CN115010692A - 一类新颖大环内酯的设计、制备及其应用 - Google Patents
一类新颖大环内酯的设计、制备及其应用 Download PDFInfo
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- CN115010692A CN115010692A CN202210558505.4A CN202210558505A CN115010692A CN 115010692 A CN115010692 A CN 115010692A CN 202210558505 A CN202210558505 A CN 202210558505A CN 115010692 A CN115010692 A CN 115010692A
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- macrolide
- preparation
- prostaglandin
- thp
- tbs
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- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 26
- 238000013461 design Methods 0.000 title abstract description 4
- 229940041033 macrolides Drugs 0.000 title description 3
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 32
- 229960003395 carboprost Drugs 0.000 claims abstract description 9
- DLJKPYFALUEJCK-MRVZPHNRSA-N carboprost Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C\CCCC(O)=O DLJKPYFALUEJCK-MRVZPHNRSA-N 0.000 claims abstract description 9
- 150000002596 lactones Chemical class 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 150000001336 alkenes Chemical group 0.000 claims description 7
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 7
- -1 methyl Grignard reagent Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 5
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 150000002373 hemiacetals Chemical class 0.000 claims description 5
- 229960002368 travoprost Drugs 0.000 claims description 5
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003138 primary alcohols Chemical class 0.000 claims description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 4
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 3
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 3
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 3
- 229940125807 compound 37 Drugs 0.000 claims description 3
- 239000011984 grubbs catalyst Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- YIKMRTHKLRXOBU-UHFFFAOYSA-N bromomethane;triphenylphosphane Chemical compound BrC.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YIKMRTHKLRXOBU-UHFFFAOYSA-N 0.000 claims description 2
- 238000005686 cross metathesis reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 150000003017 phosphorus Chemical class 0.000 claims description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 abstract description 4
- 229960002470 bimatoprost Drugs 0.000 abstract description 4
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 abstract description 3
- 229960002986 dinoprostone Drugs 0.000 abstract description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 abstract description 3
- 229960004458 tafluprost Drugs 0.000 abstract description 3
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 abstract description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000010626 work up procedure Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 238000007239 Wittig reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229940127007 Compound 39 Drugs 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- OPHUWKNKFYBPDR-UHFFFAOYSA-N copper lithium Chemical compound [Li].[Cu] OPHUWKNKFYBPDR-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VYTZWRCSPHQSFX-GBNDHIKLSA-N (-)-corey lactone Chemical compound O1C(=O)C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]21 VYTZWRCSPHQSFX-GBNDHIKLSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 description 1
- MLOSJPZSZWUDSK-UHFFFAOYSA-N 4-carboxybutyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCCCC(=O)O)C1=CC=CC=C1 MLOSJPZSZWUDSK-UHFFFAOYSA-N 0.000 description 1
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- NZHXEWZGTQSYJM-UHFFFAOYSA-N [bromo(diphenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 NZHXEWZGTQSYJM-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004653 carbonic acids Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
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- 238000002425 crystallisation Methods 0.000 description 1
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- 230000007547 defect Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011987 hoveyda–grubbs catalyst Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- KVSKGMLNBAPGKH-UHFFFAOYSA-N tribromosalicylanilide Chemical compound OC1=C(Br)C=C(Br)C=C1C(=O)NC1=CC=C(Br)C=C1 KVSKGMLNBAPGKH-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本申请公开了一类新颖大环内酯的设计、制备及其应用,属于医药中间体技术领域。从Coreylactone出发,通过5‑7步转化,得到前列腺素大环内酯中间体A‑E,从共同中间体A‑E出发,还成功地运用到Carboprost和Travoprost产品的制备中,同时也推广至Bimatoprost、Tafluprost、Latanprost和Dinoprostone等PGF2a的制备。本发明提供了共同中间体A‑E大大缩短了后续偶联反应步骤,同时将目前工艺中难以去除5,6‑双键反式异构体提前规避,经过这种高效节约化和规模化的生产,给PGs制药工业带来了效率和效益的明显提升。
Description
技术领域
本发明涉及药物化学制备技术领域,具体涉及前列腺素新颖大环内酯的设计、制备及其应用。
背景技术
前列腺素(prostaglandins,简称PGs)是一类具有广泛生理活性的重要内源性产物,存在于几乎所有哺乳动物组织中,在生殖、消化、呼吸和心血管系统中发挥着重要作用,参与体温调节、炎症反应、青光眼、妊娠、高血压、溃疡及哮喘等生理病理过程。
Org.Biomol.Chem.2017,15,6281–6301描述了PGs结构特征:具有一个五元脂环及两个侧链,上侧链α通常有7个碳酸、下侧链ω有8个碳组成20碳不饱和脂肪酸及其类似物,结构式表示如下:
PGs最早由美国学者Von Eluer在1930年发现并命名,1962年Bergstorm提取出两种PG纯品(PGFl和PGF2)并确定其化学结构;1969年Willis首次提出PGs是体内一种炎症介质后,相关各种生理和药理活性得以深入研究。
前列腺素天然来源少,提取困难,体内代谢迅速,稳定性差等缺点,科学家基于天然前列腺素的高活性,结构新颖性以及其不稳定性等特点,相继改造并合成了一系列前列腺素类似物,以满足临床需求。Nat.Chem.2021,13,692–697报道截止2019末为止,超过20种前列腺类似物进入市场,其中不乏超过十亿美元的比马前列素Bimatoprost,充分显示其在制药工业的重要性和独特价值,具体结构式如下:
目前,基于现有已发表文献或公开专利,前列腺素的制备方法大致分为两大类:
方法一:利用Corey lactone/通过Wittig-Horner反应,构建下侧链ω,得到相应中间体1,接着DIBAL-H还原内酯/Wittig反应,得到上侧链α。根据不同目标分子,将羧基变成相应乙酰胺、甲酯或异丙酯等(参考WO02096898、EP1886992、EP2143712、JP2012246301、US6720438、US2008033176、WO2010097672和US7582779),采用反应方程式表示如下:
J.Org.Chem.2008,73,7213-7218报道了采用化合物4和手性烯丙醇5,在Grubbs催化剂存在下分子间RCM,得到了前列腺素15(R)-Me-PGD2;反应方程式表示如下:
EP2837621同样以Corey Lactone为原料,按照文献操作得到化合物7,接着Wittig反应得到中间体8,然后Corey-Nicolaou酯化得到十元环内酯9,利用其形成大环而具有易结晶的特点,多次重结晶除去Wittig反应而不可避免生成的3~8%5,6-双键反式异构体以及15位R异构体,从而得到高纯度Travoprost;反应方程式表示如下:
WO2011008756以手性五元环烯酮化合物15为起始原料,采用二烷基铜锂实现侧链手性构建得到中间体16,接着在Grubbs催化剂下分子内RCM反应实现了上侧链α关环,得到Travoprost;反应方程式表示如下:
Nature,2012,489,278–281报道了前列素的制备路线:以二醛19为原料,利用手性脯氨酸诱导得到中间体20,接着醚化与二烷基铜锂22偶联反应,接着氧化/还原后得到中间体24,从而实现多前列腺素25制备;反应方程式表示如下:
Nat.Chem.2021,13,692–697报道了不对称氢化方式构建五元环的方法。从烯酮26开始,不对称还原得到中间体27,接着采用原创性方法得到前列腺素内酯30,然后利用分子间Olefin Cross Metathesis反应,构建下侧链ω,最后经过Wittig反应上侧链α,从而实现了前列腺素33等类似物的制备;反应方程式表示如下:
综合上述现有技术方法,既有基于经典Corey Lactone路线,也有充满创造性不对称合成路线,更进一步丰富了前列腺素合成方法。前述开创性策略可制备各种前列腺素,然而从制药工业角度而言,一般都是从Corey lactone为起始物料基于两点:Corey lactone工业制备工艺经过多年的优化、改进和提高,其生产成本大大降低,市售价格可接受度得到了市场接受;另一方面,复杂五元环中的四个相邻手性中心已经完美构建并确立,给后续相应前列腺素的质量提供了充分保证。
通过对比全球销量比较好PGs类似物文献调研,发现大部分都是具有上侧链α为7个碳的羧酸或羧酸酯,同时在5/6位具有一个顺式双键烯烃。然而对于具有上侧链顺式双键结构和Corey环手性特征,且能更好匹配前列系列化合物的更高级中间体(十元环内酯)仍需进一步开发。
发明内容
为了解决上述技术问题,本申请公开了具有新颖结构前列腺素大环内酯中间体A、B、C、D或E。从Corey lactone出发,通过5-7步转化,得到中间体A-E,从大大缩短了后续偶联反应步骤,同时将目前工艺中难以去除5,6-双键反式异构体提前规避,经过这种高效节约化和规模化的生产,给PGs制药工业效率和效益带来了明显提升。
从共同中间体A-E出发,还成功地运用到Carboprost和Travoprost产品的制备中,同时也推广至Bimatoprost、Tafluprost、Latanprost和–Dinoprostone等PGF2a的制备。从该类型新颖大环内酯出发,大大缩短了规模生产路线,提高了制备效率,从而增强了产品的竞争力。
本发明还提供了前列腺素大环内酯A-E的制备方法,包括如下步骤:
1、前列腺素大环内酯A的制备方法:以Corey lactone为起始物料,伯醇保护后,得到中间体34;接着DIBAL-H还原得到半缩醛35,然后与磷盐CBPBr反应得到中间体36;通过大环内酯关环得到双保护关键中间体A;采用反应方程式表示如下:
P1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP;P2选自THP、TBS、TES、TBDPS、Tr或DMTr。
2、前列腺素大环内酯B-E的制备方法:大环内酯A选择性脱伯醇保护得到中间体B,接着氧化反应得到中间体醛C;中间体醛C再与三苯基磷溴甲烷盐Wittig反应得到末端烯烃D;中间体B氢化双键还原,得到饱和十元环E;采用反应方程式表示如下:
P1选自H、Ac、Bz、Pbz、TBS、TES、TBDPS或THP;P2选自THP、TBS、TES、TBDPS、Tr或DMTr。
本发明还提供了前列腺素大环内酯在Carboprost和Travoprost产品制备中的应用。
进一步地,在上述技术方案中,在Carboprost产品制备中的应用,包括如下步骤:所述中间体C与化合物37发生Wittig-Horner反应得到烯酮38,接着与甲基格氏试剂加成得到中间体39,脱保护基后得到中间体40,最后水解得到Carboprost;采用反应方程式表示如下:
进一步地,在上述技术方案中,P1优选TBS、TES、TBDPS。
进一步地,在上述技术方案中,在Travoprost产品制备中的应用,包括如下步骤:上述端烯D在Grubbs催化剂存在下,与炔丙醇41发生分子间Olefin Cross Metathesis反应,得到化合物9;接着水解和酯化,得到无反式双键异构体Travoprost;采用反应方程式表示如下:
进一步地,在上述技术方案中,P1优选TBS、TES、TBDPS。
本发明有益效果
将现有技术中以Corey Lactone为起始物料来制备相应PGs,推进到以A、B、C、D和E为起始物料,通过节约化和规模化生产降低了生产成本。特别是对PGF2a类似物而言,从源头革除了一直以来Wittig反应而不可避免产生上侧链5,6-反式双键异构体的难题;以该新颖大环内酯为中间体作为起始物料,成功地运用到Travoprost和Carboprost的制备,同时推广到Bimatoprost、Tafluprost、Latanprost和Dinoprostone等制备中,反应路线缩短提高了产品的竞争力。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。以下实施例子按照P1 P2为=TBS、THP为例进行的。本发明所用试剂和原料均市售可得。
实施例1:中间体34的制备【P1=THP;P2=TBS】【US2013/217879】
将Corey Lactone Diol(77.8g,452.3mmol)和咪唑(43.1g,633.8mmol)溶解于450mL干燥DMF,分批加入TBSCl(68.5g,454.5mmol)。加毕搅拌过夜,反应完毕,常规处理得到100.0g单保护中间体;接着将其用400mL二氯甲烷溶解,接着加入二氢吡喃(100.0g,1.2mol)和0.5g对甲苯磺酸,室温搅拌过夜,浓缩至干,得到129.3g双保护中间体34,油状液体,收率77%。从其他Corey Lactone不同取代基原料开始,制备得到相应双保护的中间体34,结果如下:
CoreyLactoneP1= | 中间体34P2= | 收率 |
Bz | THP | 95% |
Pbz | THP | 92% |
TBS | THP | 98% |
TBS | TBS | 95% |
实施例2:中间体35的制备【P1=THP;P2=TBS】【US2013/217879】
氮气保护下,将化合物34(129.3g,0.77mol)溶解于600mL干燥甲苯中,冷却到-70℃以下。向其中滴加600mL 1.6M DIBAL-H,滴加完毕,继续保温反应直至原料消失。经处理后得到130.0g半缩醛35粗品,收率定量。
实施例3:中间体36的制备【P1=THP;P2=TBS】
氮气保护下,在带有机械搅拌3L反应瓶中,加入4-羧丁基三苯基溴化磷(359.0g,810.4mmol)和1000mL四氢呋喃,降温到-10℃,加入叔丁醇钾(181.5g,1.62mol),升至室温。接着控温-25℃至-20℃,向反应液中滴加中间体35(130.0g,0.77mol)/四氢呋喃600mL溶液。滴毕保温反应直至原料完全消失。经后处理,得到浓缩液,柱层析纯化,得到120g浅黄色油状液体有机羧酸36,收率80%。1H-NMR(400MHz,CDCl3):5.45(m,1H),5.35(m,1H),4.65(m,0.8H),4.57(m,0.2H),4.18(m,1H),4.10(m,1H),3.80(m,1H),3.60-3.30(m,3H),2.30(m,3H),2.00-1.40(m,15H),0.90(s,9H),0.00(s,6H).LC-MS:(m/z):479.3[M+Na]+。
实施例4:化合物A的制备【P1=THP;P2=TBS】
氮气保护下,在10L三口瓶中,加入上述中间体36(120.0g,262.7mmol)和4.0L甲苯,搅拌下完全溶解后,接着加入三苯基磷(183.5g,700.4mmol)和2,2-二硫二吡啶(135.0g,613.6mmol),室温搅拌过夜;然后再加入4L甲苯升温回流反应15小时。停止加热,降温。浓缩后处理,柱层析纯化得到90.0g浅黄色油状液体A,收率78%。1H-NMR(400MHz,CDCl3):5.50(m,1H),5.12(s,1H),4.57(m,1H),4.11-3.91(m,1H),3.90-3.56(m,3H),3.42(m,1H),2.40-2.37(m,4H),2.26(m,1H),2.18-1.47(m,13H),0.84(s,9H),0.00(s,6H).
实施例5:化合物B【P1=THP】的制备
在1L反应瓶中加入化合物A(90.0g,205.2mmol)和500mL四氢呋喃,搅拌下完全溶解,得到浅黄色透明体系,氮气保护下,冰水降温。控温15℃以下分批加入TBAF(88.8g,3339.6mmol),室温搅拌过夜。经过后处理,柱层析得到65.6g浅黄色油状液体B,收率98%。1H-NMR(400MHz,CDCl3):5.34(m,2H),5.15(m,1H),4.72(m,0.7H),4.55(m,0.3H),3.81-4.13(m,3H),3.64(m,1H),3.52(m,1H),3.12(brs,1H),2.34-2.52(m,4H),2.26(m,1H),2.11-1.53(m,11H),1.26(m,2H).LC-MS:(m/z):347.2[M+Na]+。
实施例6:化合物B【P1=H】的制备
在反应瓶中,加入化合物B(5.0g,15.4mmol)和50mL甲醇,搅拌下完全溶解后加入0.1g PPTS,室温搅拌过夜,浓缩至干,乙酸乙酯溶解,洗涤干燥,浓缩,重结晶,得到3.2g白色固体,收率86%。1H-NMR(400MHz,CD3OD):5.19(dd,J=4.4,8.0Hz,2H),5.03(dd,J=4.0,4.8Hz,1H),3.94(m,1H),3.65(dd,J=4.4,11.2Hz,1H),3.57(dd,J=4.4,11.2Hz,1H),2.42-2.17(m,3H),1.99(m,2H),1.73(m,2H),1.70(m,1H),1.47(m,2H).LC-MS:(m/z):263.2[M+Na]+。
实施例7:化合物C制备【P1=THP】
氮气保护下,将化合物A(5.0g,15.4mmol)溶解于50mL二氯甲烷中,冷却到0~10℃,接着加入戴斯-马丁高碘烷DMP(10.0g,23.6mmol),然后慢慢升至室温,直至原料完全消失为止。过滤,浓缩,得到5.0g中间体C粗品,收率定量。
实施例8:化合物D制备【P1=THP】
将三苯基溴甲烷(10.0g,31.0mmol)悬浮于100mL四氢呋喃溶液中,冷却到0℃以下,向其中滴加30mL 1.0M LHMDS溶液,加毕继续搅拌反应1小时,向其中滴加化合物C粗品(5.0g,15.4mmol)/四氢呋喃溶液。加毕继续反应,直至原料完全消失。经过后处理,处理后得到3.0g端烯D,无色油状液体,收率60%。1H-NMR(400MHz,CDCl3):5.75(m,1H),5.05-5.40(m,5H),4.6(m,1H),4.10-3.81(m,2H),4.20(m,1H),2.60-2.30(m,5H),2.30-2.05(m,2H),1.95-1.42(m,12H),1.12(m,1H).
实施例9:化合物E制备【P1=THP】
将化合物B(1.0g,3.1mmol)溶解于10mL乙酸乙酯溶液中,加入0.1g Pd/C,氢气气球氛下室温搅拌过夜,过滤,浓缩至干,得到1.0g油状液体E,收率定量。1H-NMR(400MHz,CDCl3):5.26(m,1H),4.77(m,0.7H),4.58(m,0.3H),3.75-4.13(m,3H),3.62-3.45(m,2H),3.52(m,1H),3.10(brs,1H),2.55(m,1H),2.36-2.20(m,2H),2.05(m,1H),1.95-1.40(m,15H),1.26(m,2H).LC-MS:(m/z):349.2[M+Na]+。
实施例10:化合物38制备【P1=TBS】
氮气保护下,在100mL四氢呋喃溶液中,加入60%NaH(1.8g,45.0mmol),冷却到0~5℃滴加化合物37(10.0g,45.0mmol),加毕搅拌反应30分钟,向其中滴加中间体醛C(10.0g,28.4mmol)。加毕继续反应,直至原料C消失。常规后处理,柱层析得到9.8g烯酮中间体38,无色油状液体,收率77%。1H-NMR(400MHz,CDCl3):6.61(dd,J=9.2,15.6Hz,1H),6.24(d,J=9.2Hz,1H),5.34(m,1H),5.23(m,2H),3.91(dd,J=8.0,16.8Hz,1H),2.60-2.37(m,7H),2.24(m,1H),2.10(m,2H),1.90-1.80(m,3H),1.39-1.21(m,4H),0.90(t,J=6.8Hz,3H),0.85(s,9H),0.00(s,6H).
实施例11:化合物39制备【P1=TBS】
氮气保护下,将化合物38(9.0g,20.1mmol)溶解于200mL甲苯溶液中,冷却到-70℃滴加3.0M MeMgCl(30mL,90.0mmol)。加毕保温搅拌30分钟,检测原料反应完毕。常规后处理,得到中间体39粗品10.0g,不经纯化直接进入下一步反应。
实施例12:化合物40制备
将实施例11得到化合物39(10.0g,20.1mmol)溶解于100mL四氢呋喃中,向其中加入TBAF(10.0g,38.2mmol),室温搅拌过夜,检测原料消失。常规后处理,柱层析得到3.5g所需构型中间体40。1H-NMR(400MHz,CDCl3):5.72(d,J=15.6Hz,1H),5.43(m,1H),5.35(m,1H),5.30(m,2H),2.60(m,1H),2.56-2.17(m,6H),1.95-1.50(m,8H),1.29(m,11H),0.88(t,J=6.8Hz,3H).LC-MS:(m/z):373.3[M+Na]+。
实施例13:化合物9制备
先按照文献Nat.Chem.2021,13,692–697报道,制备得到中间体41待用。烯醇中间体41表征数据为:1H-NMR(400MHz,CDCl3):7.40(t,J=8.0Hz,1H),7.24(t,J=8.0Hz,1H),7.15(s,1H),7.08(dd,J=8.0,2.4Hz,1H),6.00-5.92(m,1H),5.49(dt,J=17.2,1.2Hz,1H),5.30(dt,J=11.8,1.2Hz,1H),4.57(m,1H),4.06(dd,J=11.2,3.6Hz,1H),3.93(dd,J=9.2,7.2Hz,1H),2.36(brs,1H).
氮气保护下,将化合物D/P1=H(0.5g,2.1mmol)和烯醇中间体41(0.5g,2.0mmol)溶解于5mL二氯甲烷,接着加入Hoveyda-Grubbs催化剂(0.5g,0.8mmol)。室温搅拌过夜,常规处理后得到粗品9。接着将粗品进行常规后处理,柱层析得到320mg化合物9纯品,白色固体,收率47%。1H-NMR(400MHz,CDCl3):7.39(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H),7.15(s,1H),7.08(dd,J=8.0,2.0Hz,1H),5.76(dd,J=15.6,7.2Hz,1H),5.65(dd,J=15.2,8.4Hz,1H),5.34(m,1H),5.21(m,2H),4.53(m,1H),4.00(m,2H),3.86(m,1H),3.57(d,J=2.8Hz,1H),3.76(d,J=4.4Hz,1H),2.60(m,1H),2.37(m,4H),2.23(m,3H),1.90-1.50(m,4H).LC-MS:(m/z):463.2[M+Na]+。
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明原理的范围下,本发明还会有各种变化和改进,这些变化和改进均落入本发明保护的范围内。
Claims (7)
4.如权利要求1所述前列腺素大环内酯在Carboprost产品制备中的应用。
6.如权利要求1所述前列腺素大环内酯在Travoprost产品制备中的应用。
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