CN109574811B - Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid - Google Patents
Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid Download PDFInfo
- Publication number
- CN109574811B CN109574811B CN201811401127.9A CN201811401127A CN109574811B CN 109574811 B CN109574811 B CN 109574811B CN 201811401127 A CN201811401127 A CN 201811401127A CN 109574811 B CN109574811 B CN 109574811B
- Authority
- CN
- China
- Prior art keywords
- pentoxy
- terphenyl
- suzuki coupling
- palladium
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims abstract description 28
- -1 terphenyl formic acid Chemical compound 0.000 title claims abstract description 19
- 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 abstract description 18
- 235000019253 formic acid Nutrition 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 25
- 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 16
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims abstract description 14
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 12
- 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 10
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 claims abstract description 10
- 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 abstract description 9
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 claims abstract description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 40
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 30
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 20
- 229910052763 palladium 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 15
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 7
- 239000012298 atmosphere Substances 0.000 claims description 6
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- 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 6
- 230000009471 action Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 4
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 abstract description 9
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 6
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 4
- 238000011112 process operation Methods 0.000 abstract description 4
- 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
- 238000006243 chemical reaction Methods 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 14
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 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
- 150000007529 inorganic bases Chemical class 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical group [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 7
- 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
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000003786 synthesis reaction 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
- 239000007818 Grignard reagent Substances 0.000 description 5
- 239000003429 antifungal agent Substances 0.000 description 5
- 229940121375 antifungal agent Drugs 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 239000000047 product Substances 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
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 5
- 229960003348 anidulafungin Drugs 0.000 description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- BODYVHJTUHHINQ-UHFFFAOYSA-N (4-boronophenyl)boronic acid Chemical compound OB(O)C1=CC=C(B(O)O)C=C1 BODYVHJTUHHINQ-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- BLCLYCFKSCVGEF-UHFFFAOYSA-N CCCCCOC(C=CC=C1)=C1C1=CC=C(B(O)O)C=C1 Chemical compound CCCCCOC(C=CC=C1)=C1C1=CC=C(B(O)O)C=C1 BLCLYCFKSCVGEF-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 108010049047 Echinocandins Proteins 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001924 fatty-acyl group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000005457 ice water Substances 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
- 238000001291 vacuum drying 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
- 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
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical class O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940071198 eraxis Drugs 0.000 description 1
- YCBJOQUNPLTBGG-UHFFFAOYSA-N ethyl 4-iodobenzoate Chemical compound CCOC(=O)C1=CC=C(I)C=C1 YCBJOQUNPLTBGG-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
Images
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
The invention relates to a preparation method of an anidulafungin side chain intermediate p-pentoxy terphenyl formic acid. The method comprises the following steps: s1: 4-hydroxy-4 '-bromobiphenyl and 1-bromopentane undergo nucleophilic substitution reaction to obtain 4' -bromo-4-n-pentyloxybiphenyl; s2: carrying out Suzuki coupling reaction on 4 '-bromo-4-n-pentyloxybiphenyl and tetrahydroxy diboron to obtain 4-pentyloxy-4' -biphenylboronic acid; s3: carrying out Suzuki coupling reaction on 4-pentoxy-4 ' -biphenyl boric acid and 4-iodomethyl benzoate to obtain 4' ' - (pentoxy) - [1,1',4',1' ' -terphenyl ] -4-methyl formate; s4: hydrolyzing to obtain the p-pentoxy terphenyl formic acid. The invention adopts Suzuki coupling to prepare the aryl boric acid, and then adopts the Suzuki coupling and the alkaline hydrolysis method to prepare the target product, and has the advantages of low cost, simple and safe process operation.
Description
Technical Field
The invention relates to the field of medicine synthesis, and in particular relates to a preparation method of anidulafungin side chain p-pentoxy terphenyl formic acid.
Technical Field
Anidulafungin (anidulafungin) is a derivative of amphotericin B, a third-generation echinocandin semi-synthetic antifungal drug developed by viculon pharmaceutical company in the united states, with the trade name Eraxis, and sold in the united states in 2006. Anidulafungin has a larger volume of distribution and a broader spectrum of antimicrobial activity than other echinocandin antifungal agents.
Anidulafungin, a semi-synthetic antifungal agent, is derived from a cyclic peptide antifungal agent prepared by culturing various microorganisms. The structural features of all these antifungal agents are: comprising a cyclic hexapeptide core, an amino group of a cyclic amino acid bearing a fatty acyl group, the fatty acyl group forming a chain. Removing side chain by enzyme deacylation to obtain free nucleus, and acylating the amino group of nucleus to obtain semi-synthetic antifungal compound.
