CN1293067C - 海绵内酯和其类似物的制备方法 - Google Patents
海绵内酯和其类似物的制备方法 Download PDFInfo
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- CN1293067C CN1293067C CNB018137679A CN01813767A CN1293067C CN 1293067 C CN1293067 C CN 1293067C CN B018137679 A CNB018137679 A CN B018137679A CN 01813767 A CN01813767 A CN 01813767A CN 1293067 C CN1293067 C CN 1293067C
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- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- -1 ketone compound Chemical class 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003495 polar organic solvent Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000001299 aldehydes Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 229910010277 boron hydride Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- KWZWNVAHEQHCTQ-UHFFFAOYSA-N diacetyloxyboranyl acetate Chemical compound CC(=O)OB(OC(C)=O)OC(C)=O KWZWNVAHEQHCTQ-UHFFFAOYSA-N 0.000 claims description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 2
- 238000007254 oxidation reaction Methods 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 abstract description 21
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 abstract description 21
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 12
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 210000004688 microtubule Anatomy 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 7
- 102000029749 Microtubule Human genes 0.000 description 6
- 108091022875 Microtubule Proteins 0.000 description 6
- 102000004243 Tubulin Human genes 0.000 description 6
- 108090000704 Tubulin Proteins 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 229960005499 (+)-discodermolide Drugs 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 1
- WZDNFKAFEYXBOQ-UHFFFAOYSA-N 5-oxopentanamide Chemical compound NC(=O)CCCC=O WZDNFKAFEYXBOQ-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- XMWDKOYHNDFBCL-UHFFFAOYSA-N boron;trifluoromethanesulfonic acid Chemical compound [B].OS(=O)(=O)C(F)(F)F XMWDKOYHNDFBCL-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229930001119 polyketide Natural products 0.000 description 1
- 150000003881 polyketide derivatives Chemical class 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HELHAJAZNSDZJO-UHFFFAOYSA-L sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Steroid Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明提供了更为实用的海绵内酯和结构相关类似物的合成制备方法,用于该方法的新化合物,以及由该方法制备的新化合物。
Description
本发明涉及海绵内酯(DISCODERMOLIDE)和其类似物的制备方法,在该方法中采用的新化合物以及由该方法制备的新化合物。
发明背景
(+)-海绵内酯是一种新的聚酮化合物类天然产物,它是由HarborBranch Oceanographic Institution(HBOI)的研究人员从海绵Discodermolide dissoluta的提取物中分离出来的(Gunasekera SP,Gunasekera M,Longley RE,Schulte GK.海绵内酯:一种来自海绵Discodermolide dissoluta的新型生物活性多羟基内酯[出版的勘误表出现于J.Org.Chem.1991;56:1346].J.Org.Chem.1990;55:4912-15.)。海绵内酯与紫杉醇缺乏明显的结构类似性,但其与紫杉醇(药物紫杉酚中的活性物质)均具有稳定微管的能力。在机理性实验中,海绵内酯比紫杉醇更加有效。事实上,已知的可导致纯化的微管蛋白聚合的少数化合物中,海绵内酯是最有效力的。但是,作为细胞中的主要结构组分,微管并不是微管蛋白的简单平衡聚合物。它们以α和β微管蛋白异二聚体在GTP-驱动下的受调控动态组装形式存在。虽然动力学在分裂间期细胞中是相对缓慢的,但在进入有丝分裂后,生长和缩短的速度会增加20至100倍,即平均的微管更新率为每十秒钟半数微管蛋白亚单元。这种速度上的变化允许拆除细胞骨架微管网络及组装成两极纺缍形微管排列。纺锤体附着于染色体上并牵引使它们分离。微管动力学受到完全抑制后的细胞反应是死亡。但是,有丝分裂细胞更为敏感,耐受性阈值似乎是细胞类型特异性的。与微管高亲合性结合的类似紫杉醇的分子会阻断肿瘤细胞中的动力学过程,导致致死性结果,即使在所结合药物与微管蛋白的比例非常低时也是如此。海绵内酯会与紫杉醇竞争性结合微管蛋白。由于紫杉醇已证明可用于治疗某些癌症,故具有相同机理的其它化合物也会在对抗高增生性疾病中有用。
由于缺乏化合物的可靠天然来源和可行的合成路线,从而阻碍了海绵内酯或结构相关类似物的开发前景。天然存在的海绵内酯非常稀少,故收获产生该化合物的生物存在逻辑上的问题。因此,日益需要改善的合成方法,以便能够制备商业上可接受数量的海绵内酯和结构相关类似物。
发明概述
本发明涉及一种更具有实用性的海绵内酯和其类似物的合成方法。在另一个实施方案中,本发明涉及用于制备海绵内酯和其类似物的新化合物。在另一个实施方案中,本发明涉及由本发明的方法制备的新化合物。
发明详述
本发明的实质在于发现了更为实用的海绵内酯和其类似物的合成方法。更具体地说,业已发现,海绵内酯和其类似物可通过如下的三步反应制备:
步骤1
步骤2
步骤3
