US3899525A - 9{86 ,15{86 -Dihydroxy-11{60 -hydroxymethylprost-13(trans)-enoic acid derivatives - Google Patents

9{86 ,15{86 -Dihydroxy-11{60 -hydroxymethylprost-13(trans)-enoic acid derivatives Download PDF

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US3899525A
US3899525A US392113A US39211373A US3899525A US 3899525 A US3899525 A US 3899525A US 392113 A US392113 A US 392113A US 39211373 A US39211373 A US 39211373A US 3899525 A US3899525 A US 3899525A
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Osamu Oda
Kiyoshi Sakai
Takashi Yusa
Hamako Katano
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Sankyo Co Ltd
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Sankyo Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic 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
    • 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

Definitions

  • ABSTRACT Prostenoic acid derivative having the formula wherein A represents an alkylene group having from 4 to 8 carbon atoms, R represents an alkyl group having from 4 to 10 carbon atoms, R represents hydrogen atom or an alkyl group having from one to 6 carbon atoms and R represents hydrogen atom or an alkoxycarbonyl group having from one to 6 carbon atoms in the alkyl moiety and pharmaceutically acceptable salts thereof.
  • the compounds are useful as oxytocic agents and may be prepared by reducing the compound having the formula 3 R OH C wherein A, R, R and R have the meanings given above with a metal hydride complex, for example, sodium boron hydride and potassium boron hydride in the presence or absence of an inert organic solvent.
  • a metal hydride complex for example, sodium boron hydride and potassium boron hydride in the presence or absence of an inert organic solvent.
  • R may be a straight or branched alkyl group having from 4 to 10 carbon atoms, preferably, n-butyl, isobutyl, n-pentyl, isopentyl, l-methylpentyl, Z-methylpentyl, 1 l -dimethylpentyl, 1,2-dimethylpentyl, n-hexyl, isohexyl, l-methylhexyl, 1,1-dimethylhexyl, 1,2-dimethylhexyl, n-heptyl,
  • R represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and the alkyl group may be straight or branched, preferably, methyl, ethyl and n-propyl.
  • R represents hydrogen atom or an alkoxycarbonyl group having from 1 to 6 carbon atoms, e.g., ethoxycarbonyl, npropoxycarbonyl and n-butoxycarbonyl.
  • a preferred group of the prostaglandin derivatives provided by the invention are those of the formula (I) wherein A represents hexamethylene group, i.e., those having the formula wherein R, R and R are the same as above and the pharmaceutically acceptable salts thereof.
  • a bond attached to the cyclopentane nucleus which is in the oz-configuration, i.e., extends below the plane of the cyclopentane ring, is represented by a dotted line
  • a bond which is in the ,B-configuration, i.e., extends above the plane of the cyclopentane ring is represented by a solid line.
  • the wavy line indicates that either steric configuration is possible.
  • the pharmaceitucally acceptable salts of the acids of formulae (I) and (I-a) in which R is hydrogen atom include alkali and alkaline earth metal salts, e.g., the sodium, potassium, magnesium and calcium salts, quaternary ammonium salts, e.g., the ammonium, tetramethylammonium, tetraethylammonium, benzyltrimethylammonium and phenyltriethylammonium salts, aliphatic, alicyclic or aromatic amine salts, e.g., the methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine and ethylene diamine salts, heterocyclic amine salts, e.g.,
  • the compounds of the invention are useful as oxytocic agents; and the invention provides pharmaceuticalcompositions comprising a compound of formula (I), or a pharmaceutically acceptable salts thereof, and a pharmaceutical carrier or diluent.
  • the pharmaceutical compositions of the invention are generally formulated for parenteral administration.
  • the compounds of formula (I) may be administered by continuous intravenous infusion, dissolved in sterile, pyrogen-free isotonic sodium chloride solution.