WO09631228A, WO0051564A1 and JP2005325142A disclose a method for preparing p-pentyloxy terphenyl formic acid, which comprises the following steps: a. preparing aryl boric acid from aryl halide and triisopropyl borate under the action of butyl lithium; b. preparing 4 '- (pentoxy) - [1,1',4',1' -terphenyl ] -4-methyl formate from arylboronic acid and p-iodomethyl benzoate through Suzuki coupling; c. then hydrolyzing under alkaline condition to obtain the target product. The butyl lithium and air adopted by the route for preparing the boric acid are easy to burn, and the reaction system has higher requirement on moisture, so the method is not suitable for large-scale production.
CN103570530A and CN106431901A provide a method for preparing methyl terphenyl formate by a Grignard reagent and then hydrolyzing the methyl terphenyl formate to obtain p-pentoxy terphenyl formate. The specific process is as follows: carrying out Grignard reagent reaction on 1, 4-dibromobenzene and magnesium by iodine initiation, reacting with trimethyl borate after cooling, and hydrolyzing under acidic condition to prepare 1, 4-phenyl diboronic acid; preparation of 4 '- (pentyloxy) - [1,1',4',1' -terphenyl ] -4-carboxylic acid ethyl ester by Suzuki coupling of 1, 4-benzenediboronic acid, 4-pentyloxybromobenzene and 4-iodobenzoic acid ethyl ester. The route prepares the boric acid by the Grignard reagent, has higher requirement on the moisture of the solvent, and the prepared Grignard reagent needs to be filtered in a glove box to remove magnesium chips, so the operation is complicated, and the method is not suitable for large-scale production.
Therefore, the method for preparing the anidulafungin side chain intermediate boric acid, which is simple in process, mild in condition and suitable for large-scale production, has important research significance and economic value.
Disclosure of Invention
The invention aims to solve the problems of complex operation, difficult control, high risk and the like in the method for preparing boric acid by butyl lithium or Grignard reagent reaction in the prior art, and provides a preparation method of an anidulafungin side chain intermediate p-pentoxy terphenyl formic acid. The invention adopts Suzuki coupling to prepare the aryl boric acid, and then adopts the Suzuki coupling and the alkaline hydrolysis method to prepare the target product, and has the advantages of low cost, simple and safe process operation.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of an anidulafungin side chain intermediate p-pentoxy terphenyl formic acid comprises the following steps:
s1: 4-hydroxy-4 '-bromobiphenyl and 1-bromopentane undergo nucleophilic substitution reaction to obtain 4' -bromo-4-n-pentyloxybiphenyl;
s2: under the protection of inert atmosphere, carrying out Suzuki coupling reaction on 4 '-bromo-4-n-pentyloxy biphenyl and tetrahydroxy diboron under the action of a palladium catalyst and a phosphine ligand to obtain 4-pentyloxy-4' -biphenyl boric acid;
s3: under the protection of inert atmosphere, carrying out Suzuki coupling reaction on 4-pentoxy-4 ' -biphenyl boric acid and 4-iodomethyl benzoate under the action of a palladium catalyst and a phosphine ligand to obtain 4' - (pentoxy) - [1,1',4',1' -terphenyl ] -4-methyl formate;
s4: hydrolyzing 4 '- (pentoxy) - [1,1',4',1' -terphenyl ] -4-methyl formate to obtain the anidulafungin side chain intermediate p-pentoxy terphenyl formic acid.
The method selects specific raw materials, adopts Suzuki coupling to prepare the aryl boric acid, and prepares the target product by the Suzuki coupling and the alkaline hydrolysis method, and has the advantages of low cost, simple and safe process operation.
The nucleophilic substitution reaction in S1 of the present invention is a conventional reaction type, and the condition control (such as catalyst, reaction temperature, pH, etc.) can be referred to the prior art.
Preferably, tetrabutylammonium bromide is used as a catalyst in the nucleophilic substitution reaction in S1.
More preferably, the molar ratio of the tetrabutylammonium bromide to the 4-hydroxy-4' -bromobiphenyl is 0.1-0.5: 1.
Preferably, the pH of the nucleophilic substitution reaction in S1 is 8-11.
Preferably, the nucleophilic substitution reaction in S1 is performed with an inorganic base to adjust the pH.
