WO1999012899A1 - Procede de production d'analogues de prostaglandine f - Google Patents

Procede de production d'analogues de prostaglandine f Download PDF

Info

Publication number
WO1999012899A1
WO1999012899A1 PCT/US1998/018595 US9818595W WO9912899A1 WO 1999012899 A1 WO1999012899 A1 WO 1999012899A1 US 9818595 W US9818595 W US 9818595W WO 9912899 A1 WO9912899 A1 WO 9912899A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
lower alkyl
substituted
hydrogen
formula
Prior art date
Application number
PCT/US1998/018595
Other languages
English (en)
Inventor
Jack S. Amburgey, Jr.
John August Wos
Mitchell Anthony Delong
Biswanath De
Haiyan George Dai
David Lindsey Soper
Original Assignee
The Procter & Gamble Company
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 The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to AU93058/98A priority Critical patent/AU9305898A/en
Publication of WO1999012899A1 publication Critical patent/WO1999012899A1/fr

Links

Classifications

    • 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

Definitions

  • the present invention describes a process for making prostaglandin F analogs, including 13, 14-dihydro- 15,16 or 17-substituted- 16-tetranor or 17-trinor prostaglandin F ⁇ ⁇ analogs.
  • the present invention describes a process for making prostaglandin F analogs, especially 13,14-dihydro- 15,16 or 17-substituted- 16-tetranor or 17-trinor prostaglandin F ⁇ ⁇ analogs.
  • Such derivatives are useful for the treatment of many medical disorders including, for example, ocular disorder, hypertension, fertility control, and osteoporosis.
  • the prostaglandin 13, 14-dihydro PGF ⁇ ⁇ disclosed in U.S. Patent No. 3,776,938 (1973) by S. Bergstrom, et al. has a stimulatory effect on smooth muscle contraction as shown by test strips of guinea pig ileum, rabbit duodenum, or gerbil colon.
  • the prostaglandin F2 skeleton is prepared in a variety of ways, but generally from (i) the condensation of the Corey aldehyde [see, for example: Corey, E.J.; Weinshenker, N.M.; Schaaf, T.K.; Huber, W. " Stereo-Controlled Synthesis of Prostglandins F2 ⁇ and E2 (dl " J. Am. Chem. Soc.
  • Patent No. 1,456,512 For other methods to prepare the prostaglandin F2 ⁇ skeleton for conversion into the 13,14-dihydro-15,16 or 17-substituted- 16- tetranor or 17-trinor prostaglandin F ⁇ ⁇ analogs, see Collins, P. W.; Djuric, S. W. "Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs", Chemical Reviews. 93, (1993), pp. 1533-1564.
  • This intermediate allows for the rapid synthesis of final products via: 1) a Wadsworth-Horner-Emmons coupling of the desired substrate without prior protection of the alcohols, or a similar olefination reaction; 2) reduction of the unsaturated ketone with cerium salts and sodium borohydride; 3) removal, if desired, of the alkenes by hydrogenation over palladium on carbon.
  • the intermediates in these steps may be, depending on the substitution pattern, valuable biological agents in their own right, and this process is also useful for their individual preparation.
  • the present invention provides a process for making a prostaglandin F analog having a structure according to Formula (I):
  • R 1 is C0 2 H, C(0)NHOH, C0 2 R 5 , CH 2 OH, S(0) 2 R 5 , C(0)NHR 5 , C(0)NHS(0)2R 5 , or tetrazole; wherein R 5 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring; b) R 2 is hydrogen or lower alkyl; c) 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 heteroaraomatic ring; d) Y is NR 4 , S, S(O), S(0) 2 , O, or a bond, provided that no carbon has more than one heteroatom attached to it, wherein R 4 is hydrogen, lower alkyl, or acyl; e) p is
  • R 6 is a carboxylic acid, a carboxylic acid ester comprising a saturated or unsaturated, linear or branched Ci-Cs alkyl, a carbocyclic ring, a hydroxamic acid, hydroxymethyl, sulfonic acid, sulfonyl ester, sulfonyl amide, or tetrazole; and (B)(i) each R 7 is lower alkyl, or (ii) the R 7 moieties together with the two oxygen atoms form a substituted or unsubstituted 5- or 6-membered monocyclic aliphatic heterocycle or a substituted or unsubstituted 8 to 12 member bicyclic aliphatic heterocycle; or a salt or protected form thereof, wherein the preparation comprises:
  • step (b) deprotecting the acetal derivative of step (a) to form a hydroxy acetal;
  • step (c) optionally reprotecting the hydroxy acetal of step (b);
  • step (e) condensing the lactol derivative of step (d) with a phosphonium salt to form the intermediate ketal of Formula (A), or a salt or protected form thereof;
