US20040249172A1 - Process for the preparationof prostaglandins and analogues thereof - Google Patents

Process for the preparationof prostaglandins and analogues thereof Download PDF

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US20040249172A1
US20040249172A1 US10/478,513 US47851304A US2004249172A1 US 20040249172 A1 US20040249172 A1 US 20040249172A1 US 47851304 A US47851304 A US 47851304A US 2004249172 A1 US2004249172 A1 US 2004249172A1
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Alan Greenwood
Derek McHattie
David Thompson
Derek Clissold
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Resolution Chemicals Ltd
Cascade Biochem Ltd
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Assigned to CASCADE BIOCHEM LIMITED reassignment CASCADE BIOCHEM LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CLISSOLD, DEREK WYNDHAM
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F295/00—Macromolecular compounds obtained by polymerisation using successively different catalyst types without deactivating the intermediate polymer
    • 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
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Definitions

  • the present invention relates to a novel process for the synthesis of prostaglandins and prostaglandin analogues.
  • this invention relates to the synthesis of PGF 2 ⁇ and analogues thereof.
  • Prostaglandin F 2 ⁇ ⁇ PGF 2 ⁇ -7-[3,5-dihydroxy-2-(3-hydroxy-1-octenyl)-cyclopentyl]-5-heptenoic acid ⁇ has the structure:
  • This compound causes uterine contraction and is used clinically to induce and accelerate labour, and as an abortifacient.
  • Prostaglandins are generally characterised by the substituents on the cyclopentyl ring.
  • the PGF 2 ⁇ prostaglandins and prostaglandin analogues generally have two hydroxyl groups in a cis configuration relative to the cyclopentane ring, and two side chains in a trans configuration relative to each other, each side chain having one double bond.
  • Analogues of PGF 2 ⁇ can have a different number of double bonds in the side chains, and the substituents along the side chains may vary. Additionally, in some PGF 2 ⁇ analogues, the side chain carboxylic acid group may be esterified.
  • PGF 2 ⁇ analogues having therapeutic use are cloprostenol, which contains a chlorophenyl ether side chain substituent, fluprostenol, which contains a trifluoromethylphenyl ether side chain substituent, and travoprost:
  • Latanoprost [13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF 2 ⁇ -isopropyl] is an example of a PGF 2 ⁇ analogue having one saturated side chain and wherein the carboxylic acid group is esterified:
  • This compound is used in the clinic for the reduction of elevated intra-ocular pressure in patients with open angle glaucoma and ocular hypertension.
  • Prostaglandin analogues based on PGF 2 ⁇ for use in the treatment of glaucoma and ocular hypertension are described in, for example, European patent number 0 364 417 B1.
  • the procedures for the synthesis of PGF 2 ⁇ analogues described therein start from an advanced-stage intermediate, 16-phenyl-17,18,19,20-trinor PGF 2 ⁇ , or the tetranor homologue thereof.
  • European patent number EP 0 544 899 B1 describes a process for the synthesis of 13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF 2 ⁇ esters of the formula:
  • [0013] is prepared by transforming the hydroxymethyl group of the protected Corey lactone, with an oxidising agent (dicyclohexylcarbodiimide) to form the corresponding aldehyde. Reaction of the aldehyde with a phenylphosphonium salt forms the above intermediate.
  • the present invention provides a process for the preparation of prostaglandin derivatives having the Formulae (I-A) and (I-B):
  • B represents a substituent selected from the group consisting of:
  • R′′ represents C 1 -C 20 alkyl (preferably a C 1 to C 6 alkyl group, e.g. methyl, ethyl, propyl and iso-propyl), C 3 to C 8 cycloalkyl (e.g. cyclohexyl, cyclopropyl, cyclobutyl) or C 6 to C 10 aryl (preferably phenyl).
  • a preferred R′′ group is iso propyl.
  • R′′ is other than an alkyl, cycloalkyl or aryl group.
  • R′′ groups include, but are not limited to, unsaturated C 1 to C 20 alkyl, unsaturated C 3 to C 8 cycloalkyl, wherein the saturated or unsaturated alkyl or cycloalkyl groups, or aryl groups can be substituted with one or more (typically 1 to 3) substituents such as CF 3 , C 1 to C 6 alkoxy, CN.
  • R′′ groups include C 6 to C 10 heterocycloalkyl (e.g. piperidinyl), C 6 to C 10 heteroaryl (such as pyridyl) and substituted C 6 to C 10 aryl (including substituents such as CF 3 , C 1 to C 6 alkoxy, CN).
  • Scheme 1 illustrates one route to the synthesis of compounds of Formula (I-A) and (I-B), starting from a protected-Corey lactone compound of Formula (X):
  • the intermediate (VI-A) in Scheme 1 can be made by carrying out steps (a) and (b) as shown in Scheme 1, and substituting steps (c), (d), and (e) in Scheme 1 with the steps (e′), (c′) and (d′) as shown in the following Scheme 2:
  • Scheme 3 illustrates an alternative procedure for the synthesis of compounds of Formula (I-A) and (I-B), starting from intermediates of structure (IIIa) and (IIIb):
  • Scheme 4 shows an alternative procedure for the synthesis of compounds of Formula (I-B) starting from the intermediates of Formula (IIa) and (IIb):
  • A represents C 6 to C 10 aryl which may be substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl;
  • the above reaction may be carried out by electrooxidation in the presence of the organic nitroxyl radical.
  • the oxidation reaction may be carried out in the presence of a nitroxyl radical and at least one molar equivalent of a co-oxidant selected from the group consisting of m-chloroperbenzoic acid, high-valent metal salts, sodium bromite, sodium or calcium hypochlorite, N-chlorosuccinimide or hypervalent iodine compounds such as [bis(acetoxy)iodo]benzene.
  • the co-oxidant is sodium hypochlorite.
  • the stable organic radical preferably comprises a completely ⁇ -substituted piperidin-1-oxy radical, such as 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO, free radical).
  • TEMPO free radical
  • Prior art oxidation procedures for oxidising the compound of Formula (X) to form the compound of Formula (IX) include the use of dimethylsulfoxide-dicyclohexylcarbodiimide.
  • such a method requires isolation of the aldehyde (IX). Since the aldehyde (IX) is not particularly stable in solution, an amount of decomposition product is usually observed during work-up.
  • the aldehyde (IX) solution obtained in this step can be employed in the subsequent step without isolation of the aldehyde, thus minimising any decomposition.
