EP4153569A1 - Verfahren zur herstellung von butyl-(5s)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chlor-4'-(trifluormethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydrochinolin-2-carboxylat - Google Patents

Verfahren zur herstellung von butyl-(5s)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chlor-4'-(trifluormethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydrochinolin-2-carboxylat

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Publication number
EP4153569A1
EP4153569A1 EP21724712.1A EP21724712A EP4153569A1 EP 4153569 A1 EP4153569 A1 EP 4153569A1 EP 21724712 A EP21724712 A EP 21724712A EP 4153569 A1 EP4153569 A1 EP 4153569A1
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EP
European Patent Office
Prior art keywords
formula
compound
ethyl
preparation
solvates
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21724712.1A
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German (de)
English (en)
French (fr)
Inventor
Peter Fey
Marc Nowakowski
Julian Egger
Nadine Bremeyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Bayer Pharma AG
Original Assignee
Bayer AG
Bayer Pharma AG
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Publication of EP4153569A1 publication Critical patent/EP4153569A1/de
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • 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 compound of the formula (XII) is a precursor of (5S) -5 - ⁇ [2- (4-carboxyphenyl) ethyl] [2- (2 - ⁇ [3- chloro-4 '- (trifluoromethyl) [biphenyl] - 4-yl] methoxy ⁇ phenyl) ethyl] amino ⁇ -5,6,7,8-tetrahydroquinoline-2-carboxylic acid of the formula (I)
  • the compound of the formula (XII) can be converted into the compound of the formula (I) by ester cleavage.
  • the compound of the formula (I) acts as an activator of soluble guanylate cyclase and can be used as an agent for the prophylaxis and / or treatment of pulmonary, cardiopulmonary and cardiovascular diseases, such as, for example, for the treatment of pulmonary arterial hypertension (PAH), pulmonary hypertension (PH), pulmonary hypertension in connection with chronic obstructive pulmonary disease (PH-COPD), pulmonary hypertension in connection with idiopathic interstitial pneumonia (PH-IIP) or chronic thromboembolic pulmonary hypertension (CTEPH).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • PH-COPD chronic obstructive pulmonary disease
  • PH-IIP chronic obstructive pulmonary disease
  • CTEPH chronic thromboembolic pulmonary hypertension
  • WO 2014/012934 The compound of the formula (I) and a production process are described in WO 2014/012934.
  • the disadvantage of the synthesis described in WO 2014/012934 is the fact that this synthesis is not suitable for a large-scale process, since, among other things, seven chromatographic purification steps and a chiral chromatography step are necessary to separate enantiomers of a racemate. As a rule, these are technically very complex, cost-intensive and require a high consumption of solvents and should therefore be avoided if possible.
  • the separation into enantiomers takes place in an advanced phase of the synthesis by chromatography on a chiral phase. This creates a high proportion of product that can no longer be used for further synthesis.
  • Some stages of the synthesis described in WO 2014/012934 are also characterized by a long reaction time over several days and a low yield, which is a considerable disadvantage for the efficiency of a synthesis on an industrial scale.
  • the response time is to Preparation of Example 6A four days and preparation of Example 92A three days.
  • using the excess methyl 4- (2-iodoethyl) benzoate in the preparation of Example 92A can result in polymerization. This results in the formation of polystyrene, which has to be separated in a laborious manner.
  • the method according to the invention is characterized in that purification steps of the intermediates by salt formation are sufficient and therefore chromatographic purification steps can be dispensed with. Thanks to enantioselective synthesis, a chiral chromatography step for the separation of enantiomers of a racemate is not necessary. The number of synthesis stages of the method according to the invention was reduced compared to the synthesis disclosed in WO 2014/012934.
  • the process according to the invention is therefore suitable for producing the compound of the formula (I) reproducibly, in high overall yield and purity in a synthesis which is practicable on an industrial scale.
  • Scheme 1 shows the preparation of the compound of the formula (III) which is required for the preparation of the compound of the formula (XII).
  • Scheme 2 shows an overview of the synthesis steps for the preparation of the compound of the formula (XII) via the intermediate of the compound of the formula (VIII).
  • Scheme 3 shows an overview of the synthesis steps for the preparation of the compound of the formula (XII) via the intermediate of the compound of the formula (XV).