Inorganic bases conventional in the art may be used in the present invention.
More preferably, the inorganic base is sodium hydroxide.
Preferably, the temperature of the nucleophilic substitution reaction in S1 is 60-95 ℃.
Preferably, the molar ratio of 1-bromopentane to 4-hydroxy-4' -bromobiphenyl in S1 is 1.1-2.0: 1.
Preferably, the specific process of S1 is: 4-hydroxy-4 '-bromobiphenyl is used as a raw material to be catalyzed by tetrabutylammonium bromide to perform nucleophilic substitution reaction with 1-bromopentane under the condition of sodium hydroxide to prepare the 4' -bromo-4-n-pentyloxybiphenyl.
Preferably, the molar ratio of the tetrahydroxydiboron to the 4' -bromo-4-n-pentyloxybiphenyl in S2 is 1.5-4.0: 1.
Both palladium catalysts and phosphine ligands conventional in the art may be used in the present invention.
Preferably, the palladium catalyst in S2 is palladium acetate Pd (OAc)2Palladium (II) dibenzylideneacetone Pd2(dba)3Or palladium chloride PdCl2One or more of them.
Preferably, the phosphine ligand in S2 is triphenylphosphine PPh3Tri-o-methylPhenylphosphine P (o-MeC)6H4)3Tricyclohexylphosphine PCy3Or tri-tert-butylphosphine PtBu3One or more of them.
Preferably, the phosphine ligand described in S2 is dissolved in a tetrahydrofuran solution.
More preferably, the volume-to-mass ratio of the tetrahydrofuran to the 4' -bromo-4-n-pentyloxybiphenyl is 4-10: 1 mL/g.
More preferably, the palladium catalyst is palladium acetate; the phosphine ligand is tri (o-methylphenyl) phosphine.
The inventor preferably finds that the palladium catalyst and the phosphine ligand have the effects of improving the conversion rate and reducing byproducts by using palladium acetate and tri (o-methylphenyl) phosphine as the catalyst.
More preferably, the molar ratio of the palladium acetate to the 4' -bromo-4-n-pentyloxybiphenyl is 1-8: 100.
More preferably, the molar ratio of the tri-o-methylphenyl phosphine to the 4' -bromo-4-n-pentyloxy biphenyl is 1-10: 100;
preferably, the pH of the Suzuki coupling reaction in S2 is 8-11.
Preferably, the Suzuki coupling reaction in S2 is performed by adjusting the pH with an inorganic base.
Inorganic bases conventional in the art may be used in the present invention.
More preferably, the inorganic base is potassium acetate.
Preferably, the molar ratio of the potassium acetate to the 4' -bromo-4-n-pentyloxybiphenyl is 1.5-3.0: 1.
Preferably, the temperature of the Suzuki coupling reaction in S2 is 0-40 ℃.
Preferably, the tetrahydroxydiboron is dissolved in a methanol solution.
More preferably, the volume mass ratio of the methanol to the tetrahydroxy diboron is 10-20: 1.
Preferably, the inert atmosphere in S2 is a nitrogen atmosphere.
More preferably, the specific process of S2 is: under the protection of nitrogen, adding potassium acetate and 4 '-bromo-4-n-pentyloxybiphenyl into a tetrahydrofuran solution of palladium acetate and tris (o-methylphenyl) phosphine, adding a methanol solution of tetrahydroxydiboron, and preparing the 4-pentyloxy-4' -biphenylboronic acid through Suzuki coupling reaction.
Preferably, the molar ratio of the methyl 4-iodobenzoate to the 4-pentoxy-4' -biphenylboronic acid in S3 is 1.1-1.5.
Preferably, the palladium catalyst in S3 is palladium acetate Pd (OAc)2Palladium (II) dibenzylideneacetone Pd2(dba)3Or palladium chloride PdCl2One or more of them.
Preferably, the phosphine ligand in S3 is triphenylphosphine PPh3Tri-o-methyl phenylphosphine P (o-MeC)6H4)3Tricyclohexylphosphine PCy3Or tri-tert-butylphosphine PtBu3One or more of them.
More preferably, the palladium catalyst is palladium acetate and the phosphine ligand is triphenylphosphine.
The inventor preferably finds that the palladium catalyst and the phosphine ligand have the effects of improving the conversion rate and reducing byproducts by using the palladium acetate and the triphenylphosphine as the catalyst.
More preferably, the molar ratio of the palladium acetate to the 4-pentoxy-4' -biphenylboronic acid is 0.5-10: 1.
More preferably, the molar ratio of the triphenylphosphine to the 4-pentoxy-4' -biphenylboronic acid is 1-15: 1.
Preferably, the pH of the Suzuki coupling reaction in S3 is 8-11.
Preferably, the Suzuki coupling reaction in S3 is performed by adjusting the pH with an inorganic base.
Inorganic bases conventional in the art may be used in the present invention.
More preferably, the inorganic base is sodium carbonate.
Preferably, the molar ratio of the sodium carbonate to the 4-pentoxy-4' -biphenyl boric acid is 1.0-3.0.
Preferably, the methyl 4-iodobenzoate is dissolved in a toluene/n-propanol mixed solution.
More preferably, the volume ratio of the n-propanol to the toluene in the toluene/n-propanol mixed solution is 1-10: 1.
Preferably, the mass ratio of the n-propanol/toluene mixed solution to the 4-n-pentyloxy-4' -biphenylboronic acid is 8-15: 1.
Preferably, the inert atmosphere in S3 is a nitrogen atmosphere.
More preferably, the specific process of S3 is: under the protection of nitrogen, sequentially adding a sodium carbonate aqueous solution, palladium acetate and triphenylphosphine into a toluene/n-propanol mixed solution of 4-pentoxy-4 ' -biphenyl boric acid and 4-iodobenzoic acid methyl ester, and performing Suzuki coupling reaction to obtain 4' - (pentoxy) - [1,1',4',1' -terphenyl ] -4-formic acid methyl ester.
The hydrolysis reaction in S4 of the present invention is a conventional reaction type, and the condition control (such as catalyst, reaction temperature, pH, etc.) can be referred to the prior art.
Preferably, cetyl trimethyl ammonium bromide is used as the phase transfer catalyst for the hydrolysis reaction in S4.
Preferably, the methyl 4 "- (pentyloxy) - [1,1',4', 1" -terphenyl ] -4-carboxylate described in S4 is dissolved in a xylene solution.
Preferably, the pH of the hydrolysis reaction in S4 is 12-14.
Inorganic base solutions conventional in the art can be used in the present invention.
More preferably, the hydrolysis reaction in S4 is adjusted to pH with an aqueous solution of potassium hydroxide.
More preferably, the specific process of S4 is: and (3) mixing the xylene solution of 4 '- (pentoxy) - [1,1',4',1' -terphenyl ] -4-methyl formate with the aqueous solution of potassium hydroxide, and hydrolyzing under the catalysis of a phase transfer catalyst cetyl trimethyl ammonium bromide to obtain the anidulafungin side chain intermediate p-pentoxy terphenyl formic acid.
The preparation method provided by the invention can be represented as the following reaction formula:
compared with the prior art, the invention has the following beneficial effects:
the invention adopts Suzuki coupling to prepare the aryl boric acid, and then adopts the Suzuki coupling and the alkaline hydrolysis method to prepare the target product, and has the advantages of low cost, simple and safe process operation.
Drawings
FIG. 1 shows the NMR spectrum of the anidulafungin side chain intermediate p-pentoxy terphenyl formic acid provided in example 7.
Detailed Description
The invention is further illustrated by the following examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Experimental procedures without specific conditions noted in the examples below, generally according to conditions conventional in the art or as suggested by the manufacturer; the raw materials, reagents and the like used are, unless otherwise specified, those commercially available from the conventional markets and the like. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
EXAMPLE 14 Synthesis of' -bromo-4-n-pentyloxybiphenyl
Adding 1450mL of water and 21.2g of sodium hydroxide into a 2L three-necked flask, stirring for dissolving, then adding 120g of 4-hydroxy-4' -bromobiphenyl and 6g of tetrabutylammonium bromide, stirring for 10min at room temperature, then dropwise adding 87.2g of 1-bromopentane, refluxing for 5h after dropwise adding is finished, performing suction filtration after the reaction is cooled to room temperature, washing a filter cake with 400mL of water, thermally pulping the solid with 600mL of n-heptane/water (1:1) mixed solution, performing suction filtration, washing the filter cake with 60mL of n-heptane, and performing vacuum drying on the obtained solid for 5 hours at 60 ℃, wherein the yield is 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).
