Classifications

• • 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
  • 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
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
• • 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
  • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the subject of our invention is a novel process for the preparation of travoprost.
• Stereoselectivity of the enone ⁇ enol reduction is 88.7 % (Example 10.).
• the 15-epi impurity is removed by protection of the OH-groups of the diol with tert-butyl-dimethylsilyl group (TBDMS) and crystallization of the thus obtained protected diol.
• TDMS tert-butyl-dimethylsilyl group
• the overall yield is 7%.
• the starting compound of formula (II) can be prepared for example by oxidation of the PPB- Corey-lactone of formula (XII)
• the PPB-Corey-lactone is oxidized under Pfitzner-Moffatt reaction conditions into the aldehyde (Pfitzner, K.E., Moffatt J.G.; J.Am.Chem.Soc. 1963, 85, 3027), then the lower chain is built up with the help of Horner- Wadsworth-Emmons (HWE) reaction (Wadsworth, W.; Org. React., 1977, 25, 73) - by use of the appropriate phosphonate - under water-free conditions, in the presence of solid potassium hydroxide.
• HWE Horner- Wadsworth-Emmons
• potassium tert-butylate lithium carbonate
• DBU lithium- or magnesium halogenides
• triethylamine potassium hexamethyl disilazide (KHMDS) or crown ether bases - we applied solid potassium hydroxide which is economical and can be safely used in industrial scale.
• KHMDS potassium hexamethyl disilazide
• the HWE reaction is carried out in an aprotic organic solvent in a temperature range of 40-(- 50)°C, preferably at (- 10)°C, by using as solvent an aromatic hydrocarbon, such as toluene or an ether, like tetrahydrofuran, methyl tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, diethyl ether or their mixtures.
• the selective reduction of the compound of formula (II) is accomplished with a borane-type reducing agent.
• (-)-B- chlorodiisopinocampheylborane (DIP -CI) catecholborane, especially catecholborane may be applied.
• the reduction of the compound of formula (II) is carried out in the presence of a chiral catalyst.
• chiral catalyst CBS- oxazaborolidine can be used.
• the reaction is carried out in the presence of an organic solvent, at a temperature between (10°C) and (-80°C), preferably between (-10°C) and (-20°C).
• solvent toluene hexane, heptane, pentane, tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, diethyl ether or their mixtures may be applied, among others toluene - tetrahydrofuran mixtures are used.
• the resulting compound of formula (III) is purified by crystallization, while the amount of the undesired isomer is lowered in a significant manner.
• the crystalline form of the compound of formula (III) has not been known before, it is a novel form. Crystallization is carried out in polar or apolar solvents or in the mixture of them.
• the crystallization is performed between (-20)-70°C, in such a way that the material is dissolved in alcohol at reflux temperature and crystallized by cooling gradually. The crystals are then filtered off, washed and dried.
• Reduction of the compound of formula (III) may be carried out with diisobutyl-aluminum hydride (DIBAL-H).
• DIBAL-H diisobutyl-aluminum hydride
• solvent inert aprotic solvents such as THF, toluene, hexane, and heptane may be applied.
• the reaction is performed at a temperature between (-80°C) and (- 50°C), especially between (-80°C) and (-70°C).
• the PPB-protecting group may be removed in a known way by methanolysis, under basic conditions, especially in the presence of potassium carbonate.
• the resulting intermediate of formula (V) is purified by crystallization, while the amount of the undesired isomer is decreased under a strickt limit value.
• the crystalline form of the compound of formula (V) has not been described before, it is a novel form. Crystallization is carried out in the mixture of polar and apolar solvents. As for the mixture of polar and apolar solvents, an ethyl acetate - hexane mixture may be used. Transformation of the compound of formula (V) into the compound of formula (VI) is accomplished by Wittig reaction, while esterification of the compound of formula (VI) is carried out with isopropyl iodide.
• cyclic tertiary amides such as N-methylpyrrolidone and/or 1,3- dimethylimidazolidinone are used as solvents.
• the esterification is performed at a temperature between 20-90°C, especially between 40-50°C.
• a further subject of the invention is the novel compound of formula (IV)
• Travoprost In one embodiment of the invention, which starts from the PPB-Corey-lactone, the lower chain is constructed with the help of the appropriate phosphonate, by Horner- Wadsworth- Emmons reaction. For the deprotonation of the phosphonate the inexpensive and in industrial scale safely applicable solid potassium hydroxide is used. Reduction of the resulting Travoprost 1. intermediate (enone -compound of Formula (II)) is carried out in the presence of a 2-methyl-CBS-oxazaborolidine catalyst, with a borane-type reducing agent, like catecholborane, resulting in a stereoselectivity of 90%. The thus obtained Travoprost 2.
• intermediate enone -compound of Formula (II)
• a borane-type reducing agent like catecholborane
• intermediate (enol - compound of Formula (III)) is purified by crystallization and reduced with diisobutylaluminum hydride (DIBAL-H). From the resulting Travoprost 3. intermediate (PPB-triol - compound of Formula (IV)) the PPB-protecting group is removed and the thus obtained Travoprost 4. intermediate (triol - compound of Formula (V)) is purified by crystallization. Travoprost 5.
• intermediate (acid - compound of Formula VI) is prepared by Wittig reaction. Finally, the esterification is carried out with isopropyl iodide in DMI (1,3- dimethylimidazolidin-2-one) solvent to obtain the ester (Travoprost - Formula (I)).
• DMI 1,3-dimethylimidazolidinone
• EP 2 143 712 Al, WO 2011/046569 Al dimethylformamide
• DMI is a solvent used in the beauty industry.
• the formyl-impurities which generate from the widely used dimethylformamide solvent are not formed from DMI.
• the esterification reaction can be carried out with very high conversion, without forming new impurities (-100%). ⁇ The overall yield of the new process is very high, 16%, which is more than double of the yield described in WO 2011/055377 Al (7%).
• the reaction mixture is poured onto 1 M hydrochloric acid solution and the mixture is stirred.
• the precipitated crystals are filtered off and washed.
• the phases of the filtrate are separated, the organic phase is washed with 1M sodium hydrogen carbonate solution and then with diluted hydrochloric acid solution.
• the organic phase is evaporated and purified by chromatography on a silica gel column (eluent: toluene - ethyl acetate mixture).
• the main fraction is evaporated and crystallized from ethyl acetate - hexane mixture.
• a multi-neck flask is charged under nitrogen atmosphere with 701 g of enol which is then dissolved in 6.8 L of room temperature THF.
• the clear solution is cooled to -75°C and in approximately 30 minutes the pre-cooled (-75°C) 1 M hexane solution of 2921 ml diisobutylaluminum hydride (DIBAL-H) is added to it.
• DIBAL-H diisobutylaluminum hydride
• the reaction mixture is stirred at - 75 °C until the reaction is completed. After reaching the suitable conversion, the reaction mixture is poured onto the mixture of NaHS0 4 solution and ethyl acetate.
• the phases are separated, the aqueous phase is extracted with ethyl acetate, the united organic phase is washed with NaHC0 3 solution and with diluted hydrochloric acid solution, and then evaporated while adding triethylamine (TEA) to it. 639.5 g oil is obtained.
• TAA triethylamine
• the precipitated crystals are solved in 10 folds ethyl-acetate, thereafter 10 folds n-hexane is added and the solution is mixed at room temperature. To the crystal-suspension obtained 20 folds n-hexane is added and mixed at room temperature. The precipitated crystals are filtered, washed with a mixture of hexane: ethyl-acetate and dried.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Furan Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Steroid Compounds (AREA)

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