  • Scheme 4 shows an overview of the synthesis steps for the preparation of the compound of the formula (XII), the reaction procedure being analogous to that shown in Scheme 3, but not isolating various intermediates.
  • Process step 1 (schemes 2 and 3) describes the preparation of 2- (4-cyanophenyl) ethyl-4-methylbenzenesulfonate of the formula (V) from 4- (2-hydroxyethyl) benzonitrile of the formula (IV).
  • the compound of formula (IV), potassium hydroxide and 4-toluenesulfonic acid chloride (TsCl) is added to an inert solvent, for example suitable ethers such as 2-methyltetrahydrofuran (2-MTHF), tetrahydrofuran (THF) or dioxane, preferably THF, and stirred.
  • suitable ethers such as 2-methyltetrahydrofuran (2-MTHF), tetrahydrofuran (THF) or dioxane, preferably THF, and stirred.
  • the temperature is kept between -10 ° C and 0 ° C until all compounds have been added in order to avoid elimination reactions which lead to cyanostyrenes and their polymerization products.
  • the mixture is then stirred at a temperature of 0 ° C. to 30 ° C., preferably 22 ° C., until the reaction is complete.
  • the compound of the formula (V) can be isolated, for example, by aqueous work-up and subsequent crystallization.
  • aqueous work-up extractions known to the person skilled in the art are suitable, which are suitable for separating off by-products and potassium hydroxide present in excess.
  • Aqueous work-up can be carried out, for example, with dichloromethane (DCM) and water in the presence of ammonium chloride.
  • DCM dichloromethane
  • the crystallization can take place, for example, in cyclohexane.
  • the solvent is changed to cyclohexane, concentrated at a temperature of 30 ° C to 50 ° C, preferably 41 ° C under reduced pressure, cooled to a temperature of 20 ° C to 30 ° C, preferably 22 ° C, the solid is isolated and dried at a temperature of 30.degree. C. to 50.degree. C., preferably 40.degree. C., in a drying cabinet.
  • An object of the present invention is a process for the preparation of the compound of the formula (V) characterized in that the compound of the formula (IV)
  • the present invention further provides a process for the preparation of the compound of the formula (V) as described above, the inert solvent being an ether selected from a list comprising 2-methyltetrahydrofuran, tetrahydrofuran or dioxane, preferably tetrahydrofuran.
  • the inert solvent being an ether selected from a list comprising 2-methyltetrahydrofuran, tetrahydrofuran or dioxane, preferably tetrahydrofuran.
  • Another object of the present invention is a process for the preparation of the compound of the formula (V) as described above, the temperature during the addition of the compound of the formula (IV), potassium hydroxide and 4-toluenesulfonic acid chloride between -10 ° C and 0 ° C is held.
  • the present invention further provides a process for the preparation of the compound of the formula (V) as described above, the reaction taking place at a temperature of 0.degree. C. to 30.degree. C., preferably 22.degree.
  • Step 2 For the preparation of 4- (2 - ⁇ [2- (2-methoxyphenyl) ethyl] amino ⁇ ethyl) benzonitrile of the formula (VII) by process step 2 (schemes 2 and 3), 2- (4-cyanophenyl) ethyl-4- methylbenzenesulfonate of the formula
  • the compound of the formula (VII) is preferably isolated as an oil after an aqueous work-up.
  • aqueous work-up extractions known to the person skilled in the art are suitable, which are suitable for separating off by-products, for example excess toluenesulphonic acid.
  • water is added to the isolated solid, the mixture is stirred and the solid is then isolated. This process can be repeated several times.
  • the solid is preferably mixed with ethyl acetate at a temperature of 30 to 60 ° C, particularly preferably 50 ° C, stirred and the solid is isolated preferably at a temperature of 10 to 30 ° C, particularly preferably 20 ° C.
  • the solid is mixed with a mixture of ethyl acetate and hydrochloric acid, preferably 15% hydrochloric acid, in order to obtain the hydrochloride of the compound of the formula (VII), which under reduced atmospheric pressure, preferably at a temperature of 40 ° C is dried.
  • the solid obtained is dissolved in DCM and water, preferably in equal proportions by volume, and mixed with a fugitive, preferably sodium hydroxide solution, particularly preferably 45% sodium hydroxide solution, up to a pH value set between 13 and 14.
