Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D475/00—Heterocyclic compounds containing pteridine ring systems
  • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
  • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2

Definitions

• the present invention relates to a process for the preparation and enrichment of (6S, ⁇ S) or (6S, ⁇ R) tetrahydrofolic acid ester salts and tetrahydrofolic acid by mixing, in an organic solvent, equimolar or enriched mixtures of diastereomers of addition salts of tetrahydrofolic acid esters with aromatic sulfonic acids produces or dissolves, then crystallizes at least once, and if appropriate hydrolyzes them to (6S, ⁇ S) - or (6S, ⁇ R) -tetrahydrofolic acid and crystallizes them as free acid or isolates them in the form of their salts.
• the addition salts of the (6R, ⁇ S) or (6R, ⁇ R) tetrahydrofolic acid esters with the corresponding sulfonic acids can be isolated from the mother liquors and the corresponding tetrahydrofolic acids or their salts can be obtained by hydrolysis.
• the asymmetric ⁇ -C atom in the glutamic acid residue can be in the S configuration ( ⁇ S) or in the R configuration ( ⁇ R).
• the enantiomers of folic acid are referred to below as ( ⁇ S) -folic acid and ( ⁇ R) -folic acid.
• the naturally occurring folic acid corresponds to ( ⁇ S) -folic acid.
• Tetrahydrofolic acid corresponds to formula II
• the asymmetric ⁇ -C atom in the glutamic acid residue can be in the S configuration ( ⁇ S) or in the R configuration ( ⁇ R) and the asymmetric C atom 6 in the tetrahydropterin residue in the S configuration (6S) or R configuration (6R) may be present.
• the diastereomers of tetrahydrofolic acid are referred to below as (6S, ⁇ S) -, (6S, ⁇ R) -, (6R, ⁇ S) - and (6R, ⁇ R) - tetrahydrofolic acid. The same applies to the tetrahydrofolic acid esters and their derivatives.
• (6S, ⁇ S) - 6S, ⁇ R) -, (6R, ⁇ S) - and (6R, ⁇ R) - tetrahydrofolic acid esters.
• the naturally occurring tetrahydrofolic acid corresponds to (6S, ⁇ S) -tetrahydrofolic acid.
• folic acid, folic acid ester and folic acid ester salt always includes the two enantiomers ( ⁇ S) and ( ⁇ R) and the term tetrahydrofolic acid, tetrahydrofolic acid ester and tetrahydrofolic acid ester salts all possible diastereomers.
• Tetrahydrofolic acid has found widespread therapeutic use in the form of 5-formyl or 5-methyl derivatives and their physiologically tolerable salts. It has long been known that the biological activity of the naturally occurring diastereomers of reduced folates, e.g. B. the (6S, ⁇ S) - tetrahydrofolic acid, is by far the strongest. It is therefore expedient to provide therapeutic preparations which contain only the most active form or which is at least highly enriched.
• Tetrahydrofolic acid is generally produced industrially by heterogeneous hydrogenation of the two imine groups in the pterine skeleton of ( ⁇ S) -folic acid, usually giving an equimolar mixture of (6S, ⁇ S) - and (6R, ⁇ S) -tetrahydrofolic acid.
• the equimolar mixture can be used for pharmaceutical preparations. But you can also do the desired one beforehand Enrich (6S, ⁇ S) -diastereomers of tetrahydrofolic acid by fractional crystallization or obtain it in pure form, for which various processes are known, see for example EP-0495204.
• this process cannot convince from an economic point of view insofar as the sulfonic acids used for salt formation can only be separated from aqueous mother liquors at great expense, and therefore large volumes of mother liquors containing sulfonic acid have to be disposed of, which is economically unfavorable.
• EP-0682 026 describes the preparation of stable crystalline (6S, ⁇ S) and (6R, ⁇ S) tetrahydrofolic acid by crystallization from an aqueous medium at certain pH values.
• the enrichments in the fractional crystallizations are so low that several steps are necessary for an enrichment of the desired diastereomer to over 99.5%. This is associated with large substance losses and the risk of the formation of chemical degradation products.
• the enrichment of unnatural isomers is particularly complex according to this process.
