NO146280B - BIS-TETRAHYDROPYRANYLETERS FOR USE AS INTERMEDIATE FOR PREPARING A PHYSIOLOGY ACTIVE P-BIFENYLESTER OF A PROSTAGLANDIN ANALOGUE OF THE E OR F SERIES - Google Patents
BIS-TETRAHYDROPYRANYLETERS FOR USE AS INTERMEDIATE FOR PREPARING A PHYSIOLOGY ACTIVE P-BIFENYLESTER OF A PROSTAGLANDIN ANALOGUE OF THE E OR F SERIES Download PDFInfo
- Publication number
- NO146280B NO146280B NO743588A NO743588A NO146280B NO 146280 B NO146280 B NO 146280B NO 743588 A NO743588 A NO 743588A NO 743588 A NO743588 A NO 743588A NO 146280 B NO146280 B NO 146280B
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- Prior art keywords
- series
- bis
- biphenyl
- phenyl
- prostaglandins
- Prior art date
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- 150000003180 prostaglandins Chemical class 0.000 title claims description 26
- 230000035479 physiological effects, processes and functions Effects 0.000 title 1
- -1 Ar is α-furyl Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 claims 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 claims 1
- 201000006747 infectious mononucleosis Diseases 0.000 claims 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000002243 precursor Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 230000001766 physiological effect Effects 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 3
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000035558 fertility Effects 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002373 hemiacetals Chemical class 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 1
- WXYYACUWOMKZQC-UHFFFAOYSA-N 1-benzyl-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC=C1 WXYYACUWOMKZQC-UHFFFAOYSA-N 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 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
- 239000003810 Jones reagent Substances 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
- VNWKTOKETHGBQD-AKLPVKDBSA-N carbane Chemical compound [15CH4] VNWKTOKETHGBQD-AKLPVKDBSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- VONWDASPFIQPDY-UHFFFAOYSA-N dimethyl methylphosphonate Chemical compound COP(C)(=O)OC VONWDASPFIQPDY-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 244000239634 longleaf box Species 0.000 description 1
- 230000029860 luteolysis Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 230000035884 vasodepression Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-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
- C07D309/08—Heterocyclic compounds containing six-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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyrane Compounds (AREA)
- Furan Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører nye mellomprodukter The present invention relates to new intermediate products
egnet for fremstilling av visse nye analoger av naturlige forekommende prostaglandiner, særlig de nye 15-substituerte-oj-pentanorprostaglandiner beskrevet i patent nr. 145 437. suitable for the preparation of certain novel analogs of naturally occurring prostaglandins, particularly the novel 15-substituted-oj-pentanor prostaglandins described in Patent No. 145,437.
Prostaglandinene er C-2 0 umettede fettsyrer som har The prostaglandins are C-20 unsaturated fatty acids that have
diverse fysiologiske virkninger. Prostaglandinene av E- og A-seriene er f.eks. kraftige vasodilatatorer (Bergstrom et al., Acta Physiol. Scand. 64:332-33 1965 og Bergstrom et al., Life various physiological effects. The prostaglandins of the E and A series are e.g. powerful vasodilators (Bergstrom et al., Acta Physiol. Scand. 64:332-33 1965 and Bergstrom et al., Life
Sei. 6:449-455, 1967) og senker systemisk arterielt blodtrykk (vasodepresjon) ved intravenøs administrering (Weeks og King, Federation Proe. 23:327, 1964; Bergstrom, et al., 1965 op. eit.; Carlson, et al., Acta Physiol. Scand. 75:161-169, 1969). En annen velkjent fysiologisk virkning av PGE^ og PGE2 er bronko-dilatasjon (Cuthbert, Brit. Med. J. 4:723-726, 1969). Pollock. 6:449-455, 1967) and lowers systemic arterial blood pressure (vasodepression) by intravenous administration (Weeks and King, Federation Proe. 23:327, 1964; Bergstrom, et al., 1965 op. eit.; Carlson, et al. , Acta Physiol. Scand. 75:161-169, 1969). Another well-known physiological action of PGE 2 and PGE 2 is bronchodilation (Cuthbert, Brit. Med. J. 4:723-726, 1969).
En ytterligere viktig fysiologisk rolle for de naturlige prostaglandiner er i forbindelse med forplantningscyklusen. A further important physiological role for the natural prostaglandins is in connection with the reproductive cycle.
PGE2 er kjent for å ha evnen til å fremkalle veer (Karim, et al., J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), å fremkalle terapeutisk abort (Bygdeman, et al., Contraception, 4, 293 (1971) og er nyttig for å regulere fruktbarhet (Karim, Contraception 3, 173 (1971). Det er oppnådd patenter for en rekke prostaglandiner av E- og F-seriene for fremkalling av veer i pattedyr (belgisk patent 754 158 og vest-tysk patent 2 034 641) og når det gjelder anvendelsen av PGF^ F2 og F3 for regulering av fruktbarhets-cyklusen (syd-afrikansk patent 69/6089). Det har vist seg at det kan finne sted luteolyse som et resultat av administreringen av PGF2a [Labhsetwar, Nature 230 528 (1971)] og prostaglandiner kan således anvendes for fruktbarhetsregulering ved hjelp av en fremgangsmåte hvor det ikke er nødvendig med stimulering av glatt muskulatur. PGE2 is known to have the ability to induce labor (Karim, et al., J. Obstet. Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 (1971) and is useful in regulating fertility (Karim, Contraception 3, 173 (1971). Patents have been obtained for a number of prostaglandins of the E and F series for inducing labor in mammals (Belgian patent 754 158 and West German Patent 2 034 641) and regarding the use of PGF^ F2 and F3 for regulation of the fertility cycle (South African Patent 69/6089) It has been shown that luteolysis can occur as a result of the administration of PGF2a [Labhsetwar, Nature 230 528 (1971)] and prostaglandins can thus be used for fertility regulation by means of a method where smooth muscle stimulation is not necessary.