  • step II removing the ketal from the intermediate of Formula (A) formed in step I) to form an aldehyde and coupling the aldehyde with a Wadsworth-Horner-Emmons reagent or a Wittig- Horner reagent to form a product, and
  • step III conducting one or more subsequent synthetic steps on the product of step II) to form a prostaglandin F analog of Formula (I).
  • the present invention describes a process for the manufacture of prostaglandin F analogs.
  • the process is particularly useful for preparing 13,14-dihydro-15,16 or 17-substituted- 16-tetranor or 17-trinor prostaglandin Fi analogs.
  • Prostaglandin F derivatives are useful for the treatment of many medical disorders including, for example, ocular disorders, hypertension, fertility control, nasal decongestion, and osteoporosis. When the compounds made according to this process are used for treating such disorders, they are to be in a pharmaceutically acceptable form.
  • such a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable forms include salts, biohydrolyzable esters and solvates.
  • prostaglandin F analogs prepared according to the process of the present invention may be used as intermediates in the preparation of other prostaglandin analogs. That is, the compounds prepared may be reacted further, using known chemistry, to yield other active analogs, including prostaglandin A and E analogs.
  • Activated diol or “activated alcohol” is an alcohol which contains a silyl group rather than a hydrogen atom attached to the oxygen atom(s).
  • a preferred silyl group on the activated diol/alcohol is trimethylsilyl.
  • Alkyl is a saturated or unsaturated hydrocarbon chain having 1 to about 18 carbon atoms, preferably 1 to about 12, more preferably 1 to about 6, more preferably still 1 to about 4 carbon atoms.
  • “Lower alkyl” is an alkyl having from 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyls have one or two branches, preferably one branch. Preferred alkyls are saturated. Unsaturated alkyls 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 4 substituents.
  • Preferred alkyls are unsubstituted.
  • Preferred substituted alkyl are mono-, di-, or trisubstituted.
  • Preferred alkyl substituents include halo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, 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 4 substituents on the ring.
  • Preferred aromatic ring substituents include, for example, halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy, or any combination thereof. More preferred substituents include halo and haloalkyl.
  • Preferred aromatic rings include naphthyl and phenyl. The most preferred aromatic ring is phenyl.
  • Base means a basic reagent which is added to the reaction mixture to facilitate covalent bond formation in the Wadsworth-Horner-Emmons reaction.
  • Bases include nitrogen bases.
  • Preferred bases include those which are soluble in organic solvents and are volatile.
  • preferred bases include N, N diisopropylethylamine, triethylamine, trimethylamine, butylamine, pyridine, and 2,6-lutidine. The more preferred bases are 2,6-lutidine, triethylamine, and pyridine. The most preferred base is triethylamine.
  • 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. That is, 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 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. More preferred carbocyclic aliphatic rings include cyclohexyl, cycloheptyl, and cyclooctyl. The most preferred carbocyclic aliphatic ring is cycloheptyl.
  • Corey aldehyde is a common chemical name for hexahydro-5-hydroxy-4-formyl-2H- cyclopenta[b]furan-2-one, a commercially available aldehyde.
  • Deprotection refers to the removal of functional groups used to allow prior chemistries to proceed. Deprotection includes the removal of silyl ethers of alcohols or alkyl esters of carboxylic acids.
  • Ether solvent is 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 ether solvents include diethyl ether and tetrahydrofuran. The most preferred ether solvent is tetrahydrofuran.
  • Halo is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and fluoro, especially fluoro.
  • Haloalkyl is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents.
  • Preferred haloalkyl are Cj-C ⁇ . More preferred are Cj-Cg; more preferred still are C1-C3.
  • Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
  • Halocarbon solvent is a solvent which has one or more halogens bonded to a carbon chain.
  • Preferred halocarbon solvents include dichloromethane, dichloroethane, carbon tetrachloride, and chloroform. More preferred halocarbon solvents include dichloromethane and chloroform. The most preferred halocarbon solvent is dichloromethane.
  • 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 heteroalkyls have one or two branches, preferably one branch. Preferred heteroalkyls are saturated. Unsaturated heteroalkyls have one or more double bonds and/or one or more triple bonds. Preferred unsaturated heteroalkyls 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 4 substituents.
  • Preferred heteroalkyls are unsubstituted.
  • Preferred heteroalkyl substituents include halo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxyphenyl, alkyloxycarbonylphenyl, 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, alky loxycarbonylpheny lth io), amino (e.g., amino, mono- and di- CJ-C3 alkylamino, methylphenylamino,
  • 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 ring atoms (carbon and heteroatoms), preferably from 4 to 7, and most preferably from 5 to 6 atoms in the ring.
  • Bicyclic heterocyclic aliphatic rings contain from 8 to 12 ring atoms, preferably 9 or 10 atoms in the ring. Heterocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 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, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl.
  • Heteroaromatic ring is an aromatic ring system containing carbon and from 1 to about 3 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 ring atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 atoms in the ring. Bicyclic heteroaromatic rings contain from 8 to 12 ring atoms, preferably 9 or 10 atoms in the ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to 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 hydride ion in a reaction.
  • Preferred hydride reducing agents include L-selectride, sodium borohydride, lithium aluminum hydride, and diisobutyl aluminum hydride (DIBAL). More preferred hydride reducing agents include L-selectride, sodium borohydride and DIBAL. The most preferred hydride reducing agent is DIBAL.
  • Lewis acid refers to any non-protic acid which is added to the reaction mixture to facilitate covalent bond formation.
  • the preferred Lewis acids include magnesium perchlorate and triethylaluminum. The most preferred Lewis acid is magnesium perchlorate.
  • 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 preferred substitution pattern on the phenyl ring is ortho or meta.
  • the most preferred substitution pattern on the phenyl ring is ortho.
  • “Wadsworth-Horner-Emmons” reagent means any chemical agent suitable for adding to an aldehyde via a stabilized phosphonium salt to form an alkene bond in a single-pot process.
  • Preferred "Wadsworth-Horner-Emmons” reagents include: 3-(2,4-dichlorophenoxy)-dimethyl- 2-oxo-propyl phosphonate, 3-(2,4-difluorophenoxy)-dimethyl-2-oxo-propylphosphonate, 4-(2,6- difluorophenyl)-dimethyl-2-oxo-butylphosphonate, 3-(2,6-difluorothiophenoxy)-dimethyl-2- oxo-propylphosphonate, 4-(2-fluorophenyl)-2-oxo-butylphosphonate, 4-(3 -fluoro- 5- trifluoromethylphenyl)-2-oxo
  • “Wittig-Horner” reagent is the recognized chemical name for a class of phosphonium salts which form anions that are stabilized by adjacent heteroatoms.
  • a “Horner product” is the product formed by reaction of a compound with a Wittig-Horner reagent. See March, J. Advanced Org. Chem., 4 th Ed., p. 959 (Wiley, New York, 1992)
  • substituent groups may themselves be substituted. Such substitution may be with one or more substituents.
  • substituents include those listed in C. Hansch and A. Leo Substituent Constants For Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein.
  • Preferred substituents include, for example, alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl, imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
  • the compounds made by the process of this invention encompass any of a variety of prostaglandin F analogs having a structure according to Formula (I):
  • R 1 is C0 2 H, C(0)NHOH, C0 2 R 5 , CH 2 OH, S(0) 2 R 5 , C(0)NHR 5 , C(0)NHS(0)2R 5 , or tetrazole (preferably C0 H, C0 2 R 5 , C(0)NHS(0)2R 5 ); wherein R 5 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring (preferably alkyl); b) R 2 is hydrogen or lower alkyl; c) 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 (preferably hydrogen, lower alkyl, and alkoxy); d) Y is NR 4 , S, S(O), S(0) 2 , O, or
  • the process of the present invention comprises the novel synthesis of the ketal intermediate described herein, followed by removal of the ketal moiety and the reaction of the intermediate under basic conditions in the presence of a Wadsworth-Horner-Emmons reagent to give, without protection of the alcohol functional groups, prostaglandin F2 ⁇ analogs, which can be further elaborated, as known in the art and herein, to 13,14-dihydro-15,16- or 17- substituted-16-tetranor or 17-trinor prostaglandin F] ⁇ analogs.
  • the novel ketal intermediate (Slf in the reaction scheme below) is synthesized in seven (7) steps, and in good yield, from the commercially available Corey Lactone.
  • R is a carboxylic acid, carboxylic acid ester comprising a saturated or unsaturated, linear or branched Ci-Cs alkyl, aromatic hydrocarbon, hydroxamic acid, hydroxymethyl, sulfonyl amide, sulfonic acid, sulfonyl ester, or tetrazole; and b) Q is a suitable protecting group such as a tert-butyl dimethylsilyl, trimethylsilyl, benzyl, or an alkyl C1-C8 ether or aromatic ether, or a benzoyl or acetyl ester.
  • R is more preferably a carboxylic acid or a carboxylic acid ester comprising a saturated or unsaturated, linear or branched C]-C8 alkyl, or aromatic hydrocarbon.
  • R is most preferably a carboxylic acid.
  • Preferred Q protecting groups include tert-butyl dimethylsilyl, trimethylsilyl, and benzyl ethers. The most preferred protecting group is a tert-butyl dimethylsilyl ether.
  • Corey aldehyde is reacted with a bis silyl-protected glycol, and a catalytic amount of acid in a solvent that will allow the ketalization to proceed.
  • More preferred silylating agents include bis-trimethyl silyl (TMS) ethylene glycol and bis-TMS propylene glycol.
  • the most preferred ketalization agent is bis-TMS ethylene glycol.
  • Preferred acids include triflic acid and TMS triflate.
  • the most preferred acid catalyst is TMS triflate.
  • Preferred solvents include halocarbon solvents, with dichloromethane being the most preferred solvent.
  • the 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 0°C and 23°C.
  • R 6 is C0 2 H, C(0)NHOH, C0 2 R 8 , CH 2 OH, S(0) 2 R 8 , C(0)NHR 8 , C(0)NH- S(0)2R 8 , or tetrazole, wherein R 8 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, aromatic ring, or heteroaromatic ring; and each R 7 is (i) is lower alkyl; or (ii) the R 7 moieties together with the two oxygen atoms form a substituted 5-membered monocyclic aliphatic heterocycle, a substituted or unsubstituted 6-membered monocyclic aliphatic heterocycle, or a substituted or unsubstituted 8 to 12 member bicyclic aliphatic heterocycle; or a salt or protected form thereof.
  • the ketal intermediate so obtained can be isolated by methods obvious to those who are skilled in the art, such methods including extraction, solvent evaporation, distillation, or crystallization procedures. Most preferably, the ketal is purified after isolation by distillation under vacuum.
  • the ketal is reacted in the crude state with a base in a suitable solvent to remove the ester functional group from the alcohol, creating compound Sic in Scheme 1, as is typical and known in the art.
  • the reaction is neutralized, preferably with acidic ion exchange resin.
  • the product compound Sic so obtained can be isolated by methods obvious to those who are skilled in the art, such as using methods including extraction, solvent evaporation, distillation, or crystallization procedures. Most preferably, the product is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 2% MeOH in CH2CI2 as the eluent.
  • the free alcohol thus formed is reacted with a silylating agent and base in a solvent that will allow the silylation to proceed to give Sid, as is known in the art.
  • the silylated compound Sid so obtained can be isolated by methods obvious to those who are skilled in the art, such as using methods including extraction, solvent evaporation, distillation, or crystallization procedures. Most preferably, the silyl ether is purified after isolation by distillation under vacuum.
  • the product Sid so obtained is then treated with a special reducing agent to effect reduction of the lactone moiety to a lactol, Sle.
  • a special reducing agent for this process is diisobutyl aluminum hydride (DIBAL).
  • Solvents which are preferred are benzene, heptane, xylenes, hexane and toluene.
  • the most preferred solvent is toluene.
  • the reaction is carried out at the beginning of the reaction preferably at between -100°C and 0°C, more preferably between -80°C and-40°C and most preferably between -80°C and -50°C.
  • the reaction time for the initial phase of the reaction is between 5 min and 24 hours, preferably between 10 min and 4 hours, more preferably between 30 min and 3 hours. The most preferred time is between 1 hour and 2.5 hours.
  • the reaction is then warmed to complete the process.
  • the temperature for this part of the reaction is from about -20°C to about 20°C, more preferably from -10 to 5°C.
  • the most preferred temperature for the second phase of the reaction is from -5 °C to 2°C.
  • the reaction is quenched with a suitable neutralizing agent such as ammonium chloride.
  • the lactol Sle so obtained can be isolated by methods obvious to those who are skilled in the art, such as using methods including extraction, solvent evaporation, distillation, or crystallization procedures. Most preferably, the lactol is purified after isolation by solvent evaporation. However, the lactol Sle is typically not purified but is carried on to the next step, the addition of the Wittig reagent, as is commonly described in the art (see, for example: Corey, E.J.; Weinshenker, N.M.; Schaaf, T.K.; Huber, W. "Stereo-Controlled Synthesis of Prostaglandins F2 ⁇ and E2 (J/)" J- Am. Chem. Soc.
  • the alkene Slf so obtained can be isolated by methods obvious to those who are skilled in the art, such as using methods including extraction, solvent evaporation, distillation, or crystallization procedures. Most preferably, the alkene is purified after isolation by crystallization.
  • the alkene so created is useful as an intermediate in its own right, or it can be transformed into a useful ester. Methods for this transformation are well known in the art. Typically, the acid is transformed to the methyl ester, but it is contemplated that a variety of esters will prove useful.
  • diazomethane or TMS diazomethane is used to create a methyl ester.
  • the most preferred reagent is TMS diazomethane.
  • Esterification is effected by adding TMS-diazomethane dropwise to an alcoholic solution of the free acid.
  • the reaction time is essentially instantaneous at room temperature. The reaction, however, can be run from about 5 min. to 16 hours. The most preferred time is from about 5 min to about 15 min.
  • the reaction can also be run at a variety of temperatures, from -80 to +50 °C. The most preferred temperature is from 15°C to 25°C.
  • the ester so obtained can be isolated by methods obvious to those who are skilled in the art, such as using methods including extraction, solvent evaporation, distillation, or crystallization procedures. Most preferably, the alkene is purified after isolation by crystallization.
  • This ester is useful, as illustrated below, for the synthesis of biologically-active molecules of the prostaglandins.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à un procédé servant à produire des analogues de prostaglandine F, ce procédé consistant: (I) à préparer un intermédiaire ayant une structure représentée par la formule (A), où R6 et R7 sont définis dans les pièces descriptives de l'invention, intermédiaire que l'on prépare: (a) en faisant réagir un aldéhyde de Corey avec un alcool activé pour former un dérivé acétal; (b) en déprotégeant le dérivé acétal de l'étape (a) pour former un acétal hydroxy; (c) éventuellement en reprotégeant l'acétal hydroxy de l'étape (b); (d) en réduisant (b) ou (c) pour former un dérivé lactol; et (e) en condensant le dérivé lactol de l'étape (d) avec un sel phosphonium, afin de former le cétal intermédiaire de formule (A), ou un sel ou une forme protégée de celui-ci; (II) à retirer le cétal de l'intermédiaire de formule (A) formé à l'étape (I) pour obtenir un aldéhyde et à coupler cet aldéhyde avec un réactif Wadsworth-Horner-Emmons ou avec un réactif Wittig-Horner pour former un produit, et (III) à appliquer une ou plusieurs étapes de synthèse ultérieures sur le produit de l'étape (II) pour former un analogue de prostaglandine F.
PCT/US1998/018595 1997-09-09 1998-09-04 Procede de production d'analogues de prostaglandine f WO1999012899A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU93058/98A AU9305898A (en) 1997-09-09 1998-09-04 A process for making prostaglandin f analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5825397P 1997-09-09 1997-09-09
US60/058,253 1997-09-09

Publications (1)

Publication Number Publication Date
WO1999012899A1 true WO1999012899A1 (fr) 1999-03-18

Family

ID=22015641

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/018595 WO1999012899A1 (fr) 1997-09-09 1998-09-04 Procede de production d'analogues de prostaglandine f

Country Status (3)

Country Link
AU (1) AU9305898A (fr)
PE (1) PE121399A1 (fr)
WO (1) WO1999012899A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000051980A1 (fr) * 1999-03-05 2000-09-08 The Procter & Gamble Company Analogues de prostaglandines c16 fp selectives insaturees
EP1267803B1 (fr) * 2000-03-31 2005-12-14 Duke University Compositions et methodes pour traiter la chute des cheveux au moyen de tetrahydroprostaglandines aromatiques c16-c20
US7268239B2 (en) 2001-05-24 2007-09-11 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof
US8084501B2 (en) 2005-01-20 2011-12-27 Breath Limited Stable prostaglandin-containing compositions
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9006291B2 (en) 2009-02-03 2015-04-14 Pharma Patent Holding Inc. Composition, method and kit for enhancing hair
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2757919A1 (de) * 1976-12-31 1978-07-13 Erba Carlo Spa Bicyclische prostaglandine, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische oder veterinaer-zubereitung
DE2743283A1 (de) * 1977-09-27 1979-04-05 Hoechst Ag Neue prostacyclin-analoga
DE4101812A1 (de) * 1991-01-23 1992-07-30 Jenapharm Gmbh Verfahren zur herstellung von aldehyden

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2757919A1 (de) * 1976-12-31 1978-07-13 Erba Carlo Spa Bicyclische prostaglandine, verfahren zu ihrer herstellung und sie enthaltende pharmazeutische oder veterinaer-zubereitung
DE2743283A1 (de) * 1977-09-27 1979-04-05 Hoechst Ag Neue prostacyclin-analoga
DE4101812A1 (de) * 1991-01-23 1992-07-30 Jenapharm Gmbh Verfahren zur herstellung von aldehyden

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 88, no. 78, 5 June 1919, Columbus, Ohio, US; abstract no. 164625, TOGNA, G. ET AL: "Inhibition of human platelet aggregation by stable analogs of prostacyclin" XP002085510 *
CHEMICAL ABSTRACTS, vol. 94, no. 81, 8 June 1919, Columbus, Ohio, US; abstract no. 191748, GUZZI, UMBERTO ET AL: "16-methoxyprostaglandins" XP002085509 *
GAZZ. CHIM. ITAL. (1980), 110(11-12), 633-40 CODEN: GCITA9;ISSN: 0016-5603, 1980 *
JOHNSON, FRANCIS ET AL: "Prostaglandins. 2. Synthesis of prostaglandin F2.alpha. in optically active form from chiral precursors", J. AM. CHEM. SOC. (1982), 104(8), 2190-8 CODEN: JACSAT;ISSN: 0002-7863, 1982, XP002085508 *
PHARMACOL. RES. COMMUN. (1977), 9(10), 909-16 CODEN: PLRCAT;ISSN: 0031-6989, 1977 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000051980A1 (fr) * 1999-03-05 2000-09-08 The Procter & Gamble Company Analogues de prostaglandines c16 fp selectives insaturees
US6586463B2 (en) 1999-03-05 2003-07-01 The Procter & Gamble Company C16 unsaturated FP-selective prostaglandins analogs
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
EP1267803B1 (fr) * 2000-03-31 2005-12-14 Duke University Compositions et methodes pour traiter la chute des cheveux au moyen de tetrahydroprostaglandines aromatiques c16-c20
US8906962B2 (en) 2000-03-31 2014-12-09 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9346837B2 (en) 2000-03-31 2016-05-24 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US9579270B2 (en) 2000-03-31 2017-02-28 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US9675539B2 (en) 2000-03-31 2017-06-13 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US7268239B2 (en) 2001-05-24 2007-09-11 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof
US7498458B2 (en) 2001-05-24 2009-03-03 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof
US8084501B2 (en) 2005-01-20 2011-12-27 Breath Limited Stable prostaglandin-containing compositions
US9006291B2 (en) 2009-02-03 2015-04-14 Pharma Patent Holding Inc. Composition, method and kit for enhancing hair

Also Published As

Publication number Publication date
PE121399A1 (es) 2000-02-03
AU9305898A (en) 1999-03-29

Similar Documents

Publication Publication Date Title
US4055602A (en) 2-Decarboxy-2-hydroxy-methyl-5-oxa-17-phenyl-18,19,20-trinor-PGF-analogs
AU731153B2 (en) Aromatic C16-C20-substituted tetrahydro prostaglandins useful as FP agonists
CA2303763C (fr) Prostaglandines aromatiques tetrahydro substituees par c16-c20 utilisees comme agonistes fp
US4087604A (en) Substituted ω-pentanorprostaglandins
CS228916B2 (en) Method of preparing new derivatives of 9 alpha,6-nitril
IL43571A (en) Omega-pentanorprostaglandins and their preparation
IL43589A (en) 16-phenoxy-15-hydroxy derivatives of 17,18,19,20-tetranorprostaglandins and their preparation
USRE29926E (en) 2-Decarboxy-2-hydroxy-methyl-16-fluoro-PGE1 compounds
WO1999012899A1 (fr) Procede de production d'analogues de prostaglandine f
EP1082299B1 (fr) Prostaglandines c11 oxymyl et hydroxylamino utilisees comme medicaments
IE44016B1 (en) 11-deoxy-16-aryl-17,18,19,20-tetranorprostaglandins
US4028419A (en) 2-Decarboxy-2-hydroxymethyl-cis-4,5-didehydro-PGE, compounds
AU749540B2 (en) C11oxymyl and hydroxylamino prostaglandins useful as FP agonists
US6066751A (en) Process for making epoxide intermediates
US4078021A (en) Dimethyl 2-oxo-6-cyanohexyl-phosphonate
JPS6126970B2 (fr)
EP0695741B1 (fr) 7-thiaprostaglandines et procede de production de ces composes
US4094899A (en) Oxaprostaglandins
US4113766A (en) Oxaprostaglandins
CS200166B2 (en) Method of producing n-substituted prostaglandincarboxamides
IE47626B1 (en) 15-substituted-w-pentanorprostaglandin derivatives
WO2000051977A1 (fr) Intermediaires aldehydes pour l'elaboration de derives des prostaglandines
US4110341A (en) Dithio prostaglandin derivatives
US4244887A (en) Substituted ω-pentanorprostaglandins
IL42373A (en) Oxaprostagliandins and their preparation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AT AU AZ BA BB BG BR BY CA CH CN CU CZ CZ DE DE DK DK EE EE ES FI FI GB GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA