WO2000051977A1 - Intermediaires aldehydes pour l'elaboration de derives des prostaglandines - Google Patents

Intermediaires aldehydes pour l'elaboration de derives des prostaglandines Download PDF

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WO2000051977A1
WO2000051977A1 PCT/US2000/005201 US0005201W WO0051977A1 WO 2000051977 A1 WO2000051977 A1 WO 2000051977A1 US 0005201 W US0005201 W US 0005201W WO 0051977 A1 WO0051977 A1 WO 0051977A1
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ring
group
compound
dihydro
prostaglandin
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PCT/US2000/005201
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Mitchell Anthony Delong
David Lindsey Soper
John August Wos
Biswanath De
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The Procter & Gamble Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • the present invention is directed to a process for making a novel aldehyde intermediate useful for making 13,14-dihydro prostaglandin A, D, E, and F ⁇ e ⁇ vatives
  • the present invention describes a novel process for making a novel aldehyde intermediate useful for making 13,14-dihydro prostaglandin A, D, E and F derivatives
  • Naturally occurring prostaglandins (such as PGA, PGD, PGE, and PGF) are C-20 unsaturated fatty acids
  • Prostaglandin A, D, E, and F derivatives are distinguishable as such by the substituents on the alicyc c ring PGA derivatives are characterized by a ketone at C 9 and a double bond between C 10 and C,,.
  • PGD derivatives are characterized by a hydroxyl at Co and a ketone at C
  • PGE derivatives are characterized by a ketone at C 9 and a hydroxyl at C
  • PGF derivatives are characterized by hydroxyl groups at both C 9 and at C
  • Such derivatives are useful for the treatment of many medical disorders including, for example, ocular disor ⁇ ers, hypertension, fertility control, and osteoporosis
  • ⁇ disclosed in U.S Patent No 3,776,938 (1973) by Bergstrom, S , and Sjovall of the Kemiska Institutionen, Karo nska Institute, Sweden has a stimulatory effect on smooth muscle contraction as shown by test strips of guinea pig ileum, rabbit duodenum, or gerbil colon
  • Further information regarding the biological effects of 13,14-dihydro PGA, PGD, PGE and PGF derivatives are disclosed in the following references- U.S Patent No 3,882,241 issued to Phar ⁇ ss, G., May 6, 1975, G.B Patent No.
  • Prostaglandin A derivatives have generally been assembled from the PGE series by acid or base induced elimination of the C ⁇ hydroxyl group. Methods for conversion of PGE derivatives to PGA derivatives include those described in the following references: Stork et al., J. Amer. Chem. Soc. 1976, 98, p. 1583; Stork et al., J. Amer. Chem. Soc. 1978, 100, p. 8272.
  • Prostaglandin D derivatives have generally been assembled from the PGF series by differential protection at C 9 , C 11 f and C 15 followed by selective removal of the C protecting group and oxidation to the ketone.
  • Prostaglandin E derivatives have generally been assembled through the common Corey aldehyde intermediate via introduction of the omega side-chain through Wadsworth-Horner-Emmons phosphonate chemistry, reduction and protection of the C 15 position, introduction of the top chain via Wittig chemistry, oxidation of the C 9 position with Jones reagent, and finally, removal of the various protecting groups with the appropriate reagent(s).
  • the prostaglandin F201 skeleton is prepared in a variety of ways; generally from the condensation of the Corey aldehyde (see for example: Corey, E.J.; Weinshenker, N.M.; Schaaf, T.K.; Huber, W. "Stereo-Controlled Synthesis of Prostaglandins F2 ⁇ and E2 (dl)" J. Am. Chem. Soc. 1969.
  • prostaglandin F20 skeleton for conversion into the 13,14-dihydro prostaglandin F1 ⁇ derivatives, see: Collins, P.W.; Djuric, S.W. "Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs", Chemical Reviews, 93, (1993), pp. 1533-1564.
  • the present invention is directed to a process for making a novel C ⁇ C 9 , and C u - protected 7-(5-(3-oxopropyl)-2,4-dihydroxy-cyclopentyl) heptanoic acid intermediate (the
  • aldehyde intermediate This aldehyde intermediate is useful for making 13,14-dihydro prostaglandin A, D, E, and F derivatives.
  • the invention is further directed to a process for making 13,14-dihydroprostaglandin A, D, E, and F derivatives.
  • Alkyl is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms.
  • Alkyl chains may be straight or branched.
