CN109574811A - A kind of preparation method of anidulafungin side chain intermediate to amoxy terphenyl formic acid - Google Patents
A kind of preparation method of anidulafungin side chain intermediate to amoxy terphenyl formic acid Download PDFInfo
- Publication number
- CN109574811A CN109574811A CN201811401127.9A CN201811401127A CN109574811A CN 109574811 A CN109574811 A CN 109574811A CN 201811401127 A CN201811401127 A CN 201811401127A CN 109574811 A CN109574811 A CN 109574811A
- Authority
- CN
- China
- Prior art keywords
- amoxy
- preparation
- bromo
- terphenyl
- suzuki coupling
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 amoxy Chemical group 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims description 26
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical group C1=CC(OCCCCC)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@@H](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 title claims description 17
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 title claims description 13
- 235000019253 formic acid Nutrition 0.000 title claims description 13
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 title claims description 12
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 26
- DBDYXLZXTNHAFI-UHFFFAOYSA-N [4-(4-pentoxyphenyl)phenyl]boronic acid Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(B(O)O)C=C1 DBDYXLZXTNHAFI-UHFFFAOYSA-N 0.000 claims abstract description 18
- XSGGLCGBXDPDLL-UHFFFAOYSA-N 1-bromo-4-(4-pentoxyphenyl)benzene Chemical group C1=CC(OCCCCC)=CC=C1C1=CC=C(Br)C=C1 XSGGLCGBXDPDLL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000007062 hydrolysis Effects 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 12
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 48
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 36
- 239000003054 catalyst Substances 0.000 claims description 20
- 229910052763 palladium Inorganic materials 0.000 claims description 20
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 18
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 13
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 12
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 10
- 229910052796 boron Inorganic materials 0.000 claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 8
- QASKCGNZJHBTDJ-UHFFFAOYSA-N [SiH4].BrCCCCC Chemical compound [SiH4].BrCCCCC QASKCGNZJHBTDJ-UHFFFAOYSA-N 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 6
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical class COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 5
- WTAPZWXVSZMMDG-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 WTAPZWXVSZMMDG-UHFFFAOYSA-N 0.000 claims description 4
- ARUBXNBYMCVENE-UHFFFAOYSA-N 4-(4-bromophenyl)phenol Chemical group C1=CC(O)=CC=C1C1=CC=C(Br)C=C1 ARUBXNBYMCVENE-UHFFFAOYSA-N 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 claims description 4
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- ZGOWIHIGUHWAMQ-UHFFFAOYSA-N 2-(4-bromophenyl)phenol Chemical group OC1=CC=CC=C1C1=CC=C(Br)C=C1 ZGOWIHIGUHWAMQ-UHFFFAOYSA-N 0.000 claims description 2
- GHICCUXQJBDNRN-UHFFFAOYSA-N 4-iodobenzoic acid Chemical compound OC(=O)C1=CC=C(I)C=C1 GHICCUXQJBDNRN-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims 2
- XPEIJWZLPWNNOK-UHFFFAOYSA-N (4-phenylphenyl)boronic acid Chemical class C1=CC(B(O)O)=CC=C1C1=CC=CC=C1 XPEIJWZLPWNNOK-UHFFFAOYSA-N 0.000 claims 1
- ODJZWVFLHZHURI-UHFFFAOYSA-M [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] Chemical compound [Br-].C(CCC)[P+](CCCC)(CCCC)CCCC.[NH4+].[Br-] ODJZWVFLHZHURI-UHFFFAOYSA-M 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 239000003513 alkali Substances 0.000 abstract description 2
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 abstract description 2
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 abstract 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 abstract 1
- FTDZECHQBVIHKZ-UHFFFAOYSA-N 5,5-dibromo-2-phenylcyclohexa-1,3-diene Chemical group C1=CC(Br)(Br)CC=C1C1=CC=CC=C1 FTDZECHQBVIHKZ-UHFFFAOYSA-N 0.000 abstract 1
- 150000001543 aryl boronic acids Chemical class 0.000 abstract 1
- BXXLTVBTDZXPTN-UHFFFAOYSA-N methyl 2-iodobenzoate Chemical compound COC(=O)C1=CC=CC=C1I BXXLTVBTDZXPTN-UHFFFAOYSA-N 0.000 abstract 1
- 238000011112 process operation Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000004327 boric acid Substances 0.000 description 9
- 150000007529 inorganic bases Chemical class 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 229940121375 antifungal agent Drugs 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 108010064760 Anidulafungin Proteins 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 239000007818 Grignard reagent Substances 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229960003348 anidulafungin Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000001924 fatty-acyl group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- SWJPEBQEEAHIGZ-UHFFFAOYSA-N 1,4-dibromobenzene Chemical compound BrC1=CC=C(Br)C=C1 SWJPEBQEEAHIGZ-UHFFFAOYSA-N 0.000 description 1
- ILLQRHZDICIFRQ-UHFFFAOYSA-N 1-bromo-4-pentoxybenzene Chemical compound CCCCCOC1=CC=C(Br)C=C1 ILLQRHZDICIFRQ-UHFFFAOYSA-N 0.000 description 1
- JOYKGBJTAOKAAD-UHFFFAOYSA-N 1-pentoxy-4-phenylbenzene Chemical group C1=CC(OCCCCC)=CC=C1C1=CC=CC=C1 JOYKGBJTAOKAAD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940071198 eraxis Drugs 0.000 description 1
- KVFIJIWMDBAGDP-UHFFFAOYSA-N ethylpyrazine Chemical compound CCC1=CN=CC=N1 KVFIJIWMDBAGDP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种阿尼芬净侧链中间体对戊氧基三联苯甲酸的制备方法。所述方法包括如下步骤：S1：4羟基‑4’‑溴联苯和1‑溴戊烷发生亲核取代反应得到4’‑溴‑4‑正戊氧基联苯；S2：4’‑溴‑4‑正戊氧基联苯和四羟基二硼发生Suzuki偶联反应得到4‑戊氧基‑4’‑联苯硼酸；S3：4‑戊氧基‑4’‑联苯硼酸和4‑碘苯甲酸甲酯发生Suzuki偶联反应得到4''‑(戊氧基)‑[1,1',4',1''‑三联苯]‑4‑甲酸甲酯；S4：水解即得到对戊氧基三联苯甲酸。本发明采用Suzuki偶联制备芳基硼酸再经过Suzuki偶联和碱水解的方法制备目标产物，具有成本低，工艺操作简便安全的优点。
The invention relates to a preparation method of p-pentyloxyterphenylcarboxylic acid, a side chain intermediate of anidungin. The method includes the following steps: S1: 4'-bromo-4'-bromobiphenyl and 1-bromopentane undergo a nucleophilic substitution reaction to obtain 4'-bromo-4-n-pentoxybiphenyl; S2: 4'-bromobiphenyl -4-n-pentyloxybiphenyl and tetrahydroxydiboron undergo Suzuki coupling reaction to obtain 4-pentyloxy-4'-biphenylboronic acid; S3: 4-pentyloxy-4'-biphenylboronic acid and 4-pentyloxy-4'-biphenylboronic acid Suzuki coupling reaction occurs with methyl iodobenzoate to obtain 4''-(pentyloxy)-[1,1',4',1''-terphenyl]-4-methyl formate; S4: hydrolysis to obtain paraben Pentyloxyterphenylcarboxylic acid. The invention adopts Suzuki coupling to prepare the aryl boronic acid and then prepares the target product through the method of Suzuki coupling and alkali hydrolysis, and has the advantages of low cost, simple and safe process operation.
Description
Technical field
The present invention relates to medical synthesis fields, more particularly, to a kind of anidulafungin side chain to amoxy terphenyl first
The preparation method of acid.
Technical background
Anidulafungin (anidulafungin) is the derivative of both sexes moldin B, which is by U.S.'s Vicuron pharmacy
The third generation spine that company develops is from the semi-synthetic antifungal of bacteriums, and trade name Eraxis, 2006 in the granted listing in the U.S..
Compared with other spine are from bacteriums antifungal, anidulafungin has bigger distribution volume and broader spectrum of antibacterial activity.
Anidulafungin as a kind of semi-synthetic antifungal agent, is spread out as cultivating cyclic peptide antifungal agents made from various microorganisms
It is raw.The structure feature of all these antifungal agents is: including a ring hexapeptide core, an amino of cyclic amino acids has one
A fatty acyl group, the fatty acyl group form a chain.Side chain is removed to obtain Free Core by the deacylation of enzyme, then by core
Aminoacylates obtain semi-synthetic antifungal compound.
