US3876690A - 1-alkoxy-9-keto-prostenoic acid derivatives - Google Patents

1-alkoxy-9-keto-prostenoic acid derivatives Download PDF

Info

Publication number
US3876690A
US3876690A US359391A US35939173A US3876690A US 3876690 A US3876690 A US 3876690A US 359391 A US359391 A US 359391A US 35939173 A US35939173 A US 35939173A US 3876690 A US3876690 A US 3876690A
Authority
US
United States
Prior art keywords
trans
iodo
methoxy
mixture
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US359391A
Other languages
English (en)
Inventor
Jr Middleton Brawner Floyd
Martin Joseph Weiss
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Priority to US359391A priority Critical patent/US3876690A/en
Priority to CA197,722A priority patent/CA1027560A/en
Priority to AU68033/74A priority patent/AU481163B2/en
Priority to GB1874974A priority patent/GB1471070A/en
Priority to NL7405901A priority patent/NL7405901A/xx
Priority to DE2422512A priority patent/DE2422512A1/de
Priority to BE144190A priority patent/BE814869A/xx
Priority to FR7416296A priority patent/FR2228498B1/fr
Priority to JP49052777A priority patent/JPS5030850A/ja
Application granted granted Critical
Publication of US3876690A publication Critical patent/US3876690A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
    • 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
    • C07C31/13—Monohydroxylic alcohols containing saturated rings
    • C07C31/133—Monohydroxylic alcohols containing saturated rings monocyclic
    • C07C31/1333—Monohydroxylic alcohols containing saturated rings monocyclic with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/44—Halogenated unsaturated alcohols containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/14—Preparation of ethers by exchange of organic parts on the ether-oxygen for other organic parts, e.g. by trans-etherification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/164—Unsaturated ethers containing six-membered aromatic rings
    • C07C43/166—Unsaturated ethers containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/17—Unsaturated ethers containing halogen
    • C07C43/174—Unsaturated ethers containing halogen containing six-membered aromatic rings
    • C07C43/176—Unsaturated ethers containing halogen containing six-membered aromatic rings having unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/30—Compounds having groups
    • C07C43/303—Compounds having groups having acetal carbon atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • ABSTRACT This disclosure describes certain 1 1-a1koxy-9-keto-(or hydroxy)-prostenoic acid derivatives useful as antimicrobial agents, hypotensive agents. anti-ulcer agents. or as intermediates.
  • R is lower alkoxy, m-hydroxy-substituted lower alkoxy, or w-tetrahydropyranyloxy-substituted lower alkoxy;
  • R is hydrogen, lower alkyl, or triphenylmethyl;
  • R is a straight chain alkyl group having from 2 to 10 carbon atoms, a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with one or two lower alkyl groups, a straight chain alkenyl methyl group having from 3 to 10 carbon atoms, a straight chain alkenyl methyl group having from 3 to 10 carbon atoms and substituted with one or two lower alkyl groups, a cycloalkyl group having from 4 to 9 carbon atoms, lower alkyl substituted cycloalkyl group having from 5 to carbon atoms, a cycloalkylsubstituted lower alkyl group having from 6 to 12 carbon atoms and in which the cycloalkyl group is optionally substituted
  • n is an integer from 3 to 8, inclusive, p is an integer from 2 to 6 inclusive, R is an alkyl group having up to 3 carbon atoms, and R is an alkyl group having up to 3 carbon atoms, a fluorine atom or a phenyl group; and the moiety -C C is ethylene or transvinylene; with the proviso that when R is a lower alkyl group then R is hydrogen; and all optical isomers thereof.
  • non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R, is hydroxy are also embraced within the scope of the present invention.
  • the cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine, triethanolamine, procaine, and the like).
  • novel compounds of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like.
  • the cationic salts ofthe compounds when R, is hydroxy are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.
  • the hydrogen atoms attached to C-8 and C-12 are in trans-configuration.
  • the natural prostaglandins represent only one of the possible optical isomers.