  • Preferred branched alkyl have one or two branches, preferably one branch.
  • Preferred alkyl are saturated.
  • Unsaturated alkyl have one or more double bonds and/or one or more triple bonds.
  • Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond.
  • Alkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents.
  • Preferred substituted alkyl are mono-, di-, or trisubstituted.
  • alkyl substituents include halo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxphenyl, alkyioxycarbonylphenyl, halophenyl), heterocyclyl, and heteroaryl.
  • aryl e.g., phenyl, tolyl, alkyloxphenyl, alkyioxycarbonylphenyl, halophenyl
  • heterocyclyl and heteroaryl.
  • "Aromatic ring” is an aromatic hydrocarbon ring system. Aromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring.
  • Aromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
  • Preferred aromatic ring substituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include alkyl, cyano, halo and haloalkyl.
  • Biohydrolyzable ester is an ester moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or mammal.
  • Carbocyclic aliphatic ring is a saturated or unsaturated hydrocarbon ring. Carbocyclic aliphatic rings are not aromatic. Carbocyclic aliphatic rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic aliphatic rings contain from 8 to 12 carbon atoms, preferably from 9 to 10 carbon atoms in the ring.
  • Carbocyclic aliphatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
  • Preferred carbocyclic aliphatic ring substituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include halo and haloalkyl.
  • Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Halo is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and fluoro.
  • Haloalkyl is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred haloalkyl are C-
  • Heteroalkyl is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 1 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond, more preferably one double bond.
  • Heteroalkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents.
  • Preferred heteroalkyl are unsubstituted.
  • Preferred heteroalkyl substituents include halo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxyphenyl, alkyioxycarbonylphenyl, halophenyl), heterocyclyl, heteroaryl.
  • alkyl substituted with the following substituents are heteroalkyl: alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy (e.g., propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, alkyloxycarbonylphenylthio), amino (e.g., amino, mono- and di- C-1-C3 alkanylamino, methylphenylamino, methyl
  • Heteroatom is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
  • Heterocyclic aliphatic ring is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring, wherein no two heteroatoms are adjacent in the ring and no carbon in the ring that has a heteroatom attached to it also has a hydroxyl, amino, or thiol group attached to it. Heterocyclic aliphatic rings are not aromatic. Heterocyclic aliphatic rings are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic aliphatic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7, and most preferably from 5 to 6 member atoms in the ring.
  • Bicyclic heterocyclic aliphatic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Heterocyclic aliphatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring. Preferred heterocyclic aliphatic ring substituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include halo and haloalkyl. Preferred heterocyclic aliphatic rings include piperzyl, morphoiinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl.
  • Heteroaromatic ring is an aromatic ring system containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 member atoms in the ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring.
  • Preferred heteroaromatic ring substituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include halo, haloalkyl, and phenyl.
  • Preferred heteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic rings include thienyl, furanyl, and pyridyl. The most preferred heteroaromatic ring is thienyl.
  • Hydride reducing agent is any agent capable of delivering a hydride ion in a reaction.
  • Preferred hydride reducing agents include L-selectride and sodium borohydride.
  • the most preferred hydride reducing agent is sodium borohydride.
  • “Lower alkyl” is an alkyl chain radical comprised of 1 to 6, preferably 1 to 4 carbon atoms.
  • “Lower heteroalkyl” is a heteroalkyl chain radical comprised of 1 to 6, preferably 1 to 4 member atoms.
  • Non-electrophilic alcohol protecting group is an alcohol protecting group that lacks an electrophilic center, such as a carbonyl functionality.
  • Non-electrophilic alcohol protecting groups include silyl ethers, alkoxymethyl ethers, tetrahydropyranyl, tetrahydrofuranyl, and substituted or unsubstituted benzyl ethers.
  • Preferred non- electrophilic alcohol protecting groups include tetrahydropyranyl, tetrahydrofuranyl, tert- butyl dimethylsilyl, trimethylsilyl, t ethylsilyl, triisopropylsilyl, and benzyl.
  • non-electrophilic alcohol protecting groups include tert-butyl dimethylsilyl, trimethylsilyl, and benzyl.
  • the most preferred non-electrophilic alcohol protecting group is a tert-butyl dimethylsilyl.
  • Non-electrophilic alcohol protecting groups provide two advantages over electrophilic alcohol protecting groups when used with the present invention: (1 ) non- electrophilic alcohol protecting groups are more stable under anionic conditions and (2) non-electrophilic alcohol protecting groups can be removed under neutral or slightly acidic conditions whereas electrophilic alcohol protecting groups require more acidic conditions for their removal.
  • Phenyl is a six-membered monocyclic aromatic ring which may or may not be substituted with from about 1 to about 4 substituents. The substituents may be substituted at the ortho, meta or para position on the phenyl ring, or any combination thereof. Preferred phenyl substituents include: halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents on the phenyl ring include halo and haloalkyl. The most preferred substituent is halo.
  • the Novel Aldehyde intermediate is directed to a process for making a novel C C 9 , and unprotected 7-(5-(3-oxopropyl)-2,4-dihydroxy-cyclopentyl) heptanoic acid intermediate (the "aldehyde intermediate") having the following general formula:
  • R is lower alkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring.
  • Preferred R is lower alkyl.
  • the most preferred R is methyl.
  • Q ⁇ and Q 2 are non-electrophilic alcohol protecting groups; wherein Q and Q 2 are either the same non-electrophilic alcohol protecting group or different.
  • Q, and Q 2 are preferably the same non-electrophilic alcohol protecting group.
  • the most preferred non-electrophilic alcohol protecting group when Q, and Q 2 are the same is tert-butyl dimethylsilyl.
  • Q. and Q 2 are preferably different non- electrophilic alcohol protecting groups.
  • preferred Q is tert-butyl dimethylsilyl or benzyl and preferred Q 2 is trimethylsilyl.
  • preferred Q 1 is trimethylsilyl and preferred Q 2 is tert-butyl dimethylsilyl or benzyl.
  • the invention also includes optical isomers, diastereomers and enantiomers of the above structure.
  • stereochemistry e.g. Cn
  • both epimers are envisioned.
  • Preferred stereochemistry at all such stereocenters of the compounds of the invention mimic that of the corresponding naturally occurring prostaglandin.
  • This aldehyde intermediate above is useful for making 13,14-dihydro prostaglandin A, D, E, and F derivatives.
  • the invention is further directed to a process for making 13,14-dihydro prostaglandin A, D, E, and F derivatives having the following general formula:
  • R is CO 2 H, C(O)NHOH, CO 2 R 4 , CH 2 OH, S(0) 2 R 4 , C(O)NHR 4 , C(O)NHS(0) 2 R 4 , or tetrazole; wherein R 4 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring;
  • each R 3 is independently selected from the group consisting of: hydrogen, lower alkyl, alkoxy, haloalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, and heteroaromatic ring;
  • n is an integer from 0 to 5; provided that when Y is allenyl n is less than 5,
  • the invention also includes optical isomers, diastereomers and enantiomers of the above structure. Thus, at all stereocenters where stereochemistry is not defined
  • both epimers are envisioned.
  • Preferred stereochemistry at all such stereocenters of the compounds of the invention mimic that of the corresponding naturally occurring prostaglandin.
  • the 13,14-dihydro prostaglandin A, D, E, and F derivatives described directly above may themselves be used as intermediates in the preparation of other 13,14- dihydro prostaglandin A, D, E, or F derivatives. That is, the compounds prepared may be reacted further, using known chemistry, to yield other active derivatives, such as other PGA, PGD, PGE and PGF derivatives.
  • the hydrogen attached to C 15 may be replaced with a lower alkyl group, a carbocyclic ring, a heterocyclic ring, an aromatic ring, or a heteroaromatic ring.
  • Step l The process depicted above in Scheme I begins with providing a compound according to Formula ill.
  • Compounds according to Formula III can be made from known starting materials and methods known to one of ordinary skill in the art.
  • the commercially available material Methyl 7-[3-(R)-hydroxy-5-oxo-1- cyclopent-1-yl] heptanoate (Cayman Chemical Company, Ann Arbor, Ml) can be modified according to processes exemplified in the following references: House, H.O.; Chu, C. Y.; Wilkins, J.M.; Umen, M.J. "The Chemistry of Carbanions. XXVII. A Convenient Precursor for the Generation of Lithium Organocuprates" J.
  • Step 2 The next step in the process is modifying the compound according to Formula III to yield a compound according to Sla.
  • the compound according to Formula III is treated with a hydride reducing agent, such as those reported in the art (see for example Davis et al., "A Convergent Total Synthesis of (+/-) Prostaglandin F2 ⁇ via Conjugate Addition and Regiospecific Enolate Trapping" J. Org. Chem. 1979, 44(22), p.3755-3759).
  • the ketone is reacted with a hydride reducing agent in a polar protic solvent to give the C 9 alcohol.
  • Preferred polar protic solvents include methanol, ethanol, and butanol.
  • the most preferred polar protic solvent is methanol.
  • the preferred temperature range for the reduction is between -100°C and 23°C. More preferred still is between -60°C and 0°C.
  • the most preferred temperature range is between -45°C and - 20°C.
  • the product alcohol Sla so obtained can be isolated using methods known to one of ordinary skill in the art. Such methods include extraction, solvent evaporation, distillation, and crystallization procedures. Most preferably, the product is purified by flash chromatography on siiica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
  • the alcohol Sla is then protected with a non-electrophilic alcohol protecting group.
  • the non-electrophilic alcohol protecting group is a silyl protecting group
  • the reaction is carried out in the presence of base in an inert solvent.
  • bases include triethylamine, trimethylamine, and 2,6-lutidine.
  • the most preferred base is 2,6- lutidine.
  • Preferred inert solvents include halocarbon solvents with dichloromethane being the most preferred solvent. This reaction is allowed to proceed at a temperature preferably between -100°C and 100°C, more preferably between -80°C and 80°C, and most preferably between -70°C and 23°C.
  • the resulting protected compound Sib is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization.
  • the silyl ether is flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc hexanes as the eluent.
  • olefin Sib is then cleaved to an aldehyde using an olefin cleavage reagent.
  • Preferred olefin cleavage reagents include ozone, lead tetraacetate, and forms of osmium in the presence of periodate salts preferably in a solvent system where both the osmium and periodate salt are soluble.
  • osmium examples include potassium osmate, osmium tetraoxide, osmium dichloride, osmium iodide, osmium trichloride, osmium trichloride trihydrate, potassium osmium chloride, potassium osmyl chloride, and potassium osmyl oxalate. More preferred forms of osmium include potassium osmate and osmium tetraoxide. The most preferred form of osmium is potassium osmate. Preferred solvent systems are acidic.
  • Particularly preferred solvent systems include 1 :1 mixtures of acetic acid and water and 1 :1 :2 mixtures of water, acetic acid and THF.
  • the result of this treatment is the aldehyde according to Formula I.
  • the aldehyde intermediates according to Formula I are isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, it is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent, and stored at 0°C or below.
  • novel aldehyde intermediates according to Formula I can be reacted with a variety of nucleophiles ("nucleophilic anion Y-[C(R 3 )(R 3 )] n -Z " ") to provide C 9 11 -protected 13,14-dihydro-15-substituted-pentanor prostaglandin F derivatives (see for example: Org. Synth., IV, 792 (1963); Org Synth. Ill, 200 (1955); Advanced Organic Chemistry, Part B, Reactions and Synthesis, Chapter 7, pp 365-388 (Plenum Press, New York)).
  • nucleophiles nucleophilic anion Y-[C(R 3 )(R 3 )] n -Z "
  • Nucleophilic anion Y-[C(R 3 )(R 3 )] n -Z refers to any chemical agent suitable for adding to an aldehyde that will result in an intermediate according to Slla. Most suitable nucleophilic anions are unstable and are generated immediately prior to use, often at low temperatures. Further, the stoichiometry of the nucleophile must be carefully controlled as nucleophilic anions will also react with the C-1 ester group.
  • Preferred nucleophiles include alkynylphenyl, o, m, and/or p halophenylalkynyl, substituted phenyl anions, naphthyl, thianaphthyl, benzathiazole, substituted thianaphthyl and substituted naphthyl and substituted benzothiazolyl anions.
  • a standard method for preparing nucleophilic anions from their precursors involves removing a relatively acidic proton with a strong base.
  • Base means a basic reagent which is added to the reaction mixture to create the necessary anion for covalent bond formation between the aldehyde and the nucleophile.
  • Preferred bases include those which are soluble in organic solvents. Specifically, preferred bases include n-butyl lithium, s-butyl lithium, t-butyl lithium, methyl lithium, KHMDS, sodium hydride, and potassium hydride. More preferred bases include n-butyl lithium, s-butyl lithium, t- butyl lithium.
  • Preferred organic solvents for the reaction are ether solvents.
  • Preferred organic solvents include tetrahydrofuran and diethyl ether.
  • the most preferred organic solvent is tetrahydrofuran.
