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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
  • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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
  • C07D317/34—Oxygen atoms
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  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/12—Oxygen atoms acylated by aromatic or heteroaromatic carboxylic acids, e.g. cocaine

Definitions

• the invention relates to a process for the preparation of 1,3-dioxolan-2-ones of the general formula 3
• the inventive method allows a reaction under very mild basic conditions, compared to reactions in highly polar aprotic solvents provides less side reactions and higher yield.
• a synthesis of acid- and / or temperature-sensitive compounds is possible.
• the combination zeolite type 4a and tert-alkoxide catalyzes transesterification reactions with scopin without significant rearrangements take place to scopolin.
• Acetonides or derivatives of 1,3-dioxolane are cyclic ketals prepared, for example, from 1,2-diols, ketones or aldehydes. It is known in the art that acid catalysts support and / or facilitate this reaction. The cyclic ketals are synthetically valuable compounds that are useful because of their particular properties.
• the carboxylic acid functionality structurally contained therein can be activated to facilitate acylation reactions.
• volatile ketones or aldehydes emerge as reaction by-product, the reaction equilibrium is favorably promoted in the direction of acylation e.g. an alcohol (see “A new synthesis of alpha-hydroxycarboxylates and 2-hydroxybenzoates", Khalaj, Ali, Aboofazaeli, Rem, Egyptian Journal of Chemistry & Chemical Engineering (1997), 16 (1), 1-3).
• 1, 3-dioxolan-2-ones combine via the ring closure of an alpha-hydroxycarboxylic acid the protection of their individual functionalities and convert them into an ether and a lactone functionality.
• the stability of the total molecule is sometimes decisively increased.
• the stabilizing or activating effect in the molecule can dominate and be exploited.
• ketones and aldehydes as a protective group for alpha-hydroxycarboxylic acids is possible since the former can be split off again from the 1,3-dioxolan-2-ones under defined, mild conditions (acidic or basic).
• 1,3-Dioxolan-2-ones are also known starting materials for the preparation of alpha-hydroxycarboxylic acid esters and alpha-hydroxycarboxamides ("Synthesis of alpha-Hydroxycarboxamides from acetonides of alpha-Hydroxycarboxylicacids and Primary Amines" Khalaj, A .; Nahid, E .; , Synthesis (1985), (12), 1153-1155). Synthetic processes for the preparation of dioxolanes are described, for example, in
• Tiotropium salts are assigned to the anticholinergics
• X represents an anion, preferably bromide
• Tiotropium bromide is known, for example, from EP 418 716 A1.
• the present invention is therefore based on the object to provide an improved, mild, technically applicable synthesis process, which is a synthetic
• the present invention relates in a first aspect to a process (reaction Ia) for the preparation of 1,3-dioxolan-2-one of formula 3
• Ri and R 2 independently of one another each represent hydrogen or a cycloalkyl, aryl or heteroaryl radical, where the cycloalkyl, aryl or heteroaryl radical may each be optionally mono- or polysubstituted;
• R 4 and R 5 are each independently selected from hydrogen, C 1 -C 6 -alkyl, or R 4 and R 5 together form a saturated or mono- or polyunsaturated carbocyclic or heterocyclic ring containing one or more heteroatom selected from S, N or O, which may optionally be each independently or one or more times substituted, form, wherein R 4 and R 5 can not be hydrogen at the same time;
• Ri and R 2 are as defined above and
• R 3 is methyl, ethyl, propyl, isopropyl, isopropenyl, butyl, N-succinimide, N-phthalimide, phenyl, nitrophenyl, fluorophenyl, pentafluorophenyl, vinyl, 2-allyl,
• a suitable basic catalyst preferably a catalyst selected from the group of tert-alcoholates, in the presence of zeolite in one step with a compound of formula 2
• the invention further relates in a second aspect to a process (reaction Ia + reaction Ib) for the preparation of a compound of formula 5 Wonn
• Ri and R 2 are as defined above;
• R 6 is an organic radical
• Ri and R 2 are as defined above;
• R 3 is different from R 6 and is selected from methyl, ethyl, propyl, isopropyl, isopropenyl, butyl, N-succinimide, N-phthalimide, phenyl, nitrophenyl, fluorophenyl,
• a suitable solvent with the addition of a suitable basic catalyst, preferably a catalyst selected from the group of tert-alcoholates, in the presence of zeolite in one step with a compound of formula 2
• R5 2 wherein R 4 and R 5 are as defined above, to a compound of formula 3 wherein R 1 , R 2 , R 4 and R 5 have the meanings given above, and wherein
• reaction Ib the compound of formula 3 in a second step (reaction Ib) in a suitable solvent with the addition of a suitable basic catalyst, preferably a catalyst selected from the group of the tertiary alcoholates, in the presence of zeolite with a compound of formula 4
• a suitable basic catalyst preferably a catalyst selected from the group of the tertiary alcoholates
• R 6 is an organic radical other than R 3 ,
• the invention further relates, in a third aspect, to a process (reaction 2) for the preparation of a compound of formula 5
• Ri and R 2 are as defined above and
• R 6 is as defined above;
• Ri and R 2 and R 3 are as defined above;
• reaction 2 in a step (reaction 2) with a compound of formula 2, in particular acetone, which serves as a solvent, and a compound of formula 4
• R 6 -OH 4 wherein R 6 is an organic radical other than R 3 ,
• a suitable basic catalyst preferably a catalyst selected from the group of tert-alcoholates, in the presence of zeolite to a compound of formula 5.
• aryl or "aryl radical” means a 6- to 10-membered aromatic carbocycle and includes, for example, phenyl and naphthyl.
• Other terms which include as part of the term “aryl” have the same meaning for the aryl component Examples of these components are: arylalkyl, aryloxy or arylthio.
• heteroaryl or “heteroaryl radical” denotes a stable 5- to 8-membered, preferably 5- or 6-membered monocyclic or 8-membered to 11-membered bicyclic aromatic heterocycle.
• Each heterocycle consists of carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
• heteroarylene examples include: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furanyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzo furanyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, benzothiazolyl, quinazolinyl, indazolyl, or fused heteroaryl such as cyclopentenopyridine, cyclo hexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohe
• alkyl or “alkyl groups” and alkyl groups which are part of other groups, branched and unbranched alkyl groups are denoted by 1 to 6 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl, hexyl. Unless otherwise indicated, of the above designations of propyl, butyl, pentyl and hexyl all of the possible isomeric forms are included.
• propyl includes the two isomeric groups n-propyl and iso-propyl
• butyl the isomeric groups n-butyl, iso-butyl, sec. Butyl and tert-butyl.
• alkoxy or "alkoxy groups”, branched and unbranched alkyl groups having 1 to 6 carbon atoms, which are linked via an oxygen atom, are referred to. Examples include: methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy. Unless otherwise indicated, all of the possible isomeric forms are included among the above designations.
• cycloalkyl radicals having 3 to 6 carbon atoms for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl are referred to.
• heterocycle is meant a stable 5- to 8-membered, but preferably 5- or 6-membered monocyclic or 8-membered to 11-membered bicyclic heterocycle understood, which is either saturated or unsaturated and can also be aromatic, if this is chemically possible in the respective context.
• Each heterocycle consists of carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocycles are pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, 1,2,5,6-tetrahydropyridinyl, piperidinyl, morpholinyl,
• nitrogen and sulfur as well as the respective elemental symbols include any oxidized form of these and also quaternary forms of a basic nitrogen atom are intended to be encompassed.
• radicals Ri to R 6 have the meanings given above.
• Reaction Ia The process according to the invention (reaction Ia) according to the first aspect of the invention relates to the reaction of a 2-hydroxycarboxylic acid ester of the general Formula 1_ with a compound of formula 2 to a l, 3-dioxolan-2-one of general formula 3. This is shown in the following reaction scheme 2:
• radicals R 1 to R 5 have the meanings given above.
• R 3 is preferably selected from methyl, ethyl, propyl and butyl, more preferably methyl.
• Ri and R 2 are each selected from a heteroaryl radical, which may be optionally mono- or polysubstituted.
• Preferred substituents are halogen atoms such as fluorine, chlorine, bromine or iodine, -CN, C 1 -C 4 -AIlSyI, Ci-C 4 -alkoxy, hydro xy or CF 3.
• Ri and R 2 are both the same heteroaryl radical, in particular Ri and R 2 are both thienyl radicals.
• R 4 and R 5 are independently selected from C 1 -C 6 -alkyl, more preferably methyl, ethyl, butyl or pentyl. According to a preferred embodiment, R 4 and R 5 both represent the same group but not simultaneously hydrogen, more preferably R 4 and R 5 are both methyl.
• R 4 and R 5 together form a saturated or unsaturated carbocyclic or heterocyclic ring.
• the carbocyclic ring is preferably selected from cyclohexyl and cyclopentyl.
• the heterocyclic radical is preferably selected from piperidinyl, quinuclidinyl, tropinyl and pyrrolidinyl, each optionally substituted with one or more substituents.
• halogen atoms such as fluorine, chlorine, bromine or iodine, -CN, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, CF 3 and -O-COR ', where R' is a radical selected from the group consisting of C 1 -C 4 -alkyl, benzyl and phenylethyl, which may each be substituted by hydroxy, hydroxymethyl or methoxy, more preferably R 4 and R 5 together form a pyridinyl ring.
• the compound of formula 2 may also form an aromatic carbocyclic or heterocyclic ring. Examples of these are benzyl, pyrrole, furan, thiophene. After the reaction of the compound of formula 2 for 1,3-dioxolan-2-one, the ring system loses its aromatic character due to the bridging carbon atom between the two ring oxygens of the dioxolane.
• R 4 and R 5 together with a nitrogen atom form a heterocyclic ring selected from pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, morpholine,
• radicals which may optionally be substituted by one or more radicals, preferably a radical selected from the group consisting of OH, F, methyl, ethyl, methoxy and -O-COR, where R 'represents a radical selected from the group consisting of C1 -C4- Alkyl, benzyl and phenylethyl, which may each be substituted by hydroxy, hydroxymethyl or methoxy.
• the compounds of the formula 2 are not particularly limited; Known ketones or aldehydes can be used, provided that they do not impair the formation of a 1,3-dioxolan-2-one. Sterically particularly demanding residues are therefore not preferred.
• Exemplary ketones are cyclohexanone, acetone.
• Exemplary aldehydes are isobutyraldehyde, benzaldehyde, N-methyl-1,4-piperidone, tropanone, piperidone, quinuclidinone.
• the catalyst preferably a catalyst selected from the group of tert-alcoholates
• a zeolite preferably a catalyst selected from the group of tert-alcoholates
• tertiary alcoholates are meant alcoholates having sterically demanding alkyl groups containing at least one quaternary carbon center. Quaternary carbon centers are understood to mean carbon centers which do not carry a hydrogen atom but are substituted by 3 to 4 alkyl groups. Carbon centers substituted with 3 alkyl groups preferably carry the alkoxide group as the fourth substituent.
• Suitable tert-alcoholates are preferably alkali metal or alkaline earth metal alkoxides, more preferably sodium or potassium tert-butoxide or sodium or potassium tert-amylate.
• zeolites are molecular sieves which are selected from the group of molecular sieves having a basic character, consisting of alkali metal or alkaline earth metal aluminosilicates, such as sodium or potassium-containing alumino silicates, preferably molecular sieves having the empirical formula Nai 2 [(AlO 2 ) i 2 (Si0 2 ) i 2 ] x H 2 O or or Nai 2 Ali 2 Sii 2 ⁇ 36 xn H 2 O, where n is preferably ⁇ 6, molecular sieve type 4A according to the invention is particularly preferred.
• the reaction of the compound of formula 1 with the compound of formula 2 for the compound of formula 3 is preferably carried out in solution.
• the resulting solution is usually stirred until complete reaction. This can be done at room temperature (approx. 23 ° C) or optionally also at slightly elevated temperature in a range of 25- 50 0 C are worked. This depends on the reactants and the type of catalyst chosen.
• the reaction proceeds under basic reaction conditions and also works at room temperature and below.
• the reaction preferably takes place under mild conditions at a temperature of about 30 ° C., more preferably in a range from about 0 to about 30 ° C.
• Suitable solvents are preferably aprotic organic solvents, preferably weakly polar organic solvents.
• Suitable solvents according to the invention are particularly preferably acetone, pyridine, acetonitrile and tetrahydrofuran, preference being given to acetone, acetonitrile and tetrahydrofuran. It may be of particular advantage if the compound of the formula 2 can act simultaneously as a reactant and solvent. This is the case, for example, with the use of acetone as the compound of formula 2 and is particularly advantageous when the alpha-hydroxycarboxylic acid ester of formula 1_ is soluble in this solvent.
• the resulting solution is usually stirred until complete reaction. After completion of the reaction, the compounds of formula 3 are isolated from the solution.
• the products obtained may, if necessary, be purified by recrystallization from a suitable solvent.
• the product obtained is isolated and optionally dried in vacuo.
• reaction Ia The erfmdungshiele process is selective, side reactions are largely prevented.
• the process according to the invention produces 1, 3-dioxolan-2-ones having a basic structure of type A and 1,3-dioxolan-2-ones having a basic structure of type B:
• the present invention also relates to a process for the preparation of acid-sensitive 2-hydroxycarboxylic acid esters 5, it also being possible for an acid-sensitive 2-hydroxycarboxylic ester 1_ to be present as starting material.
• 1,3-dioxolan-2-ones of type B act as anticholinergics on the muscarinic receptor, similar to tiotropium salts, and can be used therapeutically in certain diseases.
• Pharmacologically active benzilic acid and mandelic acid analogs have been described, for example, in "Synthesis and Selective Activity of Cholinergic Agents with Rigid Skeletons", Shoji Takemura, Yasuyoshi Miki, Mariko Hoshida, Mayumi Shibano, Aritomo Suzuki; Chem. Pharm. Bull. 29 (10) 3019-3025 (1998)).
• the compounds of formula 610 are compounds of formula 610:
• X ' is a singly charged anion.
• anion is chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, Succi - Nat, benzoate or p-toluenesulfonate act.
• X is chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate wherein the substituents on the nitrogen are selected from methyl, ethyl, n-alkyl, iso-alkyl, alkoxyalkyl, hydroxyalkyl and the thienyl radicals may optionally have one or more substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, -CN, C 1 -C 4 -alkyl, Ci-C 4 -alkoxy, hydro xy and CF 3.
• 3-dioxolan-2-one compounds which can be prepared according to the invention are, for example, in the synthetic range for the preparation of pharmacologically active carboxylic acid esters, such as, for example, Tiotropium bromide. This can be done for example from / via compounds of type A described above.
• l, 3-dioxolan-2-ones can be used especially when acid-sensitive compounds are present, such as acid-sensitive carboxylic acid esters, for example methyl 2,2-dithienylglycolate.
• acid-sensitive carboxylic acid esters for example methyl 2,2-dithienylglycolate.
• the l, 3-dioxolan-2-ones can be returned to other (eg, pharmacologically active) carboxylic acid esters or carboxylic acid salts are converted.
• reaction Ia allows a reaction under very mild conditions, compared to reactions in highly polar aprotic
• reaction Ib furthermore relates to the preparation of 2- or alpha-hydroxycarboxylic acid esters of the general formula 5 starting from a 1,3-dioxolan-2-one of the general formula 3 under basic reaction conditions.
• Such reactions are known in the art. This is shown in the following Reaction Scheme 3:
• radicals Ri to R 6 have the meanings given above.
• the compound of the formula 3 is preferably used in one step (reaction Ib) in a suitable solvent with the addition of a suitable basic catalyst, preferably a catalyst selected from the group of the tertiary alcoholates, in the presence of zeolite with a compound of the formula 4
• a suitable basic catalyst preferably a catalyst selected from the group of the tertiary alcoholates
• the reaction temperature depends on the reactants and the type of catalyst chosen.
• the reaction proceeds under basic reaction conditions and also works at room temperature and below.
• the reaction takes place under mild
• solvents are preferably aprotic organic solvents, preferably weakly polar organic solvents in question.
• Suitable solvents according to the invention are particularly preferably acetone, pyridine, acetonitrile and tetrahydrofuran, with acetone, acetonitrile and tetrahydrofuran being particularly preferably used.
• reaction 2 further relates to the preparation of 2-hydroxycarboxylic acid esters of the general formula 5 via an intermediate in the form of a derivative of l, 3-dioxolan-2-one of the general formula 3 under basic
• radicals Ri to R 6 have the meanings given above.
• transesterification or transacylation of the ester takes place under basic reaction conditions.
• reaction Ia is carried out as described above (reaction Ia -> intermediate is isolated -> reaction Ib), to which the reaction Ib can connect.
• reaction Ia + reaction Ib reaction 2
• the compound of formula I 1 is reacted using the compound of formula 2 and the compound of formula 4 quasi in one step ("one-pot process") to form a compound of formula 5.
• reaction Ia and the reaction Ib can also be carried out in succession without isolating the intermediate; however, this is less preferred.
• R 3 is preferably selected from methyl, ethyl, propyl and butyl, more preferably methyl or ethyl.
• Ri and R 2 are particularly preferably in each case selected from a heteroaryl radical which may in each case optionally be monosubstituted or polysubstituted.
• Preferred substituents are halogen atoms such as fluorine, chlorine, bromine or iodine, -CN, C 1 -C 4 -AIlSyI, Ci-C 4 -alkoxy, hydro xy or CF 3.
• Ri and R 2 are both the same heteroaryl radical, in particular Ri and R 2 are both thienyl radicals.
• R 4 and R 5 together with a nitrogen atom form a heterocyclic ring selected from pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, morpholine, quinuclidine
• radicals which may optionally be substituted by one or more radicals, preferably a radical selected from the group consisting of OH, F, methyl, ethyl, methoxy and
• R ' represents a radical selected from the group consisting of C 1 -C 4 -alkyl, benzyl and phenylethyl, each of which may be substituted by hydroxy, hydroxymethyl or methoxy.
• Process variant (reaction 2) selected from acetone.
• This is an aprotic solvent which simultaneously acts as solvent and compound 3.
• another aprotic solvent may be used, such as acetonitrile. However, this is not preferred.
• the catalyst preferably a catalyst selected from the group of tert-alcoholates
• a zeolite preferably a catalyst selected from the group of tert-alcoholates
• tertiary alcoholates are meant alcoholates having sterically demanding alkyl groups containing at least one quaternary carbon center. Quaternary carbon centers are understood to mean carbon centers which do not carry a hydrogen atom but are substituted by 3 to 4 alkyl groups. Carbon centers substituted with 3 alkyl groups preferably carry the alkoxide group as the fourth substituent.
• Suitable tert-alcoholates are preferably alkali metal or alkaline earth metal alkoxides, more preferably sodium or potassium tert-butoxide or sodium or potassium tert-amylate.
• zeolites are molecular sieves which are selected from the group of molecular sieves having a basic character, consisting of alkali or alkaline earth-containing aluminosilicates, such as sodium or potassium-containing aluminosilicates, preferably molecular sieves having the empirical formula Nai 2 [(AlO 2 ) i 2 (Si0 2 ) i 2 ] x H 2 O or Nai 2 Ali 2 Sii 2 ⁇ 36 xn H 2 O, where n preferably ⁇ 6, (use of the molecular sieve type 4A) according to the invention is particularly preferred.
• the reaction medium used is a combination of acetone / tert.-alkoxide or acetonitrile / acetone / tert-alkoxide for the transesterification reaction according to the invention.
• the presence of zeolite also prevents the usually occurring self-condensation reactions of acetone or acetonitrile.
• the use of zeolite effectively removes the liberated alcohol from equilibrium.
• the alcohol of formula 4 is variable but limited in practice to primary or secondary alcohols. Practically any primary or secondary alcohol known to the person skilled in the art can be used for the chemical reaction, since it is also possible with any of these Alcohols due to the shift of the reaction equilibrium by removal of the alcohol formed a reaction takes place.
• the reactivity of the alcohols is greatest for primary alcohols. Tertiary alcohols do not participate in this reaction.
• the radical R 6 in the alcohol of the formula 4 represents a substantially freely selectable organic radical, which after the reaction represents the transesterified in the produced 2-hydroxycarboxylic acid ester of the formula 5 rest. By choosing the alcohol thus the desired end product can be determined.
• the organic radical R 6 may be, for example, a branched or unbranched alkyl, a saturated or unsaturated carbocycle, heterocycle, bicyclic, tricyclic, a fused cyclic system, and many others, and combinations thereof. Examples of heterocycles are given in the definitions.
• heterocycles which can be used for R 6 are selected from pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, morpholine, scopine, N-methylscopinium
• R ' is a radical selected from the group consisting of Ci-C 4- alkyl
• Benzyl and phenylethyl each of which may be substituted by hydroxy, hydroxymethyl or methoxy.
• the alcohol is therefore not limited in the context of the invention, provided that it contains no functional group which intervenes in the reaction and if it is not a tertiary alcohol.
• a particular advantage of the novel preparation process using the catalyst combination consisting of the tert-alkoxide-impregnated zeolite is obtained, for example, for the base-sensitive scopine.
• the reaction conditions are so gentle that the rearrangement to the corresponding scopoline can be avoided.
• reaction Scheme 5 for reaction Ib with the compound of formula 4> R 6 -NH 2 is then given as follows:
• radicals Ri to R 6 have the meanings given above.
• the reaction of the compound of the formula 1 with the compound of the formula 2 and the compound of the formula 4 or 4 to the compound of the formula 5 or 5 can, depending on the type of catalyst selected, be carried out at a slightly elevated temperature in a range of 25 - 50 0 C are performed.
• the reaction proceeds under basic reaction conditions and also works at room temperature (about 23 0 C) and below.
• the reaction is preferably under mild conditions at a temperature of about 30 0 C, especially sawn vorzugt in a range from about 0 to about 30 0 C.
• the resulting solution is typically stirred until reaction is complete.
• the compounds of formula 5 or 5 ⁇ are isolated from the solution.
• the products obtained If necessary, be purified by recrystallization from a suitable solvent.
• the product obtained is isolated and optionally dried in vacuo.
• reaction 2 The erfmdungshiele process (reaction 2) is selective, side reactions are largely prevented.
• reaction 2 allows a reaction under very mild conditions, which receives fewer side reactions compared to reactions in highly polar aprotic solvents.
• acetone as a solvent offers a very special advantage since the affinity (intramolecular interaction) of the methanol formed in the chemical equilibrium is very low in comparison with other solvents, such as DMF or NMP.
• DMF solvents
• the reaction can also be used, for example, for the synthesis of sensitive acid-labile and / or temperature-sensitive systems.
• reaction 2 The transesterification process according to the invention (reaction 2) has proven to be of particular advantage when the compound of formula 4 is an alcohol which can be used as the quaternary ammonium salt of hexafluorophosphoric acid because these salts are soluble in acetone.
• reaction 2 the production of tiotropium compounds is thus very easily achieved with good yields.
• a further aspect of the present invention therefore relates to a process for the preparation of tiotropium salts of formula 6
• X is a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate and trifluoromethanesulfonate, may mean
• Ri and R 2 are both thienyl and
• R 3 is a radical selected from the group consisting of methyl, ethyl, propoyl, isopropyl, isopropenyl, butyl, -N-succinimide, -N-phthalimide, phenyl, nitrophenyl, fluorophenyl, pentafluorophenyl, vinyl, 2-allyl .
• Kat + is a cation selected from the group consisting of Li + , Na + , K + , Mg 2+ , Ca 2+ , organic cations with quaternary N (eg, N, N-dialkylimidazolium, tetraalkylammonium), and X " may have the meanings given above, is converted into the compound of formula 6.
• esters which are simultaneously quaternary ammonium salts of hexafluorophosphates can be converted into other salts using lithium salts.
• the products can be isolated, for example, by a precipitation crystallization and can then optionally be recrystallized in a suitable solvent.
• quaternary ammonium salts of hexafluorophosphates according to the invention compounds are understood, which are represented by the general formula 9 below:
• R 1 , R 2 , R 3 and R 4 represent the corresponding organic radicals. These are obtained, for example, by reacting ammonium salts of the following general formula £ 1:
• Kat + is a cation selected from the group consisting of Li + , Na + , K + , Mg 2+ , Ca 2+ .
• the salts of quaternary ammonium compounds are generally very soluble in water and alcohol. However, they are extremely poorly soluble in less polar organic solvents, such as acetone, acetonitrile, hydrocarbons, halogenated hydrocarbons or ethers.
• the chemical reactions with quaternary ammonium compounds would therefore in the present case be limited to reactions in water, alcohol or strongly polar aprotic solvents, such as DMF (dimethylformamide) or NMP (N-methylpyrrolidine).
• DMF dimethylformamide
• NMP N-methylpyrrolidine
• the hexafluorophosphates After the hexafluorophosphates have been converted to the desired modified ammonium hexafluorophosphates, the hexafluorophosphate can be replaced by other anions using, for example, lithium salts (such as, for example, LiBr).
• lithium salts such as, for example, LiBr
• reaction Ia allows a reaction under very mild basic conditions, which provides fewer side reactions and higher yield compared to reactions in highly polar aprotic solvents.
• a synthesis of acid and / or temperature-sensitive compounds is possible.
• transesterification can be carried out in one step (reaction 2). It has been found to be of particular advantage if the reaction medium used is a combination of acetone / tert.-alkoxide or acetone / acetonitrile / tert.-alkoxide for the transesterification reaction according to the invention.
• the presence of zeolite also suppresses the usually occurring self-condensation reactions of acetone or acetonitrile.
• the use of zeolites also effectively removes the released alcohol from equilibrium.
• the 2-hydroxycarboxamides can also be prepared according to the invention.
• 1,3-dioxolan-2-ones of type B were also identified as anticholinergics.
• the compounds of the formula 610 are highly potent anticholinergic agents.
• 1,3-dioxolan-2-one compounds preparable according to the invention can serve as starting materials for the preparation of pharmacologically active carboxylic acid esters, such as, for example, tiotropium bromide. This can be done for example from / via compounds of type A described above.
• the following examples serve to illustrate examples of synthetic methods carried out. They are to be understood merely as possible, exemplarily illustrated procedures, without restricting the invention to their content.
• the 2-hydroxycarboxylic acid (3OmMoI) was dissolved in an excess of the corresponding ketone / aldehyde, then with a zeolite of the type NaI 2 Al 12S112O36 xn H 2 O (pore size 4 ⁇ ) (6-24 g) and a catalytic amount of a tert. Alcoholate and stirred at 20-23 0 C until the completion of the reaction.
• Example 7 THF was used as the solvent.
• Example 9 cyclohexanone was used in equimolar ratio.
• Example 2 crystals were obtained from water.
• the bromide is isolated by addition of a lithium bromide solution (8.7 g LiBr in 100 ml acetone) via a precipitation crystallization and then recrystallized from methanol.
• N-Methyltropinium PF 6 and Dithienylglycolklaremethylester be dissolved in acetone and treated according to the general procedure. Identification by RRT (with reference substance) per DC
• Benzylic acid methyl ester and N-methylscopinium hexafluorophosphate are dissolved in acetone and treated according to the general procedure. After completion of the reaction, the product is crystallized by addition of an acetonic lithium bromide solution and recrystallized from methanol.

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