  • the compounds of this invention include all possible optical isomers.
  • novel compounds of the present invention may be readily prepared from certain 4-substituted cyclopentenone intermediates which may be represented by the following general formula:
  • R is lower alkoxy or m -tetrahydropyranyloxysubstituted lower alkoxy;
  • R is tetrahydropyranyloxy or an alkoxy group having from I to 12 carbon atoms; and Z is as hereinabove defined.
  • Certain of the 4-oxycylopentenone intermediates may be prepared from the corresponding 4- unsubstituted cyclopentenones (I) in accordance with the reaction scheme of Flowsheet A, wherein Z embraces all of Z, but not cis CH CI-I CI-I(CI-I-).
  • Z embraces all of Z, but not cis CH CI-I CI-I(CI-I-
  • the requisite cyclopentenones are described in Belgium Pat. No. 786,215 (granted and laid open to inspection on Jan. 15, 1973) or can be obtained by analogous procedures to those described in the aforesaid patent.
  • R is a lower alkyl group, R" is hydroxy or an alkoxy group having from one to 12 carbon atoms, and m is an integer from two to five constitutve.
  • FLOWSHEET A unsubstituted cyclopentenones (I) is accomplished by first halogenating the 4-position with an allylic halogenating reagent, preferably N-bromosuccinimide. The resulting 4-bromocyclopentenones (II) is then solvolyzed for the introduction of the oxy function. This step is preferably carried out in the presence of a silver salt to facilitate the displacement of the halide ion. The particular 4-oxy derivative that is formed is determined by the nature of the solvent system. Treatment of the 4- bromocyclopentenone with silver fluoroborate in water-acetone (for solubility) provides the 4- hydroxycyclopentenone.
  • a particularly useful blocking group for both functions is the tetrahydropyranyl group since the group can easily be cleaved with weak acid under conditions which do not disrupt the subsequently-prepared, relatively-unstable ll-oxy- 9-keto system (,B-oxy-ketone).
  • B-oxy-ketone relatively-unstable ll-oxy- 9-keto system
  • R R',, R',, R, and Z are as defined hereinabove;
  • R,. is a lower alkyl group (each of three R, radicals bonded to a aluminum does not necessarily have to be the same),
  • R' is lower alkyl or triphenylmethyl,
  • R is hydrogen or lower alkyl and
  • R" is lower alkoxy or w-hydroxy-substituted lower alkoxy.
  • the blocked trans-vinyl iodide can also be obtained by treatment of the appropriate aldehyde (XIII) with lithium acetylide (XIV) in the usual manner, blocking the product 3-hydroxy-l-alkyne (XV) and then, in one operation, treating the resulting (XVI) successively with disiamylborane,trimethylamine N-oxide, and iodine and auqeous sodium hydroxide. to give (XI).
  • This latter procedure is preferred when R is adamatyl, contains a center of unsaturation, a cyclopropyl ring or other relatively sensitive feature.
  • the blocked vinyl iodide (XI) is then submitted to metal interchange with an alkyl lithium, e.g. n-butyl lithium, at very low temperatures, e.g. 78c., which provides the vinyl lithium derivative (XVII), the transconfiguration of the double bond being retained.
  • an alkyl lithium e.g. n-butyl lithium
  • a trialkyl aluminum [(Rg)3Al] preferably trimethyl aluminum
  • to the solution of the lithio derivative (XVII) furnishes the lithio alanate intermediate (XVIII), also with retention of the transconfiguration of the double bond.
  • the cycloalkenone (XVIII) dissolved in ether or other non-prototropic solvent, is then added to the alanate solution.
  • cycloalkenone (XVIIla) is blocked as ethers or esters, preferably, with tetrahydropyranyl and/or trialkylsilyl groups.
  • Interchange of alanate (XVIII) with cycloalkenone (XVIIIa) results in the transfer of the trans-l-alkenyl ligand in (XVIII) with retention of the trans-configuration in a 1,4-conjugate manner to the cycloalkneone (XVIIIa) furnishing, after quenching the reaction solution, the 1,4-conjugate addition product (XIX).
  • transalkenyl ligand from (XVIII) adds trans to the 4- substituent in (XVIIIa).
  • (XIX) we are however not certain of the relative configuration of the side chains to each other. The situation is indicated in structure (XIX) by the M bond between the ring and the 0 l ZC-R4 chain and is indicated in the nomenclature of the compounds involved by the designation 8E.