• aromatic sulfonic acid salts (addition salts) of tetrahydrofolic acid esters are outstandingly suitable for the preparation of optically pure diastereomers of tetrahydrofolic acid, since only the addition salts of (6S, ⁇ S) or (6S, ⁇ R) diastereomers crystallize out from organic solvents.
• the invention relates to a process for the preparation and enrichment of (6S, ⁇ S) - or (6S, ⁇ R) -tetrahydrofolic acid ester salts and -tetrahydrofolic acid, which is characterized in that equimolar or enriched mixtures of diastereomers of addition salts of tetrahydrofolic acid esters with in organic solvents produces or dissolves aromatic sulfonic acids, then crystallizes at least once, and then hydrolyzes the crystals to (6S, ⁇ S) - or (6S, ⁇ R) -tetrahydrofolic acid, crystallizes them as free acid or isolates them in the form of a salt.
• Crystallization at least once in the context of the invention means fractional crystallization to the desired purity.
• the number of crystallization steps depends mainly on the content of the desired diastereoisomer (s) in the starting product.
• the addition salts of the tetrahydrofolic acid esters can correspond to the formula III and comprise the (6S, ⁇ S), (6S, ⁇ R), (6R, ⁇ S) and (6R, ⁇ R) diastereomers,
• R is T or RH, and one of ⁇ or R 2 , or both Ri and R 2 independently of one another are a monovalent hydrocarbon radical or a heterocarbon radical bonded via a C atom and having heteroatoms selected from the group -O-, -S- and - N- represent, HA stands for an aromatic sulfonic acid, and x denotes an integer from 1 to 6 or a fractional number between 0 to 6.
• R! and R 2 can be selected independently of one another, but they are preferably identical.
• R 1 and R 2 preferably represent a hydrocarbon radical.
• R T and R 2 as the hydrocarbon radical can be aliphatic radicals having 1 to 20, preferably 1 to 12, particularly preferably 1 to 8 and particularly preferably 1 to 4 carbon atoms to cycloaliphatic or cycloaliphatic-aliphatic radicals having 3 to 8 ring carbon atoms and 1 to 6 carbon atoms in the aliphatic radical, to aromatic hydrocarbon radicals having 6 to 14 carbon atoms, particularly preferably 6 to 10 carbon atoms, or to aromatic-aliphatic Leftovers with 7 to
• the heterohydrocarbon residue can be heteroalkyl with 2 to
• the hydrocarbon radicals can, for example, be selected from the group consisting of linear and branched C 1 -C 20 -alkyl, C 3 -C 8 - and preferably C -C 7 -cycloalkyl, Cs-C ⁇ -cycloalkyl-d-Ce-alkyl and preferably C -C 7 cycloalkyl -CC 4 alkyl, C 6 -C 10 aryl or C 7 -C 2 aralkyl.
• the heterocarbon residues can be selected from, for example
• heteroaryl and C 5 -C ⁇ 2 - and preferably C 5 -C 10 heteroaralkyl, the hetero radicals
• R 1 and R 2 can be linear or branched alkyl, which preferably contains 1 to 12, more preferably 1 to 8, and particularly preferably 1 to 4 carbon atoms. Examples are methyl, ethyl, and the isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and eicosyl.
• the alkyl is preferably linear and the alkyl is preferably methyl, ethyl, n-propyl and n-butyl. Alkyl very particularly preferably represents methyl.
• R 1 and R 2 preferably contain 4 to 7 and particularly preferably 5 or 6 ring carbon atoms.
• Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cyclohexyl is particularly preferred.
• R T and R 2 preferably contain 4 to 7 and particularly preferably 5 or 6 ring carbon atoms as cycloalkyl-alkyl, and preferably 1 to 4 and particularly preferably 1 or 2 carbon atoms in the aliphatic radical.
• Examples of cycloalkyl-alkyl are
• R, and R 2 can be, for example, CrC 4 alkyl-X1-C 2 -C 4 -alkyl as heteroalkyl, where X is O or NC-C 4 alkyl. Examples are methoxyethyl and ethoxyethyl.
• Ri and R 2 may be, for example, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl or piperazinyl as heterocycloalkyl.