  • A represents C 6 to C 10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl;
  • B represents a substituent selected from the group consisting of: (i) C 1 to C 6 alkyl, (ii) C 7 to C 1-6 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 ,
  • a and B are as defined as above, and each R′′′ is the same or different (preferably the same) and each represents a C 1 to C 6 alkyl group (preferably methyl), the process being carried out in the presence of lithium chloride and an organic base (such as tertiary alkylamines, e.g. di-iso-propylethylamine).
  • an organic base such as tertiary alkylamines, e.g. di-iso-propylethylamine.
  • the compounds of Formula (IX) are commercially available or can be made from commercially available starting materials.
  • the compound of Formula (IX) may be prepared by the process described in U.S. Pat. No. 3,778,450.
  • dimethyl-(2-oxo-4-phenylbutyl)phosphonate may be produced from dimethyl-(2-oxo-propyl)phosphonate via the following reaction:
  • a strong base e.g. n BuLi
  • R y can represent any group that can form a leaving group —OR y .
  • Typical R y groups include C 1 to C 6 alkyl, such as methyl, or ethyl (methyl is preferred).
  • the product from this reaction can be typically purified by distillation.
  • this reaction is usually free of side reactions compared with the prior art process using dimethyl(2-oxopropyl)phosphonate.
  • the reaction is preferably carried out at temperatures in the range of ⁇ 20° C. to 40° C., and preferably ⁇ 10° C. to 30° C.
  • Suitable solvents for this reaction include those selected from the group consisting of benzene, toluene, acetonitrile, dichloromethane, diethylether, and mixtures thereof.
  • the group A preferably represents an unsubstituted C 6 to C 10 aryl group (e.g. phenyl).
  • substituents for the group A include those selected from C 6 to C 10 aryl group being substituted with one substituent selected from halo or phenyl. Further preferred substituents for the group A include unsubstituted or substituted phenyl wherein the substituent is selected from halo or phenyl. In a preferred process, the group A represents phenyl.
  • A represents unsubstituted C 6 to C 10 aryl
  • B represents a substituent selected from the group consisting of:
  • Suitable reducing agents for the reduction of the side chain oxo group include borane-dimethylsulfide complex, lithium tri-sec-butylborohydride, ⁇ LiB[CH(CH 3 )CH(C 2 H 5 ] 3 H ⁇ (L-Selectride RTM ) and sodium borohydride.
  • a non-stereoselective reducing agent may be used (e.g. LiAlH 4 , NaBH 4 and other metallic hydrides).
  • the reducing agent suitably comprises borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine catalyst (“Corey catalyst”) because of the greater selectivity towards the production of a major amount of the desired isomer.
  • Corey catalyst a chiral oxazaborolidine catalyst
  • a preferred reagent for the reduction reaction is borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine catalyst (Corey catalyst).
  • the group A in the compound of Formula (VII) in addition to being unsubstituted C 6 to C 10 aryl, can also represent C 6 to C 10 aryl substituted with one to three substituents independently selected from the group consisting of (i) halo, i.e. fluoro, chloro, bromo or iodo, (ii) C 1 to C 6 alkyl and (iii) Ce to C 10 aryl, such as phenyl.
  • borane-dimethylsulfide complex in combination with a Corey catalyst is especially preferred because the reaction takes place with excellent selectivity. In fact, a marked improvement in stereoselectivity is seen compared with the reaction using L-Selectride RTM .
  • a further advantage is that the reduction reaction using borane-dimethylsulfide complex can be carried out at a higher temperature (typically ⁇ 15° C. to ⁇ 18° C.) compared with L-Selectride RTM , which requires a reaction temperature of less than ⁇ 70° C.
  • the Corey catalyst comprises a chiral oxazaborolidine compound [see J. Am. Chem. Soc., 109, 5551, (1987) and J. Am. Chem. Soc. 109, 7925, (1987) and references cited in Lancaster Catalogue 2000-2001, page 819] such as (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrole[1,2-c][1,3,2]oxazaborole, may be prepared by reaction of the appropriate chiral prolinol [such as the commercially available (R)-(+)- ⁇ , ⁇ -diphenylprolinol] with a trialkyl boroxine, e.g.:
  • reaction is carried out in inert conditions in a solvent such as toluene, diethylether or tetrahydrofuran.
  • a solvent such as toluene, diethylether or tetrahydrofuran.
  • the oxazaborolidine catalyst is employed as a solution in the reduction step.
  • the dashed line forms an optional double bond
  • B represents a substituent selected from the group consisting of:
  • R′ represents the substituent:
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • A represents C 6 to C 10 aryl which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl;
  • R x , R y and R z are as defined above and X represents F, Cl, Br or I.
  • the deprotection step (a) wherein the protecting group A on the hydroxyl group of the cyclopentane ring is removed, is preferably carried out in the presence of a base.
  • Preferred bases for use in the deprotection reaction includes those selected from the group consisting of K 2 CO 3 , Na 2 CO 3 and Li 2 CO 3 , with K 2 CO 3 being particularly preferred.
  • Suitable solvents for the deprotection reaction include alcohols, such as methanol, ethanol and isopropanol.
  • step (a) The isolation of the deprotected product from step (a) may be carried out by standard chromatography procedures. However, it has been found that the deprotected product can advantageously be isolated by extraction with hexane fractions, thus avoiding the use of time consuming and expensive chromatographic procedures.
  • the hydrogenation step can be carried out using any suitable hydrogenation catalyst such as palladium, platinum or rhodium, which may be supported on an inert support, such as carbon.
  • a suitable hydrogenation catalyst is 5% palladium on carbon.
  • the hydrogenation reaction is carried out in the presence of sodium nitrite, preferably in aqueous solution.
  • This procedure avoids the formation of elimination products and thus results in improved yields (typically greater than 95%) of the compounds of Formula (VI-A).
  • Suitable solvents for the hydrogenation reaction include alcohols such as methanol and ethanol.
  • the mixture is preferably stirred with dilute hydrochloric acid to remove the nitrite (by conversion to nitrous acid, which decomposes at ambient temperature). This procedure ensures that nitrite is not carried through to the subsequent synthetic procedures.
  • the role of the sodium nitrite in the hydrogenation reaction is to avoid the formation of elimination products, that is, the elimination of a water molecule from the side chain of the starting material and, as a consequence, formation of the fully saturated deoxygenated analogue of the desired product.
  • the compound produced in step (a) having the Formula (VI) or the compound produced in step (b) having the Formula (VI-A) is reacted with a silylating agent (X)Si(R x )(R y )(R z ).
  • the groups R x , R y , and R z can be the same or different each represents a C 1 to C 6 alkyl group or a C 6 to C 10 aryl group.
  • each of the groups R x , R y , and R z are independently selected from methyl, ethyl, butyl, isopropyl.
  • silylating agents for use in step (c) are selected from the group consisting of trimethylsilyl chloride, triethylsilyl chloride and tert-butyldimethylsilyl chloride. Triethylsilyl chloride is particularly preferred.
  • the silylation step is preferably carried out in the presence of a base, for example an organic base, such as imidazole or trialkylamines, such as triethylamine.
  • a base for example an organic base, such as imidazole or trialkylamines, such as triethylamine.
  • Suitable solvents for use in the silylation reaction include polar aprotic solvents such as tetrahydrofuran or dimethylsulfoxide, or chlorinated solvents such as dichloromethane.
  • polar aprotic solvents such as tetrahydrofuran or dimethylsulfoxide
  • chlorinated solvents such as dichloromethane.
  • the reaction is carried out in a solvent comprising dimethylformamide.
  • silyl protecting groups in accordance with the present invention is advantageous because it generally results in cleaner reactions, with higher yields compared with reactions wherein the hydroxyl group is not protected.
  • silyl protecting groups in the present process has particular advantages compared with the prior art process employing, e.g. benzoyl- and para-phenylbenzoyl (PPB)-protecting groups because silyl groups are stable to the subsequent reduction reaction with e.g. DIBAL-H (di-iso-butylaluminium).
  • PPB para-phenylbenzoyl
  • a second advantage of using silyl protecting groups in the subsequent Wittig reaction [step (i) in Scheme 1], is that the formation of the desired cis isomer is favoured.
  • Silyl protecting groups have the further advantage in that they generally increase the lipophilic character of the molecules, so that their derivatives are readily soluble in organic solvents.
  • removal of the phosphine oxide by-product is facilitated because the silyl-protected Wittig reaction product [(IIIa)/(IIIb)] is soluble in hexane, whereas the triphenylphosphine oxide is insoluble, thus allowing separation by filtration.
  • Subsequent purification of the product can be carried out by silica gel filtration, rather than a full chromatographic purification.
  • a further advantage of employing silyl protecting groups is that these protecting groups can be removed under mild conditions, as discussed below.
  • [0104] can be made from compounds of Formula (VIII) by a process comprising the steps of:
  • R x , R y and R z are as defined above and X represents F, Cl, Br or I.
  • Steps (a) to (c) of this process are depicted as steps (e′), (c′) and (d′) in Scheme 2.
  • Step (d) corresponds to step (f) of Scheme 1, the product of which is a compound of Formula (V) wherein the dashed and solid line represents a single bond.
  • the hydrogenation, reduction, deprotection and silylation steps in this alternative procedure are carried out as for the immediately preceding process to form the compounds of Formula (V).
  • B represents a substituent selected from the group consisting of:
  • R′ represents the substituent:
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • a suitable reducing agent for this process is di-iso-butylaluminium hydride DIBAL-H), and the reaction may be carried out in e.g. tetrahydrofuran.
  • B represents a substituent selected from the group consisting of:
  • R′ represents the substituent:
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • R w represents C 1 to C 6 alkyl or C 6 to C 10 aryl
  • X represents fluoro, chloro, bromo or iodo.
  • the group R w represents phenyl.
  • the group X preferably represents bromo.
  • [0135] are commercially available, or can be prepared by reaction of a phosphine, P(R w ) 3 , with HO 2 C(CH 2 ) 4 —X′ (wherein X′ represents halide, e.g. F, Cl, Br or I).
  • Suitable bases for the forming the ylide include those selected from the group consisting of butyllithium, sodium amide, sodium hydride, and alkali metal alkoxides, including sodium methoxide, sodium ethoxide, potassium ethoxide and potassium tert-butoxide. Potassium tert-butoxide is a particularly preferred base.
  • a suitable solvent for this reaction is tetrahydrofuran.
  • the ylide may be formed by the reaction of (4-carboxybutyl)-triphenylphosphonium bromide with potassium tert-butoxide:
  • the ylide can be generated using 3 equivalents of the phosphonium halide and 6 equivalents of base, i.e. a ratio of phosphonium halide and base of 1:2, but is preferably generated using 2.15 equivalents of the phosphonium halide and 4 equivalents of base.
  • the silyl protecting groups of the hydroxyl substituent on the cyclopentyl ring may migrate to the hydroxyl group formed by the opening of the lactol ring, to result in a mixture of 9- and 11-silylated isomers of Formula (IIIa) and (IIIb).
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • R x , R y and R z are as defined above and X represents F, Cl, Br or I.
  • This procedure is advantageously carried out where a mixture of the compounds of Formula (IIIa) and Formula (IIIb) are formed as the products of the Wittig reaction.
  • the reaction of such a mixture with at least one molar equivalent of a silylating agent, preferably the same silylating agent as is used to protect the hydroxyl groups of the compounds of Formula (V), enables the mixture of compounds of Formula (IIIa) and (IIIb) to be “amalgamated” into a single product of Formula (XI) for subsequent reaction steps.
  • a molar equivalent of silylating agent to starting material is employed. Typically, 1.1 to 2 molar equivalents are employed. The formation of a single product allows for better control of subsequent reaction steps and purification.
  • the dashed line represents an optional double bond
  • B represents a substituent selected from the group consisting of: (i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 ;
  • R′ represents the substituent:
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
  • the mixture may be alkylated by the process indicated above, to form a mixture of 9- and 11-silylated esters of Formula (IIa) and (IIb).
  • the silylation it is also possible to carry out the silylation after the alkylation step, i.e. on the mixture of compounds of Formula (IIa) and (IIb).
  • a further aspect of the present invention provides a process for the production of a compound of Formula (XII):
  • R′ represents the substituent:
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
  • R x , R y and R z are as defined above and X represents F, Cl, Br or I.
  • this process is preferably carried out in the presence of at least a molar equivalent of silylating agent, and even more preferably 1.1 to 2 molar equivalents of silylating agent is employed. Again, this step leads to the “amalgamation” of the mixture of compounds of Formula (IIa) and (IIb) to form a single product [i.e. compounds of Formula (XII)] which facilitates control of subsequent reaction steps and purification of subsequent intermediates.
  • R′ is the same and each represents the substituent:
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • R′′ represents a C 1 to C 6 alkyl group (e.g. isopropanol) or C 3 to C 8 cycloalkyl (e.g. cyclohexanol).
  • the above process may be carried out optionally in the presence of a weak acid catalyst, such as pyridinium p-toluenesulfonate.
  • a weak acid catalyst such as pyridinium p-toluenesulfonate.
  • the reaction should be carried out in the absence of water, to avoid deprotection of the silyl groups.
  • B represents a substituent selected from the group consisting of:
  • B represents a substituent selected from the group consisting of:
  • R′′ represents C 1 to C 6 alkyl or C 3 to C 8 cycloalkyl
  • Suitable reagents for removal of the silyl groups from the compounds of Formula (IIIa), (IIIb), (XI), (IIa), (IIb) and (XII) include weak acids such as acetic acid and citric acid.
  • An especially preferred weak acid is pyridinium p-toluenesulfonate.
  • the reaction may be carried out in any suitable solvent or solvent mixtures.
  • An especially preferred solvent for the deprotection reaction comprises acetone and water.
  • the compounds of Formulae (VI), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A), (I-B), (XI), (XII) and (XIV) are single enantiomers (i.e. the wavy line in the side chain represents or ).
  • a stereoselective reducing agent e.g. borane-dimethylsulfide complex in the presence of a chiral oxazaborolidine (Corey) catalyst] in step (c) of Scheme 1, or step (c′) in Scheme 2.
  • the group B in the compounds of Formula (XII), (XI), (VII), (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) or (I-B) is selected from the group consisting of (I) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl wherein the aryl group is unsubstituted and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which is substituted with a substituent selected from halo or CF 3 .
  • solid and dashed lines in each of Formulae (XII), (XI) (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (I-A) and (I-B) forms a double bond.
  • B preferably represents —CH 2 CH 2 Ph.
  • B preferably represents a substituent selected from the group consisting of:
  • the process of the present invention is generally applicable for the synthesis of prostaglandins and prostaglandin analogues, particularly PGF 2 ⁇ and analogues thereof.
  • the process is particularly useful for the production of a compound selected from the group consisting of:
  • the present invention provides a process for the synthesis of latanoprost comprising the steps of:
  • A represents a C 6 to C 10 aryl group, preferably phenyl, which may be substituted with one to three substituents independently selected from the group consisting of (i) halo, (ii) C 1 to C 6 alkyl and (iii) unsubstituted C 6 to C 10 aryl,
  • each R′′′ the same or different and each represents a C 1 to C 6 alkyl group (preferably methyl), in the presence of lithium chloride and an organic base, to form the compound of Formula (VIII) wherein B is
  • R x , R y and R z are as defined as above (a particularly preferred silylating agent being triethylsilyl chloride) as defined above to form a compound of Formula (V) wherein B is —CH 2 CH 2 Ph:
  • R′ represents:
  • X represents F, Cl, Br or I, with a strong base (such as potassium t-butoxide), to form a compound of Formula (IIIa) or (IIIb) wherein B is —CH 2 CH 2 Ph:
  • steps (1) to (10) correspond to steps (a)-(b)-(c)-(d)-(e)-(f)-(h)-(i)-(j)-(k) in Scheme 1 above.
  • latanoprost can be formed by a procedure involving carrying out steps (1) and (2) of the preceding process, replacing steps (3), (4) and (5) with the following steps (3′), (4′) and (5′), and thereafter carrying out steps (6-(10) as described in the preceding process.
  • Steps (3′), (4′) and (5′) are as follows:
  • each R′ is as defined as above;
  • novel intermediates for the synthesis of a compound of Formula (I-A) or (I-B) as defined above include the following:
  • A represents unsubstituted C 6 to C 10 aryl
  • B represents a substituent selected from the group consisting of: (i) C 1 to C 6 alkyl, (ii) C 7 to C 16 aralkyl, wherein the aryl group may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo and CF 3 ; and (iii) —(CH 2 ) n OR a , wherein n represents 1, 2 or 3 and R a represents a C 6 to C 10 aryl group which may be unsubstituted or substituted with one to three substituents independently selected from the group consisting of C 1 to C 6 alkyl, halo or CF 3 .
  • R x , R y and R z are the same or different and each independently represents C 1 to C 6 alkyl, C 6 to C 10 aryl or C 7 to C 16 aralkyl;
  • A represents unsubstituted C 6 to C 10 aryl, and B is as defined herein;
  • the group A represents phenyl
  • the compounds of Formulae (VII), (VI), (VI-A), (V), (IV), (IIIa), (IIIb), (IIa), (IIb), (XI), (XII), (XIII) and (XIV) are single enantiomers (i.e. the wavy line in the side chain represents or ).
  • the solid and dashed lines represent a single bond and B represents —CH 2 CH 2 Ph.
  • the group R′ is preferably:
  • the group R′′ preferably represents iso-propyl.
  • the present invention further provides the use of any novel intermediate as defined as above in the manufacture of latanoprost and the use of any novel intermediate as defined as above in the manufacture of cloprostenol, fluprostenol, PGF 2 ⁇ , travoprost, or a PGF (preferably PGF 2 ⁇ ) analogue.
  • the present invention also provides the use of a silylating reagent of formula
  • the group X represents F, Cl, Br or I and R x , R y and R z are as previously defined, for protecting a hydroxyl group of an intermediate in the synthesis of a prostaglandin or prostaglandin analogue, such as prostaglandin or prostaglandin analogues based on PG-A, PG-B, PG-C PG-D or PGF.
  • a prostaglandin or prostaglandin analogue such as prostaglandin or prostaglandin analogues based on PG-A, PG-B, PG-C PG-D or PGF.
  • the use of these silylating agents is particularly suitable in the synthesis of prostaglandin PGF 2 ⁇ or prostaglandin analogues based on PGF 2 ⁇ , including latanoprost, cloprostenol, fluprostenol and travoprost. Of these, latanoprost is particularly preferred.
  • R x , R y and R z are methyl, ethyl and tert-butyl.
  • a particularly preferred silylating reagent is triethylsilylchloride.
  • hatched lines attached to the cyclopentane ring indicate bonds that are below the plane of the ring (i.e. bonds in an alpha configuration).
  • Solid wedges attached to the cyclopentane ring indicate bonds that are above the plane of the ring (rings in the beta configuration). It is to be understood that a wavy line, i.e.
  • [0286] represents bonds in either the alpha or beta configuration, and includes single enantiomers, i.e.:
  • the present invention further provides a process for the purification of latanoprost by HPLC comprising the use as an eluent, of a mixture comprising a hydrocarbon, an alcohol and, optionally, acetonitrile.
