NO138905B - PROCEDURES FOR THE PREPARATION OF 2- (6-CARBALCOXYHEXYL) -4 (R) -HYDROXYCYCLOPENT-2 ENONES - Google Patents
PROCEDURES FOR THE PREPARATION OF 2- (6-CARBALCOXYHEXYL) -4 (R) -HYDROXYCYCLOPENT-2 ENONES Download PDFInfo
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- NO138905B NO138905B NO4495/73A NO449573A NO138905B NO 138905 B NO138905 B NO 138905B NO 4495/73 A NO4495/73 A NO 4495/73A NO 449573 A NO449573 A NO 449573A NO 138905 B NO138905 B NO 138905B
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- Prior art keywords
- enol
- ether
- ester
- substituted
- solution
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- 238000000034 method Methods 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title claims description 8
- -1 enol ester Chemical class 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 27
- 150000002084 enol ethers Chemical class 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 8
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- RZKYEQDPDZUERB-UHFFFAOYSA-N Pindone Chemical group C1=CC=C2C(=O)C(C(=O)C(C)(C)C)C(=O)C2=C1 RZKYEQDPDZUERB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001351 alkyl iodides Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 150000003180 prostaglandins Chemical class 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000005917 acylation reaction Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 230000010933 acylation Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 230000006179 O-acylation Effects 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 230000002997 prostaglandinlike Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 238000010934 O-alkylation reaction Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000005837 enolization reaction Methods 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- BUZZUHJODKQYTF-UHFFFAOYSA-N 1-iodo-3-methylbutane Chemical compound CC(C)CCI BUZZUHJODKQYTF-UHFFFAOYSA-N 0.000 description 2
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910014033 C-OH Inorganic materials 0.000 description 2
- 229910014570 C—OH Inorganic materials 0.000 description 2
- 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 2
- 238000004458 analytical method Methods 0.000 description 2
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- IXOFUWJRSYPKSX-JTQLQIEISA-N 7-[(3r)-3-hydroxy-5-oxocyclopenten-1-yl]heptanoic acid Chemical class O[C@@H]1CC(=O)C(CCCCCCC(O)=O)=C1 IXOFUWJRSYPKSX-JTQLQIEISA-N 0.000 description 1
- 241000235349 Ascomycota Species 0.000 description 1
- 101100219382 Caenorhabditis elegans cah-2 gene Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- GFDUVCZENPTREI-UHFFFAOYSA-N cyclohexylmethyl-[(2-methoxyphenyl)methyl]phosphane Chemical compound COC1=CC=CC=C1CPCC1CCCCC1 GFDUVCZENPTREI-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- OIMNNAXGHPCXMA-UHFFFAOYSA-N methyl 7-(3-hydroxy-2,5-dioxocyclopentyl)heptanoate Chemical compound COC(=O)CCCCCCC1C(=O)CC(O)C1=O OIMNNAXGHPCXMA-UHFFFAOYSA-N 0.000 description 1
- OIMNNAXGHPCXMA-HCCKASOXSA-N methyl 7-[(3r)-3-hydroxy-2,5-dioxocyclopentyl]heptanoate Chemical compound COC(=O)CCCCCCC1C(=O)C[C@@H](O)C1=O OIMNNAXGHPCXMA-HCCKASOXSA-N 0.000 description 1
- PQKUWAVOSCVDCT-NSHDSACASA-N methyl 7-[(3r)-3-hydroxy-5-oxocyclopenten-1-yl]heptanoate Chemical compound COC(=O)CCCCCCC1=C[C@H](O)CC1=O PQKUWAVOSCVDCT-NSHDSACASA-N 0.000 description 1
- DDISSBMAPPWCRQ-CYBMUJFWSA-N methyl 7-[(4r)-4-hydroxy-5-oxo-2-propan-2-yloxycyclopenten-1-yl]heptanoate Chemical compound COC(=O)CCCCCCC1=C(OC(C)C)C[C@@H](O)C1=O DDISSBMAPPWCRQ-CYBMUJFWSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000005227 renal system Anatomy 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000000717 retained 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
- 150000003839 salts Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av 2-(6-car"balkoxyhexyl)-4 (R) -hydroxy-cyclopent-2-en-oner som er nøkkelforbindelser ved fremstilling av prostaglandiner eller prostaglandinlignende forbindelser. The present invention relates to a method for the production of 2-(6-carboxyhexyl)-4 (R)-hydroxy-cyclopent-2-en-ones which are key compounds in the production of prostaglandins or prostaglandin-like compounds.
Spesielt angår oppfinnelsen fremgangsmåte ved fremstilling av 2-(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopenten-l-on, In particular, the invention relates to a process for the production of 2-(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopenten-1-one,
en forbindelse som er en nøkkelforbindelse ved fremstilling av prostaglandiner. a compound that is a key compound in the production of prostaglandins.
Symbolet R som anvendt her angir den stereokjemiske konfigurasjon til en forbindelse som definert i Cahn-Ingold-Prelog nomenclatursystemet. The symbol R as used herein denotes the stereochemical configuration of a compound as defined in the Cahn-Ingold-Prelog nomenclature system.
Prostaglandinene som er cycliske, oxygenerte C2Q-fettsy-rer basert på prostansyreskjelettet, er antatt å spille en viktig rolle som terapeutiske midler på grunn av det store antall fysio-logiske responser de fremkaller i det cardiovaskulære system, i det sentrale og perifere nervesystem, i forplantningssystemet, det endocrine-, renale- og gastrointestinale system ved administrering til dyr innbefattet mennesket. Forrådet av disse materialer er for tiden meget begrenset, og de foreslåtte metoder for fremstilling av disse medfører bruk av tidkrevende spaltningsmetoder for å oppnå de ønskede optisk aktive forbindelser. The prostaglandins, which are cyclic, oxygenated C2Q fatty acids based on the prostanic acid skeleton, are believed to play an important role as therapeutic agents due to the large number of physiological responses they elicit in the cardiovascular system, in the central and peripheral nervous system, in the reproductive system, the endocrine, renal and gastrointestinal system when administered to animals including humans. The supply of these materials is currently very limited, and the proposed methods for producing them involve the use of time-consuming cleavage methods to obtain the desired optically active compounds.
Målet med denne oppfinnelse er å tilveiebringe en fremgangsmåte ved fremstilling av kirale forbindelser som er nøkkel-forbindelser ved fremstilling av prostaglandiner eller prostaglandinlignende forbindelser. The aim of this invention is to provide a method for the production of chiral compounds which are key compounds in the production of prostaglandins or prostaglandin-like compounds.
Oppfinnelsen angår således en fremgangsmåte ved fremstilling av 2-(6-carbalkoxyhexyl)-4(R)-hydroxy-cyclopent-2-enon av formelen The invention thus relates to a process for the production of 2-(6-carbalkoxyhexyl)-4(R)-hydroxy-cyclopent-2-enone of the formula
hvori R er en alkylgruppe med 1-2 carbonatomer, hvilken fremgangsmåte er kjennetegnet ved at a) et 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopentan-1,3-dion av formelen: in which R is an alkyl group with 1-2 carbon atoms, which method is characterized by a) a 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopentane-1,3-dione of the formula:
omsettes med et alkyliodid av formelen: is reacted with an alkyl iodide of the formula:
R'I RIDE
hvori R' er en isoamyl, isopropyl, isobutyl eller pivalylgruppe, under dannelse av en C-l og en C-3 enolether av formlene: wherein R' is an isoamyl, isopropyl, isobutyl or pivalyl group, forming a C-1 and a C-3 enol ether of the formulas:
eller med benzoylklorid under dannelse av en C-l og C-3 enolester av formlene: or with benzoyl chloride to form a C-1 and C-3 enol ester of the formulas:
hvor R" er fenyl, where R" is phenyl,
b) C-l enoletheren henholdsvis esteren separeres fra C-3 enoletheren- eller esteren, c) den fremstillede C-l substituerte enolester eller ether reduseres, og d) 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopent-2-enon utvinnes fra reaksjonsblandingen. b) the C-1 enol ether or ester is separated from the C-3 enol ether or ester, c) the produced C-1 substituted enol ester or ether is reduced, and d) 2-(6-carbalkoxyhexyl)-4(R)-hydroxycyclopent-2-enone is recovered from the reaction mixture.
Tidligere har R. Pappo et al. (Annals of the New York Academy of Sciences, Vol. 180, s. 64 (1971)) vist følgende metode for fremstilling av methylenoletheren fra 2-(6<1->carbomethoxyhexyl)-4-hydroxy-cyclopenten-l,3-dion: Previously, R. Pappo et al. (Annals of the New York Academy of Sciences, Vol. 180, p. 64 (1971)) showed the following method for the preparation of methyleneol ether from 2-(6<1->carbomethoxyhexyl)-4-hydroxy-cyclopentene-1,3- Dion:
Denne prosedyre ble utført ved å koke hydroxydionesteren (A) under tilbakeløp med dimethoxypropan under sure betingelser under dannelse av de to angitte isomere enolestere (B og C). This procedure was carried out by refluxing the hydroxydionester (A) with dimethoxypropane under acidic conditions to form the two indicated isomeric enol esters (B and C).
Ulempene ved den av Pappo et al. beskrevne fremgangsmåte er: (1) den gir bare ca. 40 % av den ønskede C-l enolether (C), og (2) det asymmetriske senter ved C-4 ødelegges. The disadvantages of the one by Pappo et al. described procedure is: (1) it only gives approx. 40% of the desired C-1 enol ether (C), and (2) the asymmetric center at C-4 is destroyed.
Den siste ulempe er meget alvorlig ved prostaglandinfrem-stilling under anvendelse av 1,4-addisjonsreaksjoner, da stereokjemien til prostansyreskjelettet (C-8 og C-12-stillingene i prostaglandinene) dikteres av stereokjemien ved C-4. The last disadvantage is very serious in prostaglandin preparation using 1,4-addition reactions, as the stereochemistry of the prostanic acid skeleton (the C-8 and C-12 positions in the prostaglandins) is dictated by the stereochemistry at C-4.
Fremgangsmåten ifølge oppfinnelsen medfører ikke de ulem-per som Pappo et al. prosessen er beheftet med. Det viktigste er at fremgangsmåten ifølge oppfinnelsen tillater at det asymmetriske senter ved C-4 bibeholdes slik at det dannede 2-substituert-4-hydr-oxy-2-cyclopenten-l-on er kiral, et vesentlig trekk for hvordan prostaglandinene skal fremstilles. I tillegg aktiverer fremgangsmåten ifølge oppfinnelsen preferentielt acy-lering eller alkylering av oxygenatomet ved C-l stillingen i molekylet den molekylære konfigurasjon som er._ønsket for den etterfølgende reduksjon til den ønskede forbindelse, nemlig 2-(6-carbalkoxvhexyl)-4(R)-hydr-oxy-cyclopent-2-enon. The method according to the invention does not entail the disadvantages that Pappo et al. the process is fraught with. The most important thing is that the method according to the invention allows the asymmetric center at C-4 to be retained so that the formed 2-substituted-4-hydroxy-2-cyclopenten-1-one is chiral, an essential feature for how the prostaglandins are to be produced. In addition, the method according to the invention preferentially activates acylation or alkylation of the oxygen atom at the C-1 position in the molecule the molecular configuration that is desired for the subsequent reduction to the desired compound, namely 2-(6-carbalcoxyl)-4(R)-hydr -oxy-cyclopent-2-enone.
Selvom man ikke vil bindes til teoretiske betraktninger, er det antatt at en moderat massiv gruppe må anvendes ved acyler-inq slik at acylerinqen ved sterisk hindring fortrinnsvis skjer ved oxyqenerinq av C-l stillinq. Likeledes er det antatt at 0-al-kvlerinqen ved C-l favoriseres under basiske betinqelser, oq at størrelsen av den alkylerende qruppe er av mindre betydninq enn ved acylerinqen. I alle tilfeller ble det fvftmet at de ovenfor an-qitte betinqelser tillater bibeholdelse av det asymmetriske senter ved C-4, oq at der ikke skjer noen racematdannelse. Although one does not want to be bound by theoretical considerations, it is assumed that a moderately massive group must be used for acylation so that the acylation by steric hindrance preferably takes place by oxyqenerinq of C-1 stillinq. Likewise, it is assumed that the 0-al-quelation at C-1 is favored under basic conditions, and that the size of the alkylating group is of less importance than in the case of acylation. In all cases, it was found that the above-mentioned conditions allow retention of the asymmetric center at C-4, and that no racemate formation occurs.