• R T and R 2 can be, for example, pyrrolidinylmethyl or ethyl, piperidinylmethyl or -ethyl, morpholinylmethyl or -ethyl, tetrahydropyranylmethyl or -ethyl or piperazinylmethyl or -ethyl as heterocycloalkyl-alkyl.
• R and R 2 can be, for example, thiophenyl, furanyl, pyranyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinoiinyl, oxazolyl or isooxazolyl as heteroaryl.
• Ri and R 2 can be, for example, furanylmethyl or ethyl,
• a preferred group of compounds of formula III are those in which R ⁇ and R 2 are independently dC 4 alkyl, C 5 - or C 6 cycloalkyl, phenyl, CrC 4 alkylphenyl, benzyl or C 1 -C 4 -alkylbenzyl.
• R and R 2 are preferably identical radicals.
• R and R 2 very particularly preferably represent CC 4 alkyl, for example methyl or ethyl.
• x is preferably an integer or fraction from 0.5 to 4, particularly preferably an integer or fraction from 0.5 to 3, and very particularly preferably an integer or fraction from 0.5 to 2.
• the aromatic sulfonic acids can contain one to three, preferably one or two, and particularly preferably one sulfonic acid group. Sulfonic acids of hydrocarbon aromatics are preferred.
• the aromatic sulfonic acids can be unsubstituted or with halogen, linear or branched C 1 -C 8 alkyl, preferably dC 4 alkyl, linear or branched C 1 -C 8 alkoxy, preferably CC alkoxy, and linear or branched CrC 8 haloalkyl, preferably -C-C 4 - Halogenalkyl be substituted.
• substituents are methyl, ethyl, propyl, butyl, methoxy, ethoxy, trifluoromethyl or trichloromethyl, fluorine and chlorine.
• the aromatic radical preferably contains a substituent. Among the aromatic groups, phenyl and naphthyl are preferred.
• aromatic sulfonic acids particularly preferably correspond to the formula IV,
• R 3 is phenyl, methylphenyl, fluorophenyl, chlorophenyl, trichloromethylphenyl and c trifluoromethylphenyl.
• Particularly preferred compounds of the formula III are those in which R and R 2 are each methyl, x is 1 or 2 or a fractional number between 0.5 and 2, and HA is phenyl, toluyl, fluorine, chlorine or trifluoromethylphenyl - means sulfonic acid.
• Substituted radicals are preferably p-tolyl, p-fluoro-, 10 p-chloro- or p-trifluoromethylphenyl.
• Very particularly preferred compounds of the formula III are those in which R 1 and R 2 are each methyl, x is 1 or 2 or a fractional number between 0.5 and 2, and HA is phenyl- or p-toluenesulfonic acid.
• the addition salts of the tetrahydrofolic acid esters used according to the invention are new and can be prepared, for example, by esterifying tetrahydrofolic acid in the presence of sulfonic acids, or by esterifying tetrahydrofolic acid salts in a polar organic solvent.
• 10 tetrahydrofolic acid esters can then be converted into addition salts with sulfonic acids.
• the hydrogenation can be carried out as described above with alcohol-soluble metal complexes of Ir, Rh or Ru and ditertiary diphosphines as hydrogenation catalysts.
• the hydrogenation is carried out in an alcohol as a solvent and in the presence of a sulfonic acid
• Mixtures understood that either contain equal amounts of diastereomers with (6S) and (6R) configuration or an excess of a diastereomer with (6S) or (6R) configuration. It is also possible to use mixtures of diastereomers (6S) and (6R) configurations which have either ( ⁇ S) or ( ⁇ R) configurations, or mixtures of diasteromer pairs 25 with (6S) and (6R) configurations and different ones Configuration on the ⁇ -C atom.
• the mixtures can contain the (6S, ⁇ S) or (6S, ⁇ R) diastereomer in a proportion of at least 5, preferably at least 20, and particularly preferably at least 30 percent and up to about 75 percent or more.
• Suitable organic solvents are polar organic solvents, preferably at least 1 g addition salt of a teterahydrofolic acid ester per liter Can dissolve solvents at boiling temperature.
• solvents are halogenated hydrocarbon (methylene chloride, chloroform, tetrachloroethane, chlorobenzene); Ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); Carboxylic acid esters and lactones (methyl acetate, ethyl acetate, methyl propionate,
• Valerolactone N, N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); Ketones (acetone, methyl isobutyl ketone, cyclohexanone); Sulfoxides and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfone); and alcohols (methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl- or dihydroxymethylcyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol,
• the process can be carried out, for example, by mixing equimolar or enriched mixtures of diastereomers from addition salts of tetrahydrofolic acid esters with aromatic sulfonic acids with a solvent and then heating the mixture to dissolve the addition salts of tetrahydrofolic acid esters and aromatic sulfonic acids.
• the heating can be carried out up to the boiling point of the solvent.
• the solution is then cooled to at most the fixed point of a solvent, the (6S, ⁇ S) or (6S, ⁇ R) diastereoisomer or both diastereomers either spontaneously or by inoculation with the desired diastereomer or by concentrating the solution crystallize out, and then can be separated in the usual way by filtration. It has proven to be a particular advantage that the reaction solutions of hydrogenating folate esters or hydrogenating addition salts of folate esters and aromatic sulfonic acids can also be used directly to prepare or enrich the addition salts of tetrahydrofolic acid esters with aromatic sulfonic acids.
• the observed enrichment of the (6S, ⁇ S) or (6S, ⁇ R) diastereomers in the crystals is so high and the crystallizability of these isomers is so excellent that the process according to the invention can even be used to isolate (6S, ⁇ S) - or ( 6S, ⁇ R) -diastereomers from mother liquors, which predominantly contain (6R, ⁇ S) - or (6R, ⁇ R) -diastereomers.
• the method according to the invention is outstandingly suitable for separation processes on an industrial scale.
• the addition salts of (6S, ⁇ S) - or (6S, ⁇ R) - tetrahydrofolic acid esters with sulfonic acids obtained after the separation can then be hydrolyzed in a manner known per se, for example with bases such as NaOH or KOH.
• bases such as NaOH or KOH.
• the corresponding (6S, ⁇ S) or (6S, ⁇ R) tetrahydrofolic acids are accordingly obtained.
• These tetrahydrofolic acids can be isolated in stable form as free acids by crystallization, as described for example in EP-A-0682 026.
• acids for example sulfonic acids
• the salts of tetrahydrofolic acids can also be crystallized and, if desired, further enriched (EP-0495204).
• COD stands for cyclooctadiene.
• Example A1 a Preparation of ( ⁇ S) -folic acid dimethyl ester benzenesulfonate 5,800 g of ( ⁇ S) -folic acid dihydrate (1.68 mmol) are dissolved in a solution at 40 ° C.
• the substance decomposes above 150 ° C.
• Example A2 The clear solution from Example A2 is cooled to room temperature and stirred overnight. The separated solid is filtered off, washed with methanol and tert-butyl methyl ether and dried at 30 ° C and 10 mbar. 9.62 g of colorless crystalline tetrahydrofolic acid dimethyl ester benzenesulfonate (15.24 mmol) are obtained with a (6S, ⁇ S) diastereomer fraction of 99.1%.
• the mother liquor B1c can be used to prepare the (6R, ⁇ S) dimethyl tetrahydrofolic acid benzene sulfonate as described in Example B5.
• 4 g (6.34 mmol) of the dimethyl tetrahydrofolic acid benzene sulfonate obtained with a proportion of the (6S, ⁇ S) diastereomer of 99.1% are dissolved in 220 ml of boiling methanol. The mixture is allowed to cool to room temperature, left to stand overnight and the solid which has separated off is filtered off with suction. It is washed with methanol and tert-butyl methyl ether and dried at 35 ° C. and 10 mbar.
• Example A3 The solution obtained according to Example A3 is allowed to cool to room temperature and the solution is inoculated at 60 ° C. with diastereomerically pure (6S, ⁇ S) tetrahydrofluoric acid dimethyl ester benzenesulfonate. After standing overnight, the solid which has separated out is filtered off with suction, washed with methanol and tert-butyl methyl ether and dried at 35 ° C. and 10 mbar. 3.46 g (5.48 mmol) of dimethyl tetrahydrofolic acid benzenesulfonate are obtained with a (6S, ⁇ S) -diastereomer fraction of 99.9%.

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• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)

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• 1999
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• 2000
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