TWI532711B - Intermediates useful in the synthesis of prostaglandin drugs and methods for preparing thereof - Google Patents
Intermediates useful in the synthesis of prostaglandin drugs and methods for preparing thereof Download PDFInfo
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- TWI532711B TWI532711B TW101109614A TW101109614A TWI532711B TW I532711 B TWI532711 B TW I532711B TW 101109614 A TW101109614 A TW 101109614A TW 101109614 A TW101109614 A TW 101109614A TW I532711 B TWI532711 B TW I532711B
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- compound
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- 238000000034 method Methods 0.000 title claims description 28
- 150000003180 prostaglandins Chemical class 0.000 title claims description 18
- 229940079593 drug Drugs 0.000 title claims description 5
- 239000003814 drug Substances 0.000 title claims description 5
- 239000000543 intermediate Substances 0.000 title description 16
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 230000015572 biosynthetic process Effects 0.000 title description 9
- 238000002360 preparation method Methods 0.000 claims description 39
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002373 hemiacetals Chemical class 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical class CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 238000007239 Wittig reaction Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 14
- 229910052757 nitrogen Inorganic materials 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 5
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- -1 bemetrol Chemical class 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 229960002470 bimatoprost Drugs 0.000 description 3
- 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 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VMKAFJQFKBASMU-QGZVFWFLSA-N (r)-2-methyl-cbs-oxazaborolidine Chemical compound C([C@@H]12)CCN1B(C)OC2(C=1C=CC=CC=1)C1=CC=CC=C1 VMKAFJQFKBASMU-QGZVFWFLSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical class NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- XHTUOWXUBNMVEU-UHFFFAOYSA-N 1-benzoyl-5-ethyl-5-(3-methylbutyl)-1,3-diazinane-2,4,6-trione Chemical group O=C1C(CC)(CCC(C)C)C(=O)NC(=O)N1C(=O)C1=CC=CC=C1 XHTUOWXUBNMVEU-UHFFFAOYSA-N 0.000 description 1
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- KCAFEQQLYHEUQK-UHFFFAOYSA-N decyl trifluoromethanesulfonate Chemical compound CCCCCCCCCCOS(=O)(=O)C(F)(F)F KCAFEQQLYHEUQK-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- RNIXSZHNJLUJGC-UHFFFAOYSA-N hydroxy(nitro)cyanamide Chemical compound N#CN(O)[N+]([O-])=O RNIXSZHNJLUJGC-UHFFFAOYSA-N 0.000 description 1
- 229960001160 latanoprost Drugs 0.000 description 1
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- 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 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
-
- 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
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本發明涉及用於合成前列腺素類藥物的中間體及其製備方法。The present invention relates to an intermediate for the synthesis of prostaglandins and a process for the preparation thereof.
前列腺素是一類具有20個碳原子的脂肪酸衍生物。前列腺素在激素濃度水準上調節人體多種生理作用，對血壓、平滑肌收縮、胃液分泌及血小板凝集有調節作用。其中，前列腺素F型衍生物在臨床上用於治療開角型青光眼和高眼壓症，以降低患者的眼內高壓。Prostaglandins are a class of fatty acid derivatives having 20 carbon atoms. Prostaglandins regulate various physiological functions of human body at the level of hormone concentration, and have a regulating effect on blood pressure, smooth muscle contraction, gastric juice secretion and platelet aggregation. Among them, prostaglandin F-type derivatives are clinically used for the treatment of open-angle glaucoma and ocular hypertension to reduce the intraocular hypertension of patients.
前列腺素是廣泛存在於人和動物各組織中的微量成分，含量極低，加上前列腺素F型衍生物對青光眼及其眼內高壓等疾病的極佳治療效果，天然來源的前列腺素不能滿足臨床用藥需求。為此，科學家一直致力於前列腺素類衍生物的全合成研究，迄今已取得了豐碩的成果。例如，EP1886992，EP1721894，EP2143712，US2003/187071，US2005/209337，US2008/033176，US2009/259066，US2010/056807，WO90/02553，WO94/06433，WO97/22602，WO2001/010873，WO2002/096898，WO2007/041273等專利文獻均詳細地描述了各種前列腺素F型衍生物的使用及其製備方法。Prostaglandins are trace components widely present in human and animal tissues, and their levels are extremely low. In addition, prostaglandin F-type derivatives have excellent therapeutic effects on glaucoma and its intraocular hypertension. Natural prostaglandins cannot be satisfied. Clinical medication needs. To this end, scientists have been working on the total synthesis of prostaglandin derivatives, and have achieved fruitful results so far. For example, EP1886992, EP1721894, EP2143712, US2003/187071, US2005/209337, US2008/033176, US2009/259066, US2010/056807, WO90/02553, WO94/06433, WO97/22602, WO2001/010873, WO2002/096898, WO2007/ The use of various prostaglandin F-type derivatives and methods for their preparation are described in detail in the patent documents 041273 and the like.
本發明是關於用於合成前列腺素類藥物的中間體及其製備方法。藉由中間體，可以縮短前列素類藥物的合成步驟，從而提高前列素類藥物，如貝美前列素、曲伏前列素、拉坦前列素的合成效率。The present invention relates to an intermediate for the synthesis of prostaglandins and a process for the preparation thereof. By intermediates, the synthesis steps of prostaglandins can be shortened, thereby improving the synthesis efficiency of prostaglandins such as bemetrol, travoprost and latanoprost.
本發明目的在於提供一種如式I所示的用於合成前列腺素類藥物的中間體。It is an object of the present invention to provide an intermediate for the synthesis of prostaglandins as shown in Formula I.
其中，R1、R2和R3各自分別為氫或羥基保護基，較佳地，R1、R2和R3各自分別選自氫、THP、-C(O)R6或-SiR7R8R9，其中R6、R7、R8和R9各自分別為C1-10的直鏈或支鏈烷基、C3-8的環狀烷基、或C6-10的取代或非取代芳基；R4和R5各自分別為氫、胺基、甲氧基、C1-10的直鏈或支鏈烷基、C3-8的環狀烷基、或C6-10的取代或非取代芳基，R4和R5可各自分別選自氫、甲基、乙基、丙基、丁基、苯基、胺基或甲氧基；或者R4、R5和氮原子一起形成5至8員雜環，較佳為五員環和六員環，更佳為五員環。R4和R5不能同時為胺基或甲氧基。Wherein, R 1, R 2 and R 3 are each independently hydrogen or a hydroxy protecting group, preferably, R 1, R 2 and R 3 are each independently selected from hydrogen, THP, -C (O) R 6 -SiR 7, or R 8 R 9 , wherein R 6 , R 7 , R 8 and R 9 are each a C 1-10 straight or branched alkyl group, a C 3-8 cyclic alkyl group, or a C 6-10 substitution, respectively. Or an unsubstituted aryl group; each of R 4 and R 5 is hydrogen, an amine group, a methoxy group, a C 1-10 linear or branched alkyl group, a C 3-8 cyclic alkyl group, or a C 6- group; a substituted or unsubstituted aryl group of 10 , each of R 4 and R 5 may be independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, amine or methoxy; or R 4 , R 5 and The nitrogen atoms together form a 5- to 8-membered heterocyclic ring, preferably a five-membered ring and a six-membered ring, more preferably a five-membered ring. R 4 and R 5 cannot be an amino group or a methoxy group at the same time.
在本發明的一個較佳的具體實施方案中，在式I中，R1為THP；R2為THP；R3為TIPS；R4為乙基；R5為氫；或者，R1為THP；R2為THP；R3為TIPS；R4為氫；R5為乙基。In a preferred embodiment of the invention, in Formula I, R 1 is THP; R 2 is THP; R 3 is TIPS; R 4 is ethyl; R 5 is hydrogen; or, R 1 is THP ; R 2 is THP; R 3 is TIPS; R 4 is hydrogen; and R 5 is ethyl.
本發明目的在於提供一種合成如式Ia所示中間體的製備方法，The object of the present invention is to provide a preparation method for synthesizing an intermediate represented by the formula Ia,
其特徵在於，將結構式II的半縮醛和結構式III的醯胺衍生物在鹼性條件下藉由Wittig反應製得如式Ia所示的中間體：It is characterized in that the hemiacetal of structural formula II and the decylamine derivative of formula III are subjected to Wittig reaction under basic conditions to produce an intermediate of formula Ia:
其中式III中的X為鹵素，X可選自Cl、Br或I，較佳為Br；Ar為C6-10的非取代或取代芳基，較佳為苯基。Wherein X in the formula III is a halogen, X may be selected from Cl, Br or I, preferably Br; and Ar is an unsubstituted or substituted aryl group of C 6-10 , preferably a phenyl group.
根據需要，中間體Ia經過羥基保護、或羥基脫保護、或羥基保護基團的變換來製備如式I所示中間體。The intermediate Ia is prepared as an intermediate of formula I by hydroxy protection, or hydroxy deprotection, or conversion of a hydroxy protecting group, as desired.
在本發明的一個較佳的具體實施方案中，半縮醛(結構式II，R2=H，R3=TIPS)和醯胺衍生物(結構式III，R4=Et，R5=H，Ar為苯基，X為溴；或者，R4=H，R5=Et，Ar為苯基，X為溴)的Wittig反應製得中間體Ia(結構式Ia，R2=H，R3=TIPS，R4=Et，R5=H；或者，R2=H，R3=TIPS，R4=H，R5=Et)，其較佳的反應條件為：以第三丁醇鉀作為鹼，以四氫呋喃為溶劑，以3A分子篩為活化劑，在20℃溫度進行反應。In a preferred embodiment of the invention, hemiacetal (Structure II, R 2 = H, R 3 = TIPS) and a guanamine derivative (Structure III, R 4 =Et, R 5 =H , W is an phenyl group, X is a bromine; or, R 4 =H, R 5 =Et, Ar is a phenyl group, and X is a bromine. The intermediate Ia (formula Ia, R 2 =H, R) 3 = TIPS, R 4 =Et, R 5 =H; or, R 2 =H, R 3 =TIPS, R 4 =H, R 5 =Et), the preferred reaction conditions are: third butanol Potassium was used as a base, tetrahydrofuran was used as a solvent, and 3A molecular sieve was used as an activator, and the reaction was carried out at a temperature of 20 °C.
在本發明進一步提供了一種製備貝美前列素的製備方法，The invention further provides a preparation method for preparing bemeiprost,
其中R1和R2為羥基保護基，R為C1-8烷基，其特徵在於，該方法包括如下步驟：Wherein R 1 and R 2 are a hydroxy protecting group and R is a C 1-8 alkyl group, the method comprising the steps of:
1)中間體I’經氧化反應得到中間體VI，1) Intermediate I' is oxidized to give intermediate VI,
2)中間體VI與磷酸酯IX反應得到中間體VII，2) Intermediate VI is reacted with phosphate IX to give intermediate VII,
3)中間體VII經不對稱還原得到中間體VIII，3) Intermediate VII is asymmetrically reduced to give intermediate VIII,
4)中間體VIII經脫保護基團後得到貝美前列素。4) The intermediate VIII is deprotected to give beimiprost.
本發明所述的羥基保護基是本領域已知的適當的用於羥基保護的基團，參見文獻(“Protective Groups in Organic Synthesis”，5Th.Ed. T.W.Greene & P. G.M.Wuts)中的羥基保護基團。該羥基保護基可以是(C1-8烷基或芳基)3矽烷基，例如：三乙基矽基，三異丙基矽基，第三丁基二甲基矽基，第三丁基二苯基矽基等；可以是C1-8烷基或取代烷基，例如：甲基、第三丁基、烯丙基、苄基、甲氧基甲基、乙氧基乙基、2-四氫吡喃基(THP)等；可以是(C1-8烷基或芳香基)醯基，例如：甲醯基、乙醯基、苯甲醯基等；可以是(C1-6烷基或C6-10芳基)磺醯基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。The hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th . Ed. TW Greene & PGM Wuts). . The hydroxy protecting group may be (C 1-8 alkyl or aryl) 3 fluorenyl, for example: triethyl decyl, triisopropyl decyl, tert-butyldimethyl decyl, tert-butyl Diphenyl fluorenyl or the like; may be a C 1-8 alkyl group or a substituted alkyl group, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2 a tetrahydropyranyl group (THP) or the like; may be a (C 1-8 alkyl or aryl) fluorenyl group, for example, a decyl group, an ethyl fluorenyl group, a benzamyl group or the like; may be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; also may be (C 1-6 alkoxy or C 6-10 aryloxy)carbonyl.
本發明所述的取代芳基是指芳香環被一個或多個例如選自下列的殘基所取代：鹵素、羥基、氰基、硝基、胺基、三氟甲基、C1-8烷基、C1-8烷氧基、C2-8烷醯基氧基、C6-10芳基、烯丙基等。The substituted aryl group of the present invention means that the aromatic ring is substituted by one or more residues selected, for example, from the group consisting of halogen, hydroxy, cyano, nitro, amine, trifluoromethyl, C 1-8 alkane. A group, a C 1-8 alkoxy group, a C 2-8 alkanoyloxy group, a C 6-10 aryl group, an allyl group or the like.
以下將結合具體實例詳細地解釋本發明，使得本專業技術人員更全面地理解本專利，具體實例僅用於說明本發明的技術方案，並不以任何方式限定本發明。The invention will be explained in detail below with reference to specific examples, which are intended to provide a more complete understanding of the invention.
下表為實施例中所涉及的化合物I的結構式The following table shows the structural formula of the compound I involved in the examples.
化合物Iaa按如下步驟合成：Compound Iaa was synthesized as follows:
在氮氣氛下，將三乙胺(2.5mL)加入到化合物IV(1.0g，從上海巨龍藥物研究開發有限公司購得)的二氯甲烷(50 mL)溶液中。反應體系冷卻到-78℃，加入三異丙基矽基三氟甲磺酸酯(2.9g)的二氯甲烷(10mL)溶液。兩個小時後撤去冷浴，反應體系在20℃攪拌30分鐘。反應體系減壓濃縮，殘留物以管柱層析提純得到化合物Vaa。Triethylamine (2.5 mL) was added to a solution of compound IV (1.0 g, purchased from Shanghai Julong Pharmaceutical Research and Development Co., Ltd.) in dichloromethane (50 mL) under a nitrogen atmosphere. The reaction system was cooled to -78 ° C, and a solution of triisopropyl decyl trifluoromethanesulfonate (2.9 g) in dichloromethane (10 mL). After two hours, the cooling bath was removed and the reaction system was stirred at 20 ° C for 30 minutes. The reaction system was concentrated under reduced pressure, and the residue was purified by column chromatography to afford Compound Vaa.
1H NMR(400 MHz,CDCl3): δ 4.94-4.89(m,1H),4.18-4.11(m,1H),3.84(dd,J=9.6,5.2 Hz,1H),3.69(dd,J=10.4,7.2 Hz,1H),2.79(dd,J=18,10.8 Hz,1H),2.63-2.60(m,1H),2.53-2.45(m,2H),2.70(s,1H),2.05-1.97(m,2H),1.14-1.01(m,21H) 1 H NMR (400 MHz, CDCl 3 ): δ 4.94 - 4.89 (m, 1H), 4.18 - 4.11 (m, 1H), 3.84 (dd, J = 9.6, 5.2 Hz, 1H), 3.69 (dd, J = 10.4, 7.2 Hz, 1H), 2.79 (dd, J=18, 10.8 Hz, 1H), 2.63-2.60 (m, 1H), 2.53-2.45 (m, 2H), 2.70 (s, 1H), 2.05-1.97 (m, 2H), 1.14-1.01 (m, 21H)
在氮氣氛下，將Vaa(1.675g)的甲苯溶液(30mL)冷卻到-78℃。將DIBAL-H(1.0M正己烷溶液，15.3mL)加入反應體系，混合物在-78℃攪拌2小時。加入飽和的酒石酸鈉鉀水溶液(5mL)淬滅反應，體系逐漸回到20℃，繼續攪拌直到體系澄清。反應體系用乙醚萃取，有機相用飽和食鹽水洗滌，用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物IIaa。Vaa (1.675 g) in toluene (30 mL) was cooled to -78 ° C under a nitrogen atmosphere. DIBAL-H (1.0 M n-hexane solution, 15.3 mL) was added to the reaction mixture, and the mixture was stirred at -78 ° C for 2 hr. The reaction was quenched by the addition of saturated aqueous sodium potassium tartrate (5 mL). The mixture was gradually returned to 20 ° C and stirring was continued until the system was clarified. The reaction mixture was extracted with EtOAc. The residue was purified by column chromatography to give compound IIaa.
1H NMR(400 MHz,CDCl3): δ 5.68-5.50(m,1H),4.67-4.63(m,1H),4.16-4.07(m,1H),3.85-3.74(m,1H),3.65-3.58(m,1H),2.85-2.65(m,1H),2.50-1.60(m,6H),1.14-1.01(m,21H) 1 H NMR (400 MHz, CDCl 3 ): δ 5.68-5.50 (m, 1H), 4.67-4.63 (m, 1H), 4.16-4.07 (m, 1H), 3.85-3.74 (m, 1H), 3.65- 3.58 (m, 1H), 2.85-2.65 (m, 1H), 2.50-1.60 (m, 6H), 1.14-1.01 (m, 21H)
在20℃，將第三丁醇鉀(1M四氫呋喃溶液，15.1mL)加入化合物IIIaa(3.56g，根據參考文獻J. Med. Chem. 1979,22,1340製得)，活化的3A分子篩粉末(2.5g)和四氫呋喃(15mL)的懸浮液中。然後，將IIaa(500mg)的四氫呋喃(2mL)溶液加入到形成的橘紅色葉立德中。反應體系在20℃攪拌30分鐘，加入水淬滅反應。體系用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物Iaa。Potassium tert-butoxide (1 M tetrahydrofuran solution, 15.1 mL) was added to compound IIIaa (3.56 g, according to J. Med. Chem . 1979, 22, 1340) at 20 ° C, activated 3A molecular sieve powder (2.5 g) and a suspension of tetrahydrofuran (15 mL). Then, a solution of IIaa (500 mg) in tetrahydrofuran (2 mL) was added to the formed orange-red ylide. The reaction system was stirred at 20 ° C for 30 minutes, and quenched by the addition of water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography to give the compound Iaa.
1H-NMR(400MHz,CDCl3) δ5.81(br,1H),5.41~5.36(m,2H),4.18(s,2H),3.90~3.86(m,1H),3.62~3.58(m,1H),3.29~3.23(m,2H),3.15~3.11(m,2H),2.39~2.37(m,1H),2.21~2.12(m,4H),2.06~2.03(m,1H),1.90~1.87(m,3H),1.73~1.65(m,3H),1.13~1.00(m,24H) 1 H-NMR (400MHz, CDCl 3 ) δ 5.81 (br, 1H), 5.41~5.36 (m, 2H), 4.18 (s, 2H), 3.90~3.86 (m, 1H), 3.62~3.58 (m, 1H), 3.29~3.23 (m, 2H), 3.15~3.11 (m, 2H), 2.39~2.37 (m, 1H), 2.21~2.12 (m, 4H), 2.06~2.03 (m, 1H), 1.90~ 1.87 (m, 3H), 1.73~1.65 (m, 3H), 1.13~1.00 (m, 24H)
應用合成化合物Iaa的類似方法，合成了化合物Iab。The compound Iab was synthesized using a similar method to synthesize the compound Iaa.
1H-NMR(400 MHz,CDCl3) δ5.85(s,1H),5.41~5.34(m,2H),4.16~4.11(m,2H),3.77~3.73(m,1H),3.49~3.45(m,1H),3.29~3.11(m,4H),2.39~2.33(m,1H),2.19~2.00(m,5H),1.89~1.85(m,3H),1.73~1.58(m,3H),1.13~1.09(m,3H),0.89~0.85(m,9H),0.07~0.02(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.85 (s, 1H), 5.41~5.34 (m, 2H), 4.16~4.11 (m, 2H), 3.77~3.73 (m, 1H), 3.49~3.45 (m,1H), 3.29~3.11(m,4H), 2.39~2.33(m,1H), 2.19~2.00(m,5H),1.89~1.85(m,3H),1.73~1.58(m,3H) , 1.13~1.09(m,3H), 0.89~0.85(m,9H), 0.07~0.02(m,6H)
應用合成化合物Iaa的類似方法，合成了化合物Iac。Compound Iac was synthesized in a similar manner to the synthesis of compound Iaa.
1H-NMR(400 MHz,CDCl3) δ 5.98~5.96(m,1H),5.41~5.34(m,2H),4.14~4.10(m,2H),3.76~3.72(m,1H),3.49~3.45(m,1H),3.34~3.28(m,2H),3.22~3.17(m,2H),2.40~2.32(m,1H),2.18~2.10(m,4H),2.05~1.99(m,1H),1.85~1.83(br,3H),1.71~1.58(m,3H),1.48~1.40(m,2H),1.35~1.28(m,2H),0.90~0.85(m,3H),0.84~0.83(m,9H),0.05~0.01(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.98~5.96 (m, 1H), 5.41~5.34 (m, 2H), 4.14~4.10 (m, 2H), 3.76~3.72 (m, 1H), 3.49~ 3.45(m,1H), 3.34~3.28(m,2H), 3.22~3.17(m,2H), 2.40~2.32(m,1H), 2.18~2.10(m,4H),2.05~1.99(m,1H ), 1.85~1.83(br,3H), 1.71~1.58(m,3H), 1.48~1.40(m,2H),1.35~1.28(m,2H),0.90~0.85(m,3H),0.84~0.83 (m, 9H), 0.05~0.01 (m, 6H)
應用合成化合物Iaa的類似方法，合成了化合物Iad。Compound Iad was synthesized by a similar method using synthetic compound Iaa.
1H-NMR(400 MHz,CDCl3) δ 5.91~5.77(m,2H),5.43~5.36(m,2H),4.18~4.13(m,2H),3.78~3.75(m,1H),3.50~3.46(m,1H),3.09(br,2H),2.43~2.35(m,1H),2.25~2.03(m,5H),1.88~1.75(m,3H),1.75~1.60(m,3H),0.87(s,9H),0.06~0.03(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.91~5.77 (m, 2H), 5.43~5.36 (m, 2H), 4.18~4.13 (m, 2H), 3.78~3.75 (m, 1H), 3.50~ 3.46 (m, 1H), 3.09 (br, 2H), 2.43 to 2.35 (m, 1H), 2.25 to 2.03 (m, 5H), 1.88 to 1.75 (m, 3H), 1.75 to 1.60 (m, 3H), 0.87(s,9H), 0.06~0.03(m,6H)
應用合成化合物Iaa的類似方法，合成了化合物Iae。Compound Iae was synthesized by a similar method using synthetic compound Iaa.
1H-NMR(400 MHz,CDCl3)δ8.12~8.00(m,1H),7.56~7.54(m,2H),7.32~7.28(m,2H),7.11~7.08(m,1H),5.80(s,1H),5.45~5.37(m,2H),4.19~4.18(br,2H),3.78~3.46(m,2H),3.20(br,1H),2.45~2.09(m,7H),1.9~1.60(m,5H),0.89(s,9H),0.09~0.02(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 8.12~8.00 (m, 1H), 7.56~7.54 (m, 2H), 7.32~7.28 (m, 2H), 7.11~7.08 (m, 1H), 5.80 (s,1H), 5.45~5.37(m,2H), 4.19~4.18(br,2H), 3.78~3.46(m,2H), 3.20(br,1H),2.45~2.09(m,7H),1.9 ~1.60(m,5H),0.89(s,9H),0.09~0.02(m,6H)
應用合成化合物Iaa的類似方法，合成了化合物Iaf。Compound Iaf was synthesized using a similar method to synthesize compound Iaa.
1H-NMR(400 MHz,CDCl3)δ5.42~5.38(m,2H),4.18(s,2H),3.90~3.87(m,1H),3.63~3.59(m,1H),3.18(s,1H),3.08~3.06(m,1H),2.99(s,3H),2.93(s,3H),2.42~2.30(m,4H),2.24~2.03(m,1H),1.92~1.87(m,4H),1.71~1.66(m,3H),1.11~0.99(m,21H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.42~5.38 (m, 2H), 4.18 (s, 2H), 3.90 to 3.87 (m, 1H), 3.63 to 3.59 (m, 1H), 3.18 (s) , 1H), 3.08~3.06(m,1H), 2.99(s,3H), 2.93(s,3H), 2.42~2.30(m,4H), 2.24~2.03(m,1H),1.92~1.87(m , 4H), 1.71~1.66(m, 3H), 1.11~0.99(m, 21H)
應用合成化合物Iaa的類似方法，合成了化合物Iag。The compound Iag was synthesized by a similar method using the synthetic compound Iaa.
1H-NMR(400 MHz,CDCl3)δ5.42~5.39(m,2H),4.18~4.16(br,2H),3.88~3.87(m,1H),3.62~3.59(m,1H),3.28~3.24(m,3H),3.19~3.15(m,3H),2.45~1.50(m,16H),1.1~1.01(m,21H),0.92~0.85(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.42~5.39 (m, 2H), 4.18~4.16 (br, 2H), 3.88~3.87 (m, 1H), 3.62~3.59 (m, 1H), 3.28 ~3.24(m,3H), 3.19~3.15(m,3H),2.45~1.50(m,16H),1.1~1.01(m,21H),0.92~0.85(m,6H)
應用合成化合物Iaa的類似方法，合成了化合物Iah。Compound Iah was synthesized by a similar method using synthetic compound Iaa.
1H-NMR(400MHz,CDCl3)δ6.32~5.10(m,3H),4.20~3.42(m,8H),2.25~2.09(m,5H),1.89~1.61(m,7H),0.90~0.88(m,9H),0.10~0.01(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 6.32~5.10 (m, 3H), 4.20~3.42 (m, 8H), 2.25~2.09 (m, 5H), 1.89~1.61 (m, 7H), 0.90~ 0.88 (m, 9H), 0.10~0.01 (m, 6H)
應用合成化合物Iaa的類似方法，合成了化合物Iai。Compound Iai was synthesized by a similar method using synthetic compound Iaa.
1H-NMR(400 MHz,CDCl3)δ5.43~5.40(m,2H),4.18~4.11(m,2H),3.79~3.75(m,1H),3.67(s,3H),3.51~3.47(m,1H),3.17(s,3H),2.95(s,1H),2.88(s,1H),2.46~2.42(m,3H),2.19~2.08(m,3H),1.90~1.86(m,3H),1.71~1.61(m,3H),0.85(s,9H),0.06~0.03(m,6H)1H-NMR (400 MHz, CDCl 3 ) δ 5.43~5.40 (m, 2H), 4.18~4.11 (m, 2H), 3.79~3.75 (m, 1H), 3.67 (s, 3H), 3.51~3.47 ( m,1H), 3.17(s,3H), 2.95(s,1H),2.88(s,1H),2.46~2.42(m,3H),2.19~2.08(m,3H),1.90~1.86(m, 3H), 1.71~1.61(m,3H), 0.85(s,9H), 0.06~0.03(m,6H)
應用合成化合物Iaa的類似方法，合成了化合物Iaj。Compound Iaj was synthesized by a similar method using synthetic compound Iaa.
1H-NMR(400 MHz,CDCl3)δ5.42~5.38(m,2H),4.18~4.16(m,2H),3.90~3.75(m,2H),3.30~3.23(m,2H),3.10~3.05(m,4H),2.34~2.30(m,2H),2.20~2.12(m,2H),2.05~1.52(m,13H),1.05~0.92(m,18H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.42~5.38 (m, 2H), 4.18~4.16 (m, 2H), 3.90~3.75 (m, 2H), 3.30~3.23 (m, 2H), 3.10 ~3.05(m,4H), 2.34~2.30(m,2H), 2.20~2.12(m,2H),2.05~1.52(m,13H),1.05~0.92(m,18H)
在乾燥的100mL單口瓶中加入化合物IIIaa(1.05g)和重複蒸餾的四氫呋喃溶劑(30mL)，室溫充分攪拌後加入第三丁醇鉀(1.0M四氫呋喃溶液)(5.37mL)，反應液瞬間變為深橘紅色。隨後再緩慢加入化合物IIak(200mg)的四氫呋喃溶液，反應在室溫攪拌過夜。檢測到大部分原料消失，隨後加入20mL水淬滅，用乙醚萃取多次，並將有機相用食鹽水多次洗滌、無水硫酸鈉乾燥。粗產物用矽膠管柱層析分離(二氯甲烷：甲醇=15:1)得到Iak。Add compound IIIaa (1.05g) and repeatedly distilled tetrahydrofuran solvent (30mL) to a dry 100mL single-mouth bottle, stir well at room temperature, add potassium t-butoxide (1.0M tetrahydrofuran solution) (5.37mL), and the reaction solution changes instantly. Dark orange. Compound IIak (200 mg) in tetrahydrofuran was then added slowly and the reaction was stirred at room temperature overnight. Most of the raw materials were detected to disappear, and then quenched by adding 20 mL of water, and extracted with diethyl ether several times, and the organic phase was washed with brine several times and dried over anhydrous sodium sulfate. The crude product was chromatographed on a silica gel column (dichloromethane:methanol = 15:1) to afford Iak.
1H-NMR(400 MHz,CDCl3)δ5.94(s,1H),5.45~5.33(m,2H),4.69~4.66(m,1H),4.21~4.08(m,2H),3.86~3.62(m,2H),3.51~3.35(m,2H),3.28~3.21(m,2H),2.41~2.37(m,2H),2.19~1.48(m,17H),1.12~1.08(m,3H),0.89(s,9H),0.06~0.05(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.94 (s, 1H), 5.45 to 5.33 (m, 2H), 4.69 to 4.66 (m, 1H), 4.21 to 4.08 (m, 2H), 3.86 to 3.62 (m, 2H), 3.51~3.35(m, 2H), 3.28~3.21(m, 2H), 2.41~2.37(m, 2H), 2.19~1.48(m, 17H), 1.12~1.08(m, 3H) , 0.89 (s, 9H), 0.06 ~ 0.05 (m, 6H)
應用合成化合物Iak的類似方法，合成了化合物Ial。Compound Ial was synthesized in a similar manner to the synthesis of compound Iak.
1H-NMR(400 MHz,CDCl3)δ5.85(s,1H),5.39~5.30(m,2H),4.19~4.05(m,2H),3.75~3.60(m,2H),3.28~3.21(m,2H),2.58~2.49(m,2H),2.09~1.45(m,11H),1.10~1.05(m,3H),0.91~0.88(m,18H),0.06~0.05(m,12H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.85 (s, 1H), 5.39 to 5.30 (m, 2H), 4.19 to 4.05 (m, 2H), 3.75 to 3.60 (m, 2H), 3.28 to 3.21. (m, 2H), 2.58~2.49 (m, 2H), 2.09~1.45 (m, 11H), 1.10~1.05 (m, 3H), 0.91~0.88 (m, 18H), 0.06~0.05 (m, 12H)
應用合成化合物Iak的類似方法，合成了化合物Iam。Compound Iam was synthesized using a similar method to synthesize compound Iak.
1H-NMR(400 MHz,CDCl3)δ5.82(s,1H),5.52~5.40(m,2H),4.25~4.13(m,2H),3.70~3.59(m,2H),3.21~3.18(m,2H),2.60~2.35(m,2H),2.30(s,3H),2.11~1.52(m,11H),1.11~1.08(m,3H),0.88(s,9H),0.06~0.05(m,6H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.82 (s, 1H), 5.52 to 5.40 (m, 2H), 4.25 to 4.13 (m, 2H), 3.70 to 3.59 (m, 2H), 3.21 to 3.18 (m, 2H), 2.60~2.35 (m, 2H), 2.30 (s, 3H), 2.11~1.52 (m, 11H), 1.11~1.08 (m, 3H), 0.88 (s, 9H), 0.06~0.05 (m, 6H)
應用合成化合物Iaa的類似方法，合成了化合物Ian。Compound Ian was synthesized using a similar method for the synthesis of compound Iaa.
1H-NMR(400 MHz,CDCl3)δ5.47~5.36(m,3H),4.20~4.19(m,2H),4.10~4.04(m,1H),3.91~3.87(m,1H),3.62~3.58(m,1H),2.93~2.88(br,2H),2.44~2.36(m,1H),2.21~2.02(m,5H),1.95~1.84(m,3H),1.77~1.64(m,3H),1.24~1.19(m,6H),1.14~0.94(m,21H). 1 H-NMR (400 MHz, CDCl 3 ) δ 5.47~5.36 (m, 3H), 4.20~4.19 (m, 2H), 4.10~4.04 (m, 1H), 3.91~3.87 (m, 1H), 3.62 ~3.58(m,1H), 2.93~2.88(br,2H), 2.44~2.36(m,1H), 2.21~2.02(m,5H),1.95~1.84(m,3H),1.77~1.64(m, 3H), 1.24~1.19 (m, 6H), 1.14~0.94 (m, 21H).
應用合成化合物Iaa的類似方法，合成了化合物Iao。Compound Iao was synthesized by a similar method using synthetic compound Iaa.
1H-NMR(400 MHz,CDCl3)δ6.16(s,1H),5.42~5.32(m,2H),4.18(s,2H),3.89~3.86(m,1H),3.61~3.57(m,1H),3.24~3.19(br,2H),2.68~2.64(m,1H),2.45~2.33(m,1H),2.17~1.97(m,5H),1.92~1.82(m,3H),1.73~1.61(m,3H),1.17~0.98(m,21H),0.73~0.70(m,2H),0.48~0.46(m,2H). 1 H-NMR (400 MHz, CDCl 3 ) δ 6.16 (s, 1H), 5.42 to 5.32 (m, 2H), 4.18 (s, 2H), 3.89 to 3.86 (m, 1H), 3.61 to 3.57 (m) , 1H), 3.24~3.19 (br, 2H), 2.68~2.64 (m, 1H), 2.45~2.33 (m, 1H), 2.17~1.97 (m, 5H), 1.92~1.82 (m, 3H), 1.73 ~1.61 (m, 3H), 1.17~0.98 (m, 21H), 0.73~0.70 (m, 2H), 0.48~0.46 (m, 2H).
應用合成化合物Iaa的類似方法,合成了化合物Iap。A compound Iap was synthesized using a similar method of synthesizing the compound Iaa.
1H-NMR(400 MHz,CDCl3)δ5.57~5.37(m,3H),4.22~4.17(m,3H),3.91~3.87(m,1H),3.62~3.58(m,1H),2.40~2.36(m,2H),2.21~1.89(m,10H),1.75~1.56(m,7H),1.39~1.31(m,3H),1.13~0.99(m,21H). 1 H-NMR (400 MHz, CDCl 3 ) δ 5.57~5.37 (m, 3H), 4.22~4.17 (m, 3H), 3.91~3.87 (m, 1H), 3.62~3.58 (m, 1H), 2.40 ~2.36(m,2H), 2.21~1.89(m,10H), 1.75~1.56(m,7H), 1.39~1.31(m,3H), 1.13~0.99(m,21H).
分別將DHP(10mL)和PPTS(20mg)加入到Iaa的二氯乙烷(20mL)溶液中，反應體系在20℃攪拌24小時後減壓濃縮，殘留物用乙酸乙酯溶解，分別用飽和碳酸氫鈉水溶液和飽和食鹽水洗滌。有機相用無水硫酸鈉乾燥後減壓濃縮，殘留物以管柱層析提純得到化合物Ib。DHP (10 mL) and PPTS (20 mg) were added to a solution of Iaa in dichloroethane (20 mL). The reaction was stirred at 20 ° C for 24 hours and then concentrated under reduced pressure. The aqueous sodium hydrogen solution and the saturated brine were washed. The organic phase was dried over anhydrous sodium sulfate and evaporated.
1H NMR(400 MHz,CDCl3): 5.60-5.32(m,3 H),4.70-4.57(m,2H),4.20-3.20(m,6H),3.50-3.40(m,2H),3.31-3.21(m,2F),2.40-2.01(m,6H),2.00-1.40(m,18H),1.20-1.01(m,24H) 1 H NMR (400 MHz, CDCl 3 ): 5.60-5.32 (m, 3 H), 4.70-4.57 (m, 2H), 4.20-3.20 (m, 6H), 3.50-3.40 (m, 2H), 3.31 3.21 (m, 2F), 2.40-2.01 (m, 6H), 2.00-1.40 (m, 18H), 1.20-1.01 (m, 24H)
將TBAF(4.93mL)加入到化合物Ib(300mg)的二氯甲烷溶液中，反應體系在20℃攪拌24小時後減壓濃縮，殘留物用乙酸乙酯溶解，分別用飽和碳酸氫鈉水溶液和飽和食鹽水洗滌。有機相用無水硫酸鈉乾燥後減壓濃縮，殘留物以管柱層析提純得到化合物Ic。TBAF (4.93 mL) was added to a solution of the compound Ib (300 mg) in dichloromethane. The reaction mixture was stirred at 20 ° C for 24 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate. Wash with salt water. The organic phase was dried over anhydrous sodium sulfate and evaporated.
1H-NMR(400MHz,CDCl3)δ5.40~5.36(m,3H),4.73~4.59(m,2H),4.15~3.46(m,8H),3.30~3.23(m,2H),3.00~2.85(s,1H),2.32~1.50(m,24H),1.14~1.10(m,3H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.40~5.36 (m, 3H), 4.73~4.59 (m, 2H), 4.15~3.46 (m, 8H), 3.30~3.23 (m, 2H), 3.00~ 2.85(s,1H), 2.32~1.50(m,24H), 1.14~1.10(m,3H)
在0℃，將三乙胺(35.55mg)和乙醯氯(20.79mg)加入到化合物Ic(80mg)的二氯甲烷溶液中，並在0℃攪拌2小時。反應體系淬滅後用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物Id。Triethylamine (35.55 mg) and acetonitrile (20.79 mg) were added to a solution of Compound Ic (80 mg) in dichloromethane, and stirred at 0 ° C for 2 hr. The reaction mixture was quenched with EtOAc. The residue was purified by column chromatography to give the compound Id.
1H-NMR(400MHz,CDCl3)δ5.68~5.34(m,3H),4.72~4.59(m,2H),4.21~3.81(m,6H),3.49~3.47(m,2H),3.31~3.24(m,2H),2.39~2.05(m,9H),1.95~1.45(m,18H),1.18~1.15(m,3H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.68~5.34 (m, 3H), 4.72~4.59 (m, 2H), 4.21~3.81 (m, 6H), 3.49~3.47 (m, 2H), 3.31~ 3.24 (m, 2H), 2.39~2.05 (m, 9H), 1.95~1.45 (m, 18H), 1.18~1.15 (m, 3H)
化合物Id(86mg)溶於10毫升甲醇中，加入對甲基苯磺酸水合物(133.9mg)，所得混合物加熱到40℃，然後在此溫度攪拌1小時。反應後的混合物蒸乾，然後用乙酸乙酯稀釋，並用水和飽和食鹽水依次洗滌。有機相經無水硫酸鈉乾燥後濃縮，殘留物以管柱層析提純得到化合物Ie。Compound Id (86 mg) was dissolved in 10 ml of methanol, p-toluenesulfonic acid hydrate (133.9 mg) was added, and the mixture was heated to 40 ° C, and then stirred at this temperature for 1 hour. The reacted mixture was evaporated to dryness, then diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated.
1H-NMR(400MHz,CDCl3)δ5.68(br,1H),5.42~5.39(m,2H),4.30~4.11(m,3H),4.03~3.93(m,1H),3.31~3.26(m,4H),2.47~2.39(m,1H),2.23~2.02(m,8H),1.97~1.66(m,5H),1.54~1.49(m,1H),1.16~1.13(m,3H) 1 H-NMR (400MHz, CDCl 3 ) δ 5.68 (br, 1H), 5.42~5.39 (m, 2H), 4.30~4.11 (m, 3H), 4.03~3.93 (m, 1H), 3.31~3.26 ( m,4H), 2.47~2.39(m,1H), 2.23~2.02(m,8H),1.97~1.66(m,5H),1.54~1.49(m,1H),1.16~1.13(m,3H)
化合物Ie(30mg)溶於二氯甲烷(10mL)中，所得溶液冷卻至0℃，加入三乙胺(18.18mg)和乙酸酐(91.88mg)，混合液在20℃攪拌18小時。反應體系淬滅後用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物If。Compound Ie (30 mg) was dissolved in dichloromethane (10 mL). EtOAc m. The reaction mixture was quenched with EtOAc. The residue was purified by column chromatography to give Compound If.
1H-NMR(400 MHz,CDCl3)δ5.66~5.58(m,2H),5.38~5.30(m,2H),5.10~4.97(m,2H),4.28~4.15(m,2H),3.27~3.22(m,2H),2.36~1.98(m,16H),1.80~1.64(m,4H),1.13~1.08(m,3H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.66~5.58 (m, 2H), 5.38~5.30 (m, 2H), 5.10~4.97 (m, 2H), 4.28~4.15 (m, 2H), 3.27 ~3.22(m,2H), 2.36~1.98(m,16H), 1.80~1.64(m,4H),1.13~1.08(m,3H)
在0℃，將三乙胺(50.5mg)和TBSOTf(198mg)加入到化合物Iab(100mg)的二氯甲烷溶液中，反應液在0℃攪拌2小時。反應體系淬滅後用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物Ig。Triethylamine (50.5 mg) and TBSOTf (198 mg) were added to a solution of the compound Iab (100 mg) in dichloromethane, and the mixture was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with EtOAc. The residue was purified by column chromatography to give the compound Ig.
1H-NMR(400 MHz,CDCl3)δ5.43~5.31(m,3H),4.09~4.02(m,2H),3.68~3.55(m,2H),3.31~3.24(m,2H),2.17~2.03(m,6H),1.76~1.54(m,6H),1.14~1.10(m,3H),0.88~0.84(m,27H),0.04~0.00(m,18H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.43~5.31 (m, 3H), 4.09~4.02 (m, 2H), 3.68~3.55 (m, 2H), 3.31~3.24 (m, 2H), 2.17 ~2.03(m,6H), 1.76~1.54(m,6H), 1.14~1.10(m,3H),0.88~0.84(m,27H),0.04~0.00(m,18H)
化合物Ig(50mg)溶於甲醇(5mL)中，所得溶液降溫至0℃，加入對甲基苯磺酸水合物(7.6mg)，所得混合物在0℃攪拌1小時。反應後的混合物蒸乾，然後用乙酸乙酯稀釋，並用水和飽和食鹽水依次洗滌。有機相經無水硫酸鈉乾燥後濃縮，殘留物以管柱層析提純得到化合物Ih。The compound Ig (50 mg) was dissolved in methanol (5 mL), and the obtained mixture was cooled to 0 ° C, and p-toluenesulfonic acid hydrate (7.6 mg) was added, and the mixture was stirred at 0 ° C for 1 hour. The reacted mixture was evaporated to dryness, then diluted with ethyl acetate and washed sequentially with water and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated.
1H-NMR(400 MHz,CDCl3)δ5.56~5.36(m,3H),4.12~3.98(m,2H),3.77~3.67(m,2H),3.30~3.25(m,2H),2.63(s,1H),2.21~1.91(m,6H),1.72~1..51(m,6H),1.14~1.06(m,3H),0.86~0.82(m,18H),0.09~0.05(m,12H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.56~5.36 (m, 3H), 4.12~3.98 (m, 2H), 3.77~3.67 (m, 2H), 3.30~3.25 (m, 2H), 2.63 (s,1H), 2.21~1.91(m,6H), 1.72~1..51(m,6H), 1.14~1.06(m,3H),0.86~0.82(m,18H),0.09~0.05(m , 12H)
將DHP(70mg)和PPTS(2mg)加入到化合物Ih(86mg)的1,2-二氯乙烷(5mL)溶液中，反應液在20℃攪拌18小時。反應體系淬滅後用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物Ii。DHP (70 mg) and PPTS (2 mg) were added to a solution of compound Ih (86 mg) in 1,2-dichloroethane (5 mL), and the mixture was stirred at 20 ° C for 18 hours. The reaction mixture was quenched with EtOAc. The residue was purified by column chromatography to give the compound Ii.
1H-NMR(400 MHz,CDCl3)δ5.51~5.34(m,3H),4.60~4.58(m,1H),4.14~4.01(m,2H),3.88~3.78(m,2H),3.54~3.50(m,2H),3.43~3.27(m,2H),2.24~2.07(m,6H),1.93~1.53(m,12H),1.17~1.13(m,3H),0.89(m,18H),0.09~0.06(m,12H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.51~5.34 (m, 3H), 4.60~4.58 (m, 1H), 4.14~4.01 (m, 2H), 3.88~3.78 (m, 2H), 3.54 ~3.50(m,2H),3.43~3.27(m,2H), 2.24~2.07(m,6H),1.93~1.53(m,12H),1.17~1.13(m,3H),0.89(m,18H) , 0.09~0.06(m,12H)
將TBAF(1.34mL)加入到化合物Ii(80mg)的二氯甲烷溶液中，反應液在20℃攪拌18小時。反應體系淬滅後用乙酸乙酯萃取，有機相用無水硫酸鈉乾燥後減壓濃縮。殘留物以管柱層析提純得到化合物Ij。TBAF (1.34 mL) was added to a solution of the compound Ii (80 mg) in dichloromethane, and the mixture was stirred at 20 ° C for 18 hours. The reaction mixture was quenched with EtOAc. The residue was purified by column chromatography to give compound Ij.
1H-NMR(400 MHz,CDCl3)δ5.82~5.13(m,3H),4.61~4.51(m,3H),4.20~4.19(br,2H),3.91~3.80(m,2H),3.65~3.49(m,2H),3.32~3.24(m,2H),2.42~2.31(m,2H),2.25~2.14(m,3H),2.10~1.91(m,5H),1.75~1.51(m,8H),1.22~1.12(m,3H) 1 H-NMR (400 MHz, CDCl 3 ) δ 5.82~5.13 (m, 3H), 4.61~4.51 (m, 3H), 4.20~4.19 (br, 2H), 3.91~3.80 (m, 2H), 3.65 ~3.49(m,2H), 3.32~3.24(m,2H), 2.42~2.31(m,2H), 2.25~2.14(m,3H), 2.10~1.91(m,5H),1.75~1.51(m, 8H), 1.22~1.12 (m, 3H)
貝美前列素(bimatoprost)合成過程如下：The synthetic process of bimatoprost is as follows:
在氮氣氛下，將草醯氯(0.28mL)的二氯甲烷溶液(20mL)冷卻到-78℃。將二甲亞碸(0.47mL)加入反應體系，混合物在-78℃攪拌10分鐘。將化合物Ic(150mg)的二氯甲烷(3mL)溶液加入到反應體系。半小時後，加入三乙胺(2.8mL)，反應體系逐漸回到室溫。反應體系用飽和磷酸二氫鈉水溶液(20mL)，飽和食鹽水(20 mL)洗滌，用無水硫酸鈉乾燥後減壓濃縮得到產物VIa。化合物VIa直接用於下步反應。Under a nitrogen atmosphere, a solution of dichloromethane (0.28 mL) in dichloromethane (20 mL) was cooled to -78. Dimethyl hydrazine (0.47 mL) was added to the reaction system, and the mixture was stirred at -78 ° C for 10 minutes. A solution of Compound Ic (150 mg) in dichloromethane (3 mL) was added to the reaction. After half an hour, triethylamine (2.8 mL) was added and the reaction system gradually returned to room temperature. The reaction system was washed with saturated aqueous sodium hydrogen sulfate (20 mL), brine Compound VIa was used directly in the next step.
1H NMR(400 MHz,CDCl3): 9.77~9.68(m,1H),5.75-5.22(m,3 H),4.80-4.51(m,2H),4.20-3.60(m,4H),3.59-3.17(m,4H),3.10-2.65(m,1H),2.40-1.40(m,23H),1.11(t,J=7.2 Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): 9.77 to 9.68 (m, 1H), 5.75-5.22 (m, 3 H), 4.80-4.51 (m, 2H), 4.20-3.60 (m, 4H), 3.59- 3.17 (m, 4H), 3.10-2.65 (m, 1H), 2.40 - 1.40 (m, 23H), 1.11 (t, J = 7.2 Hz, 3H).
在氮氣氛下，將152mg化合物IXa(按文獻Bioorg. Med. Chem. Lett 1998,8,2849方法製備)和氯化鋰(200mg)的乙腈混合物(10mL)冷卻到-15℃。將二異丙基乙胺(0.3mL)加入反應體系，混合物在-15℃攪拌30分鐘。將步驟1得到的化合物VIa的乙腈(3mL)溶液加入到反應體系。反應體系在-15℃攪拌30分鐘後逐漸回到室溫，攪拌過夜。將乙醚(50 mL)加入到體系中，過濾除去固體，濾液減壓濃縮。殘留物以管柱層析提純得到化合物VIIa。Under a nitrogen atmosphere, 152 mg of compound IXa (prepared by the method Bioorg. Med. Chem. Lett 1998, 8, 2849) and lithium chloride (200 mg) in acetonitrile (10 mL) were cooled to -15 °C. Diisopropylethylamine (0.3 mL) was added to the reaction system, and the mixture was stirred at -15 ° C for 30 minutes. A solution of the compound VIa obtained in the step 1 in acetonitrile (3 mL) was added to the reaction system. The reaction system was stirred at -15 ° C for 30 minutes, then gradually returned to room temperature and stirred overnight. Diethyl ether (50 mL) was added to the mixture. The residue was purified by column chromatography to give compound VIIa.
1H NMR(400 MHz,CDCl3): 7.45-7.15(m,5H),6.72-6.80(m,1H),6.26-6.19(m,1H),5.85-5.22(m,3H),4.80-4.45(m,2H),4.25-3.60(m,4H),3.51-3.17(m,4H),3.10-2.50(m,5H),2.40-1.40(m,23H),1.11(t,J=7.2 Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): 7.45-7.15 (m, 5H), 6.72-6.80 (m, 1H), 6.26-6.19 (m, 1H), 5.85-5.22 (m, 3H), 4.80-4.45 (m, 2H), 4.25-3.60 (m, 4H), 3.51-3.17 (m, 4H), 3.10-2.50 (m, 5H), 2.40-1.40 (m, 23H), 1.11 (t, J = 7.2 Hz , 3H).
室溫下，將硼烷(1 M四氫呋喃溶液,3.4mL)和(R)-CBS催化劑(1.0 M甲苯溶液，68 uL)加入四氫呋喃(10mL)中，混合物攪拌1小時。化合物VIIa(200mg)的四氫呋喃(5mL)溶液冷卻到-10℃，將上述混合物加入到溶液中。30分鐘後，加入甲醇(0.5mL)淬滅反應。反應體系減壓濃縮得到產物VIIIa。化合物VIIIa直接用於下步反應。Borane (1 M tetrahydrofuran solution, 3.4 mL) and (R)-CBS catalyst (1.0 M in toluene, 68 uL) were added to tetrahydrofuran (10 mL), and the mixture was stirred for 1 hour. A solution of compound VIIa (200 mg) in tetrahydrofuran (5 mL) was cooled to -10 ° C and the mixture was added to the solution. After 30 minutes, the reaction was quenched by the addition of methanol (0.5 mL). The reaction system was concentrated under reduced pressure to give the product VIIIa. Compound VIIIa was used directly in the next step.
1H NMR(400 MHz,CDCl3): 7.39-7.15(m,5H),5.78-5.22(m,4H),4.80-4.45(m,2H),4.25-3.60(m,5H),3.51-3.17(m,4H),2.80-2.40(m,3H),2.40-1.40(m,25H),1.11(t,J=7.2 Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): 7.39-7.15 (m, 5H), 5.78-5.22 (m, 4H), 4.80-4.45 (m, 2H), 4.25-3.60 (m, 5H), 3.51-3. (m, 4H), 2.80-2.40 (m, 3H), 2.40-1.40 (m, 25H), 1.11 (t, J = 7.2 Hz, 3H).
將步驟3得到的化合物VIIIa溶於甲醇(5mL)，加入一水合對甲苯磺酸(500mg)。體系在室溫攪拌30分鐘，減壓濃縮。殘留物溶於乙酸乙酯(30mL)，用水(30mL)和飽和食鹽水(30mL)洗滌。有機相用無水硫酸鈉乾燥後減壓濃縮，殘留物以管柱層析提純得到貝美前列素(bimatoprost)。The compound VIIIa obtained in the step 3 was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (500 mg) was added. The system was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL)EtOAc. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to afford bimatoprost.
1H NMR(400 MHz,CD3OD): 7.27-7.14(m,5H),5.61-5.30(m,4H),4.15-4.00(m,2H),3.87-3.81(m,1H),3.20-3.12(m,2H),2.70-2.65(m,2H),2.41-2.00(m,8H),1.89-1.46(m,6H),1.09(t,J=7.2 Hz,3H)。 1 H NMR (400 MHz, CD 3 OD): 7.27-7.14 (m, 5H), 5.61-5.30 (m, 4H), 4.15 - 4.00 (m, 2H), 3.87-3.81 (m, 1H), 3.20- 3.12 (m, 2H), 2.70-2.65 (m, 2H), 2.41-2.00 (m, 8H), 1.89-1.46 (m, 6H), 1.09 (t, J = 7.2 Hz, 3H).
由於已根據其特殊的實施方案描述了本發明，某些修飾和等價變化對於精通此領域的技術人員是顯而易見的且包括在本發明的範圍內。Since the present invention has been described in terms of its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are included within the scope of the invention.
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