  • the organic phase is isolated, washed with water and concentrated to an oil under reduced atmospheric pressure, preferably at a temperature of 40.degree.
  • Another object of the present invention is the compound of the formula (VII) as well as their salts, solvates and solvates of the salts.
  • the present invention also relates to the oxalate salt of the compound of the formula (VII).
  • Another object of the present invention is a process for the preparation of the compound of the formula (VII), characterized in that the compound of the formula (V) in a first step suspended in a suitable ether in the presence of a tertiary amine base with the compound of the formula (VI), is reacted and in a second step the solvent water is changed to water and a mineral acid is added.
  • the present invention further provides a process for the preparation of the compound of the formula (VII) as described above, the suitable ether being tetrahydrofuran.
  • the present invention further provides a process for the preparation of the compound of the formula (VII) as described above, the tertiary amine base being triethylamine.
  • the present invention further provides a process for the preparation of the compound of the formula (VII) as described above, the reaction taking place in the first step at reflux temperature.
  • the present invention further provides a process for the preparation of the compound of the formula (VII) as described above, the second step taking place at a temperature of 0.degree. C. to 30.degree.
  • the present invention further provides a process for the preparation of the compound of the formula (VII) as described above, the mineral acid being hydrochloric acid, preferably 25% hydrochloric acid.
  • the prior art shows the preparation of the compound of the formula (I) by reductive amination of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile (II) with the amine of the formula XVII and a subsequent alkylation reaction, whereby a racemic secondary product results.
  • the enantiomers have to be separated in a chiral chromatography stage.
  • This is technically very complex, costly and requires a high consumption of solvents.
  • an effective process for the preparation of (5R) -5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile has been found (compound of the formula (III)). With the aid of the compound of the formula (III) it is possible to obtain an enantiomerically pure secondary product, as a result of which the disadvantageous chiral chromatography step is avoided.
  • a tertiary amine base for example and preferably triethylamine and ruthenium-p-cumene-R, R-TsDPEN (CAS number: 192139-92-7), is preferred in catalytic amounts.
  • a tertiary amine base for example and preferably triethylamine and ruthenium-p-cumene-R, R-TsDPEN (CAS number: 192139-92-7)
  • formic acid is added and gases formed are discharged.
  • the mixture is stirred until conversion is complete.
  • the compound of the formula (III) is preferably isolated after work-up and subsequent crystallization.
  • the reaction mixture is mixed with preferably equal volumes of a mixture of ethyl acetate and a mineral acid, preferably hydrochloric acid, particularly preferably 1N hydrochloric acid, stirred and the upper phase is isolated.
  • a CVCV alkane becomes the upper phase.
  • preferably heptane, particularly preferably n-heptane are added and concentrated under reduced atmospheric pressure, preferably at a temperature of 20 to 50.degree. C., particularly preferably 40.degree. This step can be repeated several times.
  • the compound of the formula (III) is isolated as a solid from the mixture and dried, preferably at a temperature of 40 ° C. under reduced pressure.
  • Another object of the present invention is (5R) -5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile of the formula (III)
  • Another object of the present invention is a process for the preparation of the compound of the formula (III), characterized in that the compound of the formula (II)
  • the present invention further provides a process for the preparation of the compound of the formula (III) as described above, the amine base being triethylamine and ruthenium-p-cumene-R, R-TsDPEN being used in catalytic amounts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (III) as described above, wherein the compound of the formula (II) before the reaction in a solvent selected from a list comprising ethyl acetate, diethyl ether, dioxane and tetrahydrofuran, preferably ethyl acetate, is dissolved.
  • the present invention further provides a process for the preparation of the compound of the formula (III) as described above, the compound of the formula (II) being admixed with the amine base and ruthenium-p-cumene-R, R-TsDPEN in a first step and formic acid is added in a second step.
  • Another object of the present invention is a process for the preparation of the compound of the formula (III) as described above, the compound of the formula (II) in a first step with the amine base and ruthenium-p-cumene-R, R-TsDPEN at a temperature of 0 ° C to 40 ° C, preferably 20 ° C, and in a second step formic acid is added at a temperature of -5 ° C to 10 ° C, preferably 0 ° C to 5 ° C.