Ytterligere kjente fysiologiske virkninger for PGE^ er Additional known physiological effects for PGE^ are
ved hemningen av mavesyreutskillelsen (Shaw and Ramwell, i: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, s. 55-64) og også ved blodplateagglomereringen (Emmons, et al., Brit. Med. J. 2:468-472, 1967). by the inhibition of gastric acid secretion (Shaw and Ramwell, in: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, pp. 55-64) and also by the platelet agglomeration (Emmons, et al., Brit. Med. J. 2:468 -472, 1967).
Det er nå kjent at slike fysiologiske virkninger bare kan produseres in vivo i korte perioder efter administreringen av et prostaglandin. En stor bevismengde indikerer at grunnen til dette hurtige opphør av virkning er at de naturlige prostaglandinene hurtig og effektivt deaktiveres metabolisk ved 3-oksydasjon av karboksylsyre-sidekjeden og ved oksydasjon av 15o-hydroksylgruppen (Anggard, et al., Acta. Physiol. Scand., It is now known that such physiological effects can only be produced in vivo for short periods after the administration of a prostaglandin. A large body of evidence indicates that the reason for this rapid cessation of action is that the natural prostaglandins are quickly and efficiently deactivated metabolically by 3-oxidation of the carboxylic acid side chain and by oxidation of the 15o-hydroxyl group (Anggard, et al., Acta. Physiol. Scand. ,
81, 396 (1971) og referanser som er angitt der). Det er blitt vist at innføringen av en 15-alkylgruppe i prostaglandinet har den virkningen at den øker varighetsvirkningen sannsynligvis ved å forhindre oksydasjonen av C15-hydroksyl [Yankee og Bundy, JACS 94, 3651 (1972), Kirton and Forbes, Prostaglandins, 1, 81, 396 (1971) and references cited therein). It has been shown that the introduction of a 15-alkyl group into the prostaglandin has the effect of increasing the duration of action probably by preventing the oxidation of the C15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972), Kirton and Forbes, Prostaglandins, 1,
319 (1972)]. 319 (1972)].
Det er selvfølgelig ansett ønskelig å fremstille analoger av prostaglandiner som ville ha fysiologiske virkninger som var ekvivalente med de naturlige forbindelser, men hvor virkningsselektiviteten og virkningsvarigheten var øket. Øket virkningsselektivitet ville forventes å dempe de alvorlige bi-virkninger, spesielt mave- og tarmbivirkninger, som ofte obser-veres efteir systemisk administrering av naturlige prostaglandiner (Lancet, 536, 1971). It is of course considered desirable to produce analogues of prostaglandins which would have physiological effects which were equivalent to the natural compounds, but where the selectivity of action and the duration of action were increased. Increased selectivity of action would be expected to reduce the serious side effects, especially stomach and intestinal side effects, which are often observed after systemic administration of natural prostaglandins (Lancet, 536, 1971).
Det ansees dessuten nødvendig å fremstille forbindelser It is also considered necessary to produce compounds
som lett kan krystalliseres siden isoleringen og rensingen av ikke-krystallinske produkter krever lang tid og er lite effektiv. which can be easily crystallized since the isolation and purification of non-crystalline products requires a long time and is inefficient.
Disse krav imøtekommes av de nye fysiologisk aktive para-bifenylestere av prostaglandinanaloger av E- eller F-serien med formelen These requirements are met by the new physiologically active para-biphenyl esters of prostaglandin analogues of the E or F series with the formula
hvor where
A 0 etr il Ar2, (Cm H2 „e) r n - et elhleer lt -t(aCHll 2 -.) m fr-a OR 21 , thivl or 4, n R e_r er et ahlkeylt l mtaed ll fr<f>a<ra>A 0 etr il Ar2, (Cm H2 „e) r n - et elhleer lt -t(aCHll 2 -.) m fr-a OR 21 , thivl or 4, n R e_r is et ahlkeylt l mtaed ll fr<f>a <ra>
1 til 3 karbonatomer, Ar er a-furyl, Ø-furyl, a-tienyl, |3-tienyl, a-naftyl, &-naftyl, fenyl eller monosubstituert fenyl hvor substituenten er metoksy, metyl eller fenyl, 1 to 3 carbon atoms, Ar is α-furyl, Ø-furyl, α-thienyl, |3-thienyl, α-naphthyl, &-naphthyl, phenyl or monosubstituted phenyl where the substituent is methoxy, methyl or phenyl,
R er para-bifenyl, R is para-biphenyl,
R er hydrogen eller metyl, R is hydrogen or methyl,
W er en enkeltbinding eller cis-dobbeltbinding, W is a single bond or cis-double bond,
Z er en enkeltbinding eller trans-dobbeltbinding, og Z is a single bond or trans-double bond, and
M er okso, Ved en av fremgangsmåtene for fremstilling av de nye forbindelser med formel I ovenfor anvendes nye mellomprodukter, og i henhold til oppfinnelsen tilveiebringes mellomprodukter med formelen hvor A, R, R1, M, W og Z er som angitt ovenfor, og THP er 2-tetrahydropyranyl. M is oxo. In one of the methods for producing the new compounds of formula I above, new intermediates are used, and according to the invention, intermediates of the formula are provided where A, R, R1, M, W and Z are as stated above, and THP is 2-tetrahydropyranyl.
Foretrukne mellomprodukter er 1) en forbindelse med formelen: og 2) en forbindelse med formelen: Preferred intermediates are 1) a compound of the formula: and 2) a compound of the formula:
hvor A, R, Z, W, THP og R"'' er som ovenfor angitt. where A, R, Z, W, THP and R"'' are as indicated above.
Det vil forstås at betegnelsen "prostaglandin av "null"-seriene", f.eks. PGE^, refererer seg til prostaglandin hvor 5-6 og 13-14 dobbeltbindingene er mettede; dvs. PGEQ er 5-6, 13-14-tetrahydro-PGE2. I tillegg refererer betegnelsene "en-seriene" eller "to-seriene" til graden av umettethet i sidekjeden, f.eks. PGE2 og PGF2q, er prostaglandiner av "to-seriene" mens PGE^ og PGF^a er prostaglandiner av "en-seriene". Betegnelsen prostaglandin skal forstås å omfatte begge epimerer ved C^. Dessuten anvendes betegnelsen "lavere alkylgruppe" til alkylgrupper som inneholder fra 1 til 3 karbonatomer. Oppfinnelsen vil lettere forstås ved referanse til de følgende reaksjonsskjemaer som sammen med beskrivelsen illustrerer fremstilling av de nye mellomprodukter ifølge oppfinnelsen og anvendelse av dem ved syntesen av co-pentanorprostaglandiner. It will be understood that the term "prostaglandin of the "zero" series", e.g. PGE^, refers to prostaglandin where the 5-6 and 13-14 double bonds are saturated; i.e. PGEQ is 5-6, 13-14-tetrahydro-PGE2. In addition, the designations "one-series" or "two-series" refer to the degree of unsaturation in the side chain, e.g. PGE2 and PGF2q are prostaglandins of the "two series" while PGE^ and PGF^a are prostaglandins of the "one series". The term prostaglandin should be understood to include both epimers at C^. In addition, the term "lower alkyl group" is used for alkyl groups containing from 1 to 3 carbon atoms. The invention will be more easily understood by reference to the following reaction schemes which, together with the description, illustrate the production of the new intermediates according to the invention and their use in the synthesis of co-pentanor prostaglandins.
Som vist i skjema A er det første trinnet (1 -»■ 2) konden-sasjonen av en egnet ester med et dialkylmetylfosfonat, som gir oksofosfonat 2. Den ønskede metylester kondenseres vanligvis med dimetylmetylfosfonat. As shown in Scheme A, the first step (1-»■ 2) is the condensation of a suitable ester with a dialkylmethylphosphonate, giving oxophosphonate 2. The desired methylester is usually condensed with dimethylmethylphosphonate.
12+3 omsettes oksofosfonatet 2 med det kjente [Corey 12+3 the oxophosphonate 2 is reacted with the known [Corey
et al., J. Am. Chem. Soc. , 93 , 1491 (1971] aldehyd H for å fremstille enonet 3^. et al., J. Am. Chem. Soc. , 93 , 1491 (1971] aldehyde H to prepare the enone 3^.
Efter kromatografi eller krystallisasjon enonet 3_ over-føres til en blanding av tertiære alkoholer _13 og IA ved å omsette det egnede litiumalkyl og de isomere 13 og 14 adskilles ved kolonnekromatografi. Enonet 3_ reduseres med sinkborhydrid til en blanding av alkoholer, 4_ og _5, som kan adskilles som angitt ovenfor. Isomeradskillelsen i dette trinn er ikke abso-lutt nødvendig og den epimere blanding kan føres gjennom de følgende trinn til de resulterende prostaglandinanaloger som derefter kan adskilles. Ved denne reaksjonen anvendes vanligvis etere slik som tetrahydrofuran eller 1,2-dimetoksyetan som løsningsmidler, skjønt metanol er foretrukket av og til for å sikre spesifikk reduksjon. Ytterligere overføringer av £ er vist i skjema B: 4 + 6 er en basekatalysert hydrolyse hvor den beskyttende gruppen for p-bifenyl-karbonyl er fjernet. Dette utføres passende med kaliumkarbonat i metanol ebler metanol-tetrahydrofuran-løsningsmiddel. 6^ ■+ 1_ omfatter beskyttelsen av de to frie hydroksylgruppene med den syrelabile beskyttende gruppe, 2-tetrahydropyranyl, som innføres i molekylet ved behandling med dihydropyran og en syrekatalysator i et vannfritt medium. Katalysatoren er vanligvis p-toluensulfonsyre. After chromatography or crystallization, the enone 3_ is transferred to a mixture of tertiary alcohols _13 and IA by reacting the suitable lithium alkyl and the isomers 13 and 14 are separated by column chromatography. The enone 3_ is reduced with zinc borohydride to a mixture of alcohols, 4_ and _5, which can be separated as indicated above. The isomer separation in this step is not absolutely necessary and the epimeric mixture can be passed through the following steps to the resulting prostaglandin analogues which can then be separated. In this reaction, ethers such as tetrahydrofuran or 1,2-dimethoxyethane are usually used as solvents, although methanol is sometimes preferred to ensure specific reduction. Further transfers of £ are shown in Scheme B: 4 + 6 is a base-catalysed hydrolysis where the p-biphenyl-carbonyl protecting group is removed. This is conveniently carried out with potassium carbonate in methanol or methanol-tetrahydrofuran solvent. 6^ ■+ 1_ comprises the protection of the two free hydroxyl groups with the acid-labile protecting group, 2-tetrahydropyranyl, which is introduced into the molecule by treatment with dihydropyran and an acid catalyst in an anhydrous medium. The catalyst is usually p-toluenesulfonic acid.
7 8 er en reduksjon av laktonet 1_ til hemiacetalet 8^7 8 is a reduction of the lactone 1_ to the hemiacetal 8^
ved å anvende diisobutylaluminiumhydrid i et inert løsnings-middel. Lave reaksjonstemperaturer er foretrukne og -60° by using diisobutylaluminum hydride in an inert solvent. Low reaction temperatures are preferred and -60°
til -70°C er vanlig. Imidlertid kan det anvendes høyere temperaturer dersom det ikke finner sted overreduksjon. 8 renses om ønsket ved kolonnekromatografi. 8 + 9 er en Wittig-kondensasjon hvor hemiacetalet f5 omsettes med (4-karbohydroksy-n-butyl)-trifenylfosfoniumbromid i dimetylsulfoksyd, i nærvær av natriummetylsulfinylmetid. to -70°C is common. However, higher temperatures can be used if overreduction does not take place. 8 is purified if desired by column chromatography. 8 + 9 is a Wittig condensation where the hemiacetal f5 is reacted with (4-carbohydroxy-n-butyl)-triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinyl methide.
9 renses som ovenfor angitt. 9 is cleaned as indicated above.
9 + 10 er en oksydasjon av den sekundære alkohol £ til ketonet 10_. Dette kan utføres ved å anvende oksydasjonsmidler som ikke angriper dobbeltbindingene; imidlertid er det foretrukket å anvende Jones reagens. Produktet renses som ovenfor angitt. 9 + 10 is an oxidation of the secondary alcohol £ to the ketone 10_. This can be done by using oxidizing agents that do not attack the double bonds; however, it is preferred to use Jones reagent. The product is cleaned as indicated above.
Eventuelt kan forbindelsene med formel 5_, 1J3 og 1£ i skjema A anvendes istedenfor 4_ i skjema B for å danne tilsvarende mellomprodukter analoge med forbindelsene 9 og 10. Optionally, the compounds of formula 5_, 1J3 and 1£ in scheme A can be used instead of 4_ in scheme B to form corresponding intermediates analogous to compounds 9 and 10.
Skjema C illustrerer syntesen av forløperne til 13,14-dihydro-15-substituerte- w-pentanorprostaglandiner. 1 3.."*" il i 19<<> reduseres enonet 3^ til tetrahydroforbindelsen ved å anvende komplekse metallhydrider som reduseringsmidler, LiAlH4, NaBH4, KBH^, LiBH^ og Zn(BH4)2. Spesielt foretrukket er NaBH4. Produktene 19. °<3 19.'» avskilles fra hverandre ved kolonnekromatograf i. Scheme C illustrates the synthesis of the precursors of 13,14-dihydro-15-substituted-w-pentanorprostaglandins. 1 3.."*" il in 19<<> the enone 3^ is reduced to the tetrahydro compound by using complex metal hydrides as reducing agents, LiAlH4, NaBH4, KBH^, LiBH^ and Zn(BH4)2. Particularly preferred is NaBH4. The products 19. °<3 19.'» are separated from each other by column chromatograph i.
Forbindelsene 4^ og 5 i skjema A kan dessuten reduseres katalytisk med hydrogen til _19 og 19/ . Det trinnet som dobbeltbindingen reduseres ved er ikke kritisk, og hydreringen av J5 eller 1_ i skjema B vil også gi nyttige mellomprodukter for den påfølgende fremstilling av 13,14-dihydroprostaglandinanaloger. Denne reduksjonen kan oppnås enten med en homogen katalysator slik som tris-(trifenylfosfin)klorrodium I eller med en hetero-gen katalysator slik som platina, palladium eller rhodium. På lignende måte syntetiseres forløperne til 15-lavere alkyl-15-substituerte-cj-pentanorprostaglandiner ved å erstatte _13 og 14 med 4^ og _5 i syntesen som nettop er beskrevet. Overføringen av 1_9, 19', 20' og 20_ følger veien som er vist i skjema B når 4_ er erstattet med lj), _19' , 20' og 20 og man får de relevante 13,14-dihydro-mellomprodukter ifølge oppfinnelsen som inneholder hydrogen eller lavere alkylgruppe ved karbon 15. The compounds 4^ and 5 in scheme A can also be reduced catalytically with hydrogen to _19 and 19/ . The step at which the double bond is reduced is not critical, and the hydrogenation of J5 or 1_ in Scheme B will also provide useful intermediates for the subsequent preparation of 13,14-dihydroprostaglandin analogues. This reduction can be achieved either with a homogeneous catalyst such as tris-(triphenylphosphine)chlororhodium I or with a heterogeneous catalyst such as platinum, palladium or rhodium. In a similar manner, the precursors of 15-lower alkyl-15-substituted-cj-pentanorprostaglandins are synthesized by replacing _13 and 14 with 4^ and _5 in the synthesis just described. The transfer of 1_9, 19', 20' and 20_ follows the pathway shown in scheme B when 4_ is replaced by lj), _19' , 20' and 20 and one obtains the relevant 13,14-dihydro-intermediates according to the invention containing hydrogen or lower alkyl group at carbon 15.
Skjema D illustrerer fremstillingen av forskjellige redu-serte 15-substituerte-u)-pentanorprostaglandin-f or løpere: Scheme D illustrates the preparation of various reduced 15-substituted-u)-pentanorprostaglandin precursors:
19 -*■ 2_2 utføres som illustrert i skjema B for 4_ -»• 9_. 2_2 19 -*■ 2_2 is performed as illustrated in form B for 4_ -»• 9_. 2_2
kan anvendes både som en forløper til et 13,14-dihydro-15-sub-stituert-cQ-pentanorprostaglandin av "2-seriene" eller som et mellomprodukt til 2J3, en forløper til et 13,14-dihydro-15-substituert-03-pentanorprostaglandin av "1-seriene". 22_ •* 23_ utføres ved katalytisk hydrering ved å anvende katalysatoren som er beskrevet for reduksjonen av 4 ■> 19 i skjema C. Mellomproduktene av typen _21 fremstilles ved selektiv hydrogenering av 5,6-cis-dobbeltbindingen ved lav temperatur ved å anvende katalysator slik som de som er beskrevet for 4_ ■+ 1_9. For denne hydrogenering er spesielt foretrukket å anvende palladium på karbon som en katalysator og en reaksjonstemperatur på -20°. Mellomproduktene av typen 21 er ikke bare forløpere til 15-substituerte-w-pentanorprostaglandiner av "1-seriene", men er også forløpere til forbindelsen av typen 2_3 via den veien som er omtalt for 22 -> 2j3. can be used both as a precursor to a 13,14-dihydro-15-substituted-cQ-pentanorprostaglandin of the "2-series" or as an intermediate to 2J3, a precursor to a 13,14-dihydro-15-substituted- 03-pentanorprostaglandin of the "1 series". 22_ •* 23_ is carried out by catalytic hydrogenation using the catalyst described for the reduction of 4 ■> 19 in scheme C. The intermediates of the type _21 are prepared by selective hydrogenation of the 5,6-cis double bond at low temperature using catalyst as such as those described for 4_ ■+ 1_9. For this hydrogenation, it is particularly preferred to use palladium on carbon as a catalyst and a reaction temperature of -20°. The intermediates of type 21 are not only precursors of 15-substituted-w-pentanorprostaglandins of the "1 series", but are also precursors of the compound of type 2_3 via the pathway discussed for 22 -> 2j3.
C-^-epimerene av 21, 2/ 2 og 2_3 kan anvendes som forløpere til 15-epi-seriene av prostaglandinderivatene som beskrevet ovenfor, og 15-lavere-alkyl-15-substituerte-ou-pentanorprostaglandiner som er redusert i 5,6 og/eller 13,14-stillingen og deres C^-epimerer kan fremstilles fra de egnede substituerte analoger av 9^ og 1_9; syntesene av disse følger skjema A og B. The C-^-epimers of 21, 2/ 2 and 2_3 can be used as precursors to the 15-epi series of the prostaglandin derivatives as described above, and 15-lower-alkyl-15-substituted-ou-pentanorprostaglandins which are reduced in 5,6 and/or the 13,14 position and their C 1 -epimers can be prepared from the appropriate substituted analogues of 9 1 and 1 9 ; the syntheses of these follow schemes A and B.
13,14-dihydro-15-lavere-alkyl-15-substituerte-io-pentanorprostaglandiner er tilgjengelig fra de egnede substituerte forløpere via skjema D. 13,14-dihydro-15-lower-alkyl-15-substituted-io-pentanorprostaglandins are available from the appropriate substituted precursors via Scheme D.
Syntesen av de naturlige prostaglandiner er blitt utført The synthesis of the natural prostaglandins has been carried out
av Prof. E. J. Corey og medarbeidere (Corey, et al., J. Amer. Chem. Soc. , 92_, 2586 (1970); og refereanser angitt der), og prostaglandiner fremstilt efter denne reaksjonssekvensen, så-vel som efter andre reaksjonsskjemaer eller isolert fra naturlige materialer er egnet for anvendelse som forløpere til forbindelsene ifølge foreliggende oppfinnelse. by Prof. E. J. Corey et al. (Corey, et al., J. Amer. Chem. Soc. , 92_, 2586 (1970); and references therein), and prostaglandins prepared by this reaction sequence, as well as by other reaction schemes or isolated from natural materials are suitable for use as precursors to the compounds according to the present invention.
Innføringen av p-bifenylgruppen for å fremstille de nye p-bifenylestermellomprodukter ifølge foreliggende oppfinnelse er vist i skjema E som også illustrerer omdannelsen av mellomproduktene til de endelige prostaglandin p-bifenylestere The introduction of the p-biphenyl group to produce the new p-biphenyl ester intermediates according to the present invention is shown in Scheme E which also illustrates the conversion of the intermediates to the final prostaglandin p-biphenyl esters
("PBE"). ("PBE").
p-bifenylgruppen innføres ved hjelp av en forestringsreak-sjon som passende kan utføres ved å bringe den egnede forløper-syre i berøring med 1-10 mol av p-fenylfenol i nærvær av 1-2 The p-biphenyl group is introduced by means of an esterification reaction which can suitably be carried out by bringing the suitable precursor acid into contact with 1-10 mol of p-phenylphenol in the presence of 1-2
mol dicykloheksylkarbodiimid i et reaksjonsinert løsningsmiddel, vanligvis metylenklorid. Som angitt i skjema E, kan 9_ over-føres til 9 PBE ved forestringsreaksjonen som angitt ovenfor og 9 PBE kan overføres til 10 PBE efter de samme metoder som er angitt for overføringen av 9_ til 1_0 som tidligere angitt. moles of dicyclohexylcarbodiimide in a reaction-inert solvent, usually methylene chloride. As indicated in Scheme E, 9_ can be transferred to 9 PBE by the esterification reaction as indicated above and 9 PBE can be transferred to 10 PBE by the same methods indicated for the transfer of 9_ to 1_0 as previously indicated.
Forbindelsene 10 PBE og 9 PBE kan omdannes til henholdsvis 11 PBE og 12 PBE ved sur hydrolyse av tetrahydropyranylgruppene. Det kan anvendes en hvilken som helst syre som ikke medfører nedbrytning av molekylet mens beskyttelsesgruppen fjernes, men vanligvis anvendes 65 %ig vandig eddiksyre. Produktet renses ved kolonnekromatografi som beskrevet ovenfor. The compounds 10 PBE and 9 PBE can be converted into 11 PBE and 12 PBE respectively by acid hydrolysis of the tetrahydropyranyl groups. Any acid that does not cause breakdown of the molecule while the protecting group is removed can be used, but usually 65% aqueous acetic acid is used. The product is purified by column chromatography as described above.
p-bifenylestere slik som 9 PBE, 10 PBE, 11 PBE og 12 PBE kan anvendes som substrater for forskjellige hydrogenerings-skjemaer som tidligere er beskrevet for fremstillingen av prostaglandinanalogene av "en" og "null"-seriene for å fremstille de tilsvarende p-bifenylesterne av "en" og "null"-seriene. p-biphenyl esters such as 9 PBE, 10 PBE, 11 PBE and 12 PBE can be used as substrates for various hydrogenation schemes previously described for the preparation of the prostaglandin analogues of the "one" and "zero" series to prepare the corresponding p- the biphenyl esters of the "one" and "zero" series.
Dersom man ved de foregående fremgangsmåter ønsker å If, by the previous procedures, you want to
rense ved hjelp av kromatografi er egnede kromatografiske bærere nøytral aluminiumoksyd og silikagel, og 60-200 mesh silikagel er vanligvis foretrukne. Kromatografi utføres passende i reaksjonsinerte løsningsmidler slik som eter, etyl-acetat, benzen, kloroform, metylenklorid, cykloheksan eller n-héksan. purify by chromatography, suitable chromatographic supports are neutral alumina and silica gel, and 60-200 mesh silica gel is usually preferred. Chromatography is suitably carried out in reaction-inert solvents such as ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane or n-hexane.
Det vil fremgå at formlene angir optisk aktive forbindelser. Det fremgår imidlertid klart at de tilsvarende racemater også er nyttige for å danne endelige prostaglandin-racemater som har verdifull biologisk virkning på grunn av innholdet av den biologisk aktive optiske isomer, og slike racemater om-fattes også av de foregående formler og av kravene. Racemat-blandingene fremstilles lett efter de samme metoder som anvendes for å syntetisere de optisk aktive forbindelser ved bare å anvende de tilsvarende racemiske forløpere istedenfor de optisk aktive utgangsmaterialer. It will be seen that the formulas indicate optically active compounds. However, it is clear that the corresponding racemates are also useful for forming final prostaglandin racemates which have valuable biological action due to the content of the biologically active optical isomer, and such racemates are also covered by the preceding formulas and by the claims. The racemate mixtures are easily prepared by the same methods used to synthesize the optically active compounds by simply using the corresponding racemic precursors instead of the optically active starting materials.
De følgende eksempler er angitt for å illustrere oppfinnelsen. I eksemplene er alle temperaturer angitt i °C, og alle smelte-punkter er ukorrigerte. The following examples are given to illustrate the invention. In the examples, all temperatures are given in °C, and all melting points are uncorrected.
Eksempel 1 Example 1
p- bif enyl- 9- okso- lla, 15ot- bis- ( tetrahydropyran- 2- yloksy) - 16- f enyl-cis- 5- trans- 13- 6o- tetranorprostadienoat p-biphenyl-9-oxol-lla, 15o- bis-(tetrahydropyran-2- yloxy)-16- phenyl-cis- 5- trans- 13- 6o- tetranorprostadienoate
En løsning av 9-okso-lla,15a-bis-(tetrahydropyran-2-yloksy)-16-fenyl-cis-5-trans-13-(D-tetranorprostadiensyre (10a) (1 ekvivalent) , p-fenylfenol (10 ekvivalenter) og dicykloheksylkarbodiimid (1,25 ekvivalenter) i metylenklorid omrøres natten over, konsentreres (i vakuum) og renses ved kolonnekromatografi, og man får p-bifenyl-9-okso-lla-15a-bis-(tetrahydropyran-2-yloksy)-16-f enyl-cis-5-trans-13-u)-tetranor-prostadienoat. A solution of 9-oxo-11a,15a-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-(D-tetranorprostadic acid (10a) (1 equivalent), p-phenylphenol (10 equivalents) and dicyclohexylcarbodiimide (1.25 equivalents) in methylene chloride are stirred overnight, concentrated (in vacuo) and purified by column chromatography to give p-biphenyl-9-oxo-lla-15a-bis-(tetrahydropyran-2-yloxy) -16-phenyl-cis-5-trans-13-u)-tetranor-prostadienoate.
Uten separering hydrolyseres produktet med 65 %ig vandig eddiksyre for å danne p-bifenyl-9-okso-lla,15a-dihydroksy-16-fenyl-cis-5-trans-13-w-tetranorprostadienoat, sm.p. 120-121°C (eter-pentan), IR-spektra, massespektra og UV spektra var i overensstemmelse med strukturen. Without separation, the product is hydrolyzed with 65% aqueous acetic acid to form p-biphenyl-9-oxo-lla,15a-dihydroxy-16-phenyl-cis-5-trans-13-w-tetranorprostadienoate, m.p. 120-121°C (ether-pentane), IR spectra, mass spectra and UV spectra were consistent with the structure.
Ved å anvende fremgangsmåten ovenfor kan på lignende måte oppnås de andre 15-substituerte-o)-pentanorprostaglandin-p-bifenylestere av E-serien ifølge foreliggende oppfinnelse ved å erstatte forbindelsen 10a i eksemplet ovenfor med det passende 11,15-bis-(tetrahydropyran-2-yloksy)-15-substituert-ui-pentanor-prostaglandin. By applying the above procedure, the other 15-substituted-o)-pentanorprostaglandin-p-biphenyl esters of the E series according to the present invention can be obtained in a similar manner by replacing compound 10a in the above example with the appropriate 11,15-bis-(tetrahydropyran -2-yloxy)-15-substituted-ui-pentanor-prostaglandin.
Eksempel 2 Example 2
p- bifenyl- 9a- hydroksy- lla, 15a- bis-( tetrahydropyran- 2- yloksy)-16- f enyl- cis- 5- trans- 13- 0)- tetranorpro stad ierioat p- biphenyl- 9a- hydroxy- lla, 15a- bis-(tetrahydropyran-2- yloxy)-16- phenyl- cis- 5- trans- 13- 0)- tetranorprostad ierioate
En løsning av 9a-hydroksy-lla, 15tx-bis-(tetrahydropyran-2-yloksy) -16-f enyl-cis-5-trans-13-to-tetranorprostadiensyre (9a) (1 ekvivalent), p-fenylfenol (10 ekvivalenter) og dicyklo-heksyl-karbodiimid (1,25 ekvivalenter) i metylenklorid omrøres natten over, konsentreres (i vakuum) og renses ved kolonnekromatograf i og man får p-bifenyl-9a-hydroksy-lla, 15ci-bis-(tetrahydropyran-2-yloksy) -16-f enyl-cis-5-trans-13-u)-tetranor-prostadienoat. A solution of 9a-hydroxy-lla, 15tx-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-to-tetranorprostadic acid (9a) (1 equivalent), p-phenylphenol (10 equivalents) and dicyclohexylcarbodiimide (1.25 equivalents) in methylene chloride are stirred overnight, concentrated (in vacuo) and purified by column chromatography to give p-biphenyl-9a-hydroxy-lla, 15ci-bis-(tetrahydropyran- 2-yloxy)-16-phenyl-cis-5-trans-13-u)-tetranor-prostadienoate.
Ved å anvende fremgangsmåtene ovenfor kan man på lignende måte oppnå andre 15-substituerte-a)-pentanorprostaglandin-p-bifenylestere ifølge foreliggende oppfinnelse ved å erstatte forbindelsen 9a i eksemplet ovenfor med det egnede 11,15-bis-(tetrahydropyran-2-yloksy)-15-substituert-(D-pentanorprosta-glandin. By using the above methods, other 15-substituted-a)-pentanorprostaglandin-p-biphenyl esters according to the present invention can be obtained in a similar way by replacing compound 9a in the example above with the suitable 11,15-bis-(tetrahydropyran-2-yloxy )-15-substituted-(D-pentanorprostaglandin.
Uten separering hydrolyseres produktet med 65 %ig vandig eddiksyre for å danne p-bifenyl-9a,lia,15a-trihydroksy-16-fenyl-cis-5-trans-1 3-cj-tetranorprostadienoat, sm.p. 117-119°C. Without separation, the product is hydrolyzed with 65% aqueous acetic acid to form p-biphenyl-9a,11a,15a-trihydroxy-16-phenyl-cis-5-trans-1 3-cj-tetranorprostadienoate, m.p. 117-119°C.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US30481572A | 1972-11-08 | 1972-11-08 |
Publications (3)
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NO743588L NO743588L (en) | 1974-05-09 |
NO146280B true NO146280B (en) | 1982-05-24 |
NO146280C NO146280C (en) | 1982-09-01 |
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Application Number | Title | Priority Date | Filing Date |
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NO4290/73A NO145437C (en) | 1972-11-08 | 1973-11-07 | ANALOGY PROCEDURE FOR PREPARING A PHYSIALLY ACTIVE P-BIFENYLESTER OF A PROSTAGLANDIN ANALOGUE OF THE E OR F SERIES |
NO743588A NO146280C (en) | 1972-11-08 | 1974-10-03 | BIS-TETRAHYDROPYRANYLETERS FOR USE AS INTERMEDIATE FOR PREPARING A PHYSIOLOGY ACTIVE P-BIFENYLESTER OF A PROSTAGLANDIN ANALOGUE OF THE E OR F SERIES |
Family Applications Before (1)
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NO4290/73A NO145437C (en) | 1972-11-08 | 1973-11-07 | ANALOGY PROCEDURE FOR PREPARING A PHYSIALLY ACTIVE P-BIFENYLESTER OF A PROSTAGLANDIN ANALOGUE OF THE E OR F SERIES |
Country Status (24)
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JP (1) | JPS5644068B2 (en) |
AR (2) | AR204816A1 (en) |
AT (1) | AT347607B (en) |
BE (1) | BE807047A (en) |
CA (1) | CA1027559A (en) |
CH (1) | CH601222A5 (en) |
CS (1) | CS188175B2 (en) |
DD (2) | DD111370A5 (en) |
DE (2) | DE2365999A1 (en) |
ES (2) | ES420326A1 (en) |
FI (1) | FI58116C (en) |
FR (2) | FR2205339B1 (en) |
GB (1) | GB1456511A (en) |
HU (2) | HU171818B (en) |
IE (1) | IE39686B1 (en) |
IL (1) | IL43553A (en) |
IN (1) | IN139905B (en) |
NL (1) | NL7315240A (en) |
NO (2) | NO145437C (en) |
PH (2) | PH15504A (en) |
SE (2) | SE420198B (en) |
SU (2) | SU538659A3 (en) |
YU (2) | YU287973A (en) |
ZA (1) | ZA738593B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2361410A1 (en) * | 1972-07-13 | 1978-03-10 | Pfizer | DIALKYL ALKYLPHOSPHONATES, USEFUL AS PROSTAGLANDIN SYNTHESIS INTERMEDIARIES |
US3929862A (en) * | 1974-01-08 | 1975-12-30 | Upjohn Co | Substituted tolylesters of PGF{HD 2{B {60 |
US3998869A (en) * | 1974-11-14 | 1976-12-21 | The Upjohn Company | Substituted anilide esters of 16-substituted PGE2 |
DE2737807A1 (en) * | 1976-08-27 | 1978-03-09 | Pfizer | C LOW 1 -P-BIPHENYLESTER OF OMEGA-PENTANORPROSTAGLANDINES |
US6531504B2 (en) * | 2001-05-17 | 2003-03-11 | Allergan, Inc. | Prostanoic acid derivatives as agents for lowering intraocular pressure |
-
1973
- 1973-01-01 AR AR250900A patent/AR204816A1/en active
- 1973-11-01 GB GB5088973A patent/GB1456511A/en not_active Expired
- 1973-11-01 SE SE7314885A patent/SE420198B/en unknown
- 1973-11-02 IL IL43553A patent/IL43553A/en unknown
- 1973-11-03 DE DE2365999A patent/DE2365999A1/en not_active Withdrawn
- 1973-11-03 DE DE19732355042 patent/DE2355042A1/en not_active Withdrawn
- 1973-11-06 IN IN2443/CAL/73A patent/IN139905B/en unknown
- 1973-11-07 CA CA185,201A patent/CA1027559A/en not_active Expired
- 1973-11-07 FI FI3444/73A patent/FI58116C/en active
- 1973-11-07 AT AT937173A patent/AT347607B/en not_active IP Right Cessation
- 1973-11-07 NL NL7315240A patent/NL7315240A/xx not_active Application Discontinuation
- 1973-11-07 NO NO4290/73A patent/NO145437C/en unknown
- 1973-11-07 ES ES420326A patent/ES420326A1/en not_active Expired
- 1973-11-07 YU YU02879/73A patent/YU287973A/en unknown
- 1973-11-08 HU HU73PI00000400A patent/HU171818B/en unknown
- 1973-11-08 IE IE2013/73A patent/IE39686B1/en unknown
- 1973-11-08 PH PH15198A patent/PH15504A/en unknown
- 1973-11-08 ZA ZA738593A patent/ZA738593B/en unknown
- 1973-11-08 JP JP12501173A patent/JPS5644068B2/ja not_active Expired
- 1973-11-08 CS CS737670A patent/CS188175B2/en unknown
- 1973-11-08 BE BE1005489A patent/BE807047A/en unknown
- 1973-11-08 HU HU73PI00000453A patent/HU171945B/en unknown
- 1973-11-08 FR FR7339759A patent/FR2205339B1/fr not_active Expired
- 1973-11-08 CH CH1570273A patent/CH601222A5/xx not_active IP Right Cessation
- 1973-11-08 DD DD174537A patent/DD111370A5/xx unknown
- 1973-11-08 DD DD180196*A patent/DD113211A5/xx unknown
- 1973-11-11 SU SU1971421A patent/SU538659A3/en active
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1974
- 1974-07-31 AR AR254983A patent/AR202311A1/en active
- 1974-10-03 NO NO743588A patent/NO146280C/en unknown
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1975
- 1975-02-13 ES ES434687A patent/ES434687A1/en not_active Expired
- 1975-03-20 SU SU752115232A patent/SU1021340A3/en active
- 1975-08-18 FR FR7525565A patent/FR2275452A1/en active Granted
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1976
- 1976-03-12 PH PH18199A patent/PH13794A/en unknown
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1977
- 1977-04-15 SE SE7704369A patent/SE7704369L/en not_active Application Discontinuation
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1980
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