  • the reaction is carried out at a temperature preferably between -100°C and 20°C, more preferably between -80°C and 0°C, and most preferably between -80°C and -40°C.
  • nucleophiles to aldehydes in the presence of other reactive functional groups may be carried out using methods known to one of ordinary skill in the art. Addition of some nucleophiles is best achieved by phosphizine bases. Addition of other nucleophiles is best achieved by the formation of their Grignard or metal salt. Metal-halogen exchange and Grignard's procedure both effect nucleophilic anion formation by the exchange of a Group I or Group II zero valent metal with an organic halide in an ethereal solvent. Preferred metals include sodium, potassium, and magnesium. The most preferred metal is magnesium.
  • “Ethereal solvent” refers to a solvent which has two alkyl groups bonded to an oxygen including those in which the alkyl group and oxygen are part of a ring.
  • Preferred ethereal solvents include diethyl ether and tetrahydrofuran.
  • the most preferred ethereal solvent is tetrahydrofuran.
  • the preferred reaction temperature range is between 0°C and 80°C.
  • the most preferred reaction temperature range is between 25°C and 40°C.
  • intermediate Slla can be converted into the desired prostaglandin A, D, E, or F, derivative according to Formula II.
  • the step or steps necessary to effect this conversion depend upon which type of prostaglandin derivative is desired.
  • compounds according to Formula IIF can be made from intermediate Slla by deprotecting the alcohols at C 9 and d.
  • “Deprotection” refers to the removal of protecting groups used to protect sensitive functional groups. Deprotection may be carried out using methods known to one of ordinary skill in the art. Such methods are disclosed in Theodora Green's book entitled: Protecting Groups In Organic Chemistry.
  • Deprotection includes the removal of non-electrophilic alcohol protecting groups and alkyl esters of carboxylic acids.
  • compounds according to Formula HE can be made from intermediate Slia by selectively deprotecting the alcohol at C 9 and then oxidizing it to a ketone.
  • compounds according to Formula HA can be made from the corresponding PGE derivative according to Formula HE by eliminating the alcohol at C Conduct. Such elimination can be carried out using methods known to one of ordinary skill in the art.
  • compounds according to Formula IID can be made from intermediate Slla by selectively deprotecting the alcohol at C ⁇ and then oxidizing it to a ketone.
  • conversion of the CO 2 R ester at C, to the desired R ⁇ of Formula II can be carried out using methods known to one of ordinary skill in the art. Such methods include, but are not limited to, deprotection at C 11 f deprotection at C,, selective oxidation at C 9 , reduction at C,, base catalyzed elimination at the C ⁇ alcohol, condensation at C, with amines, and condensation at C, with hydroxylamines.
  • Methyl 7-(2-oxo-4-(1,1,2,2-tetramethyl-1-silapropoxy)cyclopent-1-(5)-enyl) heptanoate (1b): To a solution of Methyl-7-[3-(R)-hydroxy-5-oxo-1-cyclopenten-1-yl] heptanoate 1a (1 equiv.) in CH2CI2 at -78 °C is added 2,6 Lutidine (1.3 equiv.) dropwise over 15 minutes. The solution is kept at -78 °C and TBDMS Triflate (1.2 equiv.) in CH2CI2 is added dropwise over 15 minutes.
  • the reaction is warmed gradually to room temperature and stirred at room temperature for 15 hours.
  • Aqueous 10% HCI is added and the layers are separated.
  • the water layer is extracted with CH2CI2 and the organic layers are combined.
  • the organic layer is washed with brine, dried (Na2S04) and concentrated.
  • the residue is distilled under vacuum (house vacuum, 10 mm Hg) to provide the silyl ether 1b.
  • the Grignard is diluted with THF and added via cannula to a 3- necked flask equipped with mechanical stirring and charged with CuBr.DMS (2 equiv.) in a 1 :1 solution of THF/DMS at -78°C. After the addition of the Grignard (-20 minutes), the reaction is stirred 1 hour at -78°C. The color of the reaction is dark red at this point. A solution of the ketone 1b (1 equiv.) in THF is then added dropwise over 25 minutes. The reaction is stirred at -78°C for 15 minutes then allowed to warm slowly to room temperature over 2 hours. The reaction is quenched with aqueous NH 4 CI and the excess DMS allowed to evaporate overnight.
  • the reaction is partitioned between brine/CH2Cl2 and the layers separated.
  • the aqueous layer is back-extracted with CH2CI2 and the organic layers are combined and dried (Na2SO4).
  • the solvent is removed in vacuo and the residue chromatographed on SiO2 (10 % hexane/EtOAc) to give the appropriate ketone 1 c.
  • the ketone 1c (1 equiv.) is dissolved in MeOH and cooled to -40°C- Sodium borohydride (0.9 equiv.) is added portionwise over 10 minutes. After the addition is complete the reaction is stirred for 13 hours at -40°C and then 12 hours at -78°C. The reaction is quenched with water, partitioned between brine and CH2CI2 and the layers separated. The aqueous layer is back-extracted with CH2CI2 and the organic layers combined and dried (Na2SO4). The solvent is removed in vacuo and the residue chromatographed on Si ⁇ 2 (30 % EtOAc/hexanes) to give 75% of the alcohol.
  • the protected alcohol 2a (1 equiv.) is dissolved in THF and cooled to 0°C. In a separate flask, 2.1 equiv of sodium periodate is dissolved in water. Once dissolution is complete glacial acetic acid is added slowly to form a 1 :1 vol: vol mixture. To this is added a catalytic amount (5 mol %) of potassium osmate (Aldrich Chemical company). Finally, the THF solution of 2a is added. After the addition is complete the reaction is stirred for a few hours at room temperature. The reaction is partitioned between brine and CH2CI2 and the layers separated. The aqueous layer is back-extracted with CH2CI2 and the organic layers combined and dried (Na2SO4). The solvent is removed in vacuo and the residue chromatographed on Si ⁇ 2 (20% EtOAc/hexanes) to give the aldehyde 2b.
  • aldehyde 2b (1 equiv.) and dry THF are added.
  • the flask is cooled to -80°C, then is treated with the anion of thianaphthyiene (made by deprotonation of thianaphthyiene [Aldrich Chemical Co.] at -78°C with n-butyl lithium) (1.2 equiv.) (see Jones, Org. Synth. 50, 104 (1970)).
  • the cooling bath is removed and the reaction allowed to warm to 0°C under nitrogen. TLC is used to monitor the reaction.
  • the reaction is cooled to -78°C, quenched with a saturated solution of ammonium chloride, and extracted with a 5:1 mixture of Ethyl acetate : hexanes, The organic layer is washed once with 0.1 N HCI, then several times with brine to a pH of 7, dried (Na 2 SO 4 ), and concentrated. Without further purification, to this crude reaction mixture, CH3CN and HF/Pyridine are added while the flask is kept at 0°C. After 3 hours at 0°C, the reaction is warmed to room temperature and quenched with saturated NaCI.
  • aqueous layer is washed 3 times with methylene chloride, the organic layers are combined and washed with brine, dried (Na2SO4) ( and chromatographed (methylene chloride, methanol, acetic acid, 9.6, 0.4, 0.015 ). 4a is recovered.
  • aldehyde 2b (1 equiv.) and THF are added.
  • the benzothiazole anion (1.2 equiv) generated as described above for the thianaphthyl anion is added at -78°C.
  • the cooling bath is removed and the reaction allowed to warm to 0°C under nitrogen.
  • TLC is used to monitor the reaction.
  • the reaction is cooled to -78°C and quenched with a saturated solution of ammonium chloride, and extracted with a 5:1 mixture of Ethyl acetate : Hexanes, The organic layer is washed once with 0.1 N HCI, then several times with brine to a pH of 7, dried (Na 2 SO 4 ), and concentrated.
  • aqueous layer is extracted three times with CH2CI2, the organic layers are combined and washed three times with saturated NaHCO ⁇ , brine, and dried (Na2SO4). After column chromatography (95% CH2CI2, 5% MeOH), 5a is recovered.
  • the aldehyde 2b is treated with pig liver esterase (Sigma Chemical Co.) in 10% MeOH in water to remove the methyl ester.
  • the acid is isolated by acidifying the water layer to a pH ⁇ 1.0 with 0.1 N HCI and extracted with methylene chloride, dried and concentrated.
  • the free acid so obtained is placed in a 10 mL round bottomed flask, THF is added, the flask is cooled to -78°C, then the
  • NaCI NaCI.
  • the aqueous layer is extracted three times with CH2CI2, the organic layers are combined and washed three time with saturated NaHCO3, brine, and dried (Na2S ⁇ 4).
  • the protected alcohol 8a (1 equiv.) is dissolved in CH2CI2 and cooled to 0°C. In a separate flask, 2.1 equiv of sodium periodate is dissolved in water. Pyridinium chlorochromate (PCC) (Aldrich Chemical company) and molecular sieves are added. After the addition is complete, the reaction is stirred at room temperature until TLC analysis indicates the C-9 alcohol has been oxidized. The reaction is then filered through Fluorosil, the solvent is removed in vacuo, and the residue dissolved in methanol with a trace of acetic acid. After TMS removal is complete, the solvent is removed and the residue chromatographed on Si ⁇ 2 (20% EtOAc/hexanes) to give the product 8b.
  • the protected compound 10a (1 equiv.) is dissolved in acetonitrile and is cooled to 0°C. 1.1 equivalents of HF/pyridine reagent is added. The reaction is warmed gradually to room temperature and stirred at room temperature until the reaction is complete by TLC. The organic layer is successively washed with brine to neutral pH, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue is chromatographed on Si ⁇ 2 (3% MeOH/ CH2CI2) to give the C-11 deprotected alcohol. This alcohol is dissolved in CH2CI2 and cooled to 0°C. Added is excess pyridinium chlorochromate (PCC) (Aldrich Chemical company) and molecular sieves.
  • PCC pyridinium chlorochromate
  • reaction is stirred at room temperature until TLC analysis indicated the C-11 alcohol has been oxidized.
  • the reaction is then filtered through Fluorosil, the solvent is removed in vacuo, and the residue dissolved in methanol with a trace of acetic acid. After THP removal is complete, the solvent is removed and the residue chromatographed on Si ⁇ 2 (20% EtOAc/hexanes) to give 10b.

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On a découvert avec surprise qu'on pouvait éviter les inconvénients des longues procédures jusque là connues pour synthétiser les dérivés 13,14-dihydro des prostaglandines A, D, E, et F en utilisant un nouvel intermédiaire constitué par l'acide 7-(5-(3-oxopropyle)-2,4-dihydroxy-cyclopentyle) heptanoïque à protection C1, C9, et C11, et qui se synthétise à partir du méthyle 7-[3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl] heptanoate du commerce. Ce nouvel intermédiaire peut se coupler aux nucléophiles du carbone en présence d'une base pour donner les dérivés 13,14-dihydro des prostaglandines A, D, E, et F.
PCT/US2000/005201 1999-03-05 2000-02-29 Intermediaires aldehydes pour l'elaboration de derives des prostaglandines WO2000051977A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38617/00A AU3861700A (en) 1999-03-05 2000-02-29 Aldehyde intermediates for the preparation of prostaglandin derivatives

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US12301099P 1999-03-05 1999-03-05
US60/123,010 1999-03-05

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003011848A1 (fr) * 2001-07-30 2003-02-13 Millennium Pharmaceuticals, Inc. Benzoheterocycles utilises comme inhibiteurs de lipoxygenase
US7960431B2 (en) * 2007-02-01 2011-06-14 Allergan, Inc. Thiophenyl prostaglandin derivatives for treating glaucoma and ocular hypertension
US7964595B2 (en) * 2008-01-18 2011-06-21 Allergan, Inc. Thiophenyl prostaglandin derivatives for treating glaucoma and ocular hypertension

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128720A (en) * 1975-02-14 1978-12-05 Ono Pharmaceutical Company Prostaglandin analogues
GB1549047A (en) * 1975-04-18 1979-08-01 Schering Ag Prost-16-ynoic acid and derivatives and process for their manufacture

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4128720A (en) * 1975-02-14 1978-12-05 Ono Pharmaceutical Company Prostaglandin analogues
GB1549047A (en) * 1975-04-18 1979-08-01 Schering Ag Prost-16-ynoic acid and derivatives and process for their manufacture

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003011848A1 (fr) * 2001-07-30 2003-02-13 Millennium Pharmaceuticals, Inc. Benzoheterocycles utilises comme inhibiteurs de lipoxygenase
US7960431B2 (en) * 2007-02-01 2011-06-14 Allergan, Inc. Thiophenyl prostaglandin derivatives for treating glaucoma and ocular hypertension
US7964595B2 (en) * 2008-01-18 2011-06-21 Allergan, Inc. Thiophenyl prostaglandin derivatives for treating glaucoma and ocular hypertension

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AU3861700A (en) 2000-09-21
AR023089A1 (es) 2002-09-04

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