  • Another object of the present invention is a process for the preparation of the compound of the formula (III) as described above, wherein after addition of the formic acid at a temperature of 20 ° C. to 50 ° C., preferably 40 ° C., the mixture is stirred until conversion is complete will.
  • Process step 4 (scheme 2) describes the preparation of (5S) -5 - ⁇ [2- (4-cyanophenyl) ethyl] [2- (2- methoxyphenyl) ethyl] amino ⁇ -5,6,7,8-tetrahydroquinoline- 2-carbonitrile of formula (VIII).
  • a solution of (5R) -5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile (III) in one is preferred with the exclusion of water, particularly preferably under a protective gas atmosphere, such as, for example, under argon gassing suitable solvent dissolved.
  • Suitable solvents are those which are liquid at the reaction temperatures, for example THF or DCM; DCM is preferably used.
  • Suitable bases are sterically hindered secondary amines or 2,6-disubstituted pyridines, such as, for example, 2,6-lutidine or 2,6-di-tert-butylpyridine.
  • Suitable sterically hindered secondary amines are, for example, diisopropylamine, 2,5-dimethylpiperidine or 2,2,5,5-tetramethylpiperidine. Surprisingly, better yields can be achieved with these compounds compared to sterically unhindered or tertiary amines.
  • diisopropylamine is an unusual base for this type of reaction.
  • the reaction mixture is cooled to a temperature between -90.degree. C. and -50.degree. C., preferably -78.degree. C. and -65.degree.
  • the compound of the formula (VIII) is preferably isolated after an aqueous work-up and subsequent crystallization. Extractions known to the person skilled in the art, which are suitable for separating off by-products, are suitable as aqueous work-up.
  • a suitable acid preferably oxalic acid or phosphoric acid, particularly preferably oxalic acid
  • the temperature can be adjusted to a temperature of -10 to 15 ° C, preferably 0 to 5 ° C. It is mixed with kieselguhr and stirred.
  • the solid is filtered off and discarded, the liquid organic phase is washed with water and adjusted to a pH of 7.5 to 9, preferably 8, with a base, preferably ammonia solution, particularly preferably 27% ammonia solution.
  • the organic phase is isolated and concentrated to an oil, preferably under reduced atmospheric pressure.
  • the oil is dissolved in ethanol.
  • the compound of the formula (VIII) crystallizes out, preferably after seeding.
  • the solid is isolated and dried by methods known to the person skilled in the art, preferably under reduced atmospheric pressure, at a temperature of 25 ° C. and in a stream of nitrogen.
  • Another object of the present invention is the compound of the formula (VIII)
  • Another object of the present invention is the compound of the formula (VIII-1)
  • R 1 denotes Ci-Ci-alkyl, as well as their salts, solvates and solvates of the salts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (VIII- 1)
  • R 1 Ci-C t -Alkyl characterized in that at a temperature of -90 ° C to -50 ° C in a first step to the compound of the formula (III)
  • R 1 is Ci-C t -alkyl, is implemented.
  • Ci-C t -alkyl denotes a straight-chain or branched, monovalent alkyl radical with 1 to 4 carbon atoms. The following may be mentioned by way of example and by preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • the present invention further provides a process for the preparation of the compound of the formula (VIII-1) as described above, where R 1 is methyl.
  • the present invention further provides a process for the preparation of the compound of the formula (VIII-1) as described above, the reaction taking place at a temperature of -78.degree. C. to -65.degree.
  • the present invention further provides a process for the preparation of the compound of the formula (VIII-1) as described above, the sterically hindered secondary amine being selected from a list comprising diisopropylamine, 2,5-dimethylpiperidine and 2, 2.5, 5-tetramethylpiperidine.
  • Another object of the present invention is a process for the preparation of the compound of the formula (VIII-1), wherein the base is diisopropylamine.
  • the present invention further provides a process for the preparation of the compound of the formula (VIII-1), the temperature being -78.degree. C. to -65.degree. C., preferably -76.degree.
  • the present invention further provides a process for the preparation of the compound of the formula (VIII-1), the compound of the formula (III) being dissolved in tetrahydrofuran or dichloromethane, preferably dichloromethane.
  • the present invention also provides a process for the preparation of the compound of the formula (VIII-1) as described above, the base being present in a molar excess, preferably in a ratio of 3: 1, based on the compound of the formula (III).
