WO2003037353A1 - Improvements relating to prostaglandins and their analogues - Google Patents

Improvements relating to prostaglandins and their analogues Download PDF

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Publication number
WO2003037353A1
WO2003037353A1 PCT/GB2002/004926 GB0204926W WO03037353A1 WO 2003037353 A1 WO2003037353 A1 WO 2003037353A1 GB 0204926 W GB0204926 W GB 0204926W WO 03037353 A1 WO03037353 A1 WO 03037353A1
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iodolactone
ester
prostaglandin
hydrogenation
aqueous
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PCT/GB2002/004926
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French (fr)
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Derek Wyndham Clissold
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Johnson Matthey Public Limited Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • This invention relates to prostaglandins and their analogues, and in particular to the selective reduction of the 13,14-double bond in Series 2 prostaglandins. More particularly, it relates the selective conversion of PGA 2 ,
  • the present invention now provides simple, high yielding, procedures for the selective conversion of PGA 2 , PGD 2 , PGE 2 , PGF 2 ⁇ , and analogues thereof , into 13 , 14-dihydro derivatives .
  • 13 , 14-dihydro derivatives of prostaglandins, particularly of PGF 2 ⁇ analogues are of increasing importance as pharmaceutically active ingredients for the treatment of glaucoma and osteoporosis, and potentially for a number of other indications.
  • the group R 1 as shown in relevant structural formulae may be substituted or unsubstituted alkyl, arylalkyl or aryloxy and R 2 may be alkyl, especially C ⁇ -C 3 alkyl.
  • a method for the selective hydrogenation of the 13,14-double bond in Series 2 prostaglandins which comprises forming the iodolactone (4) of the prostaglandin (3) by reaction with iodine in an aqueous, organic or aqueous/organic mixed solvent, followed by catalytic hydrogenation of the 13,14-double bond of the iodolactone to give structure (5) .
  • the hydrogenation can be carried out with a heterogeneous or a homogeneous catalyst.
  • R 1 represents a substituted or unsubstituted alkyl, arylalkyl or aryloxy group.
  • the same solvent is used for the formation and the hydrogenation of the iodolactone.
  • a preferred solvent dichloromethane is illustrated in the above reaction scheme. More preferably, the two reactions can be carried out in sequence without isolation of the intermediate iodolactone (4).
  • the hydrogenated iodolactone (5) is reacted with three equivalents of trimethylsilyl chloride in the presence of organic base (such as diisopropyl amine - DIPEA) to give the trisilyl ether (6)
  • reaction mixture containing (7] can be subjected to mild aqueous acid work up to give (8), the 13,14-dihydro analogue of the original prostaglandin (3) .
  • reaction mixture containing (7) can be subjected to treatment with an alkyl alcohol (eg isopropyl alcohol) which reacts with the C-1 trimethylsilyl ester (7) to give, in situ, the alkyl ester.
  • an alkyl alcohol eg isopropyl alcohol
  • Mild aqueous acid work up then gives the 13,14- dihydro analogue of the original prostaglandin (3) as its C- 1 alkyl ester (9) .
  • R 1 represents an alkyl, substituted alkyl, benzyl, substituted benzyl, aryloxy, or substituted aryloxy group.
  • the same organic solvent is used for the formation and hydrogenation of the iodolactone, and the ring-opening of the latter to the 13, 14-dihydroprostaglandin or the corresponding C-1 ester.
  • Another aspect of the invention provides a method for the separation of 5,6-cis and 5 , 6-trans double bond isomers of prostaglandins which comprises forming the iodolactones of the mixture of prostaglandin isomers by reaction with iodine in an aqueous organic solvent, separating and regenerating the separated isomers.
  • the procedure according to the invention is also applicable to selective reduction of the 13,14-double bond in conjugated enone prostaglandins, as for example in structure (10) .
  • conversion of (10) to its iodolactone, reduction of the 13,14-double bond, regeneration of the 5,6-double bond followed by in situ treatment with isopropyl alcohol and mild aqueous acid work up gives the prostaglandin ester (11) .
  • the latter is known as unoprostone and is also a product used for the treatment of glaucoma. See the paper by Linden and Aim mentioned above.
  • a method for the chemospecific introduction of deuterium or tritium atoms at the 13, 14-positions of prostaglandins which comprises protection of the 5,6-double bond by forming the iodolactone, and reacting the resulting iodolactone with deuterium or tritium (in place of hydrogen) under catalytic conditions followed by re-generation of the 5,6 double bond as described above.
  • R 1 represents an alkyl, substituted alkyl, benzyl, substituted benzyl, aryloxy, or substituted aryloxy group.
  • groups include, but are not limited to, n-butyl, benzyl, phenoxy, m-trifluorophenoxy or m-chlorophenoxy.
  • another embodiment of the invention is the possibility of direct in situ formation of a C-1 ester (9) in the reaction mixture, from an intermediate trimethylsilyl ester during the regeneration of the cis- double bond from the iodolactone.
