DD268247A5 - IN THE OMEGA CHAIN MODIFIED NEW PROSTAGLANDIN INTERMEDIAES AND METHOD FOR THEIR MANUFACTURE - Google Patents
IN THE OMEGA CHAIN MODIFIED NEW PROSTAGLANDIN INTERMEDIAES AND METHOD FOR THEIR MANUFACTURE Download PDFInfo
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- DD268247A5 DD268247A5 DD31386588A DD31386588A DD268247A5 DD 268247 A5 DD268247 A5 DD 268247A5 DD 31386588 A DD31386588 A DD 31386588A DD 31386588 A DD31386588 A DD 31386588A DD 268247 A5 DD268247 A5 DD 268247A5
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- alkyl group
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- cyclopentyl
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- 238000000034 method Methods 0.000 title claims abstract description 13
- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 15
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- -1 iodo compound Chemical class 0.000 claims description 7
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052987 metal hydride Inorganic materials 0.000 claims description 5
- 150000004681 metal hydrides Chemical class 0.000 claims description 5
- 150000002497 iodine compounds Chemical class 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- CXLJNMDMFUNLGQ-UHFFFAOYSA-N 1-bromo-3-methylheptan-3-ol Chemical compound CCCCC(C)(O)CCBr CXLJNMDMFUNLGQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 229910001516 alkali metal iodide Inorganic materials 0.000 claims description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 4
- MEJJUZUMTCTDCF-UHFFFAOYSA-N 3-methylheptane-1,3-diol Chemical compound CCCCC(C)(O)CCO MEJJUZUMTCTDCF-UHFFFAOYSA-N 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000013067 intermediate product Substances 0.000 claims 1
- 150000004714 phosphonium salts Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 4
- ISCGGGVEXDAQCX-UHFFFAOYSA-N 1-iodo-3-methylheptan-3-ol Chemical compound CCCCC(C)(O)CCI ISCGGGVEXDAQCX-UHFFFAOYSA-N 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 1
- LIKMAJRDDDTEIG-UHFFFAOYSA-N 1-hexene Chemical compound CCCCC=C LIKMAJRDDDTEIG-UHFFFAOYSA-N 0.000 description 1
- GKUCVIBSNKXKPF-UHFFFAOYSA-N CCCCC(C)(CCP(c1ccccc1)(c1ccccc1)c1ccccc1)[IH]O Chemical compound CCCCC(C)(CCP(c1ccccc1)(c1ccccc1)c1ccccc1)[IH]O GKUCVIBSNKXKPF-UHFFFAOYSA-N 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- YLERVAXAQFOFRI-UHFFFAOYSA-M magnesium;propa-1,2-diene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C#C YLERVAXAQFOFRI-UHFFFAOYSA-M 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- OJLOPKGSLYJEMD-URPKTTJQSA-N methyl 7-[(1r,2r,3r)-3-hydroxy-2-[(1e)-4-hydroxy-4-methyloct-1-en-1-yl]-5-oxocyclopentyl]heptanoate Chemical compound CCCCC(C)(O)C\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC OJLOPKGSLYJEMD-URPKTTJQSA-N 0.000 description 1
- 229960005249 misoprostol Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000003017 phosphorus Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000006227 trimethylsilylation reaction Methods 0.000 description 1
- PGOLTJPQCISRTO-UHFFFAOYSA-N vinyllithium Chemical compound [Li]C=C PGOLTJPQCISRTO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/18—Polyhydroxylic acyclic alcohols
- C07C31/20—Dihydroxylic alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/34—Halogenated alcohols
- C07C31/36—Halogenated alcohols the halogen not being fluorine
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung von in der v-Kette modifizierten neuen Prostaglandin-Zwischenprodukten der allgemeinen Formel I, worin R fuer eine gegebenenfalls durch eine Cyclopentyl- oder Cyclohexylgruppe substituierte C1-6-Alkylgruppe mit gerader oder verzweigter Kohlenstoffkette oder fuer Cyclopentyl- oder Cyclohexylgruppe und R1 fuer C1-4-Alkylgruppe steht. Beispielsweise wird 2-(R,S)-Hydroxy-2-(2-jodaethyl)-hexan oder 3-(R,S)-Hydroxy-3-methyl-1-heptyltriphenylphosphoniumjodid hergestellt. Formel IThe invention relates to a process for the preparation of in the v-chain modified new prostaglandin intermediates of general formula I, wherein R is an optionally substituted by a cyclopentyl or cyclohexyl C1-6-alkyl group with straight or branched carbon chain or cyclopentyl or Cyclohexyl group and R1 is C1-4-alkyl group. For example, 2- (R, S) -hydroxy-2- (2-iodoethyl) -hexane or 3- (R, S) -hydroxy-3-methyl-1-heptyltriphenylphosphonium iodide is prepared. Formula I
Description
Hierzu 8 Seiten FormelnFor this 8-page formulas
Die Erfindung betrifft ein Verfahren zur Herstellung von in der ω-Kette modifizierten neuen Prostaglandin-Zwischenpi odukten.The invention relates to a process for the preparation of modified in the ω-chain new prostaglandin Zwischenpi odukten.
