其光学异构体的含量。所述重结晶的溶剂是那些在室温或略高于室温溶解式(2)、在较低温度下(例如-10~-30℃)可析晶的任何溶剂,例如非极性有机溶剂,优选烷烃,其实例可以是正戊烷、正己烷、正庚烷、异辛烷,或其混合溶剂,例如石油醚。
优选地,所述重结晶可多次反复进行。经过一次重结晶,本发明式(2)的异构体含量可控制在1%及以下,两次重结晶异构体含量可控制在1‰及以下,经过多次重结晶,异构体含量可控制在更低范围内。本领域技术人员可以理解,本发明式(2)中β-甲基所连接的手性碳原子的构型在后续的转化过程中不会再发生改变,因此与该手性碳的构型相关的纯度将得以保持。
根据本发明,所述格氏试剂的制备方法包括以下步骤:
乙烯基硅烷与卤代试剂在较低温度(例如-30~-10℃)下混合,室温下加入缚酸剂,回流反应得到卤代乙烯基硅烷。所述缚酸剂可以是有机弱碱或无机弱碱,例如是二乙胺,乙二胺,三乙胺,二异丙基胺,吡啶,碳酸钾,碳酸钠,碳酸铯等。
上述卤代乙烯基硅烷在非质子性溶剂中与金属镁或金属锂反应生成相应的格氏试剂或锂试剂。所述非质子性溶剂可以是醚类溶剂,如乙醚,二异丙醚,叔丁基甲基醚,环己基甲基醚,四氢呋喃,二氧六环等,或者烃类溶剂,如正戊烷,正己烷,正庚烷,苯,甲苯,二甲苯等。
或者,上述卤代乙烯基硅烷也可在如上所述溶剂中与其他易得格氏试剂,如甲基,乙基,正丙基,异丙基格氏试剂等,或易得烷基锂试剂,如甲基,正丁基,仲丁基,叔丁基锂,进行金属-卤素交换反应,生成相应的格氏试剂或锂试剂。
根据本发明上述式(8)化合物的制备方法,进一步包括由式(2)至式(3)的如下步骤:
其中,式(3)的X为卤素或磺酰氧基。
根据本发明,所述反应是本领域技术人员已知的卤代反应,其在合适的溶剂中,温和的反应温度下,例如0℃至室温的条件下进行。所用卤代试剂可以是X2、RCO2X、RnSiX4-n,其中X选自氯、溴、碘的卤素,且X2中的两个X可不同,R选自C1-10烷基或氟代烷基,n为1~3的整数。所述卤代试剂的实例可以是氯、溴、碘的单质,BrCl,ICl,TMSCl,TMSI,CF3CO2I等。
或者,本发明的制备方法,还进一步包括将X为卤素的式(3)化合物根据本领域已知的取代反应进一步转化为X为磺酰氧基的式(3)化合物。
根据本发明上述式(8)化合物的制备方法,进一步包括如下步骤:
由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)化合物
根据本发明,所述反应在碱性、低温条件下(-80℃~-20℃)进行,所述反应可选的使用催化量的氯化锂和溶剂。所述碱选自有机碱、无机碱或其混合物,例如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾、碳酸铯、三乙胺、吡啶、哌啶、正丁基锂(n-BuLi)中的一种或多种。所述溶剂例如是四氢呋喃、N,N-二甲基甲酰胺(DMF)、二氯乙烷、乙醚、四氯化碳、甲苯等;所述酰基化合物可以是酯、羧酸、酰卤或酸酐。根据本发明的一个实施方式,所述噁唑烷酮类手性辅基与酰卤在-80~-60℃、四氢呋喃为溶剂、氩气保护和正丁基锂的存在下反应,所述正丁基锂的质量用量约为噁唑烷酮的30-50%;或者所述噁唑烷酮类手性辅基与酸酐在-30~-20℃、四氢呋喃为溶剂、氯化锂和三乙胺的存在下反应,所述氯化锂的质量用量约为噁唑烷酮的35%-55%。
根据本发明上述式(8)化合物的制备方法,进一步包括如下步骤:由式(3)制备式(4):
所述反应在脱除分离噁唑烷酮手性辅基的条件下进行,优选在碱性条件下水解去除。
根据本发明,所述反应在-15~5℃、碱性条件和溶剂介质,以及可选的过氧化氢中进行。所述反应温度可以是-10~0℃,优选-5~0℃。所述的碱可以选自有机碱、无机碱或其混合物,例如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、碳酸铯、氢氧化锂、氢氧化锂水合物、氢氧化钠、氢氧化钾、氢氧化钙、氨水、醋酸钠、三乙胺、吡啶、哌啶中的一种或多种。所述溶剂是水与醇类,醚类,例如四氢呋喃(THF)或二氧六环,丙酮中的一种或多种形成的混合溶剂,混合溶剂中水与有机溶剂的比例(体积比)可以为约1∶1~约1∶6,优选为约1∶2~1∶3。作为本发明的一个实施方式,所述反应在-5~0℃、四氢呋喃与水的混合溶剂、一水合氢氧化锂、过氧化氢的存在下进行,所述化合物式(3)与过氧化氢与一水合氢氧化锂的质量比为12-20∶3-9∶1-6。
根据本发明上述式(8)化合物的制备方法,进一步包括如下步骤:由式(4)制备式(5):
根据本发明,所述反应在偶联剂的存在下进行,所述偶联剂可以是EDCI/DMAP,EDC/DMAP,EDC/NHS,DCC/NHS体系,所述反应在15-40℃,优选室温(20-25℃)下反应。反应溶剂可以是二氯甲烷(DCM)、四氢呋喃(THF)和二甲基甲酰胺(DMF)等。
根据本发明上述式(8)化合物的制备方法,进一步包括如下步骤:由式(5)和醛制备式(6):
根据本发明,所述反应在四氯化钛(TiCl4)和三乙胺(TEA)的存在下,以惰性气氛保护,在较低温度-10~10℃,优选0℃,进行反应,所述反应溶剂可以是二氯甲烷(DCM)等。