  • the eluent comprises a hydrocarbon, an alcohol and acetonitrile.
  • acetonitrile as a component of the eluent in the HPLC purification of latanoprost results in an improved separation of the impurities.
  • the use of acetonitrile as a component of the above eluent mixture results in a significantly improved separation of the hitherto difficult to separate 15(S)-trans isomer of latanoprost.
  • the 15(S)-trans isomer does not co-elute with the latanoprost, i.e.
  • the eluent systems in the present purification process comprises a hydrocarbon in an amount range of 80-99 volume percent and an alcohol in an amount range of 1-20 volume percent.
  • the eluent comprises a hydrocarbon in an amount range of 85-99 volume percent and an alcohol in an amount range of 1-15 volume percent.
  • an eluent comprising a hydrocarbon in an amount range of 88-98 volume percent and an alcohol in an amount range of 2-12 volume percent.
  • the eluent comprises a hydrocarbon in an amount range of 85-99 volume percent, an alcohol in an amount of 0.5-10 volume percent and acetonitrile in an amount of 0.5-5 volume percent.
  • an eluent comprises a hydrocarbon in an amount range of 86-98 volume percent, an alcohol in an amount of 1-8 volume percent and acetonitrile in an amount of 1-6 volume percent.
  • an eluent comprising a hydrocarbon in an amount range of 90-96 volume percent, an alcohol in an amount of 2-6 volume percent and acetonitrile in an amount of 2-4 volume percent.
  • the hydrocarbon is a C 5 to C 8 straight chain, branched or cyclic hydrocarbon, wherein the hydrocarbon is preferably an n-alkane. Hexane and heptane are especially preferred.
  • the hydrocarbon employed in the eluent may comprise a mixture of e.g. alkanes, such as hexane fraction. It has been found that good results have been obtained with n-heptane.
  • Preferred alcohols in the above eluent systems are C 1 to C 8 straight chain, branched or cyclic alkanols, with C 1 to C 5 straight chain or branched alkanols being particularly preferred.
  • methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol or butan-2-ol are especially useful. Good results have been obtained with propan-2-ol (isopropanol) as the alcohol component.
  • the use of ethanol as the alcohol component has also produced good separations.
  • the alcohol component of the eluent can include mixtures of one or more alkanols, e.g. combinations of two or more of isopropanol, ethanol and methanol may be used, e.g mixtures in ratios of 1:1 to 3:1 have been successfully employed.
  • a preferred eluent system comprises n-heptane:isopropanol:acetonitrile.
  • Preferred volume percent ranges of n-heptane: isopropanol:acetonitrile are 90-96%:2-7%:2-5%.
  • the ratios of n-heptane:isopropanol: acetonitrile are in the ranges 92-94%:3-5%:2-4%. Good results have been obtained with ratios of 93%: 4%:3%.
  • HPLC procedures are preferably carried out on a silica gel column.
  • suitable columns include Waters RTM Spherisorb, Phenomenex RTM Luna Cyano and Phenomenex RTM Luna Silica.
  • latanoprost that is substantially free of the 15(S)-cis isomer, the 15(S)-trans isomer and the 15(R)-trans isomer.
  • latanoprost containing less than 0.3% in total of any combination of: 15(S)-cis isomer, 15(S)-trans isomer and 15(R)-trans isomer may be produced.
  • latanoprost containing less than 0.1% each of 15(S)-cis-, 15(S)-trans- and 15(R)-trans isomers can be produced.
  • DIBAL-H di-iso-butylaluminiumhydride
  • DBU [1,8-diazabicyclo(5.4.0)undec-7-ene]
  • alkyl refers to C 1 to C 6 straight or branched carbon chains. Particularly preferred alkyl groups for the compounds and processes of the invention include methyl, ethyl, propyl, isopropyl, butyl, and tertiary butyl.
  • aryl represents a carbocyclic group containing from six to fifteen carbon atoms and having at least one aromatic ring. Particularly preferred aryl groups for any of the compounds and methods of the present invention include phenyl and naphthyl.
  • aralkyl refers to an alkyl group as defined above wherein one or more hydrogen atoms (preferably one) have been replaced by unsubstituted C 6 to C 10 aryl groups as defined above.
  • a preferred aralkyl group for the compounds and methods of the invention is benzyl.
  • halo refers to fluoro, chloro, bromo or iodo.
  • substantially free of a particular impurity refers to less than 1%, preferably less than 0.5%, more preferably, less than 0.3% and even more preferably, less than 0.1% of the impurity.
  • a 0.5M solution of potassium bromide was prepared by dissolving KBr (11.9 g) in purified water and then diluting with additional water to 200 ml.
  • PGX-6 (225.1 g, 0.556M) was dissolved in dry tetrahydrofuran (3.5 L) in an inert atmosphere and ‘Corey catalyst’ prepared according to Example 4 (0.25M in toluene, 223 ml, 0.1 eq.) added. The mixture was cooled to approximately ⁇ 15° C. and a solution of borane-methyl sulfide complex (10M BH 3 concentration, 41.7 ml, 417 mMol, 0.75 eq.) in dry tetrahydrofuran (450 ml) was added whilst maintaining the temperature at ca. 15° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC.
  • borane-methyl sulfide complex (10M BH 3 concentration, 41.7 ml, 417 mMol, 0.75 eq.
  • PGX 6 315.2 g, 0.779M was dissolved in dry tetrahydrofuran (5.7 L) in an inert atmosphere and ‘Corey catalyst’ (0.25M in toluene, 312 ml, 0.1 eq.) added. The mixture was cooled to approximately ⁇ 15° C. and a solution of borane-methyl sulfide complex (10M BH 3 concentration, 58.5 ml, 0.585M, 0.75 eq.) in dry tetrahydrofuran (630 ml) added whilst maintaining the temperature at ca. 15° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC.
  • borane-methyl sulfide complex 10M BH 3 concentration, 58.5 ml, 0.585M, 0.75 eq.
  • the crude mixture of epimers PGX-7/PGX-8 (686.5 g) made according to the synthetic procedure described in Example 5a was crystallised from heptane fraction/ethyl acetate (7:3) to give a crystalline mixture of epimers PGX-7 and PGX-8 (480.4 g) that is free of other impurities.
  • the filtrates from the crystallisation were evaporated to give an oil (150.3 g) comprising mainly impure PGX-7/PGX-8.
  • Injection 1 Injection of an aliquot of crystalline PGX-7/PGX-8 stock solution (A) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7. The column was then flushed with eluent to elute any remaining PGX-8.
  • Injection 2 Injection of an aliquot of crystalline PGX-7/PGX-8 stock solution (A) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7. Column flushed with methanol then equilibration of column with eluent.
  • Injection 3 Injection of an aliquot of impure PGX-7/PGX-8 stock solution (B) and collection of appropriate fractions containing pure PGX-7 and impure PGX-7 and impure PGX-7. Discarded silica gel and re-packed column with fresh silica gel and repeat cycle.
  • PGX-7 (152.0 g, 0.374M, 1.0 eq.) was dissolved in dry methanol (2.28 L) under an inert atmosphere and potassium carbonate (31.0 g, 0.224M, 0.6 eq.) added in one portion. The mixture was stirred at ambient temperature for 3 h until TLC showed the reaction was complete. 5M Hydrochloric acid (65.5 ml) was added to adjust the apparent pH of the solution to about 6.8-7.0 and the mixture then evaporated to dryness in vacuo. The sticky residue was treated with water (1.5 L) and the pH adjusted to 6.8-7.0 by the addition of 1M hydrochloric acid (7 ml).
  • Heptane (0.45 L) was added, the mixture agitated vigorously and the precipitated solid filtered off and washed with heptane (2 ⁇ 150 ml) on the filter. The solid was then triturated with a further quantity of heptane (2 ⁇ 150 ml). All the heptane washes were combined and added to the original filtrates. The aqueous phase was separated off, washed with heptane (2 ⁇ 150 ml) and then extracted with ethyl acetate (1 ⁇ 450 ml, 3 ⁇ 150 ml). The previously isolated solid was added to the combined ethyl acetate extracts and the mixture shaken until a solution formed.
  • PGX-9 (111.5 g 0.369M, 1.0 eq.) was dissolved in ethanol (1.67 L) and 5% palladium on carbon (5.58 g) added followed by a solution of sodium nitrite (8.90 g, 0.129M, 0.35 eq.) in water (100 ml). The mixture was then hydrogenated for 5 h until shown to be complete by TLC. 1M Hydrochloric acid (260 ml) was added and the mixture stirred for 1 h. The solids were removed by filtration through celite, the filtrates then evaporated to give an oily-solid residue which was partitioned between ethyl acetate (0.45 L) and water (0.45 L).
  • Example 7 On completion of the reaction described in Example 7, 1M hydrochloric acid was added and the reaction mixture stirred for 60 minutes as described in Example 7. The pH of the mixture was adjusted to between 5 and 6 by addition of solid sodium hydrogen carbonate prior to the filtration of the used catalyst, and evaporation of the filtrate to dryness. The work-up is then completed as described in Example 7 by extraction of the product into ethyl acetate.
  • Example 7a illustrates the improved procedure:
  • PGX 9 326.5 g, 1.08M, 1.0 eq. was dissolved in ethanol (6.5 L) and 5% palladium on carbon (16.3 g) added followed by a solution of sodium nitrite (26 g, 0.377M, 0.35 eq.) in water (200 ml). The mixture was then hydrogenated for 1.5 h until shown to be complete by TLC. 1M Hydrochloric acid (750 ml) was added and the mixture stirred for 1 h. The pH was adjusted to 5-6 by the addition of solid sodium hydrogen carbonate (55 g).
  • PGX-10 (109.7 g, 0.360M, 1.0 eq.) was dissolved in dry dimethyl formamide (720 ml) under an inert atmosphere.
  • Imidazole 29.4 g, 0.432M, 1.2 eq.
  • triethylamine (102.9 ml, 74.69 g, 0.738M, 2.05 eq.) were added and the mixture then cooled to approximately 0° C.
  • Triethylchlorosilane (111.2 g, 0.738M, 2.05 eq.) was added over 15 minutes at less than 10° C. The mixture was allowed to warm to room temperature and stirred for 2 h until TLC showed the reaction was complete.
  • PGX-11 (186.8 g, 0.3505M, 1.0 eq.) was dissolved in dry tetrahydrofuran (1.86 L) under an inert atmosphere and the solution cooled to less than ⁇ 70° C.
  • Diisobutylaluminium hydride (1.1M in toluene solution, 701 ml, 0.7711M, 2.2 eq.) was added to the reaction whilst maintaining the temperature below ⁇ 70° C. The mixture was then stirred at this temperature for 2 h until the reaction was shown to be complete by TLC. Methanol (132 ml) was added and the mixture allowed to warm to ⁇ 5° C.
  • the amount of (4-carboxybutyl)triphenylphosphonium bromide used in the above reaction is 3.0 equivalents with respect to the amount of starting material PGX-12 used.
  • it is treated with 5.6 equivalents of potassium tert-butoxide.
  • the slight deficit in the amount of potassium tert-butoxide used with respect to (4-carboxybutyl)triphenylphosphonium bromide is deliberate to ensure that all of the potassium tert-butoxide is consumed and is not present during the reaction with the lactol.
  • the organic layer was separated off and the aqueous layer acidified to pH 6 with an additional quantity of 3% aqueous citric acid solution (0.72 L) and then re-extracted with ethyl acetate (2 ⁇ 0.33 L).
  • the combined organic phases were washed with 3% aqueous citric acid solution (2 ⁇ 0.8 L), 5% sodium hydrogen carbonate solution (2 ⁇ 0.8 L) and saturated brine (2 ⁇ 1.6 L).
  • the solvent was evaporated off and heptane (1.0 L) and ethyl acetate (80 ml) added to the residue. The mixture was cooled to ⁇ 20° C. and agitated vigorously. After 30 minutes at ⁇ 20° C.
  • PGX-17 (0.504 g, 0.65 mmol) was weighed into a 50 ml round bottom flask equipped with a magnetic follower. Acetone (6.5 ml) was added and the resulting colourless solution stored at room temperature under a gentle stream of argon.
  • the crude product was purified by flash column chromatography.
  • a flash column was prepared using silica gel 60 (6 g) and hexane fraction/EtOAc (1:1) as the eluent.
  • the crude product (7 mg was removed as retention sample) was dissolved in the eluent (2 ml) and loaded onto the column.
  • the column was then eluted with hexane fraction/EtOAc mixtures as follows: Hexane fraction/EtOAc 1:1 50 ml 1:2 150 ml 1:3 80 ml
  • PGX-17 (170.0 g, 0.219M) was dissolved in acetone (1.9 L) under an inert atmosphere and a solution of pyridinium-p-toluenesulphonate (4.52 g, 18.0 mMol, 0.08 eq.) in water (0.3 L) added. The resulting mixture was stirred at ambient temperature for 3 h until TLC showed the reaction to be complete. After evaporation of the organic volatiles the residue was added to a mixture of ethyl acetate (2.1 L) and brine (2 L). The layers were separated and the aqueous phase further extracted with ethyl acetate (1 L). The organics were combined and washed with brine (0.5 L).
  • HPLC purification of latanoprost was carried out using a Waters RTM Spherisorb silica gel column.
  • the isocratic eluent system comprised a hydrocarbon and an alcohol in volume percent ranges of 88-98% and 2-12% respectively.
  • the hydrocarbons used were n-hexane, hexane fraction, n-heptane or heptane fraction.
  • the alcohols used were isopropanol, ethanol or methanol, either singly or in combination in ratios of 1:1 to 3:1.
  • HPLC separations of latanoprost were carried out using a Waters RTM Spherisorb silica gel column.
  • the isocratic eluent system comprised hydrocarbon: alcohol:acetonitrile in volume percent ratios of 90-96%: 2-6%: 2-4%.
  • the hydrocarbons used were n-hexane, hexane fraction, n-heptane or heptane fraction.
  • the alcohols used were either isopropanol or ethanol.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050261374A1 (en) * 2001-05-24 2005-11-24 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof
WO2007041273A3 (en) * 2005-09-29 2007-10-25 Eastar Chemical Corp Process for the production of intermediates for making prostaglandin derivatives such as latanoprost, travaprost, and bimatoprost
US20080033176A1 (en) * 2006-08-07 2008-02-07 Daiichi Fine Chemical Co., Ltd. Method for preparing prostaglandin derivative

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7321057B2 (en) * 2004-08-02 2008-01-22 R-Tech Ueno, Ltd. Method for manufacturing prostaglandin analogue
PL212658B1 (pl) * 2005-04-18 2012-11-30 Inst Farmaceutyczny Sposób otrzymywania pochodnych 13,14-dihydro-PGF<sub>2</sub><sub>α</sub>
US7511168B2 (en) 2006-01-18 2009-03-31 Shih-Yi Wei Processes and intermediates for the preparations of prostaglandins
US8546114B2 (en) 2006-01-18 2013-10-01 Chirogate International Inc. Processes for the preparation of optically active cyclopentenones and cyclopentenones prepared therefrom
EP2735566A1 (en) * 2006-02-07 2014-05-28 R-Tech Ueno, Ltd. Method for preparing prostaglandin derivative
JP2008037782A (ja) * 2006-08-04 2008-02-21 Daiichi Fine Chemical Co Ltd プロスタグランジン誘導体の製造方法
US20090233830A1 (en) * 2008-03-14 2009-09-17 Penny Sue Dirr Automatic detergent dishwashing composition
EP2135860A1 (en) 2008-06-20 2009-12-23 Sandoz AG Improved process for the production of bimatoprost
EP2143712A1 (en) 2008-07-10 2010-01-13 Sandoz AG Improved Process for the Production of Prostaglandins and Prostaglandin Analogs
IT1392492B1 (it) * 2008-12-24 2012-03-09 Ind Chimica Srl Processo per la purificazione del latanoprost, analogo sintetico della prostaglandina pgf2alfa.
KR101045935B1 (ko) * 2009-03-11 2011-07-01 연성정밀화학(주) 프로스타글란딘 유도체의 제조방법
US8519178B2 (en) * 2009-06-22 2013-08-27 Johnson Matthey Public Limited Company Method for the purification of prostaglandins
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EP2495235B1 (en) 2011-03-04 2015-08-05 Newchem S.p.A. Process for the synthesis of prostaglandins and intermediates thereof
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US9115109B2 (en) 2013-08-15 2015-08-25 Chirogate International Inc. Processes and intermediates for the preparations of isomer free prostaglandins
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WO2025149165A1 (en) 2024-01-12 2025-07-17 Intervet International B.V. A PROCESS FOR PURIFICATION OF INTERMEDIATES OF PROSTAGLANDIN F2Αα COMPOUNDS AND ITS USE IN THE PREPARATION OF PROSTAGLANDIN F2α COMPOUNDS

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3549688A (en) * 1967-02-16 1970-12-22 Gen Electric Process for the preparation of carboxylic acid esters
US3931279A (en) * 1973-05-21 1976-01-06 The Upjohn Company 5-Oxa prostaglandin F2.sub.α analogs
US3978229A (en) * 1974-04-11 1976-08-31 Ono Pharmaceutical Co., Ltd. Synergistic composition comprising PGF2.sub.α and PGE2
US4158667A (en) * 1976-02-04 1979-06-19 The Upjohn Company 6-Keto PGF analogs
US4346228A (en) * 1975-04-18 1982-08-24 Schering Aktiengesellschaft Novel 11-oxoprostaglandin derivatives
US4680415A (en) * 1985-06-24 1987-07-14 Hoffmann-La Roche Inc. Intermediates for 7-fluoro dihydro PGI compounds
US5223537A (en) * 1991-07-23 1993-06-29 Kabi Pharmacia Ab Method and composition for treatment of gastric and duodenal disorders
US5321128A (en) * 1988-09-06 1994-06-14 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US6184250B1 (en) * 1993-08-03 2001-02-06 Alcon Laboratories, Inc. Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3778450A (en) 1971-03-23 1973-12-11 Upjohn Co Certain bicyclic lactones
CA971957A (en) 1971-12-13 1975-07-29 Upjohn Company (The) PROCESS FOR PREPARING PROSTAGLANDIN E'S FROM PROSTAGLANDIN F.alpha.'S
US4100355A (en) 1972-09-15 1978-07-11 The Upjohn Company 8β,12α-PGE2 -type compounds
US3864387A (en) 1973-05-21 1975-02-04 Upjohn Co 5-Oxa phenyl-and phenoxy-substituted prostaglandin F{HD 1{301 {0 {B analogs
US4036832A (en) 1974-07-03 1977-07-19 Pfizer Inc. 15-Substituted-ω-pentanorprostaglandins
DE2434133C2 (de) 1974-07-12 1987-03-19 Schering AG, 1000 Berlin und 4709 Bergkamen 15,15-Äthylendioxy-Prostansäurederivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
EP0059307A1 (de) 1981-02-26 1982-09-08 Grünenthal GmbH Verfahren zur Herstellung von 2-Oxabicyclo(3.3.0)octanderivaten und danach erhältliche Produkte
US4599353A (en) 1982-05-03 1986-07-08 The Trustees Of Columbia University In The City Of New York Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma
JPS6137752A (ja) * 1984-07-30 1986-02-22 Kuraray Co Ltd 高度不飽和長鎖脂肪酸またはそのエステルの分離精製法
US4943635A (en) 1987-08-27 1990-07-24 President & Fellows Of Harvard College Enantioselective reduction of ketones
EP0394263B1 (en) 1987-09-04 1994-03-16 The Upjohn Company Process for production of prostaglandin intermediates
ATE420857T1 (de) 1988-09-06 2009-01-15 Pfizer Health Ab Prostaglandin-derivate zur behandlung von glaukom und ocularer hypertension
JP2855450B2 (ja) 1989-09-11 1999-02-10 小野薬品工業株式会社 プロスタグランジン誘導体の中間体の製造方法
SE9002596D0 (sv) 1990-08-08 1990-08-08 Pharmacia Ab A method for synthesis of prostaglandin derivatives
EP0472338A3 (en) * 1990-08-21 1993-05-19 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Method of manufacturing prostaglandin intermediate
JPH085873B2 (ja) 1990-08-21 1996-01-24 株式会社上野製薬応用研究所 プロスタグランジン中間体の製法
HU212570B (en) 1991-06-24 1996-08-29 Chinoin Gyogyszer Es Vegyeszet Process for producing 13,14-dihydro-15(r)-17-phenyl-18,19,20-trinor-pgf2alfa-isopropylester
US5688819A (en) 1992-09-21 1997-11-18 Allergan Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
JP3207203B2 (ja) 1992-09-30 2001-09-10 株式会社上野製薬応用研究所 α，β−不飽和ケトンの製造法
DE4323331A1 (de) 1993-07-08 1995-01-12 Schering Ag Neue bicyclische Lactone
US5510383A (en) 1993-08-03 1996-04-23 Alcon Laboratories, Inc. Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension
NL194919C (nl) * 1993-09-07 2003-07-04 Tno Werkwijze voor het oxideren van koolhydraten.
US5545665A (en) 1993-12-28 1996-08-13 Allergan Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents
US5698733A (en) 1994-09-30 1997-12-16 Alcon Laboratories, Inc. Use of 9-deoxy prostaglandin derivatives to treat glaucoma
HU223345B1 (hu) 1995-12-20 2004-08-30 Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. Eljárás alfa, béta-telítetlen ketonok sztereoszelektív redukciójára
ATE202557T1 (de) * 1996-11-12 2001-07-15 Alcon Lab Inc 15-fluoro-prostaglandine als augendrucksenkende mittel
SE9702681D0 (sv) 1997-07-10 1997-07-10 Pharmacia & Upjohn Ab Method and composition for treatment of impotence
SE9702706D0 (sv) 1997-07-11 1997-07-11 Pharmacia & Upjohn Ab Prostaglandin derivatives devoid of side-effects for the treatment of glaucoma
WO1999012899A1 (en) 1997-09-09 1999-03-18 The Procter & Gamble Company A process for making prostaglandin f analogs
WO2000020386A1 (en) 1998-10-05 2000-04-13 Alcon Laboratories, Inc. Stannane synthesis of prostanoids
SE9900025D0 (sv) 1999-01-08 1999-01-08 Synphora Ab Method and composition for treatment of female sexual dysfunction
WO2000040246A1 (en) 1999-01-08 2000-07-13 University Of Massachusetts Detection of human immunodeficiency virus
JP3501025B2 (ja) 1999-07-15 2004-02-23 松下電器産業株式会社 電気調理器
IL134241A (en) 2000-01-27 2006-06-11 Finetech Pharmaceutical Ltd Process for the preparation of latanoprost
AU2001233286B2 (en) 2000-02-01 2006-04-06 Cayman Chemical Company, Incorporated Internal 1,15-lactones of fluprostenol and related prostaglandin F2alpha analogs and their use in the treatment of glaucoma and intraocular hypertension
WO2001067816A1 (en) 2000-03-07 2001-09-13 Daimlerchrysler Ag Skin effect heating system for a structural member
WO2001087816A1 (en) * 2000-05-15 2001-11-22 Pharmacia & Upjohn Company Process and intermediates to prepare latanoprost
GB0112699D0 (en) 2001-05-24 2001-07-18 Resolution Chemicals Ltd Process for the preparation of prostglandins and analogues thereof
KR100581647B1 (ko) * 2001-07-17 2006-05-22 파마시아 앤드 업존 캄파니 엘엘씨 라타노프로스트 제조를 위한 방법 및 중간체

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3549688A (en) * 1967-02-16 1970-12-22 Gen Electric Process for the preparation of carboxylic acid esters
US3931279A (en) * 1973-05-21 1976-01-06 The Upjohn Company 5-Oxa prostaglandin F2.sub.α analogs
US3978229A (en) * 1974-04-11 1976-08-31 Ono Pharmaceutical Co., Ltd. Synergistic composition comprising PGF2.sub.α and PGE2
US4346228A (en) * 1975-04-18 1982-08-24 Schering Aktiengesellschaft Novel 11-oxoprostaglandin derivatives
US4158667A (en) * 1976-02-04 1979-06-19 The Upjohn Company 6-Keto PGF analogs
US4680415A (en) * 1985-06-24 1987-07-14 Hoffmann-La Roche Inc. Intermediates for 7-fluoro dihydro PGI compounds
US5321128A (en) * 1988-09-06 1994-06-14 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5223537A (en) * 1991-07-23 1993-06-29 Kabi Pharmacia Ab Method and composition for treatment of gastric and duodenal disorders
US6184250B1 (en) * 1993-08-03 2001-02-06 Alcon Laboratories, Inc. Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050261374A1 (en) * 2001-05-24 2005-11-24 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
WO2007041273A3 (en) * 2005-09-29 2007-10-25 Eastar Chemical Corp Process for the production of intermediates for making prostaglandin derivatives such as latanoprost, travaprost, and bimatoprost
US20090287003A1 (en) * 2005-09-29 2009-11-19 Jiang Xing Chen Process for the production of intermediates for making prostaglandin derivatives such as latanaprost, travaprost, and bimatoprost
US20080033176A1 (en) * 2006-08-07 2008-02-07 Daiichi Fine Chemical Co., Ltd. Method for preparing prostaglandin derivative
US7642370B2 (en) 2006-08-07 2010-01-05 Daiichi Fine Chemical Co., Ltd. Method for preparing prostaglandin derivative

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US20050261374A1 (en) 2005-11-24
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