EXAMPLE 24 Synthesis of '-bromo-4-n-pentyloxybiphenyl 1200mL of water, 17.7g of sodium hydroxide were added to a 2L three-necked flask, stirred to dissolve and clear, 100g of 4-hydroxy-4' -bromobiphenyl and 5g of tetrabutylammonium bromide were added, stirred at room temperature for 10min, then 72.7g of 1-bromopentane were added dropwise, the mixture was refluxed for 5 hours after the addition was complete, and the reaction was allowed to cool to room temperatureThe mixture was filtered off with suction, the filter cake was washed with 300mL of water, the solid obtained was slurried hot with 320mL of an n-heptane/water (1:1) mixture, filtered off with suction and the filter cake was washed with 60mL of n-heptane, and the solid obtained was dried under vacuum at 60 ℃ for 5 hours in 87% yield.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).
Example 34 Synthesis of Pentoxy-4 '-biphenylboronic acid under nitrogen protection, 5g of 4' -bromo-4-n-pentyloxybiphenyl, 88mg of palladium acetate, 4.6g of potassium acetate, 144mg of tris (o-methylphenyl) phosphine and 15mL of tetrahydrofuran were added to a 100mL three-necked flask, the temperature was lowered to 0-10 ℃ in an ice water bath, 1.84g of tetrahydroxydiboron was dissolved in 10mL of methanol and then added dropwise to the reaction, the reaction was stirred at room temperature, 30mL of ethanol was added after the disappearance of the starting materials to dilute the reaction, the reaction mixture was filtered, the filter cake was washed with 10mL of ethanol, 80mL of a dichloromethane/water mixed solvent (1:1) was added after the filtrate was spin-dried, the mixture was thermally pulped at 40 ℃ for 1h, the reaction was cooled to room temperature and then filtered, the filter cake was washed with 5mL of water and 5mL of dichloromethane in that order, and vacuum-dried at 50 ℃ to obtain 2.84g of a white solid, with a yield of 64%.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).
Example 44 Synthesis of Pentoxy-4 '-biphenylboronic acid under nitrogen protection, 1.41g of palladium acetate, 2.30g of tris (o-methylphenyl) phosphine and 480mL of tetrahydrofuran were added to a 2L three-necked flask, the temperature was reduced to 0 to 10 ℃ in an ice-water bath, 80g of 4' -bromo-4-n-pentyloxybiphenyl and 74g of potassium acetate were added, nitrogen was substituted three times, 29.4g of tetrahydroxydiboron was dissolved in 400mL of methanol and then added dropwise to the reaction system, the temperature was raised to 35 to 40 ℃ and stirred for reaction for 30min, after the reaction of the raw materials was completed, 500mL of ethanol was added for dilution, filtration was carried out, the filter cake was washed with 100mL of ethanol, after the filtrate was spin-dried, 1200mL of a dichloromethane/water mixed solvent (1:2) was added for hot slurry washing for 1h, after cooling to 10 ℃ and filtration was carried out, the filter cake was washed with a small amount of dichloromethane, and vacuum drying was carried out at 50 ℃ for 5 hours to obtain 45.2g of a white solid, the yield thereof was found to be 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).
Example 54 "- (pentyloxy) - [1,1',4', 1" -terphenyl]Under the protection of synthetic nitrogen of-4-methyl formate, 2g of 4-pentoxy-4' -biphenylboronic acid and 1.75g of 4-iodobenzoic acid methyl ester 20mL of toluene/n-propanol mixed solution (1:8) are added into a 100mL three-necked bottle and stirred uniformly at room temperature, 4mL of sodium carbonate solution (2mol/L), 18mg of palladium acetate and 50mg of triphenylphosphine are sequentially added, nitrogen is replaced for 3 times, the mixture is reacted at 85 ℃ overnight, after the raw materials are completely reacted, the mixture is cooled to room temperature and filtered, a filter cake is sequentially leached by 2mL of toluene, 4mL of water and 4mL of methyl tert-butyl ether, and the filter cake is dried under vacuum at 50 ℃ for 5 hours to obtain 1.92g of white solid, wherein the yield is 71%.1H NMR(CDCl3,400MHz)δ8.13(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).