根据本发明,上述醛的制备方法,包括如下步骤:
(I)丁二醇与RnSiX4-n在偶联剂的存在下反应得到单羟基保护的产物;
其中X选自氯、溴、碘的卤素,R选自C1-10烷基或氟代C1-10烷基,n为1~3的整数。所述卤代硅烷的实例可以是TMSCl,TMSI,TBDPSCl,TBDPSI等。
所述偶联剂可以是EDCI/DMAP,EDC/DMAP,EDC/NHS,DCC/NHS体系,所述反应在15-40℃,优选室温(20-25℃)下反应。反应溶剂可以是二氯甲烷(DCM)、四氢呋喃(THF)和二甲基甲酰胺(DMF)等。
(II)氧化步骤(I)的产物。
所述氧化是如下文所述的将醇氧化为醛或酮的任一方法。
根据本发明上述式(8)化合物的制备方法,进一步包括如下步骤:由式(6)制备式(7):
根据本发明,所述氧化是本领域技术人员已知的可实现将醇氧化为醛或酮的任何方法,例如swern氧化、Pfitzner-Moffatt氧化、Albright-Goldman氧化法。作为本发明的一个实施方式,所述氧化采用Parikh-Doering氧化法:二甲亚砜(DMSO)和三氧化硫-吡啶络合物(SO3·py)在-15~25℃、碱性条件下与醇反应。所述碱可以是三乙胺或N,N-二异丙基乙胺(DIPEA);所述反应温度优选为0℃至室温(20-25℃);所述反应可选的加入溶剂,这取决于DMSO的加入量,少量DMSO则需使用较多的溶剂,而较多的DMSO则可加入少量溶剂或不使用溶剂,所述溶剂例如是二氯甲烷、四氢呋喃、氯仿等。
根据本发明上述式(8)化合物的制备方法,进一步包括如下步骤:上述式(7)水解,得到“R2和R3与其键链的碳一起形成羰基”的式(8)。
根据本发明,所述反应是水解反应,其在15-40℃、碱性条件和溶剂介质中进行。所述反应温度可以是室温(20-25℃),所述的碱可以选自有机碱、无机碱或其混合物,例如碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、碳酸铯、氢氧化锂、氢氧化锂水合物、氢氧化钠、氢氧化钾、氢氧化钙、氨水、醋酸钠、三乙胺、吡啶、哌啶中的一种或多种。所述溶剂可以是水与醇类,醚类,例如四氢呋喃(THF)和二氧六环,丙酮中的一种或多种形成的混合溶剂,混合溶剂中水与有机溶剂的比例(体积比)可以为约1∶1-约1∶6,优选为约1∶4。作为本发明的一个实施方式,水解反应在室温、四氢呋喃与水的混合溶剂、一水合氢氧化锂存在下进行。
根据本发明上述式(8)化合物的制备方法,任选地,包括由式(6)化合物进一步得到“R2、R3相同或不同,彼此独立地选自H和ORa,Ra独立的选自H、C1-10烷基、RbSO2,其中Rb为C1-10烷基”的式(8)的步骤。所述反应是本领域所公知的羟基烷基化或磺酰化反应。
根据本发明上述式(8)化合物的制备方法,任选地,包括由“R2和R3与其键链的碳一起形成羰基”的式(8)形成“R2和R3均为ORa,且两个Ra键链形成C1-6亚烷基”的式(8)的步骤。所述反应是本领域公知的生产缩酮的反应,例如,酮与相应的二醇,例如乙二醇,丙二醇等,在对甲苯磺酸催化下,用苯或甲苯做带水剂,可得到所述缩酮。
根据本发明,所述式(8)是构建软海绵素,尤其是艾日布林或其可药用盐的C20-C26结构片段的中间体。
本发明第二方面,提供下式(2)所示的化合物及其制备方法:
其中R4、R5的定义如上所述。
式(2)化合物的制备方法,包括上述的由式(1)制备式(2)的步骤。
根据本发明,所述式(2)化合物的制备方法,还进一步包括上述的重结晶一次、两次或多次的步骤。
根据本发明,所述式(2)化合物的制备方法,还进一步包括由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)的步骤。
本发明第三方面,提供下式(3)所示的化合物及其制备方法:
其中,R4、X的定义如上所述。
式(3)化合物的制备方法,包括上述由式(2)制备式(3)的步骤。
根据本发明,所述制备方法还进一步包括上述式(2)化合物的制备方法。优选地,还进一步包括上述的重结晶式(2)化合物一次、两次或多次的步骤。
优选地,还进一步包括由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)的步骤。
本发明第四方面,提供下式(7)所示的化合物及其制备方法:
其中,R1选自羟基保护基;
R2、R3相同或不同,彼此独立地选自H和ORa,Ra独立的选自H、C1-10烷基、RbSO2,其中Rb为C1-10烷基;或者R2和R3均为ORa,且两个Ra键链形成C1-6亚烷基;或者R2和R3与其键链的碳一起形成羰基;
X选自、卤素、磺酰氧基。
优选地,R1选自甲硅烷类羟基保护基,例如TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS等。
R2、R3中的一个选自H,另一个选自ORa,且Ra为H或i-PrSO2;或者R2和R3均为ORa,且两个Ra键链形成亚正丙烷基;或者R2和R3与其键链的碳一起形成羰基;
X选自氯、溴、碘等。
所述式(7)化合物的制备方法,包括以下步骤:
方法一:R2和R3与其键链的碳一起形成羰基的式(7)由R2、R3分别为H和OH的式(7)氧化得到:
根据本发明,所述氧化是本领域技术人员已知的可实现将醇氧化为醛或酮的任何方法,例如swern氧化、Pfitzner-Moffatt氧化、Albright-Goldman氧化法。作为本发明的一个实施方式,所述氧化采用Parikh-Doering氧化法:二甲亚砜(DMSO)和三氧化硫-吡啶络合物(SO3·py)在-15~25℃、碱性条件下与醇反应。所述碱可以是三乙胺或N,N-二异丙基乙胺(DIPEA);所述反应温度优选为0℃至室温(20-25℃);所述反应可选的加入溶剂,这取决于DMSO的加入量,少量DMSO则需使用较多的溶剂,而较多的DMSO则可加入少量溶剂或不使用溶剂,所述溶剂例如是二氯甲烷、四氢呋喃、氯仿等。
方法二:R2、R3分别为H和OH的式(7)由下式化合物(5)制备得到:
根据本发明,所述反应在四氯化钛(TiCl4)和三乙胺(TEA)的存在下,以惰性气氛保护,在较低温度-10~10℃,优选0℃,进行反应,所述反应溶剂可以是二氯甲烷(DCM)等。
式(7)中R2和R3为其他定义的化合物,则可通过本领域公知的取代或缩合等常规方法,由R2和R3与其键链的碳一起形成羰基或者R2、R3分别为H和OH的式(7)化合物制备得到。
本发明第五方面,还提供化合物式(2)、式(3)、式(7)的用途,其用于制备软海绵素、尤其是艾日布林,其可药用盐及其类似物。具体的,所述式(2)、式(3)、式(7)化合物用于制备式(8)化合物,所述式(8)是构建软海绵素,尤其是艾日布林的C20-C26结构片段的中间体。
本发明第六方面,提供上文式(8)化合物的制备方法,所述方法包括如下步骤:
根据本发明式(8)化合物的制备方法,
优选地,还包括下式由R2、R3分别为H和OH的式(7)氧化反应得到R2和R3与其键链的碳一起形成羰基的式(7)的步骤:
优选地,还包括下式的式(5)和式(6)制备R2、R3分别为H和OH的式(7)的步骤:
优选地,还包括上文所述的由式(4)到式(5)化合物的步骤;
优选地,还包括上文所述的由式(3)到式(4)化合物的步骤;
优选地,还包括上文所述的由式(2)到式(3)化合物的步骤;
优选地,还包括上文所述的由式(1)到式(2)化合物的步骤;
优选地,还包括将式(2)重结晶一次、二次或多次的步骤;
优选地,还包括上文所述的噁唑烷酮类手性辅基到式(1)化合物的步骤。
本发明第七方面,提供一种制备软海绵素、艾日布林、其类似物或其可药用盐,或它们的C20-C26部分的方法,包括使用上述噁唑烷酮类手性辅基、式(1)至式(7)中的任一化合物,和/或使用上述一种或多种制备式(1)至式(8)的方法。
本发明还提供上述噁唑烷酮类手性辅基、式(1)至式(7)中的任一化合物在制备软海绵素、艾日布林、其类似物或它们的C20-C26部分中的用途。
本发明如上所描述的化合物符号、基团定义、反应条件,除有列外说明的,均与其前文具有相同定义或含义。
术语和定义
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文引用的所有专利、专利申请、公开材料的全文通过引用方式整体并入本文。
本申请说明书和权利要求书记载的数值范围,当该数值范围被理解为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“1~10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被理解为“数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如,“1~10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“软海绵素、其类似物”应理解为具有聚醚大环内酯结构的物质,其具有艾日布林的C20-C26结构片段。例如艾日布林、去甲软海绵素A-C(norhalichondrin)、软海绵素B-C(Halichondrin)、高软海绵素A-C(homohalichondrin),或其可药用盐,例如与药学上可接受的酸形成的盐,如甲磺酸盐,如艾日布林甲磺酸盐。
术语“C1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直连或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二-甲基丁基等或它们的异构体。特别地,所述基团具有1、2、3、4、5、6、个碳原子(“C1-6烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更特别地,所述基团具有1、2或3个碳原子(“C1-3烷基”),例如甲基、乙基、正丙基或异丙基。
术语“C1-6亚烷基”应理解为优选表示具有1、2、3、4、5或6个碳原子的直链或支链饱和二价烃基,例如亚甲基、亚乙基、亚正丙基,亚异丙基等。
术语“羟基保护基”意指任何能够保护其连接的氧原子免于反应或成键的基团。这些羟基保护基是本领域已知的。示例性的羟基保护基包括但不限于:酰基、酯基、碳酸酯基、氨基甲酸酯基、磺酸酯基和醚基。
如本文所定义,示例性的醚基羟基保护基包括C1-12烷基(例如,C1-8、C1-6、C1-4、C2-7、C3-12和C3-6烷基)、和甲硅烷基类(例如,三(C1-6烷基)甲硅烷基、三(C6-10芳基或C1-6杂芳基)甲硅烷基、二(C6-10芳基或C1-6杂芳基)(C1-6烷基)甲硅烷基和(C6-10芳基或C1-6杂芳基)二(C1-6烷基)甲硅烷基)。烷基的具体实例包括甲基和叔丁基,甲硅烷基的具体实例包括三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、叔丁基二甲基甲硅烷基(TBS)、叔丁基二苯基甲硅烷基(TBDPS)、三异丙基甲硅烷基(TIPS)和三苯基甲硅烷基(TPS)醚基、TBDMS、DIPS、DPS、TIPDS等。
如上文所定义的羟基保护基,可使用去除剂脱保护。所述羟基保护基去除剂是可以与具有被保护的羟基的化合物反应以提供具有去保护的羟基的化合物的那些试剂。羟基保护基去除剂和去保护反应条件可以是本领域已知的那些。在一个非限制性实例中,被掩蔽为甲硅烷基醚的羟基可以通过与氟化物源(例如,氟化物盐,例如KF或TBAF)的反应来去掩蔽。备选地,被保护为TMS或TES醚的羟基可以通过与布朗斯台德酸(例如,羧酸)的反应来去保护。在另一个非限制性实例中,被保护为酯的羟基可以通过与C1-6醇盐(例如,碱金属C1-6醇盐或碱土金属C1-6醇盐)的反应来去保护。在又一个非限制性实例中,被保护为芳基烷基醚(例如,1-芳基烷-1-基醚)的羟基可以利用还原反应(例如,与Pd/C和H2,或与Na/NH3)来去保护。备选地,被保护为烷氧基-芳基烷基醚(例如,MPM醚)的羟基可以通过与2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)的反应来去保护。在又一个非限制性实例中,被保护为烷氧基烷基醚(例如,1-烷氧基烷-1-基)或THP醚的羟基可以通过与布朗斯台德酸的反应来去保护。环状被保护的二醇(例如缩醛或缩酮(例如,2-烷基-1,3-二氧戊烷、2,2-二烷基-1,3-二氧戊烷、2-烷基-1,3-二噁烷或2,2-二烷基-1,3-二噁烷))可以通过与布朗斯台德酸(例如,羧酸)反应来去保护。
本发明所述的磺酰氧基可以是烷基磺酰氧基(例如C1-10烷基),烯基磺酰氧基(例如C2-10烯基),芳基磺酰氧基。所述实例包括但不限于:甲磺酰氧基、甲苯磺酰氧基(例如对甲苯磺酰氧基)、三氟甲磺酰氧基、硝基苯磺酰氧基(邻、对硝基苯磺酰氧基)、溴苯磺酰氧基(邻、对溴基苯磺酰氧基)。
本发明所述的甲硅烷基可以是三(C1-6烷基)甲硅烷基、三(C6-10芳基或C6-10杂芳基)甲硅烷基、二(C6-10芳基或C6-10杂芳基)(C1-6烷基)甲硅烷基和(C6-10芳基或C6-10杂芳基)二(C1-6烷基)甲硅烷基)。甲硅烷基的具体实例包括但不限于三甲基甲硅烷基(TMS)、三乙基甲硅烷基(TES)、叔丁基二甲基甲硅烷基(TBS)、叔丁基二苯基甲硅烷基(TBDPS)、三异丙基甲硅烷基(TIPS)和三苯基甲硅烷基(TPS)醚基、TBDMS、DIPS、DPS、TIPDS等。
本发明所述的合适的苯基或苄基上的取代基包括但不限于:卤素(氟、氯、溴、碘),C1-10烷基,C1-10烷氧基,羟基,硝基,氨基,被一或二C1-10烷基取代的氨基,SO3H,SO3C1-10烷基。
本发明所述的碱可以为有机碱、无机碱或其混合物,例如选自碱金属或者碱土金属碳酸盐或碳酸氢盐,例如碳酸锂、碳酸钠、碳酸钾、碳酸钙、碳酸铯、碳酸氢钠、碳酸氢钾、碳酸氢钙;碱金属醇盐,例如叔丁醇钠或者叔丁醇钾;有机锂如丁基锂或苯基锂;碱金属氢化物,例如氢化钠或者氢化钾;氨化物,例如双(三甲基甲硅烷基)氨基锂、双(三甲基甲硅烷基)氨基钾或者二异丙基氨基锂(LDA);有机胺,例如三乙胺、N-甲基吗啉、哌啶、N-甲基哌啶、N,N-二异丙基乙胺、1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂双环[5.4.0]癸-7-烯(DBU)、吡啶或者4-二甲氨基吡啶(DMAP)。
本发明所述的酸可以为有机酸、无机酸或其混合物,例如选自下列的一种或多种:盐酸,硫酸,磷酸,硝酸;羧酸,如乙酸或者三氟乙酸;磺酸,例如甲磺酸、三氟甲磺酸或者对甲苯磺酸;膦酸;盐酸、硫酸、磷酸。所述酸还包括路易斯酸。所述的路易斯酸可以为选自例如BF3·OEt2、MgCl2、MgBr2、ZnBr2、ZnI2、ZnCl2、ZnSO4、CuCl2、CuCl、Cu(O3SCF3)2、CoCl2、CoI2、FeI2、FeCl3、FeCl2、FeCl2、SnCl4、TiCl4、TiCl3、MnCl2、ScCl3、AlCl3、(i-C4H9)2AlCl、(C6H5)2AlCl、(C6H5)AlCl2、ReCl5、ZrCl4、NbCl5、VCl3、CrCl2、MoCl5、YCl3、CdCl2、LaCl3、Er(O3SCF3)3、Yb(O2CCF3)3、SmCl3、B(C6H5)3、TaCl5或三甲基三氟甲磺酸硅的一种或多种,其具体实例可以为选自BF3·OEt2、MgCl2、ZnCl2、MgBr2、ZnBr2、AlCl3、SnCl4、TiCl4或三甲基三氟甲磺酸硅的一种或多种。
本发明所述的溶剂可包括选自例如下列的一种或两种以上的混合物:水;酮类溶剂,例如丙酮和甲基乙基酮;醚类溶剂,包括无环醚和环醚,例如乙醚、四氢呋喃、二氧六环;酯类溶剂,例如乙酸乙酯或者乙酸丁酯;烷烃类溶剂,例如正己烷或正庚烷;卤代烷烃类溶剂,例如一氯甲烷、二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷;环烷烃类溶剂,例如环己烷或环庚烷;取代或未取代的芳烃类溶剂,例如苯、甲苯、二甲苯、氯苯;醇类溶剂,例如甲醇、乙醇、正-丙醇、异丙醇,正丁醇或者叔丁醇;或者其它的溶剂,例如N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、乙腈或者吡啶。优选地,所述溶剂为选自对反应底物及催化剂无反应活性的惰性溶剂。作为实例,所述惰性溶剂可以选自例如醇类溶剂(如甲醇、乙醇)、醚类溶剂(如乙醚、四氢呋喃、二氧六环)、卤代烷烃类溶剂(如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷)、取代或未取代的芳烃(如苯、甲苯、氯苯)中的一种或多种。
除非另有说明,本发明中的溶剂为无水溶剂。
有益效果
本发明提供了可用于合成软海绵素、艾日布林或其类似物,特别是其C20-C26结构片段部分的中间体、其制备方法和用途。本发明的合成路线的起始原料廉价易得,且式(2)、式(3)化合物均为结晶体,其通过简单重结晶纯化方式即可提高产物纯度。尤其是式(2)化合物在2次重结晶后,即可获得高于99.9%的光学纯度,而且该化合物β位甲基连接的手性碳原子的构型在后续步骤中不会再发生改变,从而保证了软海绵素、艾日布林或其类似物在C20-C26的光学纯度。因此本发明的构建C20-26结构片段手性中心的方法,具有较高的非对映选择性和产率,其副产物仅需重结晶等简单方法除去。所有方法步骤均在较低温和温和的反应条件下进行,尤其是式(7)化合物制备式(8)化合物的步骤,避免了因高温加热带来的产物热分解损失;整套制备方法,尤其是前端步骤的产物均为结晶状固体,易于纯化和精制。基于以上优势,本发明的方法成本低,产率和纯度高,精制纯化简单,因此更适于工业化大规模生产。
附图说明
图1:本发明实施例1的合成线路图。
具体实施方式
下文通过对本发明实施例的描述,更加详细地对本发明的上述及其他特性和优势进行解释和说明。应当理解,下列实施例旨在对本发明的技术方案进行示例性的说明,而并非旨在对由权利要求及其等价方案所限定的本发明保护范围进行任何限制。
除非另有说明,本文中的材料和试剂均为市售商品,或可由本领域技术人员根据现有技术制备。
本领域技术人员应当理解,下列实施例中的原料、试剂、中间体、目标化合物或反应式均为上文通式化合物或其反应的示例性技术方案,其中的一个或多个具体化合物或具体反应式均可与本发明上述概括性的技术方案结合,且该结合后的技术方案应当被理解为说明书记载的技术方案。
除非另有说明,下列实施例中的收率为以产品纯度为99.5%以上计。
实施例1:化合物8的制备方法一(参见附图1)
1.1化合物1的制备
方法一:
将(s)-4-苯基-2-噁唑烷酮(15.6g)加入到500ml三口瓶中,加入干燥THF(200ml)溶解,换氩气并用氩气保护,然后将反应液降温至-78℃,滴加n-BuLi的THF溶液(2.5M,38ml)(保持内温≤-60℃),滴毕,保持-78℃条件下反应15min,再滴加巴豆酰氯(10g),滴毕,保持-78℃反应30min,然后升至0℃反应1.5h。TLC检测反应完成后,缓慢加入氯化铵饱和溶液淬灭,充分搅拌至固体消失,可清晰分层。分液,水相用乙酸乙酯提取2次,合并有机相后,用饱和氯化钠溶液洗涤1次。有机相加入无水硫酸钠干燥,过滤,浓缩滤液。向所得浓缩物中加入乙酸乙酯(100ml),加热回流溶解,再加入正己烷(500ml),冷却,搅拌析晶。过滤得白色固体产品17.7g,收率80%。
方法二:
将(s)-4-苯基-2-噁唑烷酮(60g)加入到2000ml三口瓶中,加入普通(未经无水处理的试剂级别)THF(1200ml)溶解,室温条件下加入LiCl(26.4g)和TEA(91.2ml),然后慢慢滴加巴豆酸酐(82.2ml),保持内温≤25℃,滴毕,保持室温条件下反应3h。TLC监测至(s)-4-苯基-2-噁唑烷酮原料点消失,加水(800ml),反应液中固体溶解,分液,水层用乙酸乙酯提取2次,合并有机相后,用饱和氯化钠溶液洗涤1次。有机相加入无水硫酸钠干燥,过滤,滤液浓缩。向所得浓缩物中加入乙酸乙酯(400ml),加热回流溶解,再加入正己烷(2000ml),冷却,搅拌析晶。过滤得白色固体产品72g,收率85%。
1H NMR(400MHz,)δ7.44-7.23(m,6H),7.21-6.96(m,1H),5.47(dd,J=8.7,3.9Hz,1H),4.68(t,J=8.8Hz,1H),4.26(dd,J=8.9,3.9Hz,1H),1.92(dd,J=6.9,1.6Hz,3H).
1.2化合物2的制备
1)(1-溴乙烯基)三甲基硅烷的制备
将乙烯基三甲基硅烷(100g)加入到2000ml三口瓶中,然后降温至-35℃~-30℃,慢慢滴加溴水,滴加时剧烈放热,滴加过程保持内温在-30℃~-10℃之间(内温低于-30℃反应体系结成固体),滴毕,自然升至室温,缓慢滴加二乙胺(676ml),初始滴加放热,滴毕,加热回流反应1.2h。反应完成后将反应液降至室温,加入乙醚(1000ml)稀释,加水洗涤2-3次后用2N盐酸洗涤,洗至水层PH=1,有机相依次用饱和碳酸氢钠,饱和氯化钠各洗涤一次,加无水硫酸钠干燥,过滤,滤液浓缩。减压蒸馏,收集馏分80g(38-42℃)。收率45%。
1H NMR(400MHz,Chloroform-d)δ6.27(s,1H),6.19(s,3H),0.20(s,9H).
2)化合物2的制备
将Mg粒(8.4g)和碘粒(1-2粒)加入到三口瓶中,换氩气并用氩气保护。将(1-溴乙烯基)三甲基硅烷(62.7g)溶于干燥THF(159ml)中,室温条件下将其部分(20ml)加入至上述三口瓶中,给三口瓶加热,至反应瓶中反应引发,回流,继续滴加,保持回流状态,滴毕,将反应瓶移至油浴中加热回流1h。制备得到格氏试剂。
将CuI(6.69g)加入到1000ml三口瓶中,加入THF,换氩气保护,然后将反应液降温至-40℃,滴加上述格氏试剂,保持内温≤-30℃,滴毕,保持-40℃反应0.5h后滴加化合物1的THF(40.45g/40ml THF)溶液,滴毕升至0℃反应2h。TLC监测化合物1点消失,慢慢加入饱和氯化铵溶液淬灭,剧烈搅拌4-6h,得澄清两相,分液,水相用乙酸乙酯提取2次,有机相合并后用饱和食盐水洗涤2次,加入无水硫酸钠干燥,过滤,滤液浓缩得到粗品57g。将粗品常温溶于570ml正己烷中,放置-20℃冰箱,静置析晶。次日,趁冷过滤,用冷正己烷洗涤,得到42g白色固体。经过二次重结晶,纯度为99.94%。
1H NMR(500MHz,Chloroform-d)δ7.63-7.26(m,5H),5.74(d,J=1.9Hz,1H),5.51(dd,J=8.7,3.8Hz,1H),5.42(d,J=2.2Hz,1H),4.76(t,J=8.8Hz,1H),4.35(dd,J=9.0,3.8Hz,1H),3.30(q,J=9.4Hz,1H),3.08-2.84(m,2H),1.09(d,J=6.2Hz,3H),0.12(s,9H).
1.3化合物3的制备
将碘(43.2g)溶于DCM(752ml)中,0℃条件下分批加入原料2(18.8g),加毕,升至室温反应约12-20h,TLC监测原料点基本消失,加入饱和亚硫酸钠溶液淬灭,剧烈搅拌至溶液紫色褪去,变为无色,分液,水层用DCM提取1次,有机相合并后加入无水硫酸钠干燥,过滤,浓缩得到粗品20g。柱层析分离得到15g产品。将产品加热溶于正己烷-乙酸乙酯混合溶剂(70ml),冷却,搅拌析晶。过滤得到白色固体9.4g,收率43%。
1H NMR(500MHz,Chloroform-d)δ7.41-7.27(m,5H),6.09(d,J=1.6Hz,1H),5.62(d,J=1.6Hz,1H),5.43(dd,J=8.8,4.0Hz,1H),4.70(t,J=8.8Hz,1H),4.27(dd,J=9.0,4.0Hz,1H),3.23(dd,J=16.9,6.6Hz,1H),2.85(dd,J=16.9,7.0Hz,1H),2.56(q,J=6.8Hz,1H),1.04(d,J=6.7Hz,3H).
1.4化合物4的制备
将原料3(14.27g)溶于THF-H2O的混合溶液(148ml-37ml)中,然后降温至约-5℃依次加入过氧化氢(35%,15.8ml),一水合氢氧化锂的水溶液(3.1g/30ml H2O),滴毕,保持0℃反应2h。TLC监测显示原料点消失,将反应液升至室温,缓慢加入亚硫酸钠饱和溶液,至淀粉碘化钾试纸不变色,减压蒸馏去除THF,水相用DCM洗涤2-3次,至无(s)-4-苯基-2-噁唑烷酮。将水相加入到圆底烧瓶中,冷却至0℃,用10%稀盐酸溶液调节PH至1。然后用DCM萃取2-3次,干燥,过滤,浓缩得到化合物4。
1H NMR(400MHz,Chloroform-d)δ6.21(s,1H),5.90-5.59(m,1H),2.62-2.54(m,1H),2.54-2.46(m,1H),2.31(dd,J=15.0,6.4Hz,1H),1.11(d,J=6.5Hz,3H).
1.5化合物5的制备
将上述所得化合物4溶于DCM(185ml),室温条件下加入噻唑啉-2-硫酮(4.84g),EDCI(8.86g)和DMAP(0.7g)。保持室温反应,4-6h,TLC监测原料点消失。加入饱和硫酸氢钠溶液淬灭,搅拌,分液,水相用DCM萃取2次,有机相合并,依次用饱和碳酸氢钠,饱和食盐水洗涤,然后加入无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化。得到黄色糖浆状产品10.06g(静置或冷冻会固化),收率80%。
1H NMR(400MHz,Chloroform-d)δ6.22(dd,J=1.6,0.9Hz,1H),5.76(d,J=1.7Hz,1H),4.65-4.45(m,2H),3.47(dd,J=17.1,7.3Hz,1H),3.35-3.22(m,2H),1.10(d,J=6.7Hz,3H).
1.6化合物6的制备
1)4-((叔丁基二苯基硅基)氧)丁醛的制备
第一步:室温条件下将1,4-丁二醇(100ml)加入到2000ml三口瓶中,然后加入DCM(1300ml),三乙胺(59ml)和DMAP(4.7g),再慢慢滴加TBSCl。滴毕,保持室温反应过夜(约17h)。TLC监测显示TBSCl原料点消失,加入饱和氯化铵溶液淬灭,分液,水层用DCM提取2次,有机相合并后用饱和食盐水洗涤1次,加入无水硫酸钠干燥,过滤,浓缩。柱层析分离纯化,得到108g糖浆状产品,收率80%。
1H NMR(400MHz,Chloroform-d)δ7.89-7.56(m,4H),7.53-7.35(m,6H),3.68(dt,J=15.2,5.9Hz,4H),1.74-1.59(m,4H),1.05(s,9H).
第二步:将4-((叔丁基二苯基硅基)氧)丁醇(11.6g)溶于干燥DCM(71ml)中,然后降至0℃,依次加入干燥DMSO(12.6ml)和DIPEA(15.4ml),再分批加入三氧化硫吡啶(11.3g),保持内温≤10℃。加毕,升至室温反应0.5-1h,TLC监测显示原料点消失,加水淬灭反应,然后用1N稀盐酸洗涤1次,水层用DCM萃取1次,合并有机相后依次用饱和碳酸氢钠,饱和食盐水洗涤各一次,加入无水硫酸钠干燥,过滤,浓缩,得到糖浆状产品,直接用于下一步反应,故现做现用。
1H NMR(400MHz,Chloroform-d)δ9.79(s,1H),7.65(t,J=7.6Hz,4H),7.52-7.30(m,6H),3.79-3.49(m,2H),2.55(d,J=6.7Hz,2H),1.88(t,J=8.3Hz,2H),1.04(s,9H).
2)将原料5(10.1g)加入到1000ml三口瓶中,加入干燥DCM溶解,换氩气保护,然后将反应液降温至0℃,滴加四氯化钛(3.4ml),再快速加入三乙胺(3.58ml),加毕保持0℃反应1h。滴加4-((叔丁基二苯基硅基)氧)丁醛的DCM溶液(11g/20ml),滴毕,保持0℃反应4-6h,加入饱和食盐水淬灭反应,分液,水相用DCM提取2次,有机相合并后用饱和碳酸氢钠洗涤2次,用饱和食盐水洗涤1次,加入无水硫酸钠干燥,过滤,浓缩,色谱柱分离纯化。得到黄色糖浆状产品,13.1g,收率84%。
化合物6包含4个非对映异构体
异构体A:1H NMR(400MHz,Chloroform-d)δ7.65(ddd,J=7.9,4.3,1.8Hz,4H),7.44-7.35(m,6H),6.37(dd,J=1.3,0.6Hz,1H),5.84(d,J=1.4Hz,1H),5.26(dd,J=10.0,3.8Hz,1H),4.56(td,J=7.4,5.8Hz,2H),3.69(t,J=6.1Hz,3H),3.23-3.07(m,2H),2.85(d,J=10.1Hz,1H),2.67(dd,J=9.9,6.6Hz,1H),1.88-1.56(m,3H),1.07(d,J=6.7Hz,3H),1.04(s,9H).
异构体B:1H NMR(400MHz,Chloroform-d)δ7.72-7.63(m,4H),7.45-7.34(m,6H),6.17(s,1H),5.76-5.73(m,1H),4.74(dd,J=10.3,3.4Hz,1H),4.56(ddd,J=11.9,7.5,2.1Hz,1H),4.38-4.26(m,1H),3.72-3.62(m,3H),3.41(ddd,J=12.3,11.0,7.5Hz,1H),3.13(ddd,J=10.9,7.3,2.1Hz,1H),2.87(d,J=10.9Hz,1H),2.67(dd,J=10.3,6.4Hz,1H),2.21-2.06(m,1H),1.97-1.72(m,2H),1.15(d,J=5.7Hz,3H),1.04(s,9H).
异构体C的特征峰:1H NMR(400MHz,Chloroform-d)δ6.22(dt,J=1.8,0.9Hz,1H),5.72(d,J=1.5Hz,1H),5.38(dd,J=9.7,5.3Hz,1H).
异构体D的特征峰:1H NMR(400MHz,Chloroform-d)66.19-6.18(m,1H),5.76-5.75(m,1H),4.96(dd,J=10.6,5.2Hz,1H).
1.7化合物7的制备
将原料6(13.07g)溶于干燥DCM(40ml)中,然后降至0℃,依次加入干燥DMSO(6.95ml)和DIPEA(8.54ml),再分批加入三氧化硫吡啶(6.23g),保持内温≤10℃。加毕,升至室温反应0.5-1h,TLC监测显示原料点消失,加水淬灭反应,然后用1N稀盐酸洗涤1次,水层用DCM萃取1次,合并有机相后依次用饱和碳酸氢钠,饱和食盐水洗涤各一次,加入无水硫酸钠干燥,过滤,浓缩,得到糖浆状产品,柱层析纯化得到10.4g产品,收率80%。
1H NMR(400MHz,Chloroform-d)δ7.92-7.54(m,10H)(A/B),7.39(q,J=7.8,7.1Hz,10H)(A/B),6.25(d,J=8.5Hz,1H)(A),6.21(s,2H)(A/B),5.77(d,J=1.7Hz,1H)(A),5.75(d,J=1.7Hz,1H)(B),5.07(d,J=9.4Hz,1H)(A),4.61-4.08(m,2H)(A/B),4.26-4.05(m,2H)(A/B),3.69-3.61(m,4H)(A/B),3.33-3.13(m,4H)(A/B),3.00-2.86(m,1H)(A),2.79(dt,J=15.2,7.8Hz,5H)(A/B),1.81(q,J=6.9Hz,3H)(A),1.12(d,J=6.7Hz,3H)(A),1.09(d,J=6.5Hz,2H)(B),1.05(s,18H)(A/B).
1.8化合物8的制备
将原料7(10.4g)溶于THF和H2O的混合溶剂(120ml/30ml)中,室温条件下加入一水合氢氧化锂(6.54g),保持室温搅拌反应6-8h。反应完成后加水,分液,水相用正己烷提取,THF层减压浓缩后加正己烷溶解,有机相合并后用饱和磷酸二氢钠洗涤,饱和食盐水洗涤,加无水硫酸钠干燥,过滤,浓缩。柱层析纯化得到7.08g,收率87%。
1H NMR(400MHz,Chloroform-d)67.65(dd,J=7.8,1.5Hz,5H),7.54-7.27(m,5H),6.16(dd,J=1.5,0.8Hz,1H),5.70(d,J=1.7Hz,1H),3.78-3.55(m,2H),2.63(dd,J=16.4,6.5Hz,1H),2.52(td,J=7.1,1.5Hz,3H),2.29(dd,J=16.3,6.6Hz,1H),1.88-1.75(m,2H),1.05(s,9H),1.02(d,J=6.5Hz,3H).
Claims (23)
1.式(8)化合物的制备方法,
其中,R1选自羟基保护基;
R2、R3相同或不同,彼此独立地选自H和ORa,Ra独立的选自H、C1-10烷基、RbSO2,其中Rb为C1-10烷基;或者R2和R3均为ORa,且两个Ra键链形成C1-6亚烷基;或者R2和R3与其键链的碳一起形成羰基;
X选自卤素、磺酰氧基;
所述方法包括如下步骤:
其中,式(2)中的R5选自甲硅烷基;式(1)-(2)中的噁唑烷酮结构部分为噁唑烷酮类手性辅基,其中R4为C1-10烷基,未取代或卤素、C1-10烷基、C1-10烷氧基、羟基、硝基、氨基、被一或二C1-10烷基取代的氨基、SO3H、SO3C1-10烷基取代的苯基或苄基。
2.权利要求1的式(8)化合物的制备方法,其中:
R1选自甲硅烷类羟基保护基;
R2、R3中的一个选自H,另一个选自ORa,且Ra为H或i-PrSO2;或者R2和R3均为ORa,且两个Ra键链形成亚正丙烷基;或者R2和R3与其键链的碳一起形成羰基;
X选自氯、溴、碘。
3.权利要求1的式(8)化合物的制备方法,其中:
R5选自下列的甲硅烷基:TMS、TES、TBDMS、TBDPS、DIPS、DPS、TIPDS。
4.权利要求3的式(8)化合物的制备方法,其中:
R4是异丙基,未取代或羟基、硝基、二甲氨基单取代或多取代的苯基或苄基。
5.权利要求1的式(8)化合物的制备方法,其中:
还包括将式(2)重结晶一次、二次或多次的步骤。
13.权利要求1-4任一项的式(8)化合物的制备方法:
上述卤代乙烯基硅烷在非质子性溶剂中与金属镁或金属锂反应生成相应的格氏试剂或锂试剂;
或者,上述卤代乙烯基硅烷也可在所述溶剂中与其他易得格氏试剂,或易得烷基锂试剂,进行金属-卤素交换反应,生成相应的格氏试剂或锂试剂;
所述的较低温度为-30~-10℃;
所述其他易得格氏试剂是甲基、乙基、正丙基、异丙基格氏试剂;
所述易得烷基锂试剂是甲基、正丁基、仲丁基、叔丁基锂。
15.根据权利要求14的制备方法,其中RnSiX4-n的卤代硅烷为TMSCl,TMSI,TBDPSCl,TBDPSI。
17.权利要求16的式(2)化合物的制备方法,
包括权利要求1的由式(1)制备式(2)的步骤。
18.权利要求17的式(2)化合物的制备方法,
还进一步包括式(2)的重结晶一次、两次或多次的步骤。
19.权利要求17或18的式(2)化合物的制备方法,
还进一步包括权利要求7的由噁唑烷酮类手性辅基与相应的酰基化合物制备式(1)的步骤。
21.权利要求20的式(3)化合物的制备方法,包括:
上述权利要求6所述的由式(2)制备式(3)的步骤。
22.一种制备软海绵素、艾日布林、其可药用盐或它们的C20-C26部分的方法,包括权利要求1-15任一项的制备方法。
23.权利要求16或20的化合物在制备软海绵素、艾日布林、其可药用盐或它们的C20-C26部分中的用途。
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