Es ist bekannt, daß mehrere PGE-Derivate eine starke magensäuresekretionshemmende und cytoprotektive Wirkung zeigen. Solche Verbindungen sind unter anderem das Misoprostol der Formel VIII und das Risoprostyl der Formel IX (Drugs of the Future 2 (12) Seite 817 [1977]; ibid 30 (3} Seite 207 [1985]).It is known that several PGE derivatives show a strong gastric acid secretion inhibiting and cytoprotective effect. Such compounds include the misoprostol of formula VIII and the risoprostyl of formula IX (Drugs of the Future 2 (12) page 817 [1977]; ibid 30 (3) page 207 [1985]).
Die Herstellung dieser Verbindungen erfolgt in literaturbekannter Weise (Tetrahydron Lett. No49p4217[1975]; US-PS 4132 738) nach dem Reaktionsschema A in einer konjugierten Additionsrekation, die zwischen dem CylopenM-en-alkansäüreester der Formel Xl beziehungsweise dem durch eine Tetrahydropyranylgruppe (THP-Gruppe) geschützten CyclopenM-en-alkanol der Formel XII (siehe Reaktionsschema A) und dem Vinylkuprat-Reagena der Formel XIII abläuft. Die Hersteilung des Vinylkruprat-Reagens der Formel XIII ist aus der Literatur bekannt (J. Med. Chem. 20 (9] Seite 1152 [1977); BE-PS Nr. 827 '.27 und US-PS Nr.4087447) und ist im Reaktionschema B dargestellt.The preparation of these compounds is carried out in a manner known from the literature (Tetrahydron Lett., No49p4217 [1975]; U.S. Patent 4,132,738) according to Reaction Scheme A in a conjugated addition reaction between the cyclopentamethylene-ene-alkane ester of formula XI or a tetrahydropyranyl group (THP Group) protected CyclopenM-en-alkanol of formula XII (see Reaction Scheme A) and the Vinylkuprat Reagena of formula XIII runs. The preparation of the vinylcruprate reagent of formula XIII is known from the literature (J. Med. Chem. 20 (9) page 1152 [1977]; BE-PS No. 827 '.27 and U.S. Patent No. 4087447) and is Shown in Reaction Scheme B.
Gemäß dem Reaktionsschema B wird das mit einer Trirnethylsilyl-Schutzgruppe vereohono 4-MethyM -oktin-4-(RS)-ol der Formel 4, das durch Trimethylsilylierung nach der Grignard-Reaktion mit Propargylmagnesiumbromid aus 2-Hexanon gewonnen werden kann, in stereoselektiven Hydroborier-, Hydroalumlnier- oder Hydrostannier-Heakti inen in die entsprechenden trans-Vinyl-boran-, -alan- oder -stannan-Verbindungen (Formeln 5,6,7 überführt, aus denen mit elementarem Jod das entsprechende trans-Jodalken (Formel 8) gewonnen wird. Aus dem erhaltenen Jode Iken der Formel 8 odor Vi; vlstannan-Verbindung der Formel 7 wird durch Transmothalier-Reaktionen mit n-Bui/lüthium die entsprechende trans-Vinylli'hium-Verbindung dor Formet 9 gewonnen. Aus der Tetrahydrofuran-Löoung der Vinyllithium-Vei bindung der Formel 9 kann man mit einer ätherischen Lösung von mit Hexamethyl-phosphoriger Säure-triamid (HMP) aolvatiertem Kupfer(l)-pentin das Vinylkuprat-Raagens der Formel XIII gewinnon. Die Ausführung dieser Reaktionen erfordert, über ihre Kompliziertheit hinaus, eine sehr hohe Genauigkeit, spezielle Bedingungen und eine extreme Reinheit und absolute Wasserfreiheit dor Reagenzien und Lösungsmittel.According to Reaction Scheme B, the trimethylsilyl protecting group 4-methyl-4-oxo (RS) -ol of formula 4, which can be obtained by trimethylsilylation following the Grignard reaction with propargyl magnesium bromide from 2-hexanone, is converted into stereoselective hydroborate , Hydroalumlnier- or Hydrostannier- Heakti ines into the corresponding trans-vinyl-borane, -alan or -stannan compounds (formulas 5,6,7 transferred from which with elemental iodine, the corresponding trans-iodoalkene (Formula 8) The corresponding trans-vinyllithium compound of Formet 9 is obtained from the resulting iodine of the formula 8 or methylstannane compound of the formula 7 by means of transmuthalation reactions with n-butyl / lithium, from the tetrahydrofuran solution The vinyl lithium compound of the formula 9 can be recovered with an ethereal solution of hexamethyl-phosphorous acid triamide (HMP) aolvated copper (I) -pentine, the Vinylkuprat-Raagens of formula XIII gewinnon These reactions, beyond their complexity, require very high accuracy, special conditions, and extreme purity and absolute freedom from water of reagents and solvents.
Eine neuere Synthese der Verbindungen der Formeln VIII und IX sowie der Verbindung der Formel XIV kann folgendermaßen durchgeführt werden (Tetrahedron Lett. 23 (10) S. 1067 [1982]):A more recent synthesis of the compounds of the formulas VIII and IX and of the compound of the formula XIV can be carried out as follows (Tetrahedron Lett. 23 (10) p. 1067 [1982]):
Man baut die ω-Kette durch Umsetzen der Verbindungen der Formeln XV und XVI mit Phosphoran dar Formel I a in einer transselektiven Witting-Reaktion auf.The ω chain is prepared by reacting the compounds of the formulas XV and XVI with phosphorane of the formula Ia in a transselective Witting reaction.
Das Phosphoran der Formel (I a) kann nach dem Reaktionsschema C hergestellt ·» jeden, wobei sämtliche Zwischenprodukte der Reaktionsreihe unisolierbare reaktive Stoffe sind, was jegliche Reinigungemöglichkeiten ausschließt. Es ist ersichtlich, daß die bekannten Lösungen hinsichtlich ihrer praktischen Durchführbarkeit erhebliche Nacnteile aufweisen.The phosphorane of formula (Ia) can be prepared according to Reaction Scheme C "any" where all intermediates of the reaction series are uninsulable reactive species, which precludes any purification possibilities. It can be seen that the known solutions have significant Nacnteile in terms of their practicality.
Überraschenderweise wurde gefunden, daß wenn man die Oxoverbindungen der allgemeinen Formel VII, worin R für eine gegebenenfalls durch eine Cyclopentyl- oder Cyclohexylgruppe substituierte C,.e-Cyloalkylgruppe mit gerader oder verzweigter Kohlenstoffkette oder Cyclopentyl- oder Cyclohexylgruppe steht und R1 und Ci^-Alkylgruppe bedeutet mit einem Bromessigeäure-Ci-gAlkylester und Zinkmetall umsetzt (Reformatskii-Synthese), sodann die erhaltene Verbindung der allgemeinen Formel Vl, worin R und R1 die obige Bedeutung haben, mit Metallhydrid umsetzt, sodann die erhaltene Verbindung der aligemeinen Formel V, worin R und R1 die obige Bedeutung haben, mit Tripherylphosphin und Tetrabromkohlenstoff umsetzt, sodann die erhaltene Verbindung der allgemeinen Formel IV, worin R und R1 die obige Bedeutung haben mit einer anorganischen Jodverbindung umsetzt, die durch Umsetzen der erhaltenen Jodverbindung der allgemeinen Formel !!I, worin R und R1 die obige Bedeutung haben, mit Tripherylphosphin gewonnenen neuen Phosponiumsalze der allgemeinen Formel Il mit 2 Moläquivalent einer Verbindung vom Lithiumalkyl- oder Lithiumalkylamid-Typ in einem Schritt in Zwischenprodukte der allgemeinen Formel I überführt werden können.Surprisingly, it has been found that when the oxo compounds of general formula VII, wherein R is an optionally substituted by a cyclopentyl or cyclohexyl C ,. e is a straight-chain or branched-chain carbonyl or cyclopentyl or cyclohexyl-substituted cycloalkyl group and R 1 and C 1-4 -alkyl group are reacted with a bromoacetic acid C 1-6 -alkyl ester and zinc metal (Reformatskii synthesis), then the resulting compound of the general formula V 1, wherein R 1 and R 1 have the above meaning, with metal hydride, then reacting the resulting compound of the general formula V, wherein R and R 1 have the above meaning, with tripherylphosphine and carbon tetrabromide, then the resulting compound of general formula IV, wherein R and R 1 has the above meanings with an inorganic iodine compound which is prepared by reacting the resulting iodo compound of the general formula I, in which R and R 1 have the above meaning, obtained with Tripherylphosphin new Phosponiumsalze of the general formula II with 2 molar equivalent of a compound of the lithium alkyl - or lithium alkylamide type in a step in intermediates of the general In formula I can be transferred.