WO09631228A, WO0051564A1, JP2005325142A disclose a kind of prepare to amoxy terphenyl formic acid
Method, specifically: a. aryl halides and triisopropyl borate ester prepare aryl boric acid under butyl lithium effect；B. aryl boric acid
With 4-Iodobenzoic acid methyl esters by Suzuki coupling 4 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formates of preparation；
C. it hydrolyzes to obtain target product using alkaline condition.The route prepares the butyl lithium and air easy firing of boric acid use, and anti-
It answers system to the more demanding of moisture, is not suitable for large-scale production.
CN103570530A, CN106431901A provide one kind and prepare terphenyl methyl formate by Grignard Reagent, so
Hydrolysis obtains the method to amoxy terphenyl formic acid afterwards.Detailed process are as follows: a.1,4- dibromobenzene causes through iodine carries out lattice with magnesium
The reaction of family name's reagent, reacts after cooling with trimethylborate, hydrolyzed under acidic conditions prepares Isosorbide-5-Nitrae-benzene hypoboric acid；B.1,4- two boron of benzene
Acid, 4- amoxy bromobenzene and 4- iodo ethyl benzoate are coupled 4 "-(amoxy)-[1,1', 4', 1 "-three of preparation by Suzuki
Biphenyl] -4- Ethyl formate.The route prepares boric acid by Grignard Reagent, equally has higher requirement to solvent water, and prepare
Grignard Reagent need in glove box filter remove magnesium chips, it is cumbersome, be not suitable for amplification production.
Therefore, a kind of simple process is developed, mild condition is suitble to the anidulafungin side chain intermediate boric acid of large-scale production
Preparation method have important research significance and economic value.
Summary of the invention
It is an object of the invention to overcome butyl lithium in the prior art or grignard reagent reaction to prepare in the method for boric acid and deposit
It cumbersome, is difficult to control, the problems such as risk is higher, provides a kind of anidulafungin side chain intermediate to amoxy terphenyl
The preparation method of formic acid.The present invention prepares aryl boric acid using the method for Suzuki coupling and basic hydrolysis using Suzuki coupling
Target product is prepared, there is the advantages of at low cost, technological operation handy and safe.
In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical scheme:
A kind of anidulafungin side chain intermediate includes the following steps: the preparation method of amoxy terphenyl formic acid
S1:4 hydroxyl -4 '-bromo biphenyl and 1- bromo pentane silane occur nucleophilic substitution and obtain 4 '-bromo- 4- n-pentyloxy biphenyl；
S2: under inert atmosphere protection, 4 '-bromo- 4- n-pentyloxy biphenyl and two boron of tetrahydroxy are in palladium catalyst and Phosphine ligands
The lower generation Suzuki coupling reaction of effect obtains 4- amoxy -4 '-biphenylboronic acid；
S3: under inert atmosphere protection, 4- amoxy -4 '-biphenylboronic acid and 4- iodo-benzoic acid methyl esters are matched in palladium catalyst and phosphine
Suzuki coupling reaction "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate that obtains 4 occurs under the action of body；
S4:4 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate hydrolysis obtains in the anidulafungin side chain
Mesosome is to amoxy terphenyl formic acid.
The present invention selects specific raw material, prepares aryl boric acid using Suzuki coupling and buck using Suzuki coupling
The method of solution prepares target product, has the advantages of at low cost, technological operation handy and safe.
Nucleophilic substitution in S1 of the present invention is conventional reaction type, condition control (such as catalyst, reaction temperature
Degree, pH etc.) it can also refer to the prior art.
Preferably, it is catalyst that nucleophilic substitution described in S1, which selects tetrabutylammonium bromide,.
It is further preferable that 0.1~0.5:1 of the tetrabutylammonium bromide and 4- hydroxyl -4 '-bromo biphenyl molar ratio.
Preferably, the pH of nucleophilic substitution described in S1 is 8~11.
Preferably, nucleophilic substitution described in S1 selects inorganic base to adjust pH.
Inorganic base conventional in the art is used equally in the present invention.
It is further preferable that the inorganic base is sodium hydroxide.
Preferably, the temperature of nucleophilic substitution described in S1 is 60~95 DEG C.
Preferably, 1- bromo pentane silane and 4- hydroxyl -4 '-bromo biphenyl molar ratio are 1.1~2.0:1 in S1.
Preferably, the detailed process of S1 are as follows: using 4 hydroxyls -4 '-bromo biphenyl as raw material under the conditions of sodium hydroxide through the tetrabutyl
The catalysis of ammonium bromide and 1- bromo pentane silane occur nucleophilic substitution and 4 '-bromo- 4- n-pentyloxy biphenyl are prepared.
Preferably, the molar ratio of the boron of tetrahydroxy two described in S2 and 4 '-bromo- 4- n-pentyloxy biphenyl is 1.5~4.0:1.
Palladium catalyst and Phosphine ligands conventional in the art are used equally in the present invention.
Preferably, palladium catalyst described in S2 is palladium acetate Pd (OAc)2, dibenzylideneacetonepalladium palladium Pd2(dba)3Or chlorination
Palladium PdCl2One or more of.
Preferably, Phosphine ligands described in S2 are triphenylphosphine PPh3, three o-methyl-phenyl phosphine P (o-MeC6H4)3, three hexamethylenes
Base phosphine PCy3Or tri-tert-butylphosphine PtBu3One or more of.
Preferably, Phosphine ligands described in S2 are dissolved in tetrahydrofuran solution.
It is further preferable that the volume mass ratio of the tetrahydrofuran and 4 '-bromo- 4- n-pentyloxy biphenyl is 4~10:1mL/
g。
It is further preferable that the palladium catalyst is palladium acetate；The Phosphine ligands are three (o-methyl-phenyl) phosphines.
Inventor preferably has found palladium catalyst and Phosphine ligands, selects palladium acetate and three (o-methyl-phenyl) phosphine conducts
Catalyst, which has, improves conversion ratio, reduces the effect of by-product.
It is further preferable that the palladium acetate and 4 '-bromo- 4- n-pentyloxy biphenyl molar ratios are 1~8:100.
It is further preferable that the three o-methyl-phenyls phosphine and 4 '-bromo- 4- n-pentyloxy biphenyl molar ratios are 1~10:100；
Preferably, the pH of Suzuki coupling reaction described in S2 is 8~11.
Preferably, Suzuki coupling reaction described in S2 selects inorganic base to adjust pH.
Inorganic base conventional in the art is used equally in the present invention.
It is further preferable that the inorganic base is potassium acetate.
Preferably, the molar ratio of the potassium acetate and 4 '-bromo- 4- n-pentyloxy biphenyl is 1.5~3.0:1.
Preferably, the temperature of Suzuki coupling reaction described in S2 is 0~40 DEG C.
Preferably, two boron of tetrahydroxy is dissolved in methanol solution.
It is further preferable that the volume mass ratio of two boron of methanol and tetrahydroxy is 10~20:1.
Preferably, inert atmosphere described in S2 is nitrogen atmosphere.
It is further preferable that the detailed process of S2 are as follows: under nitrogen protection, to the four of palladium acetate and three (o-methyl-phenyl) phosphines
Potassium acetate and 4 '-bromo- 4- n-pentyloxy biphenyl are added in hydrogen tetrahydrofuran solution, adds the methanol solution of two boron of tetrahydroxy, passes through
4- amoxy -4 '-biphenylboronic acid is prepared in Suzuki coupling reaction.
Preferably, the methyl esters of 4- iodo-benzoic acid described in S3 and 4- amoxy -4 '-biphenylboronic acid molar ratio be 1.1~
1.5。
Preferably, palladium catalyst described in S3 is palladium acetate Pd (OAc)2, dibenzylideneacetonepalladium palladium Pd2(dba)3Or chlorination
Palladium PdCl2One or more of.
Preferably, Phosphine ligands described in S3 are triphenylphosphine PPh3, three o-methyl-phenyl phosphine P (o-MeC6H4)3, three hexamethylenes
Base phosphine PCy3Or tri-tert-butylphosphine PtBu3One or more of.
It is further preferable that the palladium catalyst is palladium acetate, the Phosphine ligands are triphenylphosphine.
Inventor preferably has found palladium catalyst and Phosphine ligands, and palladium acetate and triphenylphosphine is selected to have as catalyst
It is improved conversion ratio, reduces the effect of by-product.
It is further preferable that the palladium acetate and 4- amoxy -4 '-biphenylboronic acid molar ratio are 0.5~10:1.
It is further preferable that the triphenylphosphine and 4- amoxy -4 '-biphenylboronic acid molar ratio are 1~15:1.
Preferably, the pH of Suzuki coupling reaction described in S3 is 8~11.
Preferably, Suzuki coupling reaction described in S3 selects inorganic base to adjust pH.
Inorganic base conventional in the art is used equally in the present invention.
It is further preferable that the inorganic base is sodium carbonate.
Preferably, the sodium carbonate and 4- amoxy -4 '-biphenylboronic acid molar ratio are 1.0~3.0.
Preferably, the 4- iodo-benzoic acid methyl esters is dissolved in toluene/normal propyl alcohol mixed solution.
It is further preferable that the volume ratio of normal propyl alcohol and toluene is 1~10:1 in the toluene/normal propyl alcohol mixed solution.
Preferably, the normal propyl alcohol/toluene mixed solution and 4- n-pentyloxy -4 '-biphenylboronic acid mass ratio be 8~
15:1。
Preferably, the inert atmosphere described in S3 is nitrogen atmosphere.
It is further preferable that the detailed process of S3 are as follows: under nitrogen protection, to 4- amoxy -4 '-biphenylboronic acid and 4- iodobenzene first
Aqueous sodium carbonate, palladium acetate and triphenylphosphine are sequentially added in the toluene of sour methyl esters/normal propyl alcohol mixed solution, by Suzuki
Coupling reaction is prepared 4 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate.
Hydrolysis in S4 of the present invention is conventional reaction type, and condition controls (such as catalyst, reaction temperature, pH
Deng) it can also refer to the prior art.
Preferably, hydrolysis described in S4 selects cetyl trimethylammonium bromide as phase transfer catalyst.
Preferably, "-(amoxy)-[1,1', 4', 1 "-terphenyl 4 described in S4] to be dissolved in dimethylbenzene molten for -4- methyl formate
In liquid.
Preferably, the pH of hydrolysis described in S4 is 12~14.
Inorganic alkali solution conventional in the art is used equally in the present invention.
It is further preferable that hydrolysis described in S4 selects potassium hydroxide aqueous solution to adjust pH.
It is further preferable that the detailed process of S4 are as follows: and 4 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate
Xylene solution mixed with potassium hydroxide aqueous solution, be lauched in the catalysis of phase transfer catalyst cetyl trimethylammonium bromide
Solution to get to the anidulafungin side chain intermediate to amoxy terphenyl formic acid.
Preparation method provided by the invention is represented by following reaction formula:
Compared with prior art, the invention has the following beneficial effects:
The present invention prepares aryl boric acid using Suzuki coupling and produces using the method preparation target of Suzuki coupling and basic hydrolysis
Object has the advantages of at low cost, technological operation handy and safe.
Detailed description of the invention
Fig. 1 is that the anidulafungin side chain intermediate that embodiment 7 provides composes the nuclear magnetic spectrogram hydrogen of amoxy terphenyl formic acid.
Specific embodiment
Below with reference to embodiment, the present invention is further explained.These embodiments are merely to illustrate the present invention rather than limit this hair
Bright range.Test method without specific conditions in lower example embodiment, usually according to this field normal condition or according to system
Make condition recommended by the manufacturer；Used raw material, reagent etc., unless otherwise specified, being can be from commercial sources such as conventional markets
Obtained raw materials and reagents.It the variation for any unsubstantiality that those skilled in the art is done on the basis of the present invention and replaces
It changes and belongs to scope of the present invention.
The synthesis of embodiment 14 '-bromo- 4- n-pentyloxy biphenyl
1450mL water is added into the there-necked flask of 2L, 120g 4- hydroxyl -4 '-bromine is added after stirring dissolved clarification in 21.2g sodium hydroxide
87.2g 1- bromo pentane silane is added dropwise after stirring 10min at room temperature in biphenyl and 6g tetrabutylammonium bromide, and flow back 5h after being added dropwise to complete, to
Reaction is cooled to room temperature suctions filtration, filter cake 400mL water washing, solid it is hot with 600mL normal heptane/water (1:1) mixed solution
Mashing filters and washs filter cake with 60mL normal heptane, and obtained solid is dried in vacuo 5 hours at 60 DEG C, yield 87%.1H
NMR(d6DMSO,400MHz)δ8.04-8.02(m,2H),7.85-7.83(m,1H),7.63-7.57(m, 3H),7.02-7.00
(m, 2H), 4.01-3.98 (m, 2H), 1.75 (t, J=8.0Hz, 2H), 1.41-1.36 (m, 4H), 0.92-0.89 (m, 3H)
1200mL water, 17.7g hydroxide are added into the there-necked flask of 2L for the synthesis of embodiment 24 '-bromo- 4- n-pentyloxy biphenyl
Sodium is added 100g 4- hydroxyl -4 '-bromo biphenyl and 5g tetrabutylammonium bromide after stirring dissolved clarification, is added dropwise after stirring 10min at room temperature
72.7g 1- bromo pentane silane, flow back 5h after being added dropwise to complete, and is cooled to room temperature suction filtration wait react, filter cake 300mL water washing, consolidate
Body 320mL normal heptane/water (1:1) mixed solution hot beating filters and washs filter cake with 60mL normal heptane, and obtained solid is 60
It is dried in vacuo 5 hours at DEG C, yield 87%.1H NMR(d6DMSO,400MHz)δ8.04-8.02(m,2H),7.85-7.83(m,
1H), 7.63-7.57 (m, 3H), 7.02-7.00 (m, 2H), 4.01-3.98 (m, 2H), 1.75 (t, J=8.0Hz, 2H),
1.41-1.36(m,4H),0.92-0.89 (m,3H).
Under 3 4- amoxy -4 ' of embodiment-biphenylboronic acid synthesis nitrogen protection, it is bromo- that 5g 4 '-is added into 100mL there-necked flask
4- n-pentyloxy biphenyl, 88mg palladium acetate, 4.6g potassium acetate, (o-methyl-phenyl) phosphine of 144mg tri- and 15mL tetrahydrofuran, ice water
Bath is cooled to 0-10 DEG C, and two boron of 1.84g tetrahydroxy is added drop-wise in reaction after being dissolved in 10mL methanol, is stirred to react at room temperature, to original
Material disappear after be added 30mL ethyl alcohol dilution, filter, filter cake 10mL ethanol washing, filtrate be spin-dried for after be added 80mL methylene chloride/
Water mixed solvent (1:1) hot beating 1h at 40 DEG C, filters, filter cake successively uses 5mL water and 5mL methylene chloride after being cooled to room temperature
It washs, is dried in vacuo to obtain white solid 2.84g, yield 64% at 50 DEG C.1H NMR(d6DMSO,400MHz)δ7.98-7.96(m,
2H), 7.85- 7.83 (m, 2H), 7.62-7.57 (m, 4H), 7.02-7.00 (m, 2H), 4.02 (t, J=6.0Hz, 2H),
1.73-1.72 (m, 2H), 1.39-1.37 (m, 4H), 0.92 (t, J=6.0Hz, 3H)
Under 4 4- amoxy -4 ' of embodiment-biphenylboronic acid synthesis nitrogen protection, 1.41g palladium acetate is added into 2L there-necked flask,
(o-methyl-phenyl) phosphine of 2.30g tri- and 480mL tetrahydrofuran, ice-water bath are cooled to 0-10 DEG C, and positive penta oxygen of the bromo- 4- of 80g4 '-is added
Base biphenyl and 74g potassium acetate, nitrogen are replaced three times, and two boron of 29.4g tetrahydroxy is added drop-wise to reaction system after being dissolved in 400mL methanol
In, it is warming up to 35-40 DEG C and is stirred to react 30min, the dilution of 500mL ethyl alcohol is added after raw material fully reacting, filters, filter cake is used
100mL ethanol washing, filtrate are added 1200mL methylene chloride/water mixed solvent (1:2) heat after being spin-dried for and wash and starch 1h, are cooled to 10
It is filtered after DEG C, filter cake is washed with a small amount of water methylene chloride, and white solid 45.2g, yield are dried in vacuo 5 hours to obtain at 50 DEG C
63%.1H NMR(d6DMSO,400MHz) δ7.98-7.96(m,2H),7.85-7.83(m,2H),7.62-7.57(m,4H),
7.02-7.00 (m, 2H), 4.02 (t, J=6.0Hz, 2H), 1.73-1.72 (m, 2H), 1.39-1.37 (m, 4H), 0.92 (t, J
=6.0Hz, 3H)
Embodiment 54 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate synthesis nitrogen protection under, to
2g 4- amoxy -4 '-biphenylboronic acid, 1.75g 4- iodo-benzoic acid methyl esters 20mL toluene/normal propyl alcohol are added in 100mL there-necked flask
Mixed solution (1:8) stirs evenly at room temperature, sequentially adds 4mL sodium carbonate liquor (2mol/L), 18mg palladium acetate and 50mg tri-
Phenylphosphine, nitrogen react overnight at replacing 3 times, 85 DEG C, are cooled to room temperature and filter after raw material fully reacting, filter cake is successively used
2mL toluene, 4mL water and the elution of 4mL methyl tertiary butyl ether(MTBE), filter cake are dried in vacuo 5 hours to obtain white solid 1.92g at 50 DEG C,
Yield 71%.1H NMR(CDCl3, 400MHz) and δ 8.13 (d, J=8.0 Hz, 2H), 7.71-7.66 (m, 6H), 7.53-7.52
(m, 2H), 7.00 (d, J=8.0Hz, 2H), 4.02 (t, J=8.0Hz, 2H), 3.95 (s, 3H), 1.84-1.80 (m, 2H),
1.49-1.40 (m, 4H), 0.97 (t, J=8.0Hz, 3H)
Embodiment 64 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate synthesis nitrogen protection under, to
20g 4- amoxy -4 '-biphenylboronic acid, 17.5g 4- iodo-benzoic acid methyl esters 150mL toluene/positive third are added in 500mL there-necked flask
Mixed alkoxide solution (1:8) stirs evenly at room temperature, sequentially adds 40mL sodium carbonate liquor (2mol/L), 150mg palladium acetate and
526mg triphenylphosphine, nitrogen react overnight at replacing 3 times, 85 DEG C, are cooled to room temperature and filter after raw material fully reacting, filters
Cake successively uses 10mL toluene, and 20mL water and the elution of 15mL methyl tertiary butyl ether(MTBE), filter cake are dried in vacuo 5 hours white at 50 DEG C
Solid 20.1g, yield 80.4%.1H NMR(CDCl3, 400MHz) and δ 8.13 (d, J=8.0Hz, 2H), 7.71-7.66 (m,
6H), 7.53-7.52 (m, 2H), 7.00 (d, J=8.0Hz, 2H), 4.02 (t, J=8.0Hz, 2H), 3.95 (s, 3H), 1.84-
1.80 (m, 2H), 1.49-1.40 (m, 4H), 0.97 (t, J=8.0Hz, 3H)
Synthesis of 7 anidulafungin side chain intermediate of embodiment to amoxy terphenyl formic acid
20g 4 "-(amoxy)-[1,1', 4', 1 "-terphenyl] -4- methyl formate, 1.17g ten are added into 500mL there-necked flask
Six alkyl trimethyl ammonium bromides, 12g potassium hydroxide and 60mL dimethylbenzene are reacted 6 hours at 85 DEG C, are filtered after being cooled to room temperature,
Filter cake is washed with water (3x 100mL), and 160mL glycol dimethyl ether and 100mL dilute hydrochloric acid are simultaneously added after draining for income rate
(1mol/L) is warming up to 85 DEG C and is stirred to react 1h, filter after being cooled to room temperature, filter cake successively use 50mL methyl tertiary butyl ether(MTBE) and
The elution of 50mL methanol, rate are simultaneously dried in vacuo 5 hours at 50 DEG C, obtain white solid 18.4g, yield 95.6%.Fig. 1 is to penta
The nuclear magnetic spectrogram hydrogen of oxygroup terphenyl formic acid is composed,1H NMR(d6DMSO, 400MHz) δ 12.98 (s, 1H), 8.04 (d, J=
8.0Hz, 2H), 7.86-7.74 (m, 6H), 7.68 (d, J=8.0Hz, 2H), 7.05 (d, J=8.0Hz, 2H), 4.03 (t, J=
8.0Hz, 2H), 1.76-1.71 (m, 2H), 1.42-1.33 (m, 4H), 0.93 (t, J=8.0Hz, 3H)
The above is particular example embodiment of the invention, for those skilled in the art, of the invention not departing from
Under principle, several improvement and rhetoric can also be made.In fact, the scope of the present invention is by the attached claims and its equivalent
It limits.
Claims (10)
1. a kind of anidulafungin side chain intermediate is to the preparation method of amoxy terphenyl formic acid, which is characterized in that including as follows
Step:
S1:4 hydroxyl -4 '-bromo biphenyl and 1- bromo pentane silane occur nucleophilic substitution and obtain 4 '-bromo- 4- n-pentyloxy biphenyl；
S2: under inert atmosphere protection, 4 '-bromo- 4- n-pentyloxy biphenyl and two boron of tetrahydroxy are in palladium catalyst and Phosphine ligands
The lower generation Suzuki coupling reaction of effect obtains 4- amoxy -4 '-biphenylboronic acid；
S3: under inert atmosphere protection, 4- amoxy -4 '-biphenylboronic acid and 4- iodo-benzoic acid methyl esters are matched in palladium catalyst and phosphine
Suzuki coupling reaction occurs under the action of body and obtains 4''- (amoxy)-[1,1', 4', 1''- terphenyl] -4- methyl formate；
S4:4''- (amoxy)-[1,1', 4', 1''- terphenyl] -4- methyl formate hydrolysis obtains the anidulafungin side chain
Intermediate is to amoxy terphenyl formic acid.
2. preparation method according to claim 1, which is characterized in that nucleophilic substitution described in S1 selects tetrabutyl phosphonium bromide
Ammonium is catalyst；The pH of the nucleophilic substitution is 8 ~ 11；The temperature of the nucleophilic substitution is 60 ~ 95 DEG C.
3. preparation method according to claim 1, which is characterized in that 1- bromo pentane silane rubs with 4- hydroxyl -4 '-bromo biphenyl in S1
You are than being 1.1 ~ 2.0:1.
4. preparation method according to claim 1, which is characterized in that the boron of tetrahydroxy two described in S2 and 4 '-bromo- positive penta oxygen of 4-
The molar ratio of base biphenyl is 1.5 ~ 4.0:1.
5. preparation method according to claim 1, which is characterized in that palladium catalyst described in S2 is palladium acetate Pd (OAc)2,
Dibenzylideneacetonepalladium palladium Pd2(dba)3Or palladium chloride PdCl2One or more of；The Phosphine ligands are triphenylphosphine PPh3, three
O-methyl-phenyl phosphine P (o-MeC6H4)3, tricyclohexyl phosphine PCy3Or tri-tert-butylphosphine P t Bu3One or more of；It is described
The pH of Suzuki coupling reaction is 8 ~ 11；The temperature of the Suzuki coupling reaction is 0 ~ 40 DEG C.
6. preparation method according to claim 1, which is characterized in that the methyl esters of 4- iodo-benzoic acid described in S3 and 4- amoxy-
The molar ratio of 4 '-biphenylboronic acids is 1.1 ~ 1.5.
7. preparation method according to claim 1, which is characterized in that palladium catalyst described in S3 is palladium acetate Pd (OAc)2,
Dibenzylideneacetonepalladium palladium Pd2(dba)3Or palladium chloride PdCl2One or more of；The Phosphine ligands are triphenylphosphine PPh3, three
O-methyl-phenyl phosphine P (o-MeC6H4)3, tricyclohexyl phosphine PCy3Or tri-tert-butylphosphine P t Bu3One or more of；It is described
The pH of Suzuki coupling reaction is 8-11；The temperature of the Suzuki coupling reaction is 50 ~ 80 DEG C.
8. preparation method according to claim 7, which is characterized in that the palladium catalyst and 4- amoxy -4 '-biphenylboronic acid
Molar ratio be 0.5 ~ 10:1；The Phosphine ligands and 4- amoxy -4 '-biphenylboronic acid molar ratio are 1 ~ 15:1.
9. preparation method according to claim 1, which is characterized in that hydrolysis described in S4 selects cetyl trimethyl
Ammonium bromide is as phase transfer catalyst.
10. preparation method according to claim 1, which is characterized in that 4''- described in S4 (amoxy)-[1,1', 4',
1''- terphenyl] -4- methyl formate is dissolved in xylene solution.
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