Den asymmetriske reduksjon av 2-substituerte cyclopen-tan-l,3,4-trion til det tilsvarende 2-substituerte-4(R)-hydroxy-cyclopentan-l,3-dion utføres ved katalytisk hydroqenerinq i nærvær av et rhodiumkompleks med en kiral fosfinkjede (liqand) som katalysator. (Katalysatorer av denne type er beskrevet i Chem. Soc, Chem. Comm., 19, (1972) av W.S. Knowles et al.). Den foretrukne Katalysator ved denne fremgangsmåte kan betegnes som I^Rl^COD BF^~ The asymmetric reduction of 2-substituted cyclopentane-1,3,4-trione to the corresponding 2-substituted-4(R)-hydroxy-cyclopentane-1,3-dione is carried out by catalytic hydrogenation in the presence of a rhodium complex with a chiral phosphine chain (liqand) as catalyst. (Catalysts of this type are described in Chem. Soc, Chem. Comm., 19, (1972) by W.S. Knowles et al.). The preferred Catalyst in this method can be designated as I^Rl^COD BF^~
(tilgjengelig fra Monsanto Co., St.Louis, Mo., under typebeteg-nelsen CP71327), hvor L indikerer o-anisylcyclohexylmethylfosfin, og COD indikerer 1,5-cyclooctadien. (available from Monsanto Co., St.Louis, Mo., under the type designation CP71327), where L indicates o-anisylcyclohexylmethylphosphine, and COD indicates 1,5-cyclooctadiene.
En metode for hydrogenering av 2(6-carbomethoxyhexyl)-cyclopentan-l,3,4-trion under anvendelse av den foretrukne katalysator er angitt i det etterfølgende: Fremstilling av 2-(6-carbomethoxyhexyl)-4(R)-hydroxy-cyclopentan-1,3-dion 5,0 g 2(6-carbomethoxyhexyl)-cyclopentan-1,3,4-trion, 95,8 mg av den angitte katalysator og 2,78 ml triethylamin ble oppløst i 35 ml methanol og underkastet hydrogenering ved en at-mosfære. Efter at 92,6 % av den teoretiske mengde hydrogen var forbrukt, ble reaksjonen avsluttet ved at hydrogeneringsreaksjons-blandingen ble heldt over i HCl-I^O (ca. pH 2). Den resulterende blanding ble ekstrahert tre ganger med ethylacetat, de organiske lag ble fraskilt og vasket med natriumbicarbonatoppløsning (5 % oppløsning) inntil ingen farve var synlig i den vandige fase. De kombinerte bicarbonatekstrakter ble ekstrahert med ethylacetat, det resulterende gule vandige lag ble forsiktig surgjort til pH 2 med saltsyre og ekstrahert med ethylacetat. Det organiske lag ble fraskilt, tørket over Na2S0^ og fordampet til tørrhet. Det tørkede materiale ble oppløst i ethylacetat og derefter krystal-lisert fra dette, hvorved der ble erholdt 1,7 g produkt (34 % ut-bytte med følgende karakteristika: UV A JJ^°jj 272 nm ( £ 24 000), CDA281 nm, 6 = -58,3 x.IO<3>, 9 = A method for the hydrogenation of 2(6-carbomethoxyhexyl)-cyclopentane-1,3,4-trione using the preferred catalyst is set forth below: Preparation of 2-(6-carbomethoxyhexyl)-4(R)-hydroxy- cyclopentane-1,3-dione 5.0 g of 2(6-carbomethoxyhexyl)-cyclopentane-1,3,4-trione, 95.8 mg of the indicated catalyst and 2.78 ml of triethylamine were dissolved in 35 ml of methanol and subjected to hydrogenation at one atmosphere. After 92.6% of the theoretical amount of hydrogen had been consumed, the reaction was terminated by pouring the hydrogenation reaction mixture into HCl-I^O (approx. pH 2). The resulting mixture was extracted three times with ethyl acetate, the organic layers were separated and washed with sodium bicarbonate solution (5% solution) until no color was visible in the aqueous phase. The combined bicarbonate extracts were extracted with ethyl acetate, the resulting yellow aqueous layer was carefully acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, dried over Na 2 SO 4 and evaporated to dryness. The dried material was dissolved in ethyl acetate and then crystallized from this, whereby 1.7 g of product was obtained (34% yield with the following characteristics: UV A JJ^°jj 272 nm ( £ 24,000), CDA 281 nm , 6 = -58.3 x.IO<3>, 9 =
+60 x IO<3> ved A 262 nm (68 % ootisk renhet). Svmbolet UV betea-ner ultrafiolett, og CD betegner sirkeldikroisme. En annen mengde (1,6 %) viste ingen optisk aktivitet, filtratet praktisk talt ingen optisk aktivitet. +60 x IO<3> at A 262 nm (68% otic purity). The symbol UV stands for ultraviolet, and CD stands for circular dichroism. Another amount (1.6%) showed no optical activity, the filtrate practically no optical activity.
Trionmethylesteren anvendt som utgangsmateriale ved den ovenfor angitte hydrogeneringsreaksjon kan lett erholdes fra den tilsvarende trionsyre ifølge følgende fremgangsmåte, trionsyren kan lett erholdes efter den av Pappo et al. angitte metode: The trione methyl ester used as starting material in the hydrogenation reaction indicated above can be easily obtained from the corresponding trionic acid according to the following method, the trionic acid can be easily obtained according to that of Pappo et al. set method:
En blanding av 1 g trionsyre, 2 ml methanol, 0,2 ml kon-sentrert HC1 og 2,5 ml dimethoxypropan fikk stå ved romtemperatur over natten. Oppløsningen ble derefter fordampet til tørrhet (rotasjonsfordamper), og residuet ble oppløst i 10 ml ethylacetat. Ethylacetatlaget ble eks trahert med en mettet NaHCO-^-oppløsning (2 x 15 ml). Bicarbonatoppløsningen ble surgjort og ekstrahert med ethylacetat (4 x 25 ml). Denne ekstrakt ble vasket med en mettet NaCl-oppløsning og tørket over MgS04. Fordampning av opp-løsningsmidlet ga en rødaktig olje som stivnet ved henstand under dannelse av et gult, fast materiale (tilsetning av en krystall av trionmethylesteren lettet stivningsprosessen). A mixture of 1 g of trionic acid, 2 ml of methanol, 0.2 ml of concentrated HCl and 2.5 ml of dimethoxypropane was allowed to stand at room temperature overnight. The solution was then evaporated to dryness (rotary evaporator), and the residue was dissolved in 10 ml of ethyl acetate. The ethyl acetate layer was extracted with a saturated NaHCO 3 solution (2 x 15 mL). The bicarbonate solution was acidified and extracted with ethyl acetate (4 x 25 mL). This extract was washed with a saturated NaCl solution and dried over MgSO 4 . Evaporation of the solvent gave a reddish oil which solidified on standing to form a yellow solid (addition of a crystal of the trione methyl ester facilitated the solidification process).
Alternativt kan dionet fremstilles mikrobiologisk, som beskrevet i norsk ålment tilgjengelig søknad 3795/73 med priori-tet fra 29.september 1972, ved å underkaste 2-substituert-cyclo-penten-1,3,4-trion eller 2-substituert-3-alkoxy-2-cyclopenten-1,4-dion en fermentativ enzymatisk virkning av en mikroorganisme av klassen Ascomycetes, eller via spaltning med brucin som senere angitt. 6 g, 0,022 mol, 2-(6 -carbomethoxyhexyl)-4-hydroxy-cyclo-pentan-1,3-dion ble blandet med 8,7 g, 0,022 mol, brucin. Til denne blanding ble det tilsatt 35 ml aceton og den resulterende løsning ble kokt under tilbakeløp og under nitrogenatmosfære i 15 minutter, kjølt til romtemperatur og fikk deretter stå ved romtemperatur i 3 timer og deretter i et kjøleskap (4 - 10° C) over natten. Produktet, et brucinhydroxydionsalt utskiltes som fine krystaller. Krystallene ble filtrert fra på en buchner-trakt, vasket med kald aceton og ble omkrystallisert til konstant optisk rotasjon fra ethylacetat og Skelly B (fem omkrystallisasjoner). Skelly B er n-hexan. Alternatively, the dione can be produced microbiologically, as described in Norwegian generally available application 3795/73 with priority from 29 September 1972, by subjecting 2-substituted-cyclo-pentene-1,3,4-trione or 2-substituted-3 -Alkoxy-2-cyclopentene-1,4-dione a fermentative enzymatic action of a microorganism of the class Ascomycetes, or via cleavage with brucine as indicated later. 6 g, 0.022 mol, 2-(6-carbomethoxyhexyl)-4-hydroxy-cyclo-pentane-1,3-dione was mixed with 8.7 g, 0.022 mol, brucine. To this mixture was added 35 ml of acetone and the resulting solution was refluxed under a nitrogen atmosphere for 15 minutes, cooled to room temperature and then allowed to stand at room temperature for 3 hours and then in a refrigerator (4 - 10°C) overnight . The product, a brucine hydroxydione salt is excreted as fine crystals. The crystals were filtered off on a buchner funnel, washed with cold acetone and recrystallized to constant optical rotation from ethyl acetate and Skelly B (five recrystallizations). Skelly B is n-hexane.
Optisk rotasjon av saltet i CHCI3: Optical rotation of the salt in CHCI3:
2,2 g av det spaltede brucin-hydroxydionsalt ble løst i 2.2 g of the cleaved brucine hydroxydione salt were dissolved in
30 ml ethylacetat. Til denne løsning ble 30 ml 0,25 N HC1 tilsatt og den heterogene blanding ble omrørt meget kraftig i 2 minutter. Ved henstand dannet det seg to lag som ble separart. Det vandige lag ble ekstrahert to ganger med ethylacetat. De organiske lag fra de to ekstraksjoner ble kombinert og ble vasket med vann og mettet saltvannløsning og ble, tørket over vannfritt magnesiumsulfat. Fordampning av løsningsmidlet ga 780 mg 2-(6<1->carbomethoxyhexyl)-4(R)-hydroxy-cyclopentan-1,3-dion som et hvitt fast krystallinsk stoff. 30 ml of ethyl acetate. To this solution was added 30 ml of 0.25 N HCl and the heterogeneous mixture was stirred very vigorously for 2 minutes. During the reprieve, two teams formed and were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers from the two extractions were combined and washed with water and saturated saline and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 780 mg of 2-(6<1->carbomethoxyhexyl)-4(R)-hydroxy-cyclopentane-1,3-dione as a white crystalline solid.
Som tidligere angitt kan enoliseringen av det 2-substituerte dion utføres for omdannelse til enolester eller enoletherkonfi-gurasjon gjennom selektiv O-acylering eller selektiv O-alkylering ifølge følgende generelle metode. As previously indicated, the enolization of the 2-substituted dione can be carried out for conversion to the enol ester or enol ether configuration through selective O-acylation or selective O-alkylation according to the following general method.
Enolisering med selektiv O- acylering Enolization with selective O-acylation
Generelt kan denne reaksjon utføres etter følgende skje-matiske reaksjonsskjema: In general, this reaction can be carried out according to the following schematic reaction scheme:
hvor R og R" har de tidligere angitte betydninger. where R and R" have the previously stated meanings.
Ved den angitte O-acyleringsreaksjon er det fordelaktig In the indicated O-acylation reaction, it is advantageous
å anvende bare én ekvivalent av acyleringsmidlet, da bruk av over-skudd av acyleringsmidler er tilbøyelig til også å aktivere acylering av hydroxylgruppen. Likeledes er acyleringsgruppens stør-relse viktig med hensyn til dannelse av den ønskede fenolester, to use only one equivalent of the acylating agent, as the use of excess acylating agents tends to also activate acylation of the hydroxyl group. Likewise, the size of the acylation group is important with regard to the formation of the desired phenolic ester,
en mer massiv gruppering aktiverer dannelsen av mer av den ønskede enolform, dvs. 0,acylering av C-l-stilling. Med acetylklorid som acyleringsmiddel, hvilket er kjent, og 2(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopentan-l,3-dion som substrat dannes f.eks. to enolacylater a more massive grouping activates the formation of more of the desired enol form, ie 0,acylation of the C-1 position. With acetyl chloride as acylating agent, which is known, and 2(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopentane-1,3-dione as substrate, e.g. two enolacylates
i et forhold på 70 - 75 % av A til 30 - 25 % av B. Når imidler-tid et mer passivt acyleringsmiddel slik som pivaloylklorid anvendes, er forholdet mellom det ønskede substituerte C-l-enol-pivaloylat og det substituerte C-3-enolpivaloylat ca. 90:10. in a ratio of 70 - 75% of A to 30 - 25% of B. However, when a more passive acylating agent such as pivaloyl chloride is used, the ratio between the desired substituted C-1-enol pivaloylate and the substituted C-3-enol pivaloylate is about. 90:10.
Enolisering med selektiv O- alkylering Enolization with selective O-alkylation
O-alkyleringsreaksjonen kan utføres efter følgende reaksjonsskjema: The O-alkylation reaction can be carried out according to the following reaction scheme:
hvor R og R<1> har de tidligere angitte betydninger. where R and R<1> have the previously stated meanings.
Som bemerket med hensyn til O-acyleringen influerer denne relative størrelse alkyleringsmidlet på forholdet mellom de dannede enolethere, dvs. forholdet mellom substituert C-l-enolether i forhold til substituert C-3-enolether. Med f.eks. isopropyljodid som alkyleringsmiddel og 2(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopentan-1,3-dion som substratet ble de to enolethere As noted with respect to the O-acylation, this relative size of the alkylating agent influences the ratio of the enol ethers formed, i.e. the ratio of substituted C-1 enol ether to substituted C-3 enol ether. With e.g. isopropyl iodide as the alkylating agent and 2(6-carbomethoxyhexyl)-4(R)-hydroxy-2-cyclopentane-1,3-dione as the substrate became the two enol ethers
dannet i et forhold mellom A og B på 6:4, mens når isoamyljodid, som er en større gruppering, ble anvendt som alkyleringsmiddel var forholdet mellom den ønskede substituerte C-l-enolether til den substituerte C-3-enolether ca. 7:3. formed in a ratio between A and B of 6:4, while when isoamyl iodide, which is a larger grouping, was used as alkylating agent, the ratio of the desired substituted C-1 enol ether to the substituted C-3 enol ether was approx. 7:3.
Den etterfølgende tabell angir de relative mengder av enoletherne erholdt med de angitte alkyleringsmidler: The following table indicates the relative amounts of the enol ethers obtained with the indicated alkylating agents:
Reduksjon av den substituerte C-l-enolester eller enolether kan lett utføres med natriumdihydro-bis-(2-methoxyethoxy)-aluminat (kaldt Red-Al middel) som vist av Pappo et al., Tetra-hedron Letters, No. 26, p. 2627 (1972), Pergamon Press. Andre reduksjonsmidler slik som f.eks. lithiumborhydrid, diisobutylalu-miniumhydrid og lithiumaluminiumhydrid er også istand til å redu-sere carbonyl-funksjonen av den substituerte C-l-enolester eller ether ifølge fremgangsmåten ifølge oppfinnelsen under dannelse av de ønskede 2-substituerte-4(R)-hydroxy-2-cyclopenten-l-on-pro-dukter. Reduction of the substituted C-1 enol ester or enol ether can be easily carried out with sodium dihydro-bis-(2-methoxyethoxy)-aluminate (cold Red-Al agent) as shown by Pappo et al., Tetra-hedron Letters, No. 26, p. 2627 (1972), Pergamon Press. Other reducing agents such as e.g. lithium borohydride, diisobutylaluminum hydride and lithium aluminum hydride are also able to reduce the carbonyl function of the substituted C-1-enol ester or ether according to the method according to the invention, forming the desired 2-substituted-4(R)-hydroxy-2-cyclopentene- l-on products.
De følgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel. 1 Fremstilling av di- ertolbenzoater Example. 1 Production of di-ertol benzoates
Til en oppløsning av 120 mg (0,467 mmol) 2(6-carbometh-oxyhexyl) -4 (R) -hydroxy-cyclopentan-1, 3-dion (II), 0,4 ml (ca. 3 mmol) triethylamin (Et^N) (destillert over CaH2) i 10 ml tetrahydrofuran (THF) kjølt til -15°C ble tilsatt 0,5 ml (4,34 mmol) benzoylklorid i løpet av 5 minutter under omrøring. Efter at reaksjonsblandingen var omrørt ved -15 til 5°C i 3 timer, ble vann tilsatt, og blandingen ble ekstrahert tre ganger med diethylether. Etherlaget ble vasket henholdsvis med fortynnet HC1, vann, mettet NaHCO-j og NaCl-oppløsninger. Etherlaget ble derefter tørket over Na2S0^ og fordampet til tørrhet. Protonmagnetisk resonans (PMR) analyse viste at det tørkede produkt inneholde 90 % av det ønskede substituerte C-l-dibenzoat (Illa) som lett kunne separeres ved kolonnekromatografi ved bruk av siliciumsyre-Celite (85:15) ko-lonne (21 x 2,5 cm) med en benzen-ethylacetatgradient som beskrevet i eksempel 4. To a solution of 120 mg (0.467 mmol) 2(6-carbometh-oxyhexyl)-4 (R)-hydroxy-cyclopentane-1, 3-dione (II), 0.4 ml (ca. 3 mmol) triethylamine (Et ^N) (distilled over CaH2) in 10 ml of tetrahydrofuran (THF) cooled to -15°C was added 0.5 ml (4.34 mmol) of benzoyl chloride over 5 minutes with stirring. After the reaction mixture was stirred at -15 to 5°C for 3 hours, water was added, and the mixture was extracted three times with diethyl ether. The ether layer was washed respectively with dilute HCl, water, saturated NaHCO-j and NaCl solutions. The ether layer was then dried over Na 2 SO 4 and evaporated to dryness. Proton magnetic resonance (PMR) analysis showed that the dried product contained 90% of the desired substituted C-1-dibenzoate (IIa) which could be easily separated by column chromatography using a silicic acid-Celite (85:15) column (21 x 2.5 cm) with a benzene-ethyl acetate gradient as described in Example 4.
Eksempel 2 Fremstilling av mono- enolbenzoatesteren Example 2 Preparation of the monoenol benzoate ester
Til en avkjølt (-11° C) omrørt løsning av 102,4 mg (0,4 mmol) av hydroxydionmethylesteren (III) og 0,112 ml (ca. 0,84 mmol) triethylamin (destillert over kalsiumhydrid) i 8 ml tørr tetrahydrofuran (under ( ble tilsatt 0,046 ml (0,4 mmol) benzoylklorid i løpet av 5 minutter. Den resulterende løsning ble omrørt ved -10°C i 35 minutter. 4 ml methano.l ble tilsatt og løsningen ble oppvarmet til romtemperatur og ble deretter heldt over i 60 ml vann. Denne løsning ble ekstrahert fire ganger med 50 ml ethylacetat hver gang og de kombinerte ekstrakter ble vasket henholdsvis med 0,IN HC1 (10 ml), vann (10 ml), mettet natriumbicarbonat (10 ml) (natrium-bicarbonatvaskevannet ble surgjort og ekstrahert med ethylacetat. Ekstraktet ble vasket med mettet natriumkloridløsning og tørket over MgSO^. Fordampning av løsningsmidlet ga uomsatt hydroxydion-methylester (30 mg) II,) og mettet natriumklorid (10 ml) løsninger og tørket over MgSO^. Fordampning av løsningsmidlet ga en gul olje med følgende karakteristika: PMR 63,65 (S, 3H, OCH3, 64,48 (q, 1H, H-C-OH), 87,70 (m, 3H) og 68,18 (m, 2H) aromatiske protoner, m/e ved 360, (cx)q<4> + 35° (C, 2,0 CHCI3) , Xjj][£ s 241 nm (e 20.100), (S) 270 nm (e 8,500) hvilket identifiserte produktet som Hig. Eksempel 3 Fremstilling av isopropylenol- etheren Til 514 mg av hydroxydionesteren (II) (2,0 mmol), ble tilsatt 546 mg I^CO-j (4 mmol), og 5 ml (8,5 g, 50 mmol) isopropyljodid i 25 ml tørr aceton. Blandingen ble oppvarmet under tilbake-løpskjøling (N2-atmosfære) i 24 timer. Etter avkjøling ble reaksjonsblandingen fortynnet med Et20 og etherlaget ble vasket henholdsvis med vann, NaHCO^, vann og mettet NaCl. Løsningsmiddellaget ble deretter tørket over Na2S04 og fordampet til tørrhet hvorved det ble erholdt 560 mg av et oljeaktig residuum. Residuet ble løst i isopropylether hvorved det ble erholdt 316 mg (53 %) av et produkt med følgende karakteristika: sm.p. 60 - 62° C, A*^g 259 nm (e 20.600), PMR (CHC13) 1,35 (d, 6 „„ -""CH3 ), 63,65 (s, COOCH3) , 64,32 (q, 1, CHOH) , 4,67 (s, 1, CH^™3 ), m/e 298, (a)<* >+ 35,1 (C, 1,02 MeOH), hvilket identifiserte 3 det som Illh. Eksempel <4 >Fremstilling av isoamylenoletheren To a cooled (-11° C) stirred solution of 102.4 mg (0.4 mmol) of the hydroxydione methyl ester (III) and 0.112 ml (ca. 0.84 mmol) of triethylamine (distilled over calcium hydride) in 8 ml of dry tetrahydrofuran ( under (0.046 mL (0.4 mmol) of benzoyl chloride was added over 5 minutes. The resulting solution was stirred at -10°C for 35 minutes. 4 mL of methanol was added and the solution was warmed to room temperature and then poured into 60 mL of water. This solution was extracted four times with 50 mL of ethyl acetate each time and the combined extracts were washed respectively with 0.1N HCl (10 mL), water (10 mL), saturated sodium bicarbonate (10 mL) (sodium The bicarbonate wash was acidified and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over MgSO^. Evaporation of the solvent gave unreacted hydroxydione methyl ester (30 mg) II,) and saturated sodium chloride (10 mL) solutions and dried over MgSO^. Evaporation of the solvent gave a yellow oil of the following character ristika: PMR 63.65 (S, 3H, OCH3, 64.48 (q, 1H, H-C-OH), 87.70 (m, 3H) and 68.18 (m, 2H) aromatic protons, m/e at 360, (cx)q<4> + 35° (C, 2.0 CHCl 3 ), Xjj][£ s 241 nm (e 20,100), (S) 270 nm (e 8,500) which identified the product as Hig. Example 3 Preparation of the isopropylenol ether To 514 mg of the hydroxydionester (II) (2.0 mmol), 546 mg of I^CO-j (4 mmol) and 5 ml (8.5 g, 50 mmol) of isopropyl iodide in 25 ml of dry acetone. The mixture was heated under reflux (N2 atmosphere) for 24 hours. After cooling, the reaction mixture was diluted with Et 2 O and the ether layer was washed respectively with water, NaHCO 3 , water and saturated NaCl. The solvent layer was then dried over Na 2 SO 4 and evaporated to dryness to give 560 mg of an oily residue. The residue was dissolved in isopropyl ether whereby 316 mg (53%) of a product with the following characteristics was obtained: m.p. 60 - 62° C, A*^g 259 nm (e 20,600), PMR (CHC13) 1.35 (d, 6 „„ -""CH3 ), 63.65 (s, COOCH3) , 64.32 (q , 1, CHOH) , 4.67 (s, 1, CH^™3 ), m/e 298, (a)<* >+ 35.1 (C, 1.02 MeOH), which identified 3 it as Illh . Example <4 >Preparation of the isoamylenol ether
Til 121 mg II, 287 mg K2CC>3 i 15 ml tørr aceton ble tilsatt 2 ml isoamyljodid. Etter tilbakeløp over natten ble reaksjonsblandingen opparbeidet som beskrevet i eksempel 5. Det ble erholdt 165 mg residuum. PMR-analyse viste en isopropyldublett (60,95 J = 6HZ), kompleks region (61,1 - 3,1), methoxyl (63,65), multiplett ( y^ 64,0 - 4,5, ca. 3H basert på methoxyl) og en bred dublett (65,0, J = 6) To 121 mg of II, 287 mg of K2CC>3 in 15 ml of dry acetone was added 2 ml of isoamyl iodide. After refluxing overnight, the reaction mixture was worked up as described in example 5. 165 mg of residue was obtained. PMR analysis showed an isopropyl doublet (60.95 J = 6HZ), complex region (61.1 - 3.1), methoxyl (63.65), multiplet ( γ^ 64.0 - 4.5, ca. 3H based on methoxyl) and a broad doublet (65.0, J = 6)
(30 % 1H, basert på methoxyl), ca. 4H total integral fra 64,0 til 65,10 indikerte innbefattelse av -OH, -OCH2-CH2-CH2CHMe2 og OH-CH. Således ble produktet beregnet å inneholde ca. 70 % av den ønskede substituerte C-l enolether Uli, som lett ble fraskilt fra den substituerte C-3 enolether ved kolonnekromatografi som beskrevet i eksempel 4. (30% 1H, based on methoxyl), approx. 4H total integral from 64.0 to 65.10 indicated inclusion of -OH, -OCH2-CH2-CH2CHMe2 and OH-CH. Thus, the product was calculated to contain approx. 70% of the desired substituted C-1 enol ether Uli, which was easily separated from the substituted C-3 enol ether by column chromatography as described in Example 4.
Eksempel 5 5 Example 5 5
Reduksjon av mono- enolbenzoatesteren med " Red- Al" Reduction of the mono-enol benzoate ester with "Red-Al"
Til en kjølt (-78° C), omrørt løsning av 50 mg (0,147 To a chilled (-78° C), stirred solution of 50 mg (0.147
mmol) mono-enolbenzoat (Hig) i 10 ml tørr tetrahydrofuran under N2» ble "Red-Al" løsning (1,5 M i toluen) tilsatt i fire 0,38 ml porsjo-ner i løpet av 15 minutter. Den resulterende løsning ble omrørt ved mmol) of mono-enol benzoate (Hig) in 10 ml of dry tetrahydrofuran under N 2 , "Red-Al" solution (1.5 M in toluene) was added in four 0.38 ml portions over 15 minutes. The resulting solution was stirred at
-78° C i ytterligere 30 minutter. 2 ml iseddik ble tilsatt og løs-ningen fikk oppvarmes til romtemperatur. Løsningen ble heldt over i 40 ml vann og ekstrahert med ethylacetat (4 x 30 ml). Ethylacetatlaget ble vasket med 10 ml hver av mettet natriumbicarbonat og mettet NaCl-løsninger og tørket over MgSO^. Fordampning av en olje. Oljen ble løst i 10 ml eddiksyre-vann (75:25) løsning. Den resulterende løsning ble omrørt ved romtemperatur i 24 timer. Eddiksyre vann ble fordampet fra under redusert trykk. Den resulterende olje ble løst i ethylacetat (10 ml) og vasket med mettet natriumbicarbo-natløsning og mettet natriumkloridløsning og tørket over MgS04. Fordampning av løsningsmidlet ga en gul olje (ca. 25 - 30 mg). Kry-stallisasjon fra ethylacetat-Skelly B ga 20 mg IV, som ble identifisert ved følgende karakteristika: sm.p. 60 - 61° C, (ci)q<4> = -78° C for a further 30 minutes. 2 ml of glacial acetic acid was added and the solution was allowed to warm to room temperature. The solution was poured into 40 ml of water and extracted with ethyl acetate (4 x 30 ml). The ethyl acetate layer was washed with 10 ml each of saturated sodium bicarbonate and saturated NaCl solutions and dried over MgSO 4 . Evaporation of an oil. The oil was dissolved in 10 ml of acetic acid-water (75:25) solution. The resulting solution was stirred at room temperature for 24 hours. Acetic water was evaporated from under reduced pressure. The resulting oil was dissolved in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over MgSO 4 . Evaporation of the solvent gave a yellow oil (ca. 25 - 30 mg). Crystallization from ethyl acetate-Skelly B gave 20 mg of IV, which was identified by the following characteristics: m.p. 60 - 61° C, (c1)q<4> =
17,82° (C, 0,49 MeOH), PMR (CDCII3) 63,65 (s, 3, COOCH3), 64,93 (m, 1, H-C-OH) , 67,23 (m, 1, vinyl H) , UV xjjj£]j 222 nm (e 8 400) CD 231 nm 9 -9,9° x IO<-3> (MeOH). 17.82° (C, 0.49 MeOH), PMR (CDCII 3 ) 63.65 (s, 3, COOCH 3 ), 64.93 (m, 1, H-C-OH) , 67.23 (m, 1, vinyl H) , UV xjjj£]j 222 nm (e 8 400) CD 231 nm 9 -9.9° x 10<-3> (MeOH).
Eksempel 6 Example 6
Reduksjon av isopropylrénoletheren med Red- Al Reduction of the isopropyl renol ether with Red-Al
De 123 mg av isopropylenoletheren (Illh) (0,412 mmol) i The 123 mg of the isopropylenol ether (Illh) (0.412 mmol) i
10 ml THF, rørt under nitrogen ved -78° C, ble fire 1,1 ml's por-sjoner av en løsning av Red-Al i benzen (1,5 M) dråpevis tilsatt i løpet av 7 minutter. Reaksjonsblandingen ble omrørt ved -78° C i 45 minutter og 2 ml eddiksyre ble deretter tilsatt. Reaksjonsblandingen fikk oppvarmes til romtemperatur og ble fordampet til tørr-het. 10 ml 75 %-ig eddiksyreløsning ble tilsatt og rørt i 24 timer. Eddiksyre og vannet ble fordampet fra under trykk. Den resulterende olje ble løst i 25 ml ethylacetat og vasket med mettet NaHC03 og NaCl-løsninger og deretter tørket over .magnesiumsulfat. Krystalli-sasjon av residuet fra ethylacetat-Skelly B ga 60 mg IV, som ble identifisert ved følgende karakteristika: sm.p. 60 - 61° C, (a)D To 10 ml of THF, stirred under nitrogen at -78°C, four 1.1 ml portions of a solution of Red-Al in benzene (1.5 M) were added dropwise over 7 minutes. The reaction mixture was stirred at -78°C for 45 minutes and 2 ml of acetic acid was then added. The reaction mixture was allowed to warm to room temperature and was evaporated to dryness. 10 ml of 75% acetic acid solution was added and stirred for 24 hours. Acetic acid and water were evaporated from under pressure. The resulting oil was dissolved in 25 ml of ethyl acetate and washed with saturated NaHCO 3 and NaCl solutions and then dried over magnesium sulfate. Crystallization of the residue from ethyl acetate-Skelly B gave 60 mg of IV, which was identified by the following characteristics: m.p. 60 - 61° C, (a)D
+ 17,82° (C, 0,49 MeOH) , UV .xjjjj 222 nm (e 8.400) , CD 231 nm 9.= -9,9° x 10~<3> (MeOH). + 17.82° (C, 0.49 MeOH) , UV .xjjjj 222 nm (e 8,400) , CD 231 nm 9.= -9.9° x 10~<3> (MeOH).
Omdannelsen av forbindelsene fremstilt ifølge fremgangsmåten, nemlig., 2-(6-carbalkoxyhexyl)-4 (Rl-hydroxy-cyclopent-2-enoner til prostaglandiner eller prostaglandin-lignende forbindelser kan utfø-res etter fremgangsmåten beskrevet av Charles J. Sih et al. (J.Amer. Chem. Soc, 94' 3643 (mai 17,nde, 1972)). Såsnart den ovenfor stereospesifike forbindelse er erholdt kan omdannelsen til prostaglandiner eller prostaglandin-lignende forbindelser lett utføres med bibeholdelse av den ønskede stereokjemi. The conversion of the compounds prepared according to the method, namely, 2-(6-carbalkoxyhexyl)-4-(R1-hydroxy-cyclopent-2-enones) to prostaglandins or prostaglandin-like compounds can be carried out according to the method described by Charles J. Sih et al .(J.Amer. Chem. Soc, 94' 3643 (May 17th, 1972)) Once the above stereospecific compound is obtained, the conversion to prostaglandins or prostaglandin-like compounds can be easily accomplished while retaining the desired stereochemistry.
I tillegg til å kunne anvendes som et utgangsmateriale ved fremstilling av prostaglandiner, ble l-isopropoxy-2-(6'-carbo-methoxyhexyl) -4(R)-hydroxy-l-cyclopenten-3-on (isopropylenoletheren) funnet å ha antimikrobiell aktivitet som vist i det følgende eksempel. In addition to being able to be used as a starting material in the production of prostaglandins, l-isopropoxy-2-(6'-carbo-methoxyhexyl)-4(R)-hydroxy-l-cyclopenten-3-one (isopropylenol ether) was found to have antimicrobial activity as shown in the following example.
Eksempel 7 Example 7
25 mg l-isopropoxy-2-(6'-carbomethoxyhexyl)-4(R)-hydroxy-l-cyclopenten-3-on ble løst i 1 ml methylalkohol. , 0,1 ml av den resulterende løsning ble påført en filterpapirskive (12,7 mmol) og skiven ble deretter tørket. Hver av de tørkede skiver ble deretter plassert i en petrlskål inneholdende 10 ml antibiotica medium II (Difco) til hvilket det var tilsatt 0,03 ml av et podestoff av test-organismen. Petriskålene ble incubert ved 25° C i 48 timer og inhi-beringssonen ble målt med følgende resultater: 25 mg of 1-isopropoxy-2-(6'-carbomethoxyhexyl)-4(R)-hydroxy-1-cyclopenten-3-one was dissolved in 1 ml of methyl alcohol. , 0.1 ml of the resulting solution was applied to a filter paper disc (12.7 mmol) and the disc was then dried. Each of the dried slices was then placed in a petri dish containing 10 ml of antibiotica medium II (Difco) to which was added 0.03 ml of an inoculum of the test organism. The Petri dishes were incubated at 25°C for 48 hours and the zone of inhibition was measured with the following results:
Claims (1)
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US30976672A | 1972-11-27 | 1972-11-27 |
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JP (1) | JPS5328908B2 (en) |
AR (1) | AR198543A1 (en) |
AT (1) | AT330143B (en) |
AU (1) | AU459800B2 (en) |
BE (1) | BE807825A (en) |
BG (1) | BG21204A3 (en) |
CA (1) | CA1034139A (en) |
CH (1) | CH599098A5 (en) |
CS (1) | CS170480B2 (en) |
DD (1) | DD108516A5 (en) |
DE (1) | DE2358781C3 (en) |
ES (1) | ES420855A1 (en) |
FR (1) | FR2207905B1 (en) |
GB (1) | GB1440108A (en) |
HU (1) | HU169638B (en) |
IE (1) | IE38497B1 (en) |
IL (1) | IL43597A (en) |
NL (1) | NL7316147A (en) |
NO (1) | NO138905C (en) |
PH (1) | PH10276A (en) |
PL (1) | PL91162B1 (en) |
RO (1) | RO63011A (en) |
SE (1) | SE406462B (en) |
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AU529883B2 (en) * | 1978-09-04 | 1983-06-23 | Australian National University, The | Substituted cyclopentenones |
JPS56159683U (en) * | 1980-04-28 | 1981-11-28 | ||
US5254708A (en) * | 1987-06-16 | 1993-10-19 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
JP2696933B2 (en) * | 1987-06-16 | 1998-01-14 | 日産化学工業株式会社 | Substituted cyclic ketones and substituted cyclic enones and methods for their preparation |
US5227505A (en) * | 1987-06-16 | 1993-07-13 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
US5231208A (en) * | 1987-06-16 | 1993-07-27 | Nissan Chemical Industries, Ltd. | Substituted cyclic ketones, substituted cyclic enones, and process for producing the same |
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1973
- 1973-11-07 IE IE2003/73A patent/IE38497B1/en unknown
- 1973-11-07 CA CA185,210A patent/CA1034139A/en not_active Expired
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- 1973-11-08 AU AU62283/73A patent/AU459800B2/en not_active Expired
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- 1973-11-15 PH PH15227A patent/PH10276A/en unknown
- 1973-11-16 AR AR251028A patent/AR198543A1/en active
- 1973-11-20 CH CH1628373A patent/CH599098A5/xx not_active IP Right Cessation
- 1973-11-22 JP JP13086973A patent/JPS5328908B2/ja not_active Expired
- 1973-11-22 AT AT980073A patent/AT330143B/en not_active IP Right Cessation
- 1973-11-26 SE SE737315982A patent/SE406462B/en unknown
- 1973-11-26 SU SU731975423A patent/SU617005A3/en active
- 1973-11-26 RO RO7300076778A patent/RO63011A/en unknown
- 1973-11-26 CS CS8114A patent/CS170480B2/cs unknown
- 1973-11-26 BE BE138190A patent/BE807825A/en not_active IP Right Cessation
- 1973-11-26 BG BG25076A patent/BG21204A3/xx unknown
- 1973-11-26 DD DD174893A patent/DD108516A5/en unknown
- 1973-11-26 ES ES420855A patent/ES420855A1/en not_active Expired
- 1973-11-26 PL PL1973166812A patent/PL91162B1/en unknown
- 1973-11-26 HU HUWI246A patent/HU169638B/hu unknown
- 1973-11-26 NO NO734495A patent/NO138905C/en unknown
- 1973-11-26 DE DE2358781A patent/DE2358781C3/en not_active Expired
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BG21204A3 (en) | 1976-03-20 |
AR198543A1 (en) | 1974-06-28 |
DE2358781C3 (en) | 1979-11-08 |
CS170480B2 (en) | 1976-08-27 |
SE406462B (en) | 1979-02-12 |
JPS4982649A (en) | 1974-08-08 |
RO63011A (en) | 1978-05-15 |
DE2358781B2 (en) | 1979-01-25 |
BE807825A (en) | 1974-03-15 |
SU617005A3 (en) | 1978-07-25 |
ATA980073A (en) | 1975-09-15 |
FR2207905A1 (en) | 1974-06-21 |
ZA738581B (en) | 1974-09-25 |
IE38497L (en) | 1974-05-27 |
AU6228373A (en) | 1975-04-10 |
DD108516A5 (en) | 1974-09-20 |
PL91162B1 (en) | 1977-02-28 |
NO138905C (en) | 1978-12-06 |
IE38497B1 (en) | 1978-03-29 |
AU459800B2 (en) | 1975-04-10 |
JPS5328908B2 (en) | 1978-08-17 |
HU169638B (en) | 1976-12-28 |
ES420855A1 (en) | 1976-04-01 |
DE2358781A1 (en) | 1974-06-12 |
GB1440108A (en) | 1976-06-23 |
NL7316147A (en) | 1974-05-29 |
FR2207905B1 (en) | 1978-02-24 |
CH599098A5 (en) | 1978-05-12 |
CA1034139A (en) | 1978-07-04 |
IL43597A (en) | 1976-09-30 |
PH10276A (en) | 1976-11-03 |
IL43597A0 (en) | 1974-03-14 |
AT330143B (en) | 1976-06-10 |
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