Die Verbindungen der allgemeinen Formel VII werden in Tetrahydrofuran oder einem anderen in der Reformatskii-Synthese gebräuchlicher: Lösungsmittel mit Zinkmetall oder Bromessigsäureäthylester oder einem anderen C^-Alkylester umgesetzt. Die Verbindungen der allgemeinen Formel Vl werden mit einem komplexen Metallhydrid, vorzugsweise Lithium-Aluminiumhydrid (LAH) in Tetrahydrofuran oder einem anderen für Metallhydrid-Reaktionen geeigneten Lösungsmittel reduziert. Die primäre Hydroxylgruppe der Verbindungen der allgemeinen Formel V wird in einem Tetrabromkohlensto t-Triphenylphosphin-System, in Acetonitril-Lösungsmittei gegen ein Bromatom ausgetauucht, das Bromatom der Verbindungen der allgemeinen Formel IV hingegen wird in acetonischem Medium mit Alkalimetalljodid, vorzugsweise Natriumiodid, gegen ein Jodatom ausgev .iuscht. Die Verbindungen der allgemeinen Formel III werden unter Rückfluß in Acetonitril, in Gegenwart von 10-15 Moläquivalent Triphenylphosphin in Phosphoriumsalze der allgemeinen Formal il überführt. Die erfindungsgemäß hergestellten Verbindungen der ollgemeinen Formeln Vl, V, IV, III und Il sind stabil, isolierbar und ihre Reinigung ist leicht möglich. Die Verbindungen der allgemeinen Formeln III bis Vl können durch Destillation oder chromatographische Methoden, die salzartigen Verbindungen der allgemeinen Formel !I durch Chromatographie oder Umkristallisieren gereinigt werden. Die erfindungsgemäß hergestellten Verbindungen der allgemeinen Formeln Il bis V sind neu.The compounds of the general formula VII are reacted in tetrahydrofuran or another customary in the Reformatskii synthesis: solvent with zinc metal or ethyl bromoacetate or another C ^ alkyl ester. The compounds of general formula VI are reduced with a complex metal hydride, preferably lithium aluminum hydride (LAH) in tetrahydrofuran or another solvent suitable for metal hydride reactions. The primary hydroxyl group of the compounds of general formula V is in a Tetrabromkohlensto t- triphenylphosphine system, in acetonitrile Lösungsmittei exchanged against a bromine atom, the bromine atom of the compounds of general formula IV, however, is in an acetonic medium with alkali metal iodide, preferably sodium iodide, against an iodine atom Ausv .iuscht. The compounds of general formula III are converted under reflux in acetonitrile, in the presence of 10-15 molar equivalent of triphenylphosphine in phosphorus salts of the general formula il. The compounds according to the invention of the general formulas VI, V, IV, III and II are stable, can be isolated and their purification is easily possible. The compounds of the general formulas III to VI can be purified by distillation or chromatographic methods, the salt-like compounds of the general formula I by chromatography or recrystallization. The compounds according to the invention of the general formulas II to V are new.
Ein weiterer unerwarteter Vorteil des erfindungsgemäßen Reaktionsweges besteht darin, daß die Verbindungen der allgemeinen Formel V außerordentlich selektiv bromiert werden können (fast quantitativ), die tertiäre Hydroxylgruppe bleibt unverändert. Wie bereits erwähnt, können die Verbindungen der allgemeinen Formel Il mit 2 Moläquivalent Verbindungen vom Lithiumalkyl· oder Lithiumalkylamid-Typ in Verbindungen der allgemeinen Formel I überführt werden. Das dabei als Nebenprodukt entstehende Lithiumiodid erhöht die trans-Selektivität der als folgenden Schritt verwirklichten Wittig-Reaktion zum Beispiel zwischen den Verbindungen der Formel XV oder XVI oder XVII und den Verbindungen der Formel I erheblich (Tetrahedron Lett. 26 [3] S.313 [1985], J. Am. Chem. Soc. 103, S.2823 [1981]; Liebigs Ann. Chem. Band 708 S.1 [1967]).Another unexpected advantage of the reaction pathway according to the invention is that the compounds of general formula V can be brominated extremely selectively (almost quantitatively), the tertiary hydroxyl group remains unchanged. As already mentioned, the compounds of the general formula II can be converted with 2 molar equivalents of compounds of the lithium alkyl or lithium alkylamide type into compounds of the general formula I. The by-produced lithium iodide considerably increases the trans selectivity of the Wittig reaction implemented as the following step, for example between the compounds of the formula XV or XVI or XVII and the compounds of the formula I (Tetrahedron Lett. 26 [3] p. 1985], J. Am. Chem. Soc. 103, p.2823 [1981]; Liebigs Ann. Chem. Vol. 708 p.1 [1967]).
Die Erfindung wird in den folgenden Ausführungsbeispielen näher erläutert, ohne daß dabei der Schutzumfang auf diese Beispiele eingeschränkt wird.The invention will be explained in more detail in the following embodiments, without limiting the scope of protection to these examples.
gleichzeitig 27,5 ml Bromeesigeäureathylester und 35ml 2-Hexanon gegeben (die Reaktion ist exotherm). Danach wird dassimultaneously added 27.5 ml Bromeesigeäureathylester and 35ml 2-hexanone (the reaction is exothermic). After that it will be
gespalten. Nach der Spaltung werden die beiden enstandenen Phasen getrennt, die wäßrige Phase wird dreimal mit 80mlsplit. After cleavage, the two phases are separated and the aqueous phase is washed with 80 ml three times
1H-NMR: (CDCL3, auf TMS) δ = 0,9t (3H); δ - 1-1,5m (11 H); δ = 2,6S (3H); δ « 3,5S (1 H); = 4,2q (2H). 1 H-NMR: (CDCL 3 , on TMS) δ = 0.9t (3H); δ - 1-1.5m (11H); δ = 2.6S (3H); δ «3.5S (1H); = 4,2q (2H).
4 Volumenteile Hexan, 1 VoliimenteilÄthylacetat; Schicht: Kieselgtl 6OF (Merck); Entwicklung: 5%ige äthanolische Lösung von4 volumes of hexane, 1 volume of ethyl acetate; Layer: Kieselgtl 6OF (Merck); Development: 5% ethanolic solution of
kein Ausgangsstoff mehr nachgewiesen werden kann, wird das Rcaktionsgemisch, sein LAH-Überschuß mit 10ml Äthylacetatzerlegt, dann wird 'Jas Reaktionsgemisch vorsichtig mit 50ml Wasser verdünnt. Danach werden die abgesonderten Lithium- undIf no starting material can be detected anymore, the reaction mixture, its LAH excess, is diluted with 10 ml of ethyl acetate, then the reaction mixture is carefully diluted with 50 ml of water. After that, the separate lithium and
eäulenchromatographlsch gereinigt.cleaned by column chromatography.
Ausbeute: 5,7g (82%).Yield: 5.7 g (82%).
'Η-abgekoppelt 13C-NMR: (CDCL3, auf TMS) cT= 14,1; 23,3; 26,3; 26,5; 41,4; 42,3; 59,4; 73,8 ppm.'Η-decoupled 13 C-NMR: (CDCL 3 , on TMS) cT = 14.1; 23.3; 26.3; 26.5; 41.4; 42.3; 59.4; 73.8 ppm.