其中,R1为(C1-6)烷基、苄基或酸不稳定性羟基保护基;R2为(C1-6)烷基或苄基;R3为氢、(C1-6)烷基、苄基、C(O)(C1-12)烷基、C(O)Ph、C(O)O(C1-12)烷基、C(O)OPh、C(O)NH(C1-12)烷基、C(O)NHPh或酸不稳定性羟基保护基;R3″为酸不稳定性羟基保护基;R4为氢或甲基;且X为O、NH、NCH3、S或CH2,条件是,当式I的化合物中X为O且R3为酸不稳定性羟基保护基时,式V化合物中的“-X-R3”部分为-OH。
关于各步骤,步骤1涉及式I的酮化合物与式II的醛化合物通过羟醛反应进行偶合而获得式III的β-羟基酮化合物。相对于式II的醛化合物,该偶合反应可方便地以1至20,优选5至15当量的式I酮化合物进行反应。偶合反应在下述试剂存在下进行:1)卤化二烷基硼或三氟甲磺酸二烷基硼,优选手性氯化硼或三氟甲磺酸硼,更优选β-氯二异松莰烯基硼烷;2)碱,优选胺,更优选三乙胺;和3)极性有机溶剂,优选醚,更优选乙醚,反应温度为-100℃至20℃,优选-78℃至-20℃,反应时间为2至72小时,优选16小时。
步骤2涉及式III的β-羟基酮化合物的还原反应,更具体地说是对该类化合物共同的酮基进行还原而获得式IV的1,3-二醇化合物。该还原反应在下述试剂存在下进行:1)酮还原剂,优选硼氢化物,如三乙酰氧基硼氢化四甲基铵;2)极性有机溶剂,优选乙腈;和3)质子溶剂,优选羧酸,如乙酸,反应温度为-78℃至20℃,优选-40℃至-10℃,反应时间为2至72小时,优选16小时。
步骤3涉及式IV化合物的内酯化和酸不稳定性羟基保护基的脱保护反应以获得式V化合物。内酯化和脱保护反应在下述试剂存在下进行:1)质子酸(protic acid),优选含水质子酸溶液,优选卤化氢的水溶液,如氯化氢水溶液;和2)极性有机溶剂,优选多种极性有机溶剂的混合物,更优选脂族醇与醚的混合物,如甲醇和四氢呋喃,反应温度为-20℃至40℃,优选20℃至25℃,反应时间为8小时至7天,优选16至72小时,更优选24至48小时。
在另一个实施方案中,本发明涉及新的式I酮化合物:
其中,R1为(C1-6)烷基、苄基或酸不稳定性羟基保护基;
R2为(C1-6)烷基或苄基;
R3为氢、(C1-6)烷基、苄基、C(O)(C1-12)烷基、C(O)Ph、C(O)O(C1-12)烷基、C(O)OPh、C(O)NH(C1-12)烷基、C(O)NHPh或酸不稳定性羟基保护基;
R4为氢或甲基;且
X为O、NH、NCH3、S或CH2。
优选的化合物为下式Ia的化合物:
其中,R1′和R2′均为(C1-6)烷基;
X为O或CH2;且
R3和R4如前定义。
更优选的化合物为式Ib的化合物:
其中,R3′为(C1-6)烷基、C(O)(C1-12)烷基、苄基、C(O)O(C1-12)烷基或酸不稳定性羟基保护基;和
R1′和R2′如前定义。
甚至更优选的化合物为式Ic的化合物:
其中,R3″为酸不稳定性羟基保护基。
在上述定义中,本文中使用的术语“(C1-6)烷基”是指仅由碳和氢组成的并含有1至6个碳原子的直链或支链基团,而本文中使用的术语“(C1-12)烷基”是指仅由碳和氢组成的并含有1至12个碳原子的直链或支链基团。“烷基”基团的实例包括甲基、乙基、丙基、丁基、戊基、3-甲基戊基等。
本文中使用的术语“酸不稳定性羟基保护基”是指在暴露于酸后会被除去的任何氧结合基团。这类基团的众多实例是本领域技术人员公知的,可参看下述文献:Greene和Wuts,有机合成中的保护基团(Protective Groupsin Organic Synthesis),第2版,John Wiley&Sons,New York,1991。其具体实例包括但不限于:叔丁基二甲基甲硅烷基、三乙基甲硅烷基、叔丁基二苯基甲硅烷基、三异丙基甲硅烷基、甲氧基甲基和四氢吡喃基。
在另一个实施方案中,本发明涉及式I新化合物的制备方法。更具体地说,式I化合物可按照下述步骤制备:
步骤A
步骤B
其中R1、R2、R3、R4和X如前定义。
关于各步骤,步骤A涉及甲基或乙基基团与式VI的醛化合物的加成以获得式VII的醇化合物。加成反应在下述试剂存在下进行:1)有机金属试剂,优选烷基锂或烷基镁卤化物,如溴化甲基镁;和2)极性有机溶剂,优选醚,如乙醚,反应温度为-78℃至40℃,优选-78℃至0℃,更优选约-40℃,反应时间为5分钟至24小时,优选30分钟至2小时,更优选约1小时。
步骤B涉及式VII醇化合物的氧化反应,获得所需的式I酮化合物。该氧化反应在下述试剂存在下进行:1)氧化剂,优选二甲亚砜与活化剂的组合,更优选二甲亚砜和三氧化硫与吡啶的配合物的组合;2)碱,优选有机碱,更优选三烷基胺,如三乙胺;和3)极性有机溶剂,优选氯代烃,如二氯甲烷。该氧化反应适宜在-78℃至40℃,优选5℃至20℃下进行,反应时间为5分钟至24小时,优选1至12小时,更优选4至6小时。
式II和VI的醛化合物或者是公知的,或者可采用与文献中提出的用于其它结构类似的醛类化合物的方法相类似的方法制备。
在另一个实施方案中,本发明涉及新的式IIIβ-羟基酮化合物和新的式IV 1,3-二醇化合物。
尽管,如果需要的话,上述每一反应中的产物均可采用常规技术进行纯化,如采用色谱法或重结晶法(如果为固体的话)纯化,但有利的是可以将一个反应的粗产物不经纯化就用于下一反应中。
对本领域技术人员很明显的是,式I和III-V化合物均包含不对称碳原子,因而,可以理解,各立体异构体均被认为包括在本发明的范围内。
下述实施例仅用于举例说明目的,并不旨在以任何方式对本发明范围构成限制。
实施例1
(2R,3S,4R)-3-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-N-甲氧基-N,2,4-三甲基-5-氧代-己酰胺
在0℃下,向步骤1.1制备的13.1g(39.5mmol)非对映体混合物在包含150mL二氯甲烷,50mL二甲亚砜和25mL三乙胺的混合物中的溶液中经加料漏斗滴加在150mL二甲亚砜中的19.0g(120mmol)三氧化硫吡啶配合物。将形成的溶液在0℃下搅拌一个半小时,此后,反应混合物用旋转蒸发器在<10℃的冰浴中浓缩。然后,溶液用200mL乙醚稀释,再依次用200mL的1M硫酸氢钠溶液和200mL盐水萃取。然后有机层用硫酸钠干燥,粗混合产物进行快速色谱纯化,初始用己烷作为洗脱剂,然后用5%乙酸乙酯的己烷溶液混合物作为洗脱剂,得到所需的化合物,为一种澄清油状物。
1H NMR(300MHz,CDCl3)δ4.23(dd,J=7.5,4.2Hz,2H),3.61(s,3H),3.01(s,3H),2.92(m,2H),2.64(m,2H),2.08(s,3H),1.03(d,J=6.8Hz,3H),0.98(d,J=7.2Hz,3H),0.81(s,9H),0.00(s,6H)。
步骤1.1:(2R,3S,4S)-3-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-5-羟基-N-甲氧基-N,2,4-三甲基-己酰胺
在-40℃下,向6.9g(21.8mmol)(2R,3S,4R)-3-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-N-甲氧基-N,2,4-三甲基-5-氧代-戊酰胺在50mL乙醚中的溶液中滴加入10.2mL(30.5mmol)3M溴化甲基镁的乙醚溶液,此后,将混合物在-20℃下搅拌1小时。然后将反应混合物用200mL乙醚稀释,0℃下向反应混合物中加入20g的碎冰使反应停止。然后,混合物用100mL1M硫酸氢钠溶液洗涤,用两份150mL的乙醚进行分配。合并有机层,用硫酸钠干燥。将粗混合产物进行色谱处理,初始采用20%乙酸乙酯的己烷溶液混合物作为洗脱剂,再用40%乙酸乙酯的己烷溶液混合物作为洗脱剂,得到两种非对映体,为浅黄色油状物,其不经纯化即可用于下一步骤。
非对映体1:1H NMR(300MHz,CDCl3):δ4.08(dd,J=9.8,6.8Hz,2H),3.64(s,3H),3.54(d,J=2.6Hz,2H),3.08(s,3H),3.00(m,2H),1.48(m,2H),1.07(d,J=6.8Hz,3H),1.05(d,J=6.4Hz,3H),0.81(s,9H),0.76(d,J=7.2Hz,2H),0.01(d,J=3.8Hz,6H)。
非对映体2:1H NMR(300MHz,CDCl3):δ4.19(dd,J=12.1,6.0Hz,2H),3.86(dd,J=9.0,1.51Hz,2H),3.56(s,3H),3.18(m,2H),3.01(s,3H),1.28(m,2H),1.06(d,J=6.8Hz,3H),0.94(d,6.4Hz,3H),0.88(d,7.2Hz,3H),0.78(s,9H),0.01(d,1.3Hz,6H)。
实施例2