  • the optimum dosage of the compounds of the invention will vary with the body weight and age of the patient; but the parenteral total daily dosage for full-term pregnant women will generally be from about 0.5 g. to
  • the compound having the formula (I) may be prepared by reducing a compound having the formula wherein A, R R and R are the same as above with a metal hydride complex in the presence or absence of an inert organic solvent.
  • the reduction maybe preferably carried out by contacting the compound (II), (III) or (IV) with the metal hydride complex in the presence of an inert organic solvent.
  • the metal hydride complex include alkali metal boron hydrides, e.g., sodium boron hydride, potassium boron hydride, lithium boron hydride, sodium cyano boron hydride, lithium 9b-boro-perhydrophenalene hydride; alkali metal aluminum hydrides, e.g., aluminum tri-tert.-butoxylithium hydride, aluminum trimethoxylithium hydride; and zinc boron hydride.
  • alkali metal boron hydrides e.g., sodium boron hydride, potassium boron hydride, lithium boron hydride, sodium cyano boron hydride, lithium 9b-boro-perhydrophenalene hydride
  • alkali metal aluminum hydrides e.g., aluminum tri
  • the inert organic solvent include alcohols, e.g., methanol and ethanol; ethers, e.g., diethyl ether, tetrahydrofuran, dioxane, diglyme; and dialkylformamides, e. g., dimethylformamide.
  • the reduction is preferably carried out at relatively low temperatures, usually at a temperature from lOC. to room temperature.
  • the reaction period will depend mainly upon the reaction temperature and a kind of the reducing agent. It is usually from about 30 minutes to 3 hours.
  • the desired product may be recovered from the reaction mixture by conventional means.
  • organic acids e.g., formic acid and acetic acid
  • the reaction mixture is extracted with an organic solvent.
  • the extract is washed with water and dried and the solvent is'distilled off to give the desired product.
  • the product thus obtained may be further purified, if necessary, by conventional means, forv example, column chromatography or thin-layer chromatography.
  • the compounds of the formula (I) and their salts can exist as four different optical isomers, depending up n the configuration of the hydroxy groups attached to the cyclopentane nucleusand the side-chain.
  • the racemic mixtures of these isomers can be resolved by "16 con.- ventional techniques. so as to obtain the desir ucts in he form of optically pure diastereoisomers formulae (I) and (l-a') are used to represent both diastereoisomeric forms. as well as the racemic mixtures. but the pure isomers are included within the scope of the invention, as well as their mixtures.
  • the hydroxyand carboxy-protecting group may be removed by conventional means, for example, by treating the compound (II), (III) or (IV) with an acid, e.g., acetic acid, hydrochloric acid or with a base, e.g., sodium hydroxide, sodium carbonate.
  • an acid e.g., acetic acid, hydrochloric acid
  • a base e.g., sodium hydroxide, sodium carbonate.
  • R R R, R R and R are the same as above, R R R, R R and R may be the same or different and each represents an alkyl group having from 1 to 6 carbon atoms.
  • Each of theabove steps may be illustrated as follows: i v
  • the compound (VI) may be prepared by reacting the compound (V) with ethylene glycol in the presence of a Lewis acid, e.g., boron trifluoride.
  • a Lewis acid e.g., boron trifluoride.
  • the reaction is preferably carried out in an inert organic solvent such as dichloromethane, chloroform or benzene at a temperature ranging from 0C. to room temperature.
  • the compound (VII) may be prepared by reacting the compound (VI) with an alkali metal compound, e.g., sodium methoxide, potassium ethoxide, sodium hydroxide.
  • the reaction is preferably carried out in an inert organic solvent such as tetrahydrofuran, dioxane or methanol at a temperature ranging from OC.'to a reflux temperature of the reaction mixture.
  • an inert organic solvent such as tetrahydrofuran, dioxane or methanol at a temperature ranging from OC.'to a reflux temperature of the reaction mixture.
  • the bond of the group COOR is changed from B-configuration to a-con'figuration.
  • the compound (VIII) may be prepared by reducing the compound (VII) with a metal hydride compound such as sodium boron hydride, potassium boron hydride, lithium boron hydride, trimethoxylithium aluminum hydride or aluminum, lithium hydride.
  • a metal hydride compound such as sodium boron hydride, potassium boron hydride, lithium boron hydride, trimethoxylithium aluminum hydride or aluminum, lithium hydride.
  • the reaction is preferably carried out in an inert organic solvent such as methanol, tetrahydrofuran or ether at a temperature ranging from 0C. to a reflux temperature of the reaction mixture.
  • the compound (IX) or (XVI) may be prepared respectively by reacting the compound (VIII) or (XV) with a compound having the formula X COOR or X COOR wherein R and R are the same as above and X and X represent a halogen atom, e.g., chlorine, bromine, iodine in the presence of a base such as sodium carbonate, sodium' bicarbonate, triethylamine, pyridine or N-methylpiperazine.
  • a base such as sodium carbonate, sodium' bicarbonate, triethylamine, pyridine or N-methylpiperazine.
  • the reaction is preferably carried out below room temperature.
  • the compound (X) may be prepared by reacting the compound (IX) with an acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid or sufuric acid.
  • the reaction is preferably carried out in a solvent such as water, methanol, ether or acetone at a temperature ranging from 0C. to 60C.
  • the compound (XI) may be prepared by reacting the compound (X) with an alkali metal compound such as alkali metal alkoxides, e.g., sodium methoxide, potassium ethoxide, potassium tert.-butoxide; alkali metal hydrides, e.g., sodium hydride, potassium hydride; or alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide.
  • the reaction is preferably carried out in an inert organic solvent such as tetrahydrofuran, ether and benzene at a temperature ranging from -50C. to 80C. in an inert gas atmosphere, for example in argon or helium atmosphere.
  • the compound (XII) may be prepared by reacting the compound (XI) with a compound having the formula X A COOR wherein A and R are the same as above and X represents a halogen atom, e.g., bromine, chlorine, in the presence of an alkali metal compound such as alkali metals, e.g., metallic sodium; alkali metal hydroxides, e.g., sodium hydroxide, potassium hydroxide; or alkali metal alkoxides, e.g., sodium methoxide, potassium ethoxide.
  • the reaction is preferably carried out in an inert organic solvent, e.g., benzene, ether, tetrahydrofuran, dimethyl sulfoxide, below room temperature in an inert gas atmosphere, for example in argon or helium atmosphere.
  • the compound (XIII) may be prepared by reacting the compound (XII) with an alkali metal compound such as sodium hydroxide, potassium hydroxide, so-
  • the reaction is preferably carried out in a solvent, e.g., water, methanol, ether, dioxane, a mixture of water and such an organic solvent, at a temperature ranging from room temperature to reflux temperature of the reaction mixture in an inert gas atmosphere, for example, in an argon or helium atmosphere.
  • a solvent e.g., water, methanol, ether, dioxane, a mixture of water and such an organic solvent
  • the compound (XIV) may be prepared by contacting the compound (XIII) with an oxidizing agent such as chromic acid, chromic anhydride, chromic anhydride-pyridine complex, sodium bichromate dimethyl sulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride.
  • an oxidizing agent such as chromic acid, chromic anhydride, chromic anhydride-pyridine complex, sodium bichromate dimethyl sulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride.
  • the reaction is preferably carried out in a solvent such as acetic acid, dichloromethane and chloroform at a temperature ranging from 0C. to room temperature.
  • the compound (XV) may be prepared by contacting the compound (XIV) with an acid such as formic acid, acetic acid, hydrochloric acid or sulfric acid, or with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.
  • an acid such as formic acid, acetic acid, hydrochloric acid or sulfric acid
  • an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.
  • the reaction is preferably carried out in a solvent, e.g., water, methanol, ether at a temperature ranging from room temperature to reflux temperature of the reaction mixture.
  • the compound (XVII) may be prepared by reacting the compound (XV) with an alcohol, e.g., diazomethane and diazoethane.
  • the compound (II) may be prepared by reacting the compound (XIV), (XV), (XVI) or (XVII) with a Wittig reagent having the formula wherein R is the same as above and R represents an alkyl group having'from l to 6 carbon atoms or phenyl group. At least I mole of the Wittig reagent is used per mole of the compound (XIV), (XV), (XVI) or (XVII) and preferably from 2 to 10 moles of the Wittig agent is used.
  • the reaction is generally carried out in an inert organic solvent such as ether, benzene, toluene, hexane, dimethyl sulfoxide, tetrahydrofuran, methylene chloride or chloroform, at a temperature ranging from O C. to a reflux temperature of the reaction mixture, preferably at room temperature or below and in an inert gas atmosphere, for example, in an argon or helium atmosphere.
  • the reaction is carried out for a period of Shows to 30 hours depending on the temperature and concentration of the reaction mixture and the specific Wittig reagent used.
  • the product obtained in each step of the above process may be recovered from the reaction mixture in a conventional manner, for example, by evaporating the solvent from the reaction mixture or by adding water and extracting with a water-immiscible solvent.
  • the crude product can be purified by conventional means such as recrystallization or chromatography.
  • the compound (XVII) may be prepared by reacting the compound (XIII) with ethylene glycol in the presence of a Lewis acid, e.g., boron trifluoride.
  • a Lewis acid e.g., boron trifluoride.
  • the reaction is preferably carried out in an inert organic solvent such as dichloromethane, chloroform or benzene at a temperature ranging from 0C. to room temperature.
  • the compound (XIX) may be prepared by contacting the compound (XVIII) with an oxidizing agent such as chromic acid, chromic anhydride, chromic anhydride-pyridine complex, sodium bichromate, dimethyl sulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride.
  • an oxidizing agent such as chromic acid, chromic anhydride, chromic anhydride-pyridine complex, sodium bichromate, dimethyl sulfoxide-chlorine complex, dimethyl sulfoxide-acetic anhydride.
  • the reaction is preferably carried out in a solvent such as acetic acid, dichloromethane, chloro- 60 perature of the reaction mixture.
  • the compound (XXI) may be prepared by reacting the compound (XIX) or (XX) with a Wittig reagent having the formula wherein R is the same as above and R represents an alkyl group having from 1 to 6 carbon atoms or phenyl group. At least 1 mole of the Wittig reagent is used per mole of the compound (XIX) or (XX) and preferably from 2 to 10 moles of the Wittig agent is used.
  • the reaction is generally carried out in an inert organic solvent such as ether, benzene, toluene, hexane, dimethyl sulfoxide, tetrahydrofuran, methylene chloride or chloroform, at a temperature ranging from 0C.
  • reaction mixture preferably at room temperature or below and in an inert gas atmosphere, for example, in an argon or helium atmosphere.
  • the reaction is carried out for a period of'5 hours to 3O or dimethylforrnamide, at relatively low temperatures,
  • room I group usually at a temperature ranging from -l0C. to room I group may be prepared by reacting the compound hours depending on the temperature andconcentrati'on of the reaction mixture and the specific Wittig reagent used.
  • the compound (XXII) may be prepared by reducing The reaction is preferably carried out in an inert organic solvent such'a's methanol, ethanol, ether, dioxane (XXII) with an acid and reacting the product thus obtained with a compound having the formula X COOR
  • the compound (XXIII) may be prepared by reacting the compound (XIII) with dihydropyran in the presence of a mineral acid, e.g., hydrochloric acid, hydrobromic acid or an organic acid, e.g., p-toluenesulfonic acid.
  • a mineral acid e.g., hydrochloric acid, hydrobromic acid or an organic acid, e.g., p-toluenesulfonic acid.
  • the reaction is preferably carried out in an inert organic solvent such as benzene, toluene or chloroform at a temperature ranging from C. to room temperature.
  • the compound (XXIV) may be prepared by reducing the compound (XXIII) with a metal hydride compound such as sodium boron hydride, potassium boron hydride, lithium boron hydride, trimethoxylithium aluminum hydride and aluminum lithium hydride.
  • a metal hydride compound such as sodium boron hydride, potassium boron hydride, lithium boron hydride, trimethoxylithium aluminum hydride and aluminum lithium hydride.
  • the reaction is preferably carried out in an inert organic solvent such as methanol, tetrahydrofuran or ether at a temperature ranging from 0C. to a reflux temperature of the reaction mixture.
  • the compound (XXV) may be prepared by contacting the compound (XXIV) with a halide or anhydride of an alkanoic acid or benzoic acid, e.g., acetic anhydride, acetyl chloride, benzoic anhydride, benzoyl chloride.
  • a halide or anhydride of an alkanoic acid or benzoic acid e.g., acetic anhydride, acetyl chloride, benzoic anhydride, benzoyl chloride.
  • the compound (XXVI) may be prepared by contacting the compound (XXV) with a dilute acid solution, for example, a dilute solution of acetic acid, hydrochloric acid or sulfuric acid.
  • a dilute acid solution for example, a dilute solution of acetic acid, hydrochloric acid or sulfuric acid.
  • the compound (XXVII) may be prepared by contacting the compound (XXVI) with an oxidizing agent, e.g., chromic acid, dimethyl sulfoxide-chlorine complex, dimethylsulfoxide-acetic anhydride, N- bromoacetamide and aluminum tert.-butoxide.
  • an oxidizing agent e.g., chromic acid, dimethyl sulfoxide-chlorine complex, dimethylsulfoxide-acetic anhydride, N- bromoacetamide and aluminum tert.-butoxide.
  • the reaction is carried out at a temperature ranging 20C. to room temperature in a solvent, e.g., benzene, acetic acid, dichloromethane and aqueous tert.-butanol.
  • the compound (XXVIII) may be prepared by reacting the compound (XXVII) with a Witting reagent having the formula (R P CH CO R wherein R is the same as above and R represents an alkyl group from I to 6 carbon atoms or phenyl group. At least 1 mole of the Wittig reagent is used per mole of the compound (XXVII) and preferably from 2 to 10 moles of the Wittig agent is used.
  • the compound (IV) in which R is an alkyl group and R is hydrogen atom may be prepared by contacting the compound (XXVIII) withan acid such as formic acid, acetic acid. hydrochloric acid or sulfuric acid or with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.
  • an acid such as formic acid, acetic acid. hydrochloric acid or sulfuric acid or with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.
  • the compound (IV) in which R and R are hydrogen atom may be prepared by reacting the compound (XXVIII) with an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.
  • an alkali metal compound such as sodium hydroxide, potassium hydroxide or sodium carbonate.
  • the compound (IV) in which R is hydrogen atom and R is alkoxycarbonyl group may be prepared by reacting the compound (XXVIII) with an alkali metal compound and reacting the product thus obtained with a compound having the formula x cooR wherein X represents a halogen atom, e.g., chlorine, bromine, iodine and R represents an alkyl group having from 1 to 6 carbon atoms in the presence of an alkali metal compound such as sodium carbonate, sodium bicarbonate.
  • X represents a halogen atom, e.g., chlorine, bromine, iodine
  • R represents an alkyl group having from 1 to 6 carbon atoms in the presence of an alkali metal compound such as sodium carbonate, sodium bicarbonate.
  • the product obtained in each step of the above process may be recovered from the reaction mixture in a conventional means, for example, by evaporating the solvent from the reaction mixture or by adding water and extracting with a water immiscible solvent.
  • the crude product can be purified by conventional means such as recrystallization or chromatography.
  • Preparations l and 2 illustrate the preparation of the compound (II).
  • Preparations 3 and 5 illustrate the preparation of the compound (III).
  • Preparation 4 illustrates the preparation of the compound (IV).
  • Examples 1 and 2 illustrate the preparation of the compound (I) from the compound (II).
  • Example 3, 4, 6 and 7 illustrate the preparation of the compound (I) from the compound (III).
  • Example 5 illustrates the preparation of the compound (I) from the compound (IV).
  • the re action mixture was added dropwise to 1.5 l. of a saturated aqueous sodium bicarbonate containing pieces of ice in order to decompose the excess of the boron trifluoride etherate.
  • the mixture was extracted three times with l l. of ether.
  • the extract was washedwith a saturated aqueous sodium chloride and a saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate.
  • the solvent was distilled off from the extract to give 135.7 g. of the desired product as colorless oil.
  • the ether was separated from the reaction mixture by decantation.
  • the aqueous layer was extracted with ether and further subjected to evaporation under reduced pressure.
  • the residue was extracted with absolute ethanol. All of the extract were combined and dried over anhydrous sodium sulfate.
  • the solvent was distilled off to give 68.4 g. of the desired product as pale yellow oil.
  • the solvent was distilled off from the reaction mixture under reduced pressure to give 2.52 g. of oil.
  • the oil was subjected to column chromatography using 20 g. of silica gel and eluted successively with n-hexane-nhexane-benzene (5:1 The eluates were collected and the solvent was distilled to give 1.52 g. of the desired product as oil.
  • the solvent was distilled off to give 2.3 g of pale yellow oils.
  • the oils were subjected to column chromatography using 12.5 g. of silica gel and eluted some amounts of n-hexane and next successively with n-hexane-benzene 2:l-1 :1 (2: 1-1 :1 were collected and the solvent was distilled to give 1.25 g. of the desired product as oil.
  • the eluates with benzeneethyl acetate (3:2) were collected and the solvent was distilled off to give 150 mg. of the mixture of 9-oxo- 1 1 a-hydroxymethyl- 1 SB-hydroxyprost- 1 3(trans)-enoic acid and 9-oxo-1 1a-hydroxymethyl-15a-hydroxyprost- 13(trans)-enoic acid.
  • the eluates with benzene-ethyl acetate (1:1) were collected and the solvent was distilled off to give 108 mg. of 9-oxo-1 loz-hydroxymethyl- ISa-hydroxyprost-l3(trans)-enoic acid.
  • PREPARATION 4 Preparation of methyl 9 ⁇ -hydroxy-l la-hydroxymethyl-15-oxoprost-l3(trans)- enoate (1V) 1 1-Oxo-2oz-methoxycarbonylhexyl-3 ,8- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane (XXlll) To 3.584 g. of 1-oxo-2a-methoxycarbonylhexyl-3B- hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane in 50 ml. of dry benzene were added 1.68 g. of dihydropyran and 15 mg.
  • the product thus obtained was acetylated with 10 ml. of acetic anhydride in 50 ml. of dry pyridine at room temperature to give 4.82 g. of oil.
  • the oil was subjected to column chromatography using 40 g. of silica gel and eluted with n-hexane-benzene (1:8)-benzene to give 4.01 g. of 1-acetoxy-Za-methoxycarbonylhexyl-3B- tetrahydropyranyloxymethyl-4aethoxycarbonyloxymethylcyclopentane.
  • hydroxymethyl-4a-ethoxycarbonyloxymethylcyclopentane (XXVI) In a mixture of 40 m1. of acetic acid, 40 ml. of water and 6 ml. of tetrahydrofuran was dissolved 4.00 g. of 1f-acetoxy-2a-methoxycarbonylhexyl-3B- tetrahydropyranyloxymethyl-4w ethoxycarbonyloxymethylcyclopentane and the solution was stirred for 4.5 hours at 45C.
  • the reaction mixture was poured into ice water and extracted with ethyl acetate, washed with a saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and the solvent was distilled off to give 3.86 g. of oil.
  • the oil was subjected to column chromatography using 30 g. of silica gel and eluted with benzene-ethyl acetate (99:1 )-(90:l0) to give 3.01 g. of the desired product.
  • the product was reacted with diazomethane in acetic anhydride to give 810 mg. of oil.
  • the oil was subjected to column chromatography using 8.0 g. of silica gel and eluted with benzene ethyl acetate (85:15) to give 351 mg. of methyl 9ahydroxy-l la-hydroxymethyl-l5-oxopr0st- 13(trans)enoate and with benzene ethyl acetate (60:40) to give 307 mg. of methyl 9a-hydroxy-11ahydroxymethyll 5-oxoprostl 3(trans)-enoate.
  • the extract was dried over anhydrous sodium sulfate and the solvent was distilled off.
  • the residue was subjected to column chromatography using 20 g. of silica gel and eluted with -20% ethyl acetate in benzene to give 1.8 g. ofthe desired product.
  • EXAMPLE 1 l 5-Dihydroxy-1 la-hydroxymethylprost- 1 3(trans enoic acid To a solution of 170 mg. of 9,15-diox o-l 1ahydroxymethylprost-l3(trans)-enoic acid in 8 of ethanol was added 70 mg. of sodium boron hydride in 4 ml. of ethanol under ice cooling and the mixture was stirred for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 3.5-4.0 by addition of acetic acid at 0C.
  • Mass spectram M 370 Using the above procedure, but replacing methyl 9a, 1 Sa-dihydroxy- 1 1 a-hydroxymethylprostl 3 (trans- )enoate by methyl 9oz, ISa-dihydroxy- 1 1ahydroxymethylprost-l3(trans)-enoate, there was ob tained 9,8. ISa-dihydroxy-l la-hydroxymethylprostl3(trans)enoic acid.
  • EXAMPLE 4 9oz( and ,8), 1 5 ,B-Dihydroxy-l la-hydroxymethylprost- 1 3(trans)- enoic acid 1.
  • Methyl 9a(and B) ISB-dihydroxy-l 1ahydroxymethylprost- 1 3( trans)-enoate
  • 109 mg. of sodium boron hydride under ice cooling and the mixture was stirred for 1 hour in ice bath.
  • the mixture was diluted with a cooled 2% aqueous hydrochloric acid and subjected to salting out by addition of sodium chloride.
  • the mixture was extracted three times with ml. of ethyl acetate.
  • the organic layer was washed two times with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate.
  • the solvent was distilled off to give 1.09 g. of methyl 95, ISB-dihydroxy-l la'hydroxymethylprost-l3(trans)-enoate as oil.
  • the oil was subjected to column chromatography using 30 g. of silica gel and 4.10 (2H, multiplet.
  • thylprost-l3(trans)-enoic acid To a solution of 350 mg. of 9-oi o-l lahydroxymethyll Sa-hydroxy-l 6,1 6-dimethylprost' l3(trans)-enoic acid in. ml. of methanol was added 100 mg. of sodium boron hydrideunder ice cooling and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction mixture was made acidic by addition of acetic acid. The mixture was extracted with ethyl acetate and the solvent was distilled off. The residuewas subjected to column chromatography using 10 g. of silica gel and eluted with ethyl acetate-benzene 1:1) to give 1 mg.
  • EXAMPLE 7 9a( and B),l5 .-D ihydroxy-l l a-hydroxymethyll 6, 1 6-dimethylprostl3(trans)-enoic acid sin-
  • a solution of 295 mg. of ,9-oxo-l lahydroxymethybl SB-hydroxy-l 6, 1 6-dimethylprostl3(trans)enoic acid in 10 ml. of methanol was added 1 l5 mg.,of sodium'boron hydride under ice cooling and the mixture was stirred for minutes. After completion of the reaction, the reaction mixture was treated in the same procedure as in Example 3 to give 85 g.

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  • Furan Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US392113A 1972-09-01 1973-08-27 9{86 ,15{86 -Dihydroxy-11{60 -hydroxymethylprost-13(trans)-enoic acid derivatives Expired - Lifetime US3899525A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991083A (en) * 1974-01-23 1976-11-09 Merck & Co., Inc. 2α-(2-Loweralkanoyloxy-2-carboxyvinyl)-3β-hydroxy-5-oxo-1β-c
US3992412A (en) * 1974-01-23 1976-11-16 Merck & Co., Inc. 2α-(2-Carboxy-2-oxoethyl)-3β-hydroxy-5-oxo-1β-cyclopentaneheptanoic acid and process
US3992411A (en) * 1974-01-23 1976-11-16 Merck & Co., Inc. 2α-Formyl-3β-[(methoxalyl)oxy]-5-oxo-1β-cyclopentaneheptanoic acid and process
US3996263A (en) * 1975-05-05 1976-12-07 Sankyo Company Limited 9-Oxo-11α-methyl-15Ε-hyroxyprost-13(trans)-enoic acid derivatives and process for the preparaion thereof
US3998849A (en) * 1974-01-23 1976-12-21 Merck & Co., Inc. 2α-(2-Carboxy-2-formylethyl)-3β-hydroxy-5-oxo-β-cyclopentaneheptanoic acid and process
US4005106A (en) * 1974-01-23 1977-01-25 Merck & Co., Inc. 3β-[(Methoxalyl)oxy]-2α-(3-oxo-1-octenyl)-5-oxo-1β-cyclopentaneheptanoic acid and process

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE384853B (sv) * 1972-04-04 1976-05-24 Haessle Ab Forfarande for framstellning av nya aminer
US3931282A (en) * 1974-02-21 1976-01-06 Syntex (U.S.A.) Inc. 11α-Hydroxymethyl prostaglandins

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3455992A (en) * 1966-05-10 1969-07-15 American Home Prod Process for preparing 11-desoxyprostaglandin and homologs thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3455992A (en) * 1966-05-10 1969-07-15 American Home Prod Process for preparing 11-desoxyprostaglandin and homologs thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3991083A (en) * 1974-01-23 1976-11-09 Merck & Co., Inc. 2α-(2-Loweralkanoyloxy-2-carboxyvinyl)-3β-hydroxy-5-oxo-1β-c
US3992412A (en) * 1974-01-23 1976-11-16 Merck & Co., Inc. 2α-(2-Carboxy-2-oxoethyl)-3β-hydroxy-5-oxo-1β-cyclopentaneheptanoic acid and process
US3992411A (en) * 1974-01-23 1976-11-16 Merck & Co., Inc. 2α-Formyl-3β-[(methoxalyl)oxy]-5-oxo-1β-cyclopentaneheptanoic acid and process
US3998849A (en) * 1974-01-23 1976-12-21 Merck & Co., Inc. 2α-(2-Carboxy-2-formylethyl)-3β-hydroxy-5-oxo-β-cyclopentaneheptanoic acid and process
US4005106A (en) * 1974-01-23 1977-01-25 Merck & Co., Inc. 3β-[(Methoxalyl)oxy]-2α-(3-oxo-1-octenyl)-5-oxo-1β-cyclopentaneheptanoic acid and process
US3996263A (en) * 1975-05-05 1976-12-07 Sankyo Company Limited 9-Oxo-11α-methyl-15Ε-hyroxyprost-13(trans)-enoic acid derivatives and process for the preparaion thereof

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FR2197591A1 (fr) 1974-03-29
BE804342A (fr) 1974-02-28
NL7312143A (fr) 1974-03-05
DE2344058A1 (de) 1974-03-07
JPS5146113B2 (fr) 1976-12-07
JPS4943947A (fr) 1974-04-25
FR2197591B1 (fr) 1976-12-24
GB1410853A (en) 1975-10-22

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