  • This can be accomplished (according to the method of A. Brook and T. H. Chan, [Synthesis, (1983) pp. 201], by adding an alkyl alcohol, eg. isopropyl alcohol, to the reaction mixture immediately mild aqueous acid work up. This should be done after TLC analysis has indicated that all the iodolactone has been converted into intermediate trimethylsilyl ester (7).
  • these reactions may be carried out in the presence of an iodine absorber, such as 2-methyl-2- butene, see S.W. Wright, E.Y. Kuo and E.J. Corey J. Org. Chem. (1987) , 52 , 4399-4401 .
  • an iodine absorber such as 2-methyl-2- butene
  • a further embodiment of the invention is the chemospecific introduction, via iodolactonisation, of deuterium or tritium atoms (rather than hydrogen) at the 13,14 positions in a range of prostaglandins.
  • acetone methyl ethyl ketone and methyl isobutyl ketone
  • ethers and cyclic ethers eg diethyl ether, isopropyl ether, dimethoxyethane or tetrahydrofuran
  • dimethyl formamide, dimethylsulphoxide and other dipolar aprotic solvents Generally, the only requirement for the solvents is that they should not be reactive under the reaction conditions involved.
  • a further embodiment of the invention is the use of iodolactone formation from a mixture of 5,6 cis- and trans- double bond prostaglandins in order to effect facile separation of the cis- and trans- double bond compounds from each other.
  • a saturated aqueous solution of sodium hydrogen carbonate (110 ml) was added to a solution of PGF 2 ⁇ (3a) (17.72g, 50 mmol) in dichloromethane (150 ml) .
  • the two phase mixture was cooled to 0-5°C (ice, salt water bath) and stirred rapidly for ca.lO min. to create an emulsion.
  • To the cold (0-5°C) stirred emulsion was added, over 30 min., part of a solution of iodine crystals (12.7g, 100 mmol) in dichloromethane (150 ml) .
  • the iodine colouration was initially discharged during the addition, which was continued up to the point where the iodine colour just persisted to give a pale yellow solution. Approximately 55 mmol of iodine, by volume, was consumed. The emulsified mixture was stirred at 0-5°C for a further 10 minutes, the stirring and cooling were stopped, and the layers were allowed to separate. A TLC check at this point indicated complete reaction to iodolactone. The pale yellow bottom layer of dichloromethane was run off, and the upper aqueous layer was extracted with a further 50 ml of dichloromethane.
  • the two phase mixture was cooled to 0-5°C (ice, salt water bath) and stirred rapidly for ca.lO min. to create an emulsion.
  • To the cold (0-5°C) stirred emulsion was added, over 30 min., part of a solution of iodine crystals (12.7g, 100 mmol) in dichloromethane (150 ml) .
  • the iodine colouration was initially discharged during the addition, which was continued up to the point where the iodine colour just persisted to give a pale yellow solution. Approximately 55 mmol of iodine, by volume, was consumed. The emulsified mixture was stirred at 0-5°C for a further 10 minutes, the stirring and cooling were stopped, and the layers were allowed to separate. A TLC check at this point indicated complete reaction to iodolactone. The pale yellow bottom layer of dichloromethane was run off, and the upper aqueous layer was extracted with a further 50 ml of dichloromethane.
  • the homogeneous catalyst [Rh(nbd) (diphos-4) ] BF (2.7 g, 10 mol%) was added to a solution of 18g (37.5 mmole) of iodolactone (4a) in dry dichloromethane (100 ml) under argon with stirring to complete dissolution.
  • the solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to an atmospheric pressure hydrogen source. Stirring was continued under atmospheric hydrogen pressure until TLC indicated that the reaction was complete (ca. 2 hr) The reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel
  • the homogeneous catalyst [Rh (nbd) (diphos-4) ] BF 4 (2.7 g, 10 mol%) was added to a solution of 19.3g (37.5 mmole) of iodolactone (4b) in dry dichloromethane (100 ml) under argon with stirring to complete dissolution.
  • the solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to an atmospheric pressure hydrogen source. Stirring was continued under atmospheric hydrogen pressure until TLC indicated that the reaction was complete (ca. 2 hr) .
  • the reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel.
  • the solvent was evaporated to give 18.6g (96%) of (5b) as a colourless oil, which was used without further purification in the next step.
  • the spectroscopic data obtained were fully consistent with structure (5b) .

Abstract

A method for the selective hydrogenation of the 13,14-double bond in Series 2 prostaglandins which comprises forming the iodolactone (4) of the prostaglandin (3) by reaction with iodine in an aqueous, organic or aqueous/organic mixed solvent, followed by catalytic hydrogenation of the 13, 14-double bond of the iodolactone to give structure (5). The hydrogenation can be carried out with a heterogeneous or a homogeneous catalyst. Wherein R1 represents a substituted or unsubstituted alkyl, arylalkyl or aryloxy group. The two reactions can be carried out in sequence without isolation of the intermediate iodolactone (4). The free 9, 11 and 15 hydroxyl groups can be protected as their trimethylsilyl ethers. Mild aqueous acid work up gives the 13,14-dihydro analogue of the original prostaglandin (3).