2,4g 2-(P..S!-Hydroxy-2-(2'-h> JroxyäthyD-hexan werden in 10ml Acetonitril gelöst, dann werden 4,7g Tripheny!phosphin zum2.4 g of 2- (P..S! -Hydroxy-2- (2'-h) hydroxyethyl-hexane are dissolved in 10 ml of acetonitrile, then 4.7 g of triphenyl phosphine are added
die Lösung wird 3 Stunden lang gerührt. Danach wird die Reaktion chromatographisch kontrolliert. (Bedingungen wie inThe solution is stirred for 3 hours. Thereafter, the reaction is monitored by chromatography. (Conditions like in
chromatographisch gereinigt. (Säule: 0 = 2cm, l· Dllhöhe: 20cm, Füllung: Kieselgel 60F284 [Merck]; Eluens: Hexan-Äthylacetat4:1 Volumenanteile, Druck: 2 bar).purified by chromatography. (Column: 0 = 2 cm, l · height of dell: 20 cm, filling: silica gel 60F 284 [Merck], eluent: hexane-ethyl acetate4: 1 by volume, pressure: 2 bar).
Ausbeute: 3,3g (97%)Yield: 3.3 g (97%)
1H-NMR: (CDCLj/TMS) δ = (ppm 0,9t [3*1; 1,2S (3H]; 1.2-1,5m [7H]; 1,95-2,2m [2H]; 3,4-3,6m [2H]). 1 H-NMR: (CDCLj / TMS) δ = (ppm 0.9t [3 * 1; 1.2S (3H]; 1.2-1.5m [7H]; 1.95-2.2m [2H]; 3 , 4-3.6m [2H]).
2,1 g 2-(R,S)-Hydroxy-2-(2'-bromäthyl)-hexan werden in 10ml mit Natriumiodid gesättigtem Aceton gelöst. Das2.1 g of 2- (R, S) -hydroxy-2- (2'-bromoethyl) -hexane are dissolved in 10 ml of sodium iodide-saturated acetone. The
einen Filter gegeben, und die durch den Filter filtrierten Salze werden weitere dreimal mit 10ml η-Hexan gewaschen.a filter is added and the salts filtered through the filter are washed an additional three times with 10 ml of η-hexane.
Ausbeute: 2,3g (90%).Yield: 2.3 g (90%).
1H-NMR: (CDCLj/TMS) δ = (ppm) = 0,92t (3H); 1,17S (3H); 1,2-1,6m (7H); 2,03-2,22m (2H); 3,15-3,3Em (2H)^-abgekoppelt 13C-NMR: (CDCL3ZTMS); δ = (ppm) = -0,55; 14,0; 23,1; 25,0; 25,3; 41,6; 46,8; 74,0. 1 H NMR: (CDCLj / TMS) δ = (ppm) = 0.92t (3H); 1.17S (3H); 1.2-1.6m (7H); 2.03-2.22m (2H); 3.15-3.3Em (2H) ^ - decoupled 13 C-NMR: (CDCL 3 ZTMS); δ = (ppm) = -0.55; 14.0; 23.1; 25.0; 25.3; 41.6; 46.8; 74.0.
gekocht. Nachdem die Reaktionszeit verstrichen ist, wird überprüft, ob die Ausgangs-Jodverbindung verschwunden ist.cooked. After the reaction time has elapsed, it is checked whether the starting iodine compound has disappeared.
(Kontrolle .inter den in Beispiel 2 beschriebenen Bedingungen; Ausgangs-Jodverbindung: Rf bei 0,5).(Control according to the conditions described in Example 2; starting iodine compound: Rf at 0.5).
zweimal mit 20ml Acetonitril gewaschen. Die Mutterlauge und die Acetonitril-Waichlauge werden dann vereinigt undlösungsmittelfrei gemacht. Das Produkt wird chromatographisch vom Triphenylphosphinüberschuß gereinigt: Auf der inwashed twice with 20 ml acetonitrile. The mother liquor and the acetonitrile weigh liquor are then combined and made solvent-free. The product is purified by chromatography from Triphenylphosphinüberschuß: On the in
das Produkt mit einem Aceton-Äthylacetat-uoinisch im Volumenteilverhältnis von 2:1 eluiert Danach wird das Lösungsmitte!the product is eluted with an acetone-ethyl acetate-uoinisch in a volume ratio of 2: 1 Then the solvent is!
vom Produkt vorsichtig (im Vakuum) abdestilliert, und durch Vermischen mit Hexen bei Raumtemperatur herauskristallisiert.the product is carefully distilled off (in vacuo), and crystallized by mixing with hexene at room temperature.
Ausbeute:3,4g (84%).Yield: 3.4g (84%).
1H-NMR: (CDCL3ZTMS); δ (ppm): 0,85t (3H); 1.3S (3H); 1.4-1.9m (8H); 3,4-3,85m (3H); 7,7-8m (15H)^-abgekoppelt 13C: (CDCLj/TMS); δ (ppm): 14,1 (C7); 17,5; 19,6(C2); 23,0(Ce); 26,1; 25,2(CM.lhyi); 33,9; 34,0 (C4); 41,5 (C8); 71,8;72,3(C3); 116,4; 119,8(C1); 130,4; 130,8; 133,3; 133.7:135,1; 135,2 (C.tom„lKh). 1 H NMR: (CDCL 3 ZTMS); δ (ppm): 0.85t (3H); 1.3S (3H); 1.4-1.9m (8H); 3,4-3,85m (3H); 7,7-8m (15H) ^ - decoupled 13 C: (CDCLj / TMS); δ (ppm): 14.1 (C 7 ); 17.5; 19.6 (C 2 ); 23.0 (C e ); 26.1; 25.2 (C M, lh yi); 33.9; 34.0 (C 4 ); 41.5 (C 8 ); 71.8; 72.3 (C 3 ); 116.4; 119.8 (C 1 ); 130.4; 130.8; 133.3; 133.7: 135.1; 135.2 (C. tom " lKh ).
Claims (9)
2-(R,S)-Hydroxy-2-(2-bromäthyl)-hexan,
2-(R,S)-Hydroxy-2-(2'-jodäthyl)-hexanoder
3-(R,S)-Hydroxy-3-methyl-1-heptyltriphenyl-phosphoniumjodid herstellt.2- (R, S) -hydroxy-2- (2-hydroxyethyl) hexane,
2- (R, S) -hydroxy-2- (2-bromoethyl) hexane,
2- (R, S) -hydroxy-2- (2'-ethyl iodide) -hexanoder
3- (R, S) -hydroxy-3-methyl-1-heptyltriphenyl-phosphonium iodide.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU128187A HU198503B (en) | 1987-03-24 | 1987-03-24 | Process for producing triphenyl phosphonium salts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD268247A5 true DD268247A5 (en) | 1989-05-24 |
Family
ID=10953674
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD31386588A DD268247A5 (en) | 1987-03-24 | 1988-03-21 | IN THE OMEGA CHAIN MODIFIED NEW PROSTAGLANDIN INTERMEDIAES AND METHOD FOR THEIR MANUFACTURE |
Country Status (5)
| Country | Link |
|---|---|
| CS (1) | CS266349B2 (en) |
| DD (1) | DD268247A5 (en) |
| HU (1) | HU198503B (en) |
| PL (1) | PL153699B1 (en) |
| WO (1) | WO1988007537A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7276531B2 (en) | 2003-03-03 | 2007-10-02 | Applied Research Systems Ars Holding N.V. | G-lactam derivatives as prostaglandin agonists |
| BRPI0509757A (en) * | 2004-04-09 | 2007-10-16 | Valorisation Rech Soc En Comma | phosphate salts derivatives and their uses as solubility control aids |
-
1987
- 1987-03-24 HU HU128187A patent/HU198503B/en not_active IP Right Cessation
-
1988
- 1988-03-21 DD DD31386588A patent/DD268247A5/en not_active IP Right Cessation
- 1988-03-23 CS CS881898A patent/CS266349B2/en unknown
- 1988-03-23 WO PCT/HU1988/000016 patent/WO1988007537A1/en unknown
- 1988-03-24 PL PL27141388A patent/PL153699B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS266349B2 (en) | 1989-12-13 |
| PL271413A1 (en) | 1989-03-06 |
| HUT46333A (en) | 1988-10-28 |
| PL153699B1 (en) | 1991-05-31 |
| HU198503B (en) | 1989-10-30 |
| WO1988007537A1 (en) | 1988-10-06 |
| CS189888A2 (en) | 1989-02-10 |
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