(2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21E)-19-[(氨羰基)氧基]-3,11,17-三[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-7-羟基-N-甲氧基-N,2,4,10,12,14,16,18,20-九甲基-5-氧代-8,13,21,23-二十四碳四烯酰胺
在0℃下,向搅拌中的2.18g(6.79mmol,10当量)(+)-β-氯二异松莰烯基硼烷的4mL乙醚溶液中加入1.04mL(11当量,用氢化钙蒸馏)的三乙胺,然后加入2.25g(6.79mmol,10当量)实施例1化合物的3mL乙醚溶液。在0℃下搅拌2小时后,将混合物冷却至-78℃,此后,经套管加入预冷却(-78℃)的450mg(0.679mmol)(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15E)-13-[(氨基-羰基)氧基]-5,11-二[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-4,6,8,10,12,14-六甲基-2,7,15,17-十八碳四烯醛的4mL乙醚溶液。将所得混合物在-78℃下维持3小时后,将其转移至冰库(-27℃)中16小时。然后,在0℃下用8mL甲醇(其pH值用12mL的缓冲液调节至7)和4mL的50%过氧化氢溶液使反应停止。在25℃下搅拌2小时后,分离有机层。然后水层用25mL一份的二氯甲烷萃取五次。合并后的有机层用硫酸镁干燥,用旋转蒸发器浓缩并进行色谱处理(Biotage,硅胶,10-30%梯度乙酸乙酯/己烷),得到所需化合物,为无色高粘稠性油状物。
[α]D+12.56°(c=1.0,CH2Cl2);IR(CH2Cl2)3547(m,OH),3359(m,CONH2),2958(vs),2990(vs),1729(vs,C=O),1664(m),1462(s),1385(s),1254(s),1037(s),1037(s),1004(s),835(vs);1H NMR(500MHz,CDCl3)δ6.61(1H,ddd,J=17.1,10.5,10.5Hz,H23),6.03(1H,dd,J=11.0,11.0Hz,H22),5.50(1H,dd,J=10.6,10.6Hz,H9),5.37(1H,dd,J=10.6,10.5Hz,H21),5.35(1H,dd,J=10.8,8.5Hz,H8),5.23(1H,dd,J=15.3,2.1Hz,H24A),5.13(1H,d,J=10.2Hz,H24B),5.05(1H,d,J=10.0Hz,H13),4.79(1H,t,J=8.0Hz,H7),4.72(1H,t,J=5.9Hz,H19),4.60-4.50(2H,br,CONH2),4.33(1H,dd,J=6.9,4.3Hz,H3),3.74(3H,s,NOCH3),3.43(1H,dd,J=5.0,4.1Hz,H17),3.31(1H,dd,J=5.2,5.1Hz,H11),3.13(3H,s,NCH3),3.08(1H,br,OH),3.00(1H,m,H20),2.78-2.69(2H,m,H4+H6A),2.70-2.62(1H,m,H10),2.66-2.54(2H,m,H2+H6B),2.49-2.45(1H,m,H12),2.12(1H,dd,J=12.4,12.3Hz,H15A),1.93-1.86(2H,m,H16+H18),1.76-1.65(1H,m,H15B),1.62(3H,s,Me14),1.14(3H,d,J=7.0Hz,Me2),1.11(3H,d,J=7.0Hz,Me4),1.00(3H,d,J=3.1Hz,Me20),0.99(3H,d,J=3.3Hz,Me10),0.96-0.90(21H,m,Me18+2xSiC(CH3)3),0.88(3H,d,J=6.6Hz,Me12),0.83(9H,s,SiC(CH3)3),0.73(3H,d,J=6.7Hz,Me16),0.10&0.08&0.04&0.03&0.03&0.01(6x3H,3xSi(CH3)2);