Description

IMPROVEMENTS RELATING TO PROSTAGLANDINS AND THEIR ANALOGUES
This invention relates to prostaglandins and their analogues, and in particular to the selective reduction of the 13,14-double bond in Series 2 prostaglandins. More particularly, it relates the selective conversion of PGA2,
PGD2, PGE2, PGF2 and their analogues into the corresponding 13,14-dihydro derivatives. For the numbering system applied to prostaglandin molecules see structure (10) below.
There are a number of examples in the literature of the selective reduction of the 5,6 double bond of PGF2α and PGE2 (1) to give PGFχα and PGEi (2) , respectively. See, for example, Andrist and Graas (Prostaglandins, Vol. 18, No. 4 (1979) , pp. 631-638) .
Figure imgf000003_0001
(1) (2)
There are, however, no straightforward methods available for the selective reduction of the 13 , 14 double bond (in the presence of the 5, 6 double bond) in these and related prostaglandins .
The present invention now provides simple, high yielding, procedures for the selective conversion of PGA2, PGD2, PGE2, PGF2α, and analogues thereof , into 13 , 14-dihydro derivatives . 13 , 14-dihydro derivatives of prostaglandins, particularly of PGF2α analogues, are of increasing importance as pharmaceutically active ingredients for the treatment of glaucoma and osteoporosis, and potentially for a number of other indications. See, for example, C. Linden and A. Aim, "Prostaglandin Analogues in the Treatment of Glaucoma", Drugs & Ageing, Vol. 14 No. 5 (1999) pp. 387-398. This document specifically mentions latanoprost [formula (9), where R1 = benzyl, R2 = isopropyl] as being applicable for this purpose.
Figure imgf000004_0001
(9)
The present invention provides aspects of such procedures as set out in the following description and in the appended claims, and such variations thereof as will be apparent to one skilled in the art.
In certain preferred embodiments of the invention, the group R1 as shown in relevant structural formulae may be substituted or unsubstituted alkyl, arylalkyl or aryloxy and R2 may be alkyl, especially Cι-C3 alkyl.
According to one embodiment of the present invention, there is provided a method for the selective hydrogenation of the 13,14-double bond in Series 2 prostaglandins which comprises forming the iodolactone (4) of the prostaglandin (3) by reaction with iodine in an aqueous, organic or aqueous/organic mixed solvent, followed by catalytic hydrogenation of the 13,14-double bond of the iodolactone to give structure (5) . The hydrogenation can be carried out with a heterogeneous or a homogeneous catalyst.
Figure imgf000005_0001
(5)
wherein R1 represents a substituted or unsubstituted alkyl, arylalkyl or aryloxy group.
In a preferred embodiment of the invention, the same solvent is used for the formation and the hydrogenation of the iodolactone. A preferred solvent dichloromethane is illustrated in the above reaction scheme. More preferably, the two reactions can be carried out in sequence without isolation of the intermediate iodolactone (4).
In order to avoid unwanted reaction (with subsequently generated trimethylsilyl iodide) at the free 9, 11 and 15 hydroxyl groups they can be protected as their trimethylsilyl ethers. Thus in a preferred embodiment, the hydrogenated iodolactone (5) is reacted with three equivalents of trimethylsilyl chloride in the presence of organic base (such as diisopropyl amine - DIPEA) to give the trisilyl ether (6)
Figure imgf000006_0001
(6)
which, without isolation, is then reacted with a further equivalent of trimethylsilyl chloride and sodium iodide to generate in situ the required trimethylsilyl iodide. The trimethylsilyl iodide, so generated, then opens the iodolactone ring to give the 13,14-dihydro analogue of the original prostaglandin (3) as its C-1 trimethylsilyl ester and still protected as its trisilyl ether as shown in structure (7) .
Figure imgf000006_0002
(7)
In a further embodiment the reaction mixture containing (7] can be subjected to mild aqueous acid work up to give (8), the 13,14-dihydro analogue of the original prostaglandin (3) .
Figure imgf000006_0003
(8) In a further embodiment the reaction mixture containing (7) can be subjected to treatment with an alkyl alcohol (eg isopropyl alcohol) which reacts with the C-1 trimethylsilyl ester (7) to give, in situ, the alkyl ester. See for example the paper by A. Brook and T. H. Chan, [Synthesis, (1983) pp. 201] . Mild aqueous acid work up then gives the 13,14- dihydro analogue of the original prostaglandin (3) as its C- 1 alkyl ester (9) .
Figure imgf000007_0001
wherein R1 represents an alkyl, substituted alkyl, benzyl, substituted benzyl, aryloxy, or substituted aryloxy group.
If desired, the same organic solvent is used for the formation and hydrogenation of the iodolactone, and the ring-opening of the latter to the 13, 14-dihydroprostaglandin or the corresponding C-1 ester.