Example 64 "- (pentyloxy) - [1,1',4', 1" -terphenyl]Under the protection of synthetic nitrogen of-4-methyl formate, 20g of 4-pentoxy-4' -biphenylboronic acid and 17.5g of methyl 4-iodobenzoate 150mL of toluene/n-propanol mixed solution (1:8) are added into a 500mL three-necked bottle and stirred uniformly at room temperature, 40mL of sodium carbonate solution (2mol/L), 150mg of palladium acetate and 526mg of triphenylphosphine are sequentially added, nitrogen is replaced for 3 times, the mixture is reacted at 85 ℃ overnight, after the raw materials are completely reacted, the mixture is cooled to room temperature and filtered, a filter cake is sequentially leached by 10mL of toluene, 20mL of water and 15mL of methyl tert-butyl ether, and the filter cake is dried under vacuum at 50 ℃ for 5 hours to obtain 20.1g of white solid, and the yield is 80.4%.1H NMR(CDCl3,400MHz)δ8.13(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).
Example 7 Synthesis of anidulafungin side chain intermediate p-pentyloxy terphenyl carboxylic acid
To a 500mL three-necked flask was added 20g of 4 "- (pentyloxy) - [1,1',4', 1" -terphenyl]-4-methyl formate, 1.17g cetyltrimethylammonium bromide, 12g potassium hydroxide and 60mL xylene, reacting at 85 ℃ for 6 hours, cooling to room temperature and suction filtering, washing the filter cake with water (3X 100mL), recovering the product and pumpingAnd after drying, adding 160mL of ethylene glycol dimethyl ether and 100mL of dilute hydrochloric acid (1mol/L), heating to 85 ℃, stirring for reaction for 1h, cooling to room temperature, carrying out suction filtration, sequentially leaching a filter cake with 50mL of methyl tert-butyl ether and 50mL of methanol, drying in vacuum at 50 ℃ for 5h to obtain 18.4g of white solid, wherein the yield is 95.6%. FIG. 1 is the hydrogen spectrum of nuclear magnetism spectrum of p-pentoxy terphenyl formic acid,1H NMR(d6DMSO,400MHz)δ12.98(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).
while the foregoing is directed to particular example embodiments of the present invention, numerous modifications and adaptations may be made by those skilled in the art without departing from the principles of the present invention. Rather, the scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A preparation method of an anidulafungin side chain intermediate p-pentoxy terphenyl formic acid is characterized by comprising the following steps:
s1: 4-hydroxy-4 '-bromobiphenyl and 1-bromopentane undergo nucleophilic substitution reaction to obtain 4' -bromo-4-n-pentyloxybiphenyl;
s2: under the protection of inert atmosphere, carrying out Suzuki coupling reaction on 4 '-bromo-4-n-pentyloxy biphenyl and tetrahydroxy diboron under the action of a palladium catalyst and a phosphine ligand to obtain 4-pentyloxy-4' -biphenyl boric acid; the palladium catalyst in S2 is palladium acetate Pd (OAc)2Palladium (II) dibenzylideneacetone Pd2(dba)3Or palladium chloride PdCl2One or more of the above; the temperature of the Suzuki coupling reaction is 0-40 ℃; the phosphine ligand is triphenylphosphine PPh3Or tri-o-methylphenylphosphine P: (o-MeC6H4)3One or two of them;
s3: under the protection of inert atmosphere, carrying out Suzuki coupling reaction on 4-pentoxy-4 ' -biphenyl boric acid and 4-iodomethyl benzoate under the action of a palladium catalyst and a phosphine ligand to obtain 4' ' - (pentoxy) - [1,1',4',1' ' -terphenyl ] -4-methyl formate;
s4: 4'' - (pentoxy) - [1,1',4',1'' -terphenyl ] -4-methyl formate is hydrolyzed to obtain the anidulafungin side chain intermediate p-pentoxy terphenyl formic acid.
2. The preparation method according to claim 1, wherein tetrabutylammonium bromide is used as a catalyst in the nucleophilic substitution reaction in S1; the pH value of the nucleophilic substitution reaction is 8-11; the temperature of the nucleophilic substitution reaction is 60-95 ℃.
3. The method according to claim 1, wherein the molar ratio of 1-bromopentane to 4-hydroxy-4' -bromobiphenyl in S1 is 1.1 to 2.0: 1.
4. The method according to claim 1, wherein the molar ratio of tetrahydroxydiboron to 4' -bromo-4-n-pentyloxybiphenyl in S2 is 1.5 to 4.0: 1.
5. The method according to claim 1, wherein the pH of the Suzuki coupling reaction in S2 is 8 to 11.
6. The method according to claim 1, wherein the molar ratio of methyl 4-iodobenzoate to 4-pentyloxy-4' -biphenylboronic acid in S3 is 1.1 to 1.5.
7. The method according to claim 1, wherein the palladium catalyst in S3 is palladium acetate Pd (OAc)2Palladium (II) dibenzylideneacetone Pd2(dba)3Or palladium chloride PdCl2One or more of the above; the phosphine ligand is triphenylphosphine PPh3Tri-o-methyl phenylphosphine P (A), (B), (C) and (C)o-MeC6H4)3Tricyclohexylphosphine PCy3Or tri-tert-butylphosphine P t Bu3One or more of the above; the pH value of the Suzuki coupling reaction is 8-11; the temperature of the Suzuki coupling reaction is 50-80 ℃.
8. The preparation method according to claim 7, wherein the molar ratio of the palladium catalyst to the 4-pentyloxy-4' -biphenylboronic acid is 0.5 to 10: 1; the molar ratio of the phosphine ligand to the 4-pentoxy-4' -biphenyl boric acid is 1-15: 1.
9. The method according to claim 1, wherein the hydrolysis reaction in S4 employs cetyltrimethylammonium bromide as a phase transfer catalyst.
10. The process according to claim 1, wherein said methyl 4 "- (pentyloxy) - [1,1',4', 1" -terphenyl ] -4-carboxylate in S4 is dissolved in a xylene solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811401127.9A CN109574811B (en) | 2018-11-22 | 2018-11-22 | Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811401127.9A CN109574811B (en) | 2018-11-22 | 2018-11-22 | Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109574811A CN109574811A (en) | 2019-04-05 |
| CN109574811B true CN109574811B (en) | 2021-12-24 |
Family
ID=65923530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811401127.9A Active CN109574811B (en) | 2018-11-22 | 2018-11-22 | Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109574811B (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275984A (en) * | 1997-09-08 | 2000-12-06 | 联邦科学和工业研究组织 | Process for preparing organic acid derivatives using diboronic acid |
| EP1160233A2 (en) * | 2000-06-02 | 2001-12-05 | Sharp Kabushiki Kaisha | Novel terphenyl compounds |
| CN1345230A (en) * | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | Processes for making pharmaceutical oral ECB formulations and compositions |
| CN1345333A (en) * | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | Echinocandin/carbohydrate complexes |
| CN100335122C (en) * | 1999-03-03 | 2007-09-05 | 伊莱利利公司 | Echinocandin pharmaceutical formulations containing micelle-forming surfactants |
| CN103570530A (en) * | 2012-07-26 | 2014-02-12 | 山东新时代药业有限公司 | Preparation method of anidulafungin side chain intermediate |
| CN104530107A (en) * | 2014-12-31 | 2015-04-22 | 大连联化化学有限公司 | Synthetic method for 3-amino-4-fluorophenylboronic acid |
| CN106431901A (en) * | 2015-08-11 | 2017-02-22 | 天津领世生物科技开发有限公司 | Method for preparing anidulafungin side chain intermediate |
| CN107759461A (en) * | 2017-11-08 | 2018-03-06 | 天津狄克特科技有限公司 | Preparation method of the one-step synthesis method anidulafungin intermediate to amoxy terphenyl formic acid |
| CN108997286A (en) * | 2018-09-03 | 2018-12-14 | 吉林大学 | A kind of perfluor replaces dianhydride and preparation method thereof and is preparing the application in polyimides |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105766A1 (en) * | 2006-03-14 | 2007-09-20 | Santen Pharmaceutical Co., Ltd. | Novel 1,2,3,4-tetrahydroquinoxaline derivative having glucocorticoid receptor binding activity |
-
2018
- 2018-11-22 CN CN201811401127.9A patent/CN109574811B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1275984A (en) * | 1997-09-08 | 2000-12-06 | 联邦科学和工业研究组织 | Process for preparing organic acid derivatives using diboronic acid |
| CN1345230A (en) * | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | Processes for making pharmaceutical oral ECB formulations and compositions |
| CN1345333A (en) * | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | Echinocandin/carbohydrate complexes |
| CN100335122C (en) * | 1999-03-03 | 2007-09-05 | 伊莱利利公司 | Echinocandin pharmaceutical formulations containing micelle-forming surfactants |
| EP1160233A2 (en) * | 2000-06-02 | 2001-12-05 | Sharp Kabushiki Kaisha | Novel terphenyl compounds |
| CN103570530A (en) * | 2012-07-26 | 2014-02-12 | 山东新时代药业有限公司 | Preparation method of anidulafungin side chain intermediate |
| CN104530107A (en) * | 2014-12-31 | 2015-04-22 | 大连联化化学有限公司 | Synthetic method for 3-amino-4-fluorophenylboronic acid |
| CN106431901A (en) * | 2015-08-11 | 2017-02-22 | 天津领世生物科技开发有限公司 | Method for preparing anidulafungin side chain intermediate |
| CN107759461A (en) * | 2017-11-08 | 2018-03-06 | 天津狄克特科技有限公司 | Preparation method of the one-step synthesis method anidulafungin intermediate to amoxy terphenyl formic acid |
| CN108997286A (en) * | 2018-09-03 | 2018-12-14 | 吉林大学 | A kind of perfluor replaces dianhydride and preparation method thereof and is preparing the application in polyimides |
Non-Patent Citations (6)
| Title |
|---|
| 3-氨基-4-甲基苯硼酸的合成工艺改进;马超等;《化学工程与装备》;20150630(第6期);第57-58页 * |
| 4，，-烷氧基-1,1，：4,1，，-三联苯-4-羧酸的合成;刘红明;《药学实践杂志》;20101125;第28卷(第6期);第415-417页 * |
| Palladium-Catalyzed, Direct Boronic Acid Synthesis from Aryl Chlorides: A Simplified Route to Diverse Boronate Ester Derivatives;Gary A. Molander等;《J. AM. CHEM. SOC.》;20101124;第17701-17703页 * |
| Total synthesis and structureeactivity relationships of new echinocandin-like antifungal cyclolipohexapeptides;Jianzhong Yao等;《European Journal of Medicinal Chemistry》;20120204;第196-208页 * |
| 芳基硼酸类化合物合成研究进展;徐玉良等;《有机化学》;20180430;第38卷(第4期);第740页左栏 * |
| 镍催化卤化物和类卤化物的硼化反应研究;范陈锐等;《安徽化工》;20180831;第44卷(第4期);第58-60页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109574811A (en) | 2019-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106905305A (en) | A kind of En Gelie net preparation method | |
| WO2017201846A1 (en) | Preparation method of antibacterial oxazolidinone medicine and intermediate thereof | |
| CN103570530B (en) | A kind of preparation method of anidulafungin side chain intermediate | |
| CN105384788A (en) | Tildipirosin preparation method | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| CN109574811B (en) | Preparation method of anidulafungin side chain intermediate p-pentoxy terphenyl formic acid | |
| CN105399672A (en) | Reversible acetylcholinesterase inhibitor huperzine-A synthesis method | |
| CN102952169A (en) | Synthetic method of 6-methyl-17alpha-acetoxyl-19-norpregna-4,6-dialkyl-3,20-diketone | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
| CN102030779A (en) | Preparation method of chemiluminescence material AMPPD (4-methoxy-4-(3-phenylphosphonic)spiro[1,2-dioxetane-3,2'-adamantane]disodium salt) for immunoassay | |
| CN103553931A (en) | Method for synthesizing chiral diketone compound | |
| CN103254202A (en) | Preparation method of asenapine | |
| CN104370953B (en) | (R)-tert-butyl dimethyl siloxy-glutaric acid monoester preparation method | |
| CN102786541A (en) | Preparation method and application of potassium (iso)quinoline thifluoroborate | |
| CN109503477B (en) | Triarylmethane compound and high-efficiency catalytic synthesis method thereof | |
| CN102432594A (en) | Method for preparing 1-(3-hydroxymethylpyridine-2-yl)-2-phenyl-4-methyl piperazine serving as medicinal intermediate | |
| CN106749232B (en) | A kind of synthetic method of imidazo isoquinoline compound | |
| CN109232301A (en) | A kind of preparation method of the tetra isopropyl hydrazine of low cost and high yield | |
| CN112745205B (en) | Preparation method of simod intermediate | |
| CN113045475A (en) | Preparation method of 5-bromo-7-methylindole | |
| CN103665064A (en) | Method for preparing 2,3,4,6-tetra-O-benzyl -D-galactose | |
| CN111825716B (en) | Naphthoxazole phosphine oxide compound, synthesis method thereof and catalytic application of naphthoxazole phosphine oxide compound as ligand | |
| CN102219736B (en) | Preparation method for 8-quinolinecarboxylic ester and 8-quinolinecarboxylic acid | |
| CN110950898B (en) | Synthetic method of nitrogen-containing deuterated methyl compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |