CN102757459B - For the synthesis of the intermediate and preparation method thereof of prostanoid medicine - Google Patents
For the synthesis of the intermediate and preparation method thereof of prostanoid medicine Download PDFInfo
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- CN102757459B CN102757459B CN201110113844.3A CN201110113844A CN102757459B CN 102757459 B CN102757459 B CN 102757459B CN 201110113844 A CN201110113844 A CN 201110113844A CN 102757459 B CN102757459 B CN 102757459B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 229940127293 prostanoid Drugs 0.000 title claims abstract description 9
- 150000003814 prostanoids Chemical class 0.000 title claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 title abstract description 12
- 238000003786 synthesis reaction Methods 0.000 title abstract description 11
- 229960002470 bimatoprost Drugs 0.000 claims abstract description 12
- 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 claims abstract description 12
- 238000007239 Wittig reaction Methods 0.000 claims abstract description 4
- 150000002373 hemiacetals Chemical class 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- -1 methoxyl group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 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
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 150000003180 prostaglandins Chemical class 0.000 abstract description 9
- 229960001160 latanoprost Drugs 0.000 abstract description 2
- 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 abstract description 2
- 229960002368 travoprost Drugs 0.000 abstract description 2
- 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 abstract description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 85
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 238000003756 stirring Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 3
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 3
- 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 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- CXDHJGCWMIOAQP-UHFFFAOYSA-N 2-pyridin-3-yl-1,4,5,6-tetrahydropyrimidine;hydrochloride Chemical group Cl.C1CCNC(C=2C=NC=CC=2)=N1 CXDHJGCWMIOAQP-UHFFFAOYSA-N 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
- 206010030043 Ocular hypertension Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 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
- 238000010511 deprotection reaction Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 201000007094 prostatitis Diseases 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical class OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910000085 borane 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
- 238000005352 clarification Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000004880 oxines Chemical class 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 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
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000007787 solid Substances 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
- 239000000725 suspension Substances 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the intermediate and preparation method thereof for the synthesis of prostanoid medicine.The present invention relates to a kind of intermediate for the synthesis of prostanoid medicine (structural formula I), and the preparation method of this intermediate, this intermediate can be used for synthesis of prostaglandins class medicine, such as Bimatoprost (bimatoprost), travoprost, latanoprost etc.This intermediate can be obtained by the Wittig reaction of hemiacetal and derivatize thereof.
Description
Technical field
The present invention relates to the intermediate and preparation method thereof for the synthesis of prostanoid medicine.
Background technology
Prostaglandin(PG) is the derivative of fatty acid that a class has 20 carbon atoms.Prostaglandin(PG) regulates the multiple physiological action of human body in hormone concentration level, has regulating effect to blood pressure, smooth muscle contraction, gastric secretion and platelet aggregation.Wherein, prostaglandin F-type derivant is used for the treatment of open angle glaucoma and ocular hypertension clinically, to reduce the ocular hypertension of patient.
Prostaglandin(PG) be extensively be present in humans and animals respectively organize in trace ingredients, content is extremely low, and add the splendid result for the treatment of of prostaglandin F-type derivant to the disease such as glaucoma and ocular hypertension thereof, the prostaglandin(PG) of natural origin can not meet clinical application demand.For this reason, scientist is devoted to the complete synthesis research of prostaglandin(PG) analog derivative always, achieves great successes so far.Such as, EP1886992, EP1721894, EP2143712, US2003/187071, US2005/209337, US2008/033176, US2009/259066, US2010/056807, WO90/02553, WO94/06433, WO97/22602, WO200I/010873, the patent documentations such as WO2002/096898, WO2007/041273 all describe in detail use of various prostaglandin F-type derivant and preparation method thereof.
Summary of the invention
The invention relates to the intermediate and preparation method thereof for the synthesis of prostanoid medicine.By intermediate, the synthesis step of prostatitis element class medicine can be shortened, thus improve prostatitis element class medicine, as the combined coefficient of Bimatoprost, travoprost, latanoprost.
The object of the invention is to provide a kind of such as formula the intermediate for the synthesis of prostanoid medicine shown in I.
Wherein, R
1, R
2and R
3be respectively hydrogen or hydroxyl protecting group separately, preferably, R
1, R
2and R
3be selected from hydrogen, THP ,-C (O) R respectively separately
6or-SiR
7r
8r
9, wherein R
6, R
7, R
8and R
9be respectively C separately
1-10straight or branched alkyl, C
3-8cyclic alkyl or C
6-10substituted or non-substituted aryl; R
4and R
5be respectively hydrogen, amido, methoxyl group, C separately
1-10straight or branched alkyl, C
3-8cyclic alkyl or C
6-10substituted or non-substituted aryl, R
4and R
5hydrogen, methyl, ethyl, propyl group, butyl, phenyl, amido or methoxyl group can be selected from respectively separately; Or R
4, R
5form 5-8 unit heterocycle together with nitrogen-atoms, preferred five-ring and six-ring, be more preferably five-ring.R
4and R
5can not be amido or methoxyl group simultaneously.
In a preferred specific embodiments of the present invention, in formula I, R
1for THP; R
2for THP; R
3for TIPS; R
4for ethyl; R
5for hydrogen; Or, R
1for THP; R
2for THP; R
3for TIPS; R
4for hydrogen; R
5for ethyl.
The object of the invention is the preparation method providing a kind of synthesis such as formula intermediate shown in Ia,
It is characterized in that, by obtained such as formula the intermediate shown in Ia by Wittig reaction in the basic conditions for the amide derivatives of the hemiacetal of formula II and formula II I:
X wherein in formula III is halogen, and X can be selected from Cl, Br or I, is preferably Br; Ar is C
6-10non-substituted or substituted aryl, be preferably phenyl.
As required, intermediate compound I a is prepared such as formula intermediate shown in I through the conversion of hydroxyl protection or hydroxyl deprotection or hydroxy-protective group.
In a preferred specific embodiments of the present invention, hemiacetal (formula II, R
2=H, R
3=TIPS) and amide derivatives (formula II I, R
4=Et, R
5=H, Ar are phenyl, and X is bromine; Or, R
4=H, R
5=Et, Ar are phenyl, and X is bromine) Wittig reaction obtained intermediate compound I a (structural 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), its preferred reaction conditions is: using potassium tert.-butoxide as alkali, take tetrahydrofuran (THF) as solvent, with 3A molecular sieve for activator, reacts at 20 DEG C of temperature.
Invention further provides a kind of preparation method preparing Bimatoprost,
Wherein R
1and R
2for hydroxyl protecting group, R is C
1-8alkyl, is characterized in that, the method comprises the steps:
1) intermediate compound I ' obtain intermediate VI through oxidizing reaction,
2) intermediate VI and phosphoric acid ester IX is obtained by reacting intermediate VII,
3) intermediate VII obtains intermediate VIII through asymmetric reduction,
4) intermediate VIII obtains Bimatoprost after deprotection group.
Hydroxyl protecting group of the present invention is the group for hydroxyl protection suitably known in the art, see document (" ProtectiveGroupsinOrganicSynthesis ", 5
th.Ed.T.W.Greene & P.G.M.Wuts) in hydroxy-protective group.Described hydroxyl protecting group can be (C
1-8alkyl or aryl)
3silylation, such as: triethyl is silica-based, triisopropylsilyl, t-Butyldimethylsilyl, tert-butyl diphenyl is silica-based; Can be C
1-8alkyl or substituted alkyl, such as: methyl, the tertiary butyl, allyl group, benzyl, methoxymethyl, ethoxyethyl group, 2-THP trtrahydropyranyl (THP) etc.; Can be (C
1-8alkyl or aromatic base) acyl group, such as: formyl radical, ethanoyl, benzoyl etc.; Can be (C
1-6alkyl or C
6-10aryl) alkylsulfonyl; Also can be (C
1-6alkoxyl group or C
6-10aryloxy) carbonyl.
Substituted aryl of the present invention refer to aromatic nucleus by one or more be such as selected from following residue replace: halogen, hydroxyl, cyano group, nitro, amido, trifluoromethyl, C
1-8alkyl, C
1-8alkoxyl group, C
2-8alkyloyl oxygen base, C
6-10aryl, allyl group etc.
Abbreviation table:
| Abbreviation | Full name |
| DHP | 3,4-dihydro (2H) pyrans |
| DIBAL-H | Diisobutyl aluminium hydride |
| PPTS | Tosic acid pyridinium salt |
| TBAF | Tetrabutyl ammonium fluoride |
| TBS | T-butyldimethylsilyi |
| TBSOTf | T-Butyldimethylsilyl triflate |
| THP | 2-THP trtrahydropyranyl |
| TIPS | Tri isopropyl silane base |
Embodiment
Explain the present invention in detail below with reference to specific examples, make those skilled in the art comprehend this patent, specific examples only for illustration of technical scheme of the present invention, and limits the present invention never in any form.
Following table is the structural formula of Compound I involved in embodiment
Embodiment 1: preparation Compound I aa
Compound I aa synthesizes as follows:
Step 1):
Under nitrogen atmosphere, triethylamine (2.5mL) is joined methylene dichloride (50mL) solution of compound IV (1.0g buys from Shanghai Julong Pharmaceutical R & D Co., Ltd.).Reaction system is cooled to-78 DEG C, adds methylene dichloride (10mL) solution of triisopropylsilyl triflate (2.9g).Remove cryostat after two hours, reaction system stirs 30 minutes at 20 DEG C.Reaction system concentrating under reduced pressure, residue is purified with column chromatography and is obtained compound Vaa.
1HNMR(400MHz，CDCl
3)：δ4.94-4.89(m，1H)，4.18-4.11(m，1H)，3.84(dd，J＝9.6，5.2Hz，1H)，3.69(dd，J＝10.4，7.2Hz，1H)，2.79(dd，J＝18，10.8Hz，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)
Step 2):
Under nitrogen atmosphere, the toluene solution (30mL) of Vaa (1.675g) is cooled to-78 DEG C.DIBAL-H (1.0M hexane solution, 15.3mL) is added reaction system, and mixture stirs 2 hours at-78 DEG C.Add saturated aqueous sodium potassium tartrate (5mL) quencher reaction, system gets back to 20 DEG C gradually, continues to stir until system clarification.Reaction system extracted with diethyl ether, organic phase saturated common salt water washing, with concentrating under reduced pressure after anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound II per aa.
1HNMR(400MHz，CDCl
3)：δ5.68-5.50(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)
Step 3):
At 20 DEG C, by potassium tert.-butoxide (1M tetrahydrofuran solution, 15.1mL) add compound III aa (3.56g, according to reference J.Med.Chem.1979,22,1340 obtain), in the 3A molecular sieve powder (2.5g) of activation and the suspension of tetrahydrofuran (THF) (15mL).Then, tetrahydrofuran (THF) (2mL) solution of IIaa (500mg) is joined in the orange ylide of formation.Reaction system stirs 30 minutes at 20 DEG C, adds water quencher reaction.System is extracted with ethyl acetate, concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound I aa.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 2: preparation Compound I ab
The similar approach of application synthetic compound Iaa, has synthesized Compound I ab.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 3: preparation Compound I ac
The similar approach of application synthetic compound Iaa, has synthesized Compound I ac.
1H-NMR(400MHz，CDCl
3)δ5.98～5.96(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)
Embodiment 4: preparation Compound I ad
The similar approach of application synthetic compound Iaa, has synthesized Compound I ad.
1H-NMR(400MHz，CDCl
3)δ5.91～5.77(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)
Embodiment 5: preparation Compound I ae
The similar approach of application synthetic compound Iaa, has synthesized Compound I ae.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 6: preparation Compound I af
The similar approach of application synthetic compound Iaa, has synthesized Compound I af.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 7: preparation Compound I ag
The similar approach of application synthetic compound Iaa, has synthesized Compound I ag.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 8: preparation Compound I ah
The similar approach of application synthetic compound Iaa, has synthesized Compound I ah.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 9: preparation Compound I ai
The similar approach of application synthetic compound Iaa, has synthesized Compound I ai.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 10: preparation Compound I aj
The similar approach of application synthetic compound Iaa, has synthesized Compound I aj.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 11: preparation Compound I ak
The tetrahydrofuran solvent (30mL) adding compound III aa (1.05g) and heavily steam in the 100mL single port bottle of drying, add potassium tert.-butoxide (1.0M tetrahydrofuran solution) (5.37mL) after fully stirring under room temperature, reaction solution becomes dark orange instantaneously.Slowly add the tetrahydrofuran solution of Compound II per ak (200mg) subsequently again, reaction is at room temperature stirred and is spent the night.Detect that most of raw material disappears, add 20mL shrend subsequently and go out, with extracted with diethyl ether repeatedly, and organic phase salt solution is repeatedly washed, anhydrous sodium sulfate drying.Crude product purified by silica gel column chromatography for separation (methylene dichloride: methyl alcohol=15: 1) obtain Iak.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 12: preparation Compound I al
The similar approach of application synthetic compound Iak, has synthesized Compound I al.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 13: preparation Compound I am
The similar approach of application synthetic compound Iak, has synthesized Compound I am.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 14: preparation Compound I an
The similar approach of application synthetic compound Iaa, has synthesized Compound I an.
1H-NMR(400MHz，CDCl
3)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).
Embodiment 15: preparation Compound I ao
The similar approach of application synthetic compound Iaa, has synthesized Compound I ao.
1H-NMR(400MHz，CDCl
3)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).
Embodiment 16: preparation Compound I ap
The similar approach of application synthetic compound Iaa, has synthesized Compound I ap.
1H-NMR(400MHz，CDCl
3)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).
Embodiment 17: prepare compounds ib
Respectively DHP (10mL) and PPTS (20mg) is joined in ethylene dichloride (20mL) solution of Iaa, reaction system stirs concentrating under reduced pressure after 24 hours at 20 DEG C, residue with Ethyl acetate dissolves, and uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing respectively.Concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying, residue is purified with column chromatography and is obtained compounds ib.
1HNMR(400MHz，CDCl
3)：5.60-5.32(m，3H)，4.70-4.57(m，2H)，4.20-3.20(m，6H)，3.50-3.40(m，2H)，3.31-3.21(m，2H)，2.40-2.01(m，6H)，2.00-1.40(m，18H)，1.20-1.01(m，24H)
Embodiment 18: preparation Compound I c
TBAF (4.93mL) is joined in the dichloromethane solution of compounds ib (300mg), reaction system stirs concentrating under reduced pressure after 24 hours at 20 DEG C, residue with Ethyl acetate dissolves, and uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing respectively.Concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying, residue is purified with column chromatography and is obtained Compound I c.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 19: preparation Compound I d
At 0 DEG C, triethylamine (35.55mg) and Acetyl Chloride 98Min. (20.79mg) are joined in the dichloromethane solution of Compound I c (80mg), and stir 2 hours at 0 DEG C.Be extracted with ethyl acetate after reaction system quencher, concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound I d.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 20: preparation Compound I e
Compound I d (86mg) is dissolved in 10 ml methanol, and add p-methyl benzenesulfonic acid hydrate (133.9mg), gained mixture is heated to 40 DEG C, then stirs 1 hour at this temperature.Reacted mixture evaporate to dryness, then uses diluted ethyl acetate, and washs successively with water and saturated aqueous common salt.Organic phase is concentrated after anhydrous sodium sulfate drying, and residue is purified with column chromatography and obtained Compound I e.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 21: preparation Compound I f
Compound I e (30mg) is dissolved in methylene dichloride (10mL), and gained solution is cooled to 0 DEG C, and add triethylamine (18.18mg) and diacetyl oxide (91.88mg), mixed solution stirs 18 hours at 20 DEG C.Be extracted with ethyl acetate after reaction system quencher, concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound I f.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 22: prepare Compound Ig per
At 0 DEG C, join in the dichloromethane solution of Compound I ab (100mg) by triethylamine (50.5mg) and TBSOTf (198mg), reaction solution stirs 2 hours at 0 DEG C.Be extracted with ethyl acetate after reaction system quencher, concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound Ig per.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 23: preparation Compound I h
Compound Ig per (50mg) is dissolved in methyl alcohol (5mL), and gained solution is cooled to 0 DEG C, adds p-methyl benzenesulfonic acid hydrate (7.6mg), and gained mixture stirs 1 hour at 0 DEG C.Reacted mixture evaporate to dryness, then uses diluted ethyl acetate, and washs successively with water and saturated aqueous common salt.Organic phase is concentrated after anhydrous sodium sulfate drying, and residue is purified with column chromatography and obtained Compound I h.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 24: preparation Compound I i
Join in 1,2-ethylene dichloride (5mL) solution of Compound I h (86mg) by DHP (70mg) and PPTS (2mg), reaction solution stirs 18 hours at 20 DEG C.Be extracted with ethyl acetate after reaction system quencher, concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound I i.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 25: preparation Compound I j
Join in the dichloromethane solution of Compound I i (80mg) by TBAF (1.34mL), reaction solution stirs 18 hours at 20 DEG C.Be extracted with ethyl acetate after reaction system quencher, concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying.Residue is purified with column chromatography and is obtained Compound I j.
1H-NMR(400MHz，CDCl
3)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)
Embodiment 26: prepare Bimatoprost (bimatoprost)
Bimatoprost (bimatoprost) building-up process is as follows:
Step 1):
Under nitrogen atmosphere, the dichloromethane solution (20mL) of oxalyl chloride (0.28mL) is cooled to-78 DEG C.Methyl-sulphoxide (0.47mL) is added reaction system, and mixture stirs 10 minutes at-78 DEG C.Methylene dichloride (3mL) solution of Compound I c (150mg) is joined reaction system.After half an hour, add triethylamine (2.8mL), reaction system gets back to room temperature gradually.Reaction system saturated biphosphate sodium water solution (20mL), saturated aqueous common salt (20mL) washs, and obtains product VI a with concentrating under reduced pressure after anhydrous sodium sulfate drying.Compound VI a is directly used in the next step.
1HNMR(400MHz，CDCl
3)：9.77～9.68(m，1H)，5.75-5.22(m，3H)，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＝7.2Hz，3H)。
Step 2):
Under nitrogen atmosphere, 152mg Compound I Xa (by document Bioorg.Med.Chem.Lett1998,8,2849 method preparations) and the acetonitrile mixture (10mL) of lithium chloride (200mg) are cooled to-15 DEG C.Diisopropylethylamine (0.3mL) is added reaction system, and mixture stirs 30 minutes at-15 DEG C.Acetonitrile (3mL) solution of compound VI a step 1 obtained joins reaction system.Reaction system stirs after 30 minutes and gets back to room temperature gradually at-15 DEG C, and stirring is spent the night.Ether (50mL) is joined in system, solids removed by filtration, filtrate reduced in volume.Residue is purified with column chromatography and is obtained compound VI Ia.
1HNMR(400MHz，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＝7.2Hz，3H)。
Step 3):
Under room temperature, borine (1M tetrahydrofuran solution, 3.4mL) and (R)-CBS catalyzer (1.0M toluene solution, 68uL) are added in tetrahydrofuran (THF) (10mL), mixture stirs 1 hour.Tetrahydrofuran (THF) (5mL) solution of compound VI Ia (200mg) is cooled to-10 DEG C, is joined in solution by said mixture.After 30 minutes, add methyl alcohol (0.5mL) quencher reaction.Reaction system concentrating under reduced pressure obtains product VII Ia.Compound VI IIa is directly used in the next step.
1HNMR(400MHz，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)，3.51-3.17(m，4H)，2.80-2.40(m，3H)，2.40-1.40(m，25H)，1.11(t，J＝7.2Hz，3H)。
Step 4):
Compound VI IIa step 3 obtained is dissolved in methyl alcohol (5mL), adds a hydration tosic acid (500mg).System at room temperature stirs 30 minutes, concentrating under reduced pressure.Residue is dissolved in ethyl acetate (30mL), with water (30mL) and saturated aqueous common salt (30mL) washing.Concentrating under reduced pressure after organic phase anhydrous sodium sulfate drying, residue is purified with column chromatography and is obtained Bimatoprost (bimatoprost).
1HNMR(400MHz，CD
3OD)：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＝7.2Hz，3H)。
Because special according to it embodiment describes the present invention, some modification and equivalent variations are apparent for the technician being proficient in this field and comprise within the scope of the invention.
Claims (13)
1. the intermediate for the preparation of prostanoid medicine as shown in structural formula (I), described prostanoid medicine is Bimatoprost,
Wherein, R
1, R
2for hydrogen, R
3for hydroxyl protecting group; R
4and R
5be respectively hydrogen, amido, methoxyl group, C separately
1-10straight or branched alkyl, C
3-8cyclic alkyl or C
6-10substituted or non-substituted aryl; Or R
4, R
55-8 unit heterocycle is formed together with nitrogen-atoms; R
4and R
5can not be amido or methoxyl group simultaneously.
2. intermediate according to claim 1, wherein, R
4, R
5five-ring or six-ring is formed together with nitrogen-atoms.
3. intermediate according to claim 1, wherein said hydroxyl protecting group is selected from THP ,-C (O) R
6or-SiR
7r
8r
9, wherein R
6, R
7, R
8and R
9be respectively C separately
1-10straight or branched alkyl, C
3-8cyclic alkyl or C
6-10substituted or non-substituted aryl.
4. the intermediate according to claims 1 to 3 any one, wherein R
4and R
5be selected from hydrogen, methyl, ethyl, propyl group, butyl, phenyl, amido or methoxyl group respectively separately; R
4and R
5can not be amido or methoxyl group simultaneously.
5. intermediate according to claim 4, wherein R
4for ethyl and R
5for hydrogen; Or R
4for hydrogen and R
5for ethyl.
6. prepare a method for the intermediate as shown in structural formula (Ia),
It is characterized in that, by obtained such as formula the intermediate shown in (Ia) by Wittig reaction in the basic conditions for the amide derivatives of the hemiacetal of structural formula (II) and structural formula (III):
Its Chinese style (Ia) and the middle R of formula (II)
2for hydrogen, R
3for hydroxyl protecting group; Formula (Ia) and the middle R of formula (III)
4and R
5be respectively hydrogen, amido, methoxyl group, C separately
1-10straight or branched alkyl, C
3-8cyclic alkyl or C
6-10substituted or non-substituted aryl; Or R
4, R
55-8 unit heterocycle is formed together with nitrogen-atoms; R
4and R
5can not be amido or methoxyl group simultaneously; X in formula (III) is halogen, and Ar is C
6-10substituted or non-substituted aryl.
7. the method for the intermediate of preparation according to claim 6 as shown in structural formula (Ia), its Chinese style (Ia) and the middle R of formula (III)
4, R
5five-ring or six-ring is formed together with nitrogen-atoms.
8. the preparation method according to claim 6 or 7, wherein said hydroxyl protecting group is selected from THP ,-C (O) R
6or-SiR
7r
8r
9, wherein R
6, R
7, R
8and R
9be respectively C separately
1-10straight or branched alkyl, C
3-8cyclic alkyl or C
6-10substituted or non-substituted aryl.
9. the preparation method according to claim 6 or 7, wherein R
2for hydrogen, R
3for TIPS.
10. the preparation method according to claim 6 or 7, wherein R
4and R
5be selected from hydrogen, methyl, ethyl, propyl group, butyl, phenyl, amido or methoxyl group respectively separately; R
4and R
5can not be amido or methoxyl group simultaneously.
11. preparation method according to claim 10, wherein R
4for ethyl and R
5for hydrogen; Or R
4for hydrogen and R
5for ethyl.
12. preparation methods according to claim 6 or 7, X is selected from Cl, Br or I.
13. preparation methods according to claim 6 or 7, wherein Ar is phenyl.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110113844.3A CN102757459B (en) | 2011-04-29 | 2011-04-29 | For the synthesis of the intermediate and preparation method thereof of prostanoid medicine |
| PCT/CN2012/071839 WO2012146085A1 (en) | 2011-04-29 | 2012-03-02 | Intermediate for synthesizing prostaglandin medicines and preparation method therefor |
| TW101109614A TWI532711B (en) | 2011-04-29 | 2012-03-21 | Intermediates useful in the synthesis of prostaglandin drugs and methods for preparing thereof |
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| CN201110113844.3A CN102757459B (en) | 2011-04-29 | 2011-04-29 | For the synthesis of the intermediate and preparation method thereof of prostanoid medicine |
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| CN116332992A (en) * | 2023-03-29 | 2023-06-27 | 厦门大学 | Synthesis and application of quaternary phosphonium salt hydrazide oligosaccharide mass spectrum derivatization reagent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3954741A (en) * | 1972-06-07 | 1976-05-04 | Pfizer Inc. | N-substituted prostaglandin carboxamides |
| AU729318B2 (en) * | 1996-05-28 | 2001-02-01 | Allergan, Inc. | Cyclopentan(en)e heptenoic acid, 2-alkenyl derivatives as therapeutic agents in the treatment of ocular hypertension |
| US6248783B1 (en) * | 2000-09-20 | 2001-06-19 | Allergan Sales, Inc. | Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents |
| CN1639117A (en) * | 2002-03-01 | 2005-07-13 | 阿勒根公司 | Preparation of prostamides |
| WO2010109476A2 (en) * | 2009-01-19 | 2010-09-30 | Matrix Laboratories Ltd | Improved process for the preparation of prostaglandins and analogues thereof |
| IT1393112B1 (en) * | 2009-02-27 | 2012-04-11 | Sifavitor S R L | PROCEDURE FOR THE PREPARATION OF PROSTAGLANDINE DERIVATIVES |
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2011
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| TW201309636A (en) | 2013-03-01 |
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