Another aspect of the invention provides a method for the separation of 5,6-cis and 5 , 6-trans double bond isomers of prostaglandins which comprises forming the iodolactones of the mixture of prostaglandin isomers by reaction with iodine in an aqueous organic solvent, separating and regenerating the separated isomers.
The procedure according to the invention is also applicable to selective reduction of the 13,14-double bond in conjugated enone prostaglandins, as for example in structure (10) . Thus conversion of (10) to its iodolactone, reduction of the 13,14-double bond, regeneration of the 5,6-double bond followed by in situ treatment with isopropyl alcohol and mild aqueous acid work up gives the prostaglandin ester (11) . The latter is known as unoprostone and is also a product used for the treatment of glaucoma. See the paper by Linden and Aim mentioned above.
Figure imgf000008_0001
In another aspect of the invention, a method is provided for the chemospecific introduction of deuterium or tritium atoms at the 13, 14-positions of prostaglandins which comprises protection of the 5,6-double bond by forming the iodolactone, and reacting the resulting iodolactone with deuterium or tritium (in place of hydrogen) under catalytic conditions followed by re-generation of the 5,6 double bond as described above. ,
It is known from the paper by R. A. Johnson, F. H. Lincoln et . al. "Synthesis and Characterisation of Prostacyclin, 6- Ketoprostaglandin Fx, Prostaglandin Iχ and Prostaglandin I3", Journal of the American Chemical Society, Vol. 100 No. 24 (1978) pp. 7690-7705, that a dichloromethane solution of PGF2 methyl ester (12) when treated with iodine in the presence of sodium carbonate gives a mixture of two cyclic iodo ethers (13) , that can be further converted into prostacyclin by dehydrohalogenation.
Figure imgf000008_0003
(12) PGF2α ~ methy' ester
Figure imgf000008_0002
In contrast to this it has been discovered that PGF2α free acid (formula (3), R1 = n-butyl), when treated with iodine in a two phase dichloromethane/aqueous sodium hydrogen carbonate mixture, gives exclusively the iodolactone herein referred to as (4a), ie formula (4) in which R1 = n-butyl. Under these conditions the C-1 carboxylate anion can form, which then reacts preferentially (over the C-9 hydroxyl) with the presumed in situ formed 5,6 iodonium species to give the iodolactone (4a) .
In the above formulae, R1 represents an alkyl, substituted alkyl, benzyl, substituted benzyl, aryloxy, or substituted aryloxy group. Examples of such groups include, but are not limited to, n-butyl, benzyl, phenoxy, m-trifluorophenoxy or m-chlorophenoxy.
We have found that the 13,14-traι-s double bond of iodolactone (4) is cleanly reduced to the 13,14- dihydrolactone (5) with hydrogen in the presence of heterogeneous or homogeneous catalysts. Hydrogenation is also possible by transfer hydrogenation with hydrogen donors such as cyclohexene, see the paper by Johnstone, Wilby and Entwistle, Chemical Reviews, Vol. 85 (1985) pp. 129 et seg.. When using certain homogeneous catalysts (including Wilkinson's rhodium catalyst RhCl(PPh3)3, Crabtree's iridium catalyst [Ir (cod) py (PCy3) ] PFβ and Evan's rhodium catalyst [Rh(nbd) (diphos-4) ] BF4 or CF3S03 ~) no loss of the iodine atom by hydrogenolysis takes place. See the papers by J. M. Brown, "Directed Homogeneous Hydrogenation", Angew. Chem. Int . Ed. Engl . , Vol. 26 (1987) pp. 190-203 and K. R. Januskiewicz, H. Alper, Can. J. Chem. , Vol. 62 (1984) pp.1031. Hydrogenation may be carried out at atmospheric pressure or at an elevated pressure. Reaction of the 13, 14-dihydroiodolactone (5) with three equivalents of trimethylsilyl chloride forms the 9,11,15 trimethylsilyl ether (6) in situ and reaction with further trimethylsilyl chloride and sodium iodide in acetonitrile at 23°C opens the iodolactone (6) to the intermediate silyl ester (7) . Aqueous, mildly acidic, work up effects hydrolysis of the intermediate trimethylsilyl ester and removal of the silyl ether protecting groups and affords the stereochemically pure (i.e. exclusively cis- 5,6 double bond) 13,14-dihydro prostaglandin (8). These elimination conditions, previously utilised in a procedure for the purification of polyunsaturated fatty acids by E. J. Corey and S. W. Wright, "A Simple Process for the Purification of Arachidonic Acid", Tetrahedron Letters, Vol. 25 (1984) pp. 2729-2730), allow co-ordination of in si tu generated trimethylsilyl iodide with the lactone function, thus activating the system for iodide-promoted attack to form the intermediate prostaglandin trimethylsilyl ester (7) by a concerted, antiperiplanar elimination. Alternatively, inclusion of an alcohol, eg. isopropyl alcohol, prior to mild acid work up, leads to formation of the ester (9) corresponding to the acid (8) .
In a further embodiment of the invention, since all reactions may be carried out in the same solvent, such as dichloromethane, the 9, 11, 15-trimethylsilyl ether protected iodolactone (6) and the subsequent intermediate (7) need not be isolated, thus providing a simple 'one pot' procedure for selective reduction of 13,14-double bonds in a variety of prostaglandin structures.
As previously mentioned, another embodiment of the invention is the possibility of direct in situ formation of a C-1 ester (9) in the reaction mixture, from an intermediate trimethylsilyl ester during the regeneration of the cis- double bond from the iodolactone. This can be accomplished (according to the method of A. Brook and T. H. Chan, [Synthesis, (1983) pp. 201], by adding an alkyl alcohol, eg. isopropyl alcohol, to the reaction mixture immediately mild aqueous acid work up. This should be done after TLC analysis has indicated that all the iodolactone has been converted into intermediate trimethylsilyl ester (7).
If desired, these reactions, involving formation of the trialkyl ethers and their subsequent reaction to form acids and esters of formulae (8) and (9), may be carried out in the presence of an iodine absorber, such as 2-methyl-2- butene, see S.W. Wright, E.Y. Kuo and E.J. Corey J. Org. Chem. (1987) , 52 , 4399-4401 .
A further embodiment of the invention is the chemospecific introduction, via iodolactonisation, of deuterium or tritium atoms (rather than hydrogen) at the 13,14 positions in a range of prostaglandins.
All the above-mentioned reactions should be carried out under mild conditions. Generally, they should be carried out at ambient temperature, or at a slightly lower temperature. Temperatures below -20°C should be avoided, because reaction is very slow at such temperatures, while temperatures above +40°C may lead to decomposition. Various non-aqueous solvents may be used in the reactions: examples include haloalkanes, e.g. dichloromethane and chloroform; acetonitrile; aromatic vj hydrocarbons, e.g. benzene or toluene; aliphatic hydrocarbons, e.g. pentane, hexane or heptane; ketones, e.g. acetone, methyl ethyl ketone and methyl isobutyl ketone; ethers and cyclic ethers, eg diethyl ether, isopropyl ether, dimethoxyethane or tetrahydrofuran; and dimethyl formamide, dimethylsulphoxide and other dipolar aprotic solvents. Generally, the only requirement for the solvents is that they should not be reactive under the reaction conditions involved.
A further embodiment of the invention is the use of iodolactone formation from a mixture of 5,6 cis- and trans- double bond prostaglandins in order to effect facile separation of the cis- and trans- double bond compounds from each other.
Various embodiments of the invention will be further illustrated in the following non-limiting specific examples.
Example 1
Preparation of Iodolactone (4a)
(formula (4) , R1 = n-butyl)
A saturated aqueous solution of sodium hydrogen carbonate (110 ml) was added to a solution of PGF2α (3a) (17.72g, 50 mmol) in dichloromethane (150 ml) . The two phase mixture was cooled to 0-5°C (ice, salt water bath) and stirred rapidly for ca.lO min. to create an emulsion. To the cold (0-5°C) stirred emulsion was added, over 30 min., part of a solution of iodine crystals (12.7g, 100 mmol) in dichloromethane (150 ml) . The iodine colouration was initially discharged during the addition, which was continued up to the point where the iodine colour just persisted to give a pale yellow solution. Approximately 55 mmol of iodine, by volume, was consumed. The emulsified mixture was stirred at 0-5°C for a further 10 minutes, the stirring and cooling were stopped, and the layers were allowed to separate. A TLC check at this point indicated complete reaction to iodolactone. The pale yellow bottom layer of dichloromethane was run off, and the upper aqueous layer was extracted with a further 50 ml of dichloromethane. The combined dichloromethane layers were washed with a saturated solution of sodium sulphite (50 ml) , the layers were separated, and the now-colourless dichloromethane layer was dried over anhydrous sodium sulphate. Filtration and evaporation gave 20.7 g (86%) of (4a) as a colourless oil, which was used without further purification in the next step. The spectroscopic data obtained were fully consistent with structure (4a) .
Example 2
Preparation of Iodolactone (4b)
A saturated aqueous solution of sodium hydrogen carbonate (110 ml) was added to a solution of the PGF2α analogue (3b, R1= benzyl) (19.43g, 50 mmol) in dichloromethane (150 ml). The two phase mixture was cooled to 0-5°C (ice, salt water bath) and stirred rapidly for ca.lO min. to create an emulsion. To the cold (0-5°C) stirred emulsion was added, over 30 min., part of a solution of iodine crystals (12.7g, 100 mmol) in dichloromethane (150 ml) . The iodine colouration was initially discharged during the addition, which was continued up to the point where the iodine colour just persisted to give a pale yellow solution. Approximately 55 mmol of iodine, by volume, was consumed. The emulsified mixture was stirred at 0-5°C for a further 10 minutes, the stirring and cooling were stopped, and the layers were allowed to separate. A TLC check at this point indicated complete reaction to iodolactone. The pale yellow bottom layer of dichloromethane was run off, and the upper aqueous layer was extracted with a further 50 ml of dichloromethane. The combined dichloromethane layers were washed with a saturated solution of sodium sulphite (50 ml) , the layers were separated, and the now-colourless dichloromethane layer was dried over anhydrous sodium sulphate. Filtration and evaporation gave 21.6 g (84%) of (4b) as a colourless oil, which was used without further purification in the next step. The spectroscopic data obtained were fully consistent with structure (4b) .
Example 3
Preparation of Reduced Iodolactone (5a) (formula (5) , R1 = n-butyl)
The homogeneous catalyst [Rh(nbd) (diphos-4) ] BF , (2.7 g, 10 mol%) was added to a solution of 18g (37.5 mmole) of iodolactone (4a) in dry dichloromethane (100 ml) under argon with stirring to complete dissolution. The solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to an atmospheric pressure hydrogen source. Stirring was continued under atmospheric hydrogen pressure until TLC indicated that the reaction was complete (ca. 2 hr) The reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel
(Merck 60H) . The solvent was evaporated to give 17.2g (95%) of (5a) as a colourless oil, which was used without further purification in the next step. The spectroscopic data obtained were fully consistent with structure (5a) .
Example 4
Preparation of Reduced Iodolactone (5b) (formula (5) , R1 = benzyl)
The homogeneous catalyst [Rh (nbd) (diphos-4) ] BF4 , (2.7 g, 10 mol%) was added to a solution of 19.3g (37.5 mmole) of iodolactone (4b) in dry dichloromethane (100 ml) under argon with stirring to complete dissolution. The solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to an atmospheric pressure hydrogen source. Stirring was continued under atmospheric hydrogen pressure until TLC indicated that the reaction was complete (ca. 2 hr) . The reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel. The solvent was evaporated to give 18.6g (96%) of (5b) as a colourless oil, which was used without further purification in the next step. The spectroscopic data obtained were fully consistent with structure (5b) .
Example 5
De-iodolactonisation of (5a) to give (8a) (formula (8) , R1 = n-butyl)
To a stirred solution of 16. lg (33 mmol) of iodolactone (5a) in dry acetonitrile (100 ml) at 23°C under argon there were added 3.15 equivalents of trimethylsilyl chloride and 3.3 equivalents of diisopropylethylamine . The mixture was stirred for 30 min at room temperature, when TLC analysis indicated that the hydroxyl groups at positions 9, 11, and 15 were all converted into their trimethylsilyl ethers. Sodium iodide (2.5 equiv. ) and 2-methyl-2-butene (3 equiv. ) were now added with continued stirring to complete dissolution. Trimethylsilyl chloride (2 equiv. ) was now added dropwise over ca. 20 min. and the mixture was stirred until the reaction was complete (ca. lhr) , as determined by work up of small aliquots and TLC examination. A solution of sodium sulphite (2 equiv.) and citric acid (1 equiv.) in water (200 ml) was added, and the mixture was stirred at 23°C for 20 min., and then extracted with 3 x 100 ml of 4:1 hexane-dichloromethane. The combined extracts were washed with water (2 x 100 ml) and brine (100 ml) and dried over anhydrous sodium sulphate. Filtration and evaporation gave (8a) as a colourless oil in an amount of 10.7g (91%). The spectroscopic, TLC and HPLC data obtained were fully consistent with structure (8a) .
Example 6
De-iodolactonisation of (5b) to give (8b) (formula (8), R1 = benzyl)
To a stirred solution of 17g (33 mmol) of iodolactone (5b) in dry acetonitrile (100 ml) at 23°C under argon there were added 3.15 equivalents of trimethylsilyl chloride and 3.3 equivalents of diisopropylethylamine. The mixture was stirred for 30 min. at room temperature, when TLC analysis indicated that the hydroxyl groups at positions 9, 11, and 15 were all converted into their trimethylsilyl ethers. Sodium iodide (2.5 equiv.) and 2-methyl-2-butene (3 equiv.) were now added with continued stirring to complete dissolution. Trimethylsilyl chloride (2 equiv.) was now added dropwise over ca. 20 min. and the mixture was stirred until the reaction was complete (ca. Ihr) , as determined by work up of small aliquots and TLC examination. A solution of sodium sulphite (2 equiv.) and citric acid (1 equiv.) in water (200 ml) was added, and the mixture was stirred at 23°C for 20 min., and then extracted with 3 x 100 ml of 4:1 hexane-dichloromethane. The combined extracts were washed with water (2 x 100 ml) and brine (100 ml) and dried over anhydrous sodium sulphate. Filtration and evaporation gave (8b) as a colourless oil in an amount of 11.5g (89%) . The spectroscopic, TLC and HPLC data obtained were fully consistent with structure (8b) . Example 7
De-iodolactonisation and in situ ester if icat ion to give (9a) isopropyl ester (formula (9) , R1 = n-butyl , R2 = iso-propyl)
To a stirred solution of 16. lg (33 mmol) of iodolactone (5a) in dry acetonitrile (100 ml) at 23°C under argon there were added 3.15 equivalents of trimethylsilyl chloride and 3.3 equivalents of diisopropylethylamine . The mixture was stirred for 30 min at room temperature, when TLC analysis indicated that the hydroxyl groups at positions 9, 11, and 15 were all converted into their trimethylsilyl ethers. Sodium iodide (2.5 equiv.) and 2-methyl-2-butene (3 equiv.) were now added with continued stirring to complete dissolution. Trimethylsilylchloride (2 equiv.) was now added dropwise over ca. 20 min. and the mixture was stirred until the reaction was complete (ca. lhr) , as determined by work up of small aliquots and TLC examination. Isopropyl alcohol (10 equivalents) was then added, and the mixture was stirred at 23°C until TLC indicated that complete reaction had taken place (ca. 1 hr) . A solution of sodium sulphite (2 equiv.) and citric acid (1 equiv.) in water (200 ml) was added, and the mixture was stirred at 23°C for 20 min., and then extracted with 3 x 100 ml of 4:1 hexane-dichloromethane . The combined extracts were washed with water (2 x 100 ml) and brine (100 ml) and dried over anhydrous sodium sulphate. Filtration and evaporation gave (10) as a colourless oil in an amount of 10.7g (91%). The spectroscopic, TLC and HPLC data obtained were fully consistent with structure (9a) in which R1 is n-butyl and R2 is isopropyl. Example 8
De-iodolactonisation and in situ esterification to give (9b) isopropyl ester (formula (9) , R1= benzyl , R2 = iso-propyl) ,
Latanoprost
To a stirred solution of 17g (33 mmol) of iodolactone (5b) in dry acetonitrile (100 ml) at 23°C under argon there were added 3.15 equivalents of trimethylsilyl chloride and 3.3 equivalents of diisopropylethylamine . The mixture was stirred for 30 min at room temperature, when TLC analysis indicated that the hydroxyl groups at positions 9, 11, and 15 were all converted into their trimethylsilyl ethers. Sodium iodide (2.5 equiv.) and 2-methyl-2-butene (3 equiv.) were now added with continued stirring to complete dissolution. Trimethylsilyl chloride (2 equiv.) was now added dropwise over ca. 20 min. and the mixture was stirred until the reaction was complete (ca. lhr) , as determined by work up of small aliquots and TLC examination. Isopropyl alcohol (10 equivalents) was then added, and the mixture was stirred at 23°C until TLC indicated that complete reaction had taken place (ca. 1 hr) . A solution of sodium sulphite (2 equiv.) and citric acid (1 equiv.) in water (200 ml) was added, and the mixture was stirred at 23°C for 20 min., and then extracted with 3 x 100 ml of 4:1 hexane- dichloromethane. The combined extracts were washed with water (2 x 100 ml) and brine (100 ml) and dried over anhydrous sodium sulphate. Filtration and evaporation gave (9b) as a colourless oil in an amount of 12.84g (90%). The spectroscopic, TLC and HPLC data obtained were fully consistent with structure (9b) in which R1 is benzyl and R2 is isopropyl.

Claims

Claims :
1 A 6-iodo-l,5 δ-lactone of a series 2 prostaglandin.
2 A method for the preparation of a 6-iodo-l,5 δ-lactone of a prostaglandin containing a 5,6-double bond, which comprises reacting the prostaglandin with iodine in an aqueous, organic or mixed aqueous/organic solvent.
3 A 13,14 dihydro derivative of a 6-iodo-l,5 δ-lactone of a series 2 prostaglandin.
4 A method for the selective hydrogenation of the 13,14- double bond in Series 2 prostaglandins which comprises forming the iodolactone of the prostaglandin by reaction with iodine in an aqueous, organic or mixed aqueous/organic solvent, followed by catalytic hydrogenation of the iodolactone.
5 A method as claimed in claim 4 wherein the hydrogenation is carried out with gaseous hydrogen over a heterogeneous or homogeneous catalyst.
6 A method as claimed in claim 4 wherein the hydrogenation is carried out by transfer hydrogenation with a hydrogen donor over a heterogeneous or homogeneous catalyst
7 A method as claimed in any one of claims 4 to 6 wherein the hydroxy groups of hydrogenated iodolactone are reacted with trialkylsilyl halide to give the protected corresponding trialkylsilyl ether iodolactone. 8 A method as claimed in any one of claims 4 to 7 wherein the 13,14-dihydro analogue of the original prostaglandin or a C-1 ester thereof is regenerated from the hydrogenated iodolactone.
9 A method as claimed in claim 8 wherein the same solvent is used for the formation and hydrogenation of the iodolactone and for regeneration of the original prostaglandin as its 13,14-dihydro analogue or C-1 ester thereof.
10 A method as claimed in any of claims 7 to 9 wherein the 13,14-dihydro analogue of the original unsaturated prostaglandin is formed by ring opening of the hydrogenated lactone with trialkyl silyliodide, and hydrolysis or esterification, with an alcohol, of the resulting intermediate trialkylsilyl ester.
11 A method as claimed in claim 10 wherein the hydrogenated iodolactone is reacted with trialkylsilyl halide to form the corresponding trialkylsilyl ether which, without isolation, is reacted in the same solvent with more trialkylsilyl halide and alkali metal iodide to generate trimethylsilyl iodide in si tu, which reacts with the iodolactone ring to form the intermediate C-1 trialkylsilyl ester.
12 A method as claimed in any one of claims 8 to 11 wherein the C-1 ester is formed and the reaction mixture containing the ester is subjected to mild aqueous acid work up to give the 13,14-dihydro analogue of the original prostaglandin C-1 acid as its C-1 ester. 13 A method as claimed in claim 11 wherein the trilkylsilyl halide is a trimethylsilyl halide and the reaction mixture containing the ester is subjected to treatment with an alkyl alcohol which reacts with the C-1 trimethylsilyl ester to give, in situ, the corresponding alkyl ester, and the mixture is then subjected to mild aqueous acid work up to give the 13,14-dihydro analogue of the original prostaglandin as its C-1 alkyl ester.
14 A method as claimed in any one of claims 4 to 13 wherein the same organic solvent is used for all of the respective steps of formation, hydrogenation, silyl ether protection, and ring-opening of the iodolactone, and subsequent hydrolysis or esterification.
15 A method for the preparation of unoprostone (11) from the corresponding conjugated enone (10), comprising the sequence iodolactonisation, hydrogenation, regeneration of the 5,6 double bond and either mild acid hydrolysis to give the C-1 acid and subsequent esterification or treatment of the intermediate C-1 trialkylsilyl ester with isopropanol to provide the corresponding C-1 isopropyl ester.
16 A method for the preparation of latanoprost (formula (9) wherein R1 is benzyl and R2 is isopropyl) comprising the sequence iodolactonisation, hydrogenation, regeneration of the 5,6 double bond and either mild acid hydrolysis to give the C-1 acid and subsequent esterification or treatment of the intermediate C-1 trialkylsilyl ester with isopropanol to provide the corresponding C-1 isopropyl ester.
17 A method for the separation of 5,6-cis and 5, 6-trans double bond isomers of prostaglandins which comprises forming the iodolactones of the mixture of prostaglandin isomers by reaction with iodine in an aqueous, organic or aqueous/organic solvent, separating and regenerating the separated isomers.
18 A method for the chemospecific introduction of deuterium or tritium atoms at the 13, 14-positions of prostaglandins which comprises protection of the 5,6- double bond by forming the iodolactone, and reacting the resulting iodolactone with deuterium or tritium in accordance with any one of claims 4 to 6.
19 A method in accordance with any one of claims 2 and 4 to 18, comprising at least one stage substantially as herein described with reference to any one of the specific examples .
20 The product of a method as claimed in any one of claims 2 and 4 to 19.
21 A pharmacological composition comprising a product according to claim 20 and an acceptable excipient, diluent or carrier.
PCT/GB2002/004926 2001-10-31 2002-10-31 Improvements relating to prostaglandins and their analogues WO2003037353A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037857A2 (en) * 2001-10-31 2003-05-08 Johnson Matthey Public Limited Company Improvements relating to prostaglandins and their analogues

Citations (4)

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Publication number Priority date Publication date Assignee Title
US3954787A (en) * 1974-06-18 1976-05-04 Pfizer Inc. Stabilized E-series prostaglandins
DE3742437A1 (en) * 1986-12-15 1988-06-23 Chinoin Gyogyszer Es Vegyeszet 5-HYDROXI-PGF (DOWN ARROW) 1 (DOWN ARROW) (DOWN ARROW) (ALPHA) (DOWN ARROW) -1,5-LACTONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS
EP0342003A1 (en) * 1988-05-11 1989-11-15 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Use of 15-ketoprostaglandin E or F compounds for uterine contraction
WO1997045405A1 (en) * 1996-05-28 1997-12-04 Allergan Sales, Inc. Cyclopentan(en)oic acid, 2-alkenyl derivatives as therapeutic agents in the treatment of ocular hypertension

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3954787A (en) * 1974-06-18 1976-05-04 Pfizer Inc. Stabilized E-series prostaglandins
DE3742437A1 (en) * 1986-12-15 1988-06-23 Chinoin Gyogyszer Es Vegyeszet 5-HYDROXI-PGF (DOWN ARROW) 1 (DOWN ARROW) (DOWN ARROW) (ALPHA) (DOWN ARROW) -1,5-LACTONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS
EP0342003A1 (en) * 1988-05-11 1989-11-15 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Use of 15-ketoprostaglandin E or F compounds for uterine contraction
WO1997045405A1 (en) * 1996-05-28 1997-12-04 Allergan Sales, Inc. Cyclopentan(en)oic acid, 2-alkenyl derivatives as therapeutic agents in the treatment of ocular hypertension

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037857A2 (en) * 2001-10-31 2003-05-08 Johnson Matthey Public Limited Company Improvements relating to prostaglandins and their analogues
WO2003037857A3 (en) * 2001-10-31 2003-09-12 Johnson Matthey Plc Improvements relating to prostaglandins and their analogues

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