  • deblocking to (XX) with acid e.g. treatment with acetic acid: tetrahydrofuran: water in the ratio of 3:12! at 35-45C. for from 3 to 48 hours, results in the transrelationship between the chains.
  • reaction can also be carried out in a solvent such as tetrahydrofuran, usually in an approximate 2:1 mixture with benzene or hexane; in which case the reaction requires somewhat more vigorous conditions, usually heating at about 70C75C. for about eighteen hours.
  • a solvent such as tetrahydrofuran
  • the subsequent reaction with methyl or n-butyl lithium (R -Li) is preferably carried out in a mixture of the above solvents with an ethertype solvent such as diethyl ether, dibutyl ether, tetrahydrofuran and the like. This reaction is rapid and is preferably carried out at OCl0C. with cooling.
  • the conjugate 1,4-addition of the resulting alanate salt (XXV) to the 4-oxy-cyclopent-2 -en-l-one (XXIV) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also best carried out in an ether-type solvent such as diethyl ether,
  • the 9-keto derivatives (XXVIII) of this invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9aand 9B- hydroxy derivatives (XXIX) and (XXX) as set forth in the following reaction scheme:
  • Those compounds of this invention embodying the CH CH lingage at C C may be prepared from the corresponding A derivatives, obtained via the alanate process, by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.
  • an a-sub' stituent at the 8-, 9-, l lor l2-positions is behind the plane of the paper whereas a B-substituent at these positions is in front of the plane of paper. This is usually represented by a a bond for an a-substituent, a
  • novel compounds of the present invention have utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric crosion, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor, agents for the induction of menses, fertilitycontrolling agents, central Nervous system regulatory agents, analgesic agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents, serum-cholesterol lowering agents, antiinflammatory agents and as agents for the inhibition of platelet aggregation, and for the treatment of periodontal disease, glucoma, uveitis, sickle cell anemia and psoriasis.
  • Certain of the novel commpounds of this invention possess utility as intermediates for the prepara tion of other of the novel compounds of this invention.
  • the compounds of this invention also provide protection against the ulcerogenic properties of certain nonsteroidal anti-inflammatory agents, e.g., indomethacin, aspirin, and phenylbutazone.
  • certain nonsteroidal anti-inflammatory agents e.g., indomethacin, aspirin, and phenylbutazone.
  • novel compounds of the present invention are useful as hypotensive agents and their hypotensive activity was demonstrated in the following test procedure. This procedure is a modification of the technique described by Pike et al., Prostaglandins, Nobel Symposium 2, Stockholm, June, 1966; p. 165.
  • test compounds were prepared by ultrasonic dispersion in a saline-Tween 8O vehicle.
  • a constant intravenous dose volume of 0.5 ml. was administered and test doses ranged from 0.1 to 10.0 mg./kg. of body weight. Increasing or decreasing doses were selected depending on the dose response obtained.
  • Table I below are set forth doses at which at least a decrease of about mm. in diastolic blood pressure was observed for typical compounds of the present invention.
  • EXAMPLE 2 Preparation of 2-( 6-carboxyheptyl )cyclopent-Z-en- 1 -one This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyheptyl)cyclopent-2- en-l-one by substituting diethyl methyl malonate for diethyl ethylmalonate.
  • the 37 13 I ;P;2 Y- crude product is purified by chromatography on silica ,,,f 'i, y gel to give in order of elution: the subject compound as 38 I3 4-meth0 yfl an oil; )tmax. MeOH 219 mu (8860);-vmax. 1735 Pfj fvfgig (ester carbonyl group), 1725 ketone carbonyl group).
  • the exothermic 4s reaction is controlled to give a temperature of 29C., thoxy-5.5-dimethylhexand after 1 minute the mixture is treated during 1 min- 46 a 3i ute with 8.6 g. (80 mmole) of 2,6-lutidine.
  • the mixture g ,,g g is stirred at ambient temperature for 2 hours.
  • the filtrate is diluted with sat- 47 ifig igigg ifi urated sodium chloride solution and extracted with pent-Z-cn-l-one ether.
  • EXAMPLE 127 Preparation of 3-triphenylmethoxy-l-octyne A mixture of 1.26 g. (10.0 mmoles) of 1-octyn-3-o1, 4.85 g. 15.0 mmoles) of triphenylmethyl bromide, and 50 ml. of dry pyridine is heated at 95C. for 60 minutes with occasional swirling. The solution is cooled, treated with water, and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on Florisil and recrystallization from petroleum ether to give white crystals, m.p. 6566C. A max. (KBr) 3280 (acetylenic hydrogen), 1605, 1030, and 702 cm (triphenylmethoxy group).
  • EXAMPLE 128 Preparation of liodo-3-triphenylmethoxy-transl octene To a mixture of 0.650 g. (16.91 mmole) of sodium borohydride and 3.17 g. (45.2 mmoles) of 2-methy1-2- butene in 40 ml. of diglyme cooled to 5C. under an inert atmosphere is added over 15 minutes 3.24 g. (22.6 mmoles) of boron trifluoride etherate and the resulting mixture is stirred at C. for 2 hours. To this mixture is then added over minutes 8.32 g.
  • the organic phase is separated and the aqueous phase is washed with ether.
  • the combined organic phase and washings are decolorized with 5% sodium thiosulfate solution. washed with saturated brine, dried (Na SO and evaporated.
  • the residue is dry-columned chromatographed upon alumina using hexane is eluent and the title compound is isolated as an oil.
  • EXAMPLE 138A Preparation of 3-methoxy-1-octyne To an ice-cooled solution of 63 g. of 1-octyn-3-ol in 300 ml. of dimethoxyethane is added under an inert atmosphere 312 ml. of 1.6 M n-butyllithium in hexane dropwise over 1 hour. To the mixture is then added 145 g. of methyl iodide and the resulting mixture is stirred at ambient temperatures for 24 hours and then heated to 60C. for 1 hour. The mixture is cooled and poured into cold dilute hydrochloric acid.
  • EXAMPLE 150 Preparation of 4,4-dimethyl-3tetrahydropyranyloxy- 1 -octyne
  • EXAMPLE 151 Preparation of 4,4-dimethyl-l-iodo-trans-l-octen-3-ol
  • 23.8 g. (0.100 mole) 4,4-dimethyl-3-tetrahydropyranyloxy-l-octyne (Example 150).
  • the mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours.
  • the solution is cooled to 0C. and 22.5 g.
  • EXAMPLE 155 Preparation of 5,5-dimethyl-l-iodo-trans-l-octen-3-ol Treatment of 23.8 g. (0.100 mole) of5,5-dimethyl-3- tetrahydropyranyloxy-l-octyne (Example 154) successively with 233 mg. of 0.43 M disiamylborane in diglyme, 22.5 g. of trimethylamine oxide, 150 ml. of l N sodium hydroxide, 25.4 g. of iodine, and 900 ml. of
  • EXAMPLE 156 Preparation of 5 ,S-dimethyll -iodo-3-triphenylmethoxy-transl octene Treatment of 6.0 g. of 5.5-dimethyl-l-iodo-trans-locten-3-ol (Example with 6.9 g. of triphenylmethyl bromide in 30 ml. of pryridine and purification on Florisil all as described in Example 127 gives the title compound.
  • EXAMPLE 157 Preparation of 1,l-dimethoxy-cis-3,4-methanohexane (cisl -ethyl-2-( 2,2-dimethoxyethyl )-cyclopropane) To an ethereal suspension of zinc-silver couple, prepared according to the procedure of].
  • M. Danis, C. Girand, and J. M. Conia, Synthesis, 1972, 549 from 0.400 g. of silver acetate, 400 ml. of acetic acid, 68 g. of granular zinc, silver wool, and 600 ml. of ether, is added dropwise 136 g. of diiodomethane at a rate to maintain a gentle reflux.
  • EXAMPLE 159 Preparation of cis-5,6-methano-1-octyn-3-ol To a solution of 15.2 g. (0.165 mole) of lithium acetylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide is added 16.8 g. (0.150 mole) of cis-3,4-methano-l-hexanol (Example 158) in 25 ml. of dimethylsulfoxide at a rate to maintain a temperature of 25C. (cooling). The mixture is then maintained at 25C. for 2 hours and is poured onto ice and excess hydrochloric acid. The mixture is extracted with ether and the organic phase is washed with water and saturated brine, dried (Na SO and evaporated to an oil. Distillation in vacuo yields the title compound as a colorless oil.
  • EXAMPLE 177 Preparation of 1-ch1oro-4-cyc1openty1-1-trans-buten-3-one
  • a three-necked flask filtered with a stirrer, a gas inlet tube and a gas outlet tube protected with a calcium chloride tube is surrounded by an ice-water bath.
  • the system is flushed with acetylene for 3 minutes.
  • Carbon tetrachloride 150 ml.
  • acetylene is bubbled through at a fast rate for 3 minutes.
  • A1- uminium chloride (59 g.) is added and acetylene is bubbled through the mixture for 5 minutes.
  • the gas inlet tube is replaced by a dropping funnel protected by a calcium chloride drying tube.
  • Cyclopentaneacetyl chloride (55.4 g., Example 176) is added to the reaction mixture with stirring over a period of about 20 minutes.
  • the dropping funnel is replaced by the gas inlet tube and with stirring, acetylene gas is bubbled through at a rate in excess of the saturation rate. After about minutes the rate of absorption of acetylene suddenly becomes very rapid, and the acetylene is passed through as rapidly as it is absorbed. The introduction of acetylene is continued for 45 minutes after rapid absorption (which lasts about 1 hour) has subsided.
  • the reaction mixture is poured with stirring onto 430 g. of ice 180 ml. of saturated sodium chloride solution.
  • the aqueous phase is extracted three times more with ether.
  • the combined extracts are dried with anhydrous magnesium sulfate and evaporated to dryness in vacuo.
  • 1.5 g. of hydroquinone the residual oil is distilled to give 57 g. (89%) of oil, b.p. 67-69C. (0.14 mm.).
  • EXAMPLE 178 Preparation of 4-cyc1openty1-1-iodo-1-trans-buten-3-one
  • EXAMPLE 179 Preparation of 4-cyc1openty1-1-iodo-1-trans-buten-3-ol
  • a solution containing 87 g. of 4- cyclopentyl-l-iodo-trans-buten-B-one (Example 178) in 160 ml. of absolute alcohol.
  • the temperature is 'maintained at 5-10C.
  • EXAMPLE 201 Preparation of 4-cyclopentyll -iodo-3-( pmethoxyphenyldiphenyl)methoxyl trans-butene
  • a solution of g. of 4-cyclopentyl-l-iodo-l-transbuten-3-ol (Example 179) and g. of panisylchlorodiphenylmethane in I70 ml. of dry pyridine is kept at 60C. for 18 hours, then at 70C. for 3 hours.
  • the cooled solution is poured into 850 ml. of iced water.
  • the resulting solution is partitioned between ether and water.
  • the ether layer is washed with water.
  • EXAMPLE 224 Preparation of 1iodo-trans-1-octen-3-one A mixture of 54.5 g. (0.364 mole) of sodium iodide and 40 g. (0.249 mole) of l-chloro-trans-1-octen-3-one (Example 222) in 360 ml. of acetone is stirred and refluxed for 24 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between water and ether. The organic phase is washed with dilute sodium bicarbonate solution, brine, dried (MgSO and evaporated to an oil. This material is used directly without purification.
  • EXAMPLE 225 Preparation of l-iodo-trans-1-octen-3-ol A solution of 78.2 g. (0.310 moles) of l-iodo-trans-locten-3-one (Example 224) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 l. of water.
  • the gral e l i orislfpac sl e extract is washed with water and concentrated using P O i f e u g ga 3 5 toluene for azeotropic removal of aqueous acetic acid. 828; 6 pro uc yle S a CO or ess O1 The residue is chromatographed on silica gel to yield ton) the title product and its l5-epimer.
  • EXAMPLE 226 EXAMPLE 228-393 Preparation of 40 Treatment of 1rodo-3-trrphenylmethoxy (or 1'lodo'?”(p-anlsyldlphenylmethoxyHrans'loctene 3methoxy)-trans-l-alkene listed in Table 12 below A mixture of 14.92 g. (0.0588 mole) of l-iodo-transwith n-butyl lithium followed by treatment of the re p and 182 g- (00588 mOle) sulting trans-l-alkenyl lithium derivative with trimethof p-anisyldiphenylmetl yl chloride in 165 ml.
  • angiogvapo the 1S-S-triphjenylmithgl-S-fidergvatrges correspond% rated.
  • the residue is c romatpgrap e upon g. 0 ing to t e pro ucts o t e ta e. urt er treatment 0
  • acetic acid:tetrahydrofuran:- hexane and 4:1 hexane-benzene the yield a colorelss water as described in Example 227 gives the products oil. of the table.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US359391A 1973-05-11 1973-05-11 1-alkoxy-9-keto-prostenoic acid derivatives Expired - Lifetime US3876690A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US359391A US3876690A (en) 1973-05-11 1973-05-11 1-alkoxy-9-keto-prostenoic acid derivatives
CA197,722A CA1027560A (en) 1973-05-11 1974-04-17 Prostenoic acid derivatives and method for preparing same
AU68033/74A AU481163B2 (en) 1973-05-11 1974-04-18 Novel prostenoic acid derivatives and method for preparing same
GB1874974A GB1471070A (en) 1973-05-11 1974-04-29 Prostenoic acid derivatives and method for preparing same
NL7405901A NL7405901A (en:Method) 1973-05-11 1974-05-02
DE2422512A DE2422512A1 (de) 1973-05-11 1974-05-09 Prostansaeurederivate und verfahren zu deren herstellung
BE144190A BE814869A (fr) 1973-05-11 1974-05-10 Nouveaux derives d'acides 11-alcoxy prostanoiques utiles notamment comme hypotenseurs
FR7416296A FR2228498B1 (en:Method) 1973-05-11 1974-05-10
JP49052777A JPS5030850A (en:Method) 1973-05-11 1974-05-11

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US359391A US3876690A (en) 1973-05-11 1973-05-11 1-alkoxy-9-keto-prostenoic acid derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US05540352 Division 1975-01-10

Publications (1)

Publication Number Publication Date
US3876690A true US3876690A (en) 1975-04-08

Family

ID=23413612

Family Applications (1)

Application Number Title Priority Date Filing Date
US359391A Expired - Lifetime US3876690A (en) 1973-05-11 1973-05-11 1-alkoxy-9-keto-prostenoic acid derivatives

Country Status (8)

Country Link
US (1) US3876690A (en:Method)
JP (1) JPS5030850A (en:Method)
BE (1) BE814869A (en:Method)
CA (1) CA1027560A (en:Method)
DE (1) DE2422512A1 (en:Method)
FR (1) FR2228498B1 (en:Method)
GB (1) GB1471070A (en:Method)
NL (1) NL7405901A (en:Method)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3985798A (en) * 1975-01-27 1976-10-12 American Cyanamid Company 11α-HOMO-PROSTANOIC ACIDS AND ESTERS
US4035415A (en) * 1974-09-25 1977-07-12 Carlo Erba, S.P.A. Omega-nor-cycloalkyl-13,14-dehydro-prostaglandins
US4085272A (en) * 1977-03-30 1978-04-18 American Cyanamid Company 11-(2-Hydroxyethylthio)prostenoic acid E2 series derivatives
US4169145A (en) * 1974-09-25 1979-09-25 Carlo Erba S.P.A. ω-Nor-cycloalkyl-13,14-dehydro-prostaglandins
US4189597A (en) * 1977-03-30 1980-02-19 American Cyanamid Company 11-(2-Hydroxyethylthio)prostenoic acid E series derivatives
US4218566A (en) * 1977-03-30 1980-08-19 American Cyanamid Company 11-(2-Hydroxyethylthio) prostenoic acid E and F series derivatives
EP1008588A4 (en) * 1997-02-10 2000-06-14 Ono Pharmaceutical Co 11,15-O-DIALKYLPROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THEM, AND MEDICINAL PRODUCTS CONTAINING THEM AS ACTIVE INGREDIENT

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5361706U (en:Method) * 1976-10-27 1978-05-25

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3735005A (en) * 1970-08-19 1973-05-22 Alza Corp Method for preparing a viable platelet concentrate
US3751463A (en) * 1970-05-27 1973-08-07 May & Baker Ltd Cyclopentane derivatives
US3781325A (en) * 1971-05-04 1973-12-25 Upjohn Co 15-methoxy-pgf2a

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3751463A (en) * 1970-05-27 1973-08-07 May & Baker Ltd Cyclopentane derivatives
US3735005A (en) * 1970-08-19 1973-05-22 Alza Corp Method for preparing a viable platelet concentrate
US3781325A (en) * 1971-05-04 1973-12-25 Upjohn Co 15-methoxy-pgf2a

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4035415A (en) * 1974-09-25 1977-07-12 Carlo Erba, S.P.A. Omega-nor-cycloalkyl-13,14-dehydro-prostaglandins
US4169145A (en) * 1974-09-25 1979-09-25 Carlo Erba S.P.A. ω-Nor-cycloalkyl-13,14-dehydro-prostaglandins
US3985798A (en) * 1975-01-27 1976-10-12 American Cyanamid Company 11α-HOMO-PROSTANOIC ACIDS AND ESTERS
US4085272A (en) * 1977-03-30 1978-04-18 American Cyanamid Company 11-(2-Hydroxyethylthio)prostenoic acid E2 series derivatives
US4189597A (en) * 1977-03-30 1980-02-19 American Cyanamid Company 11-(2-Hydroxyethylthio)prostenoic acid E series derivatives
US4218566A (en) * 1977-03-30 1980-08-19 American Cyanamid Company 11-(2-Hydroxyethylthio) prostenoic acid E and F series derivatives
EP1008588A4 (en) * 1997-02-10 2000-06-14 Ono Pharmaceutical Co 11,15-O-DIALKYLPROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THEM, AND MEDICINAL PRODUCTS CONTAINING THEM AS ACTIVE INGREDIENT

Also Published As

Publication number Publication date
AU6803374A (en) 1975-10-23
DE2422512A1 (de) 1974-11-21
FR2228498A1 (en:Method) 1974-12-06
CA1027560A (en) 1978-03-07
NL7405901A (en:Method) 1974-11-13
JPS5030850A (en:Method) 1975-03-27
FR2228498B1 (en:Method) 1977-03-11
GB1471070A (en) 1977-04-21
BE814869A (fr) 1974-11-12

Similar Documents

Publication Publication Date Title
Bernady et al. Prostaglandins and congeners. 20. Synthesis of prostaglandins via conjugate addition of lithium trans-1-alkenyltrialkylalanate reagents. A novel reagent for conjugate 1, 4-additions
US3873607A (en) 3-Oxa(and thia) 11-deoxy PGE
CH647222A5 (de) 9-desoxy-9a-methylen-isostere von pgi-2 und verfahren zu deren herstellung.
Stapp Reaction of. alpha.-olefins with paraformaldehyde and hydrogen halides. Novel tetrahydropyran synthesis
US3876690A (en) 1-alkoxy-9-keto-prostenoic acid derivatives
US3932479A (en) Lithium 3-triphenylmethoxy-1-trans-alkenyl-dialkyl alanates
US4060540A (en) Novel 3-triphenylmethoxy-1-alkynes, 3-triphenyl-methoxy-1-trans-alkenyl-dialkyl-alanes, and lithium 3-triphenylmethoxy-1-trans-alkenyl-dialkyl alanates
US4236027A (en) Novel 11-alkoxy-9-keto (or hydroxy)-prostenoic acid derivatives and method for preparing same
AT367747B (de) Verfahren zur herstellung von optisch aktiven oder racemischen prostaglandinen und ihren salzen
US3884969A (en) Novel prostaglandins
US4608388A (en) Novel [4,2,0]bicyclooctane derivatives with valuable therapeutic properties
US4076947A (en) Cycloalkyl and cycloalkenyl prostaglandin congeners
US3993674A (en) Novel prostaglandins
CA1045131A (en) Derivatives of 9-hydroxy-13-trans-prostenoic acid
US4007210A (en) Novel 3-triphenylmethoxy-1-alkynes, 3-triphenylmethoxy-1-trans-alkenyl-dialkyl-alanes, and lithium 3-triphenyl-methoxy-1-trans-alkenyl-dialkyl-alanates
US4678805A (en) Novel 8-(lower alkyl)bicyclo[4.2.0]octane derivatives with valuable therapeutic properties
US4180677A (en) Novel prostaglandins
US2369164A (en) Synthesis of vitamin a
US4123456A (en) Novel 11-hydroxy-9-keto-5,6-cis-13,14-cis-prostadienoic acid derivatives
US4090019A (en) Geminal prostaglandin analogs
DE2425573A1 (de) Neue prostaglandine
US3897483A (en) Novel 1-acyloxy-2-(omega-carboalkoxyalkyl)cycloalk-1-enes
US4179574A (en) Novel 2-substituted-3,4-epoxycyclopentan-1-ones, 2-substituted-3,4-epoxycyclopentan-1-ols, and various 2-substituted-cyclo-pentenones
US4343949A (en) Novel 2-substituted-3,4-epoxycyclopentan-1-ones, 2-substituted-3,4-epoxycyclopentan-1-ols, and various 2-substituted-cyclopentenones
US2369160A (en) Synthesis of vitamin a