13C NMR(100.6MHz,CDCl3)δ212.9,175.9,156.9,136.0,133.7,132.1,131.9,131.3,129.8,129.6,117.9,80.6,78.7,76.8,73.6,64.9,62.1,61.3,54.7,53.1,51.7,49.0,45.1,44.9,37.9,37.1,36.2,35.9,35.0,34.4,30.0,29.1,26.26,26.24,25.97,23.0,18.51,18.5,18.43,18.14,17.43,16.44,13.5,10.99,10.1,-3.29,-3.4,-3.5,-3.9,-4.1,-4.4;m/z(ESI+)1017(100(MNa+))。
实施例3
(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21E)-19-[(氨羰基)氧基]-3,11,17-三[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-5,7-二羟基-N-甲氧基-N,2,4,10,12,14,16,18,20-九甲基-8,13,21,23-二十四碳四烯酰胺
向1.02g(3.9mmol)三乙酰氧基硼氢化四甲基铵的2.2mL无水乙腈溶液中加入2.2mL无水乙酸,将混合物在室温下搅拌30分钟。再将混合物冷却至-29℃,向冷却后的混合物中加入450mg(0.453mmol)实施例2化合物的1mL无水乙腈溶液。将形成的混合物再于-29℃下搅拌18小时,此后,用2mL 0.5N的酒石酸钾钠水溶液使反应停止。再将混合物缓慢升温至室温,此后,用二氯甲烷对其稀释,并用饱和碳酸氢钠洗涤。之后,水层用二氯甲烷萃取四次。合并后的有机层用盐水洗涤,用硫酸钠干燥并真空浓缩。将形成的残余物用快速色谱(Biotage,硅胶,10-30%梯度乙酸乙酯/己烷)纯化,得到所需的化合物,为白色固体。
[α]+29.75度(c=0.87,CH2Cl2);1H NMR(499.87MHz,CDCl3)δ6.60(1H,ddd,J=16.8,10.5,10.5Hz,H23),6.02(1H,t,J=11.0,H22),5.48(1H,dd,J=10.0,9.8Hz,H9),5.37(1H,dd,J=10.6,11.2Hz,H21),5.35(1H,dd,J=10.8,8.5Hz,H8),5.22(1H,d,J=15.8Hz,H24A),5.12(1H,d,J=10.2Hz,H24B),4.98(1H,d,J=10.1Hz,H13),4.79(1H,t,J=6.3Hz,H7),4.65(1H,t,J=5.9Hz,H19),4.60-4.50(2H,br,CONH2),4.20(1H,dd,J=7.7,2.3Hz,H3),3.92,(1H,m,H5),3.73(3H,s,NOCH3),3.45(1H,br,OH-5),3.41(1H,dd,J=10.9,4.7Hz,H17),3.31(1H,dd,J=5.2,5.1Hz,H11),3.18(3H,s,NCH3),3.08(1H,br,OH),2.99(1H,m,H20),267(1H,m,H10),2.43-2.41(2H,m),2.11(1H,t,J=12.3Hz),1.90-1.87(2H,m),1.76-1.58(10H,m),1.25(3H,t,Me),1.17(3H,d,J=7.1Hz,Me),0.99(3H,d,J=6.4Hz,Me),0.97(3H,d,J=6.5Hz,Me),0.93-0.83(30H,m,Me+3xSiC(CH3)3),0.71(3H,d,J=6.8Hz,Me),0.10&0.08&0.04&0.03&0.03&0.01(6x3H,3xSi(CH3)2)。13C NMR(100.6MHz,CDCl3)δ156.88,140.02,134.19,133.66,132.10,131.88,131.40,131.30,131.11,130.06,129.79,117.91,115.44,80.79,80.69,78.61,78.32,74.31,70.68,65.55,61.66,45.69,40.38,38.36,37.92,37.83,37.29,36.29,35.07,34.91,34.45,32.36,29.68,26.21,26.12,26.03,25.95,22.95,18.52,18.43,18.12,17.41,17.07,16.57,13.44,12.29,10.32,10.14,-3.20,-3.43,-3.96,-4.16,-4.48.m/z(ESI+)1019(100(MNa+))。
实施例4
制备(+)-海绵内酯
向450mg(0.452mmol)实施例3化合物的56mL四氢呋喃溶液中加入56mL 4N盐酸水溶液。将形成的溶液在室温下搅拌24小时,再加入10mL的甲醇,然后将溶液于室温下再搅拌24小时。向溶液中加入50mL的乙酸乙酯,之后0℃下加入碳酸氢钠至pH值8。然后用盐水洗涤有机溶液。水层用30mL一份的乙酸乙酯萃取三次,合并后的萃取液用硫酸钠干燥。过滤和浓缩后用快速色谱处理,初始采用50二氯甲烷的乙酸乙酯溶液混合物作为洗脱剂,再用100%的乙酸乙酯洗脱,得到(+)-海绵内酯。
[α]+22.0°(c=1.41,MeOH);mp 122-124℃;13C NMR(100.6MHz,CDCl3)δ176.8,160.33,134.17.133.92,133.88,133.59,133.28,131.59,131.00,118.80,80.66,80.22,78.48,76.48,73.66,63.70,44.56,42.60,38.79,37.71,36.92,36.77,36.69,34.97,34.62,23.45,19.73,18.25,18.11,16.05,15.84,13.27,9.44.m/z(ESI+)594(100(M+1+))。
Claims (12)
1.式V化合物的制备方法:
该方法包括,
第一步,使式I的酮化合物
与式II的醛化合物
在卤化二烷基硼或三氟甲磺酸二烷基硼、胺碱和极性有机溶剂存在下偶合,获得式III的β-羟基酮
第二步,在极性有机溶剂和质子溶剂中用硼氢化物试剂对第一步中获得的酮化合物进行还原,获得式IV的1,3-二醇
和第三步,用溶解于极性溶剂或多种溶剂的混合物中的卤化氢处理第二步中获得的1,3-二醇进行内酯化和酸不稳定性羟基保护基的脱保护,获得所需的式V化合物,其中R1为(C1-6)烷基、苄基或酸不稳定性羟基保护基;R2为(C1-6)烷基或苄基;R3为氢、(C1-6)烷基、苄基、C(O)(C1-12)烷基、C(O)Ph、C(O)O(C1-12)烷基、C(O)OPh、C(O)NH(C1-12)烷基、C(O)NHPh或酸不稳定性羟基保护基;R3″为酸不稳定性羟基保护基;R4为氢或甲基;且X为O,条件是,当式I化合物中X为O且R3为酸不稳定性羟基保护基时,式V化合物中的“-X-R3”部分为-OH。
2.根据权利要求1的方法,其中,偶合步骤在-78℃至-20℃下,在β-氯二异松莰烯基硼烷、三乙胺和乙醚存在下进行。
3.根据权利要求1的方法,其中,还原步骤在-40℃至-10℃下,在三乙酰氧基硼氢化四甲基铵、乙腈和乙酸存在下进行。
4.根据权利要求1的方法,其中内酯化和酸不稳定性羟基保护基的脱保护步骤在-20℃至40℃下,在含水氯化氢、甲醇和四氢呋喃存在下进行。
7.根据权利要求6的式Ib的化合物:
其中,R3′为(C1-6)烷基、C(O)(C1-12)烷基、苄基、C(O)O(C1-12)烷基或酸不稳定性羟基保护基;且
R1′和R2′如权利要求6中的定义。
8.根据权利要求7的式Ic的化合物:
其中,R3″为酸不稳定性羟基保护基。
9.根据权利要求8的化合物,其为(2R,3S,4R)-3-[[(1,1-二甲基乙基)二甲基甲硅烷基]氧基]-N-甲氧基-N,2,4-三甲基-5-氧代-己酰胺,具有下式
10.根据权利要求5的式I化合物的制备方法,该方法包括,第一步,在极性有机溶剂存在下使甲基或乙基有机金属试剂与式VI的醛
进行加成反应,获得式VII的醇
以及,第二步,在极性有机溶剂中用氧化剂和碱处理第一步中制备的醇化合物进行氧化,获得所需的式I化合物,其中,R1、R2、R3、R4和X如权利要求5中的定义。
11.根据权利要求10的方法,其中,加成步骤在-78℃至40℃下,在溴化甲基镁和乙醚存在下进行。
12.根据权利要求10的方法,其中,氧化步骤在-78℃至40℃下,在三氧化硫-吡啶配合物、三乙胺和二氯甲烷存在下进行。
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