  • the present invention also provides a process for the preparation of the compound of the formula (VIII-1) as described above, wherein trifluoromethanesulfonic anhydride is added in a molar excess, preferably in a ratio of 1.5: 1 based on the compound of the formula (III) .
  • Another object of the present invention is a process for the preparation of the compound of the formula (VIII-1) as described above, the compound of the formula (VII-1) in a molar ratio of 1: 1 to 1.1: 1 based on the compound of the formula (III) is used.
  • the present invention also provides a process for the preparation of the compound of the formula (VIII-1) as described above, the process taking place with the exclusion of water, preferably under a protective gas atmosphere, particularly preferably under argon gassing.
  • the present invention also provides a process for the preparation of the compound of the formula (VIII-1) as described above, the temperature preferably taking place with the exclusion of water, preferably under a protective gas atmosphere, particularly preferably under argon gassing.
  • Example 5
  • aluminum chloride is first mixed with a suitable alkylthiol, preferably n-dodecanethiol (dodecyl mercaptan ), preferably in a molar ratio between 1: 1 and 1: 3, particularly preferably 1: 1.8, stirred until dissolved.
  • a suitable alkylthiol preferably n-dodecanethiol (dodecyl mercaptan )
  • the complex can then be dissolved in a suitable solvent, preferably THF, and the compound of the formula (XIII) can be released from the complex by adding a tartrate, preferably potassium-sodium tartrate solution in a molar excess based on the compound of the formula (VII).
  • a tartrate preferably potassium-sodium tartrate solution in a molar excess based on the compound of the formula (VII).
  • the release from the complex by adding a tartrate can be repeated several times.
  • the compound of the formula (XIII) is preferably isolated after an aqueous-basic work-up. Extractions known to the person skilled in the art, which are suitable for separating off by-products, are suitable as aqueous-basic work-up.
  • the solvent is changed to DCM for this purpose, aqueous ammonia solution, preferably 27% ammonia solution, is added, washed with water and the organic phase is concentrated to an oil.
  • Another object of the present invention is the compound of the formula (XIII)
  • the present invention further provides a process for the preparation of the compound of the formula (XIII), characterized in that, in a first step, aluminum chloride is mixed with a suitable alkylthiol and, in a second step, with the compound of the formula (VII) is reacted in the solvent dichloromethane or toluene.
  • the present invention further provides a process for the preparation of the compound of the formula (XIII) as described above, the suitable alkylthiol being n-dodecanethiol.
  • the present invention also provides a process for the preparation of the compound of the formula (XIII) as described above, the solvent being toluene and / or dichloromethane, preferably dichloromethane.
  • the present invention further provides a process for the preparation of the compound of the formula (XIII) as described above, the suitable alkylthiol in a molar ratio of 1: 1 to 1: 3 based on the compound of the formula (VII) being particularly preferred is added in a molar ratio of 1: 1.8 based on the compound of the formula (VII).
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIII) as described above, wherein the compound of the formula (VII) at a temperature of 0 ° C to 40 ° C, preferably 10 ° C to 20 ° C , is added.
  • the present invention further provides a process for the preparation of the compound of the formula (XIII) as described above, the reaction being carried out in the second step at a temperature of 30 ° C. to 50 ° C., particularly preferably 40 ° C.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIII) as described above, wherein the resulting insoluble compound of the formula (XIII) is isolated, dissolved in tetrahydrofuran and a tartrate solution is added.
  • Example 6
  • Process steps 6A and 6B describe the preparation of 4- (2 - ⁇ [2- (2 - ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ phenyl) ethyl] amino ⁇ ethyl) benzonitrile of the formula (XIV).
  • a suitable solvent for example an ether or a halogenated hydrocarbon, preferably DCM.
  • a suitable solvent for example an ether or a halogenated hydrocarbon, preferably DCM.
  • a silyl protective group for example trimethylsilyl (TMS), triethylsilyl (TES), Triisopropylsilyl (TIPS), tert.
  • the compound of the formula (XIII) is treated with a corresponding silyl chloride, preferably tert-butyldimethylsilyl chloride, in the presence of an amine base, preferably imidazole, at a temperature of 0 ° C. to 40 ° C., preferably 20 ° C. to 35 ° C., up to complete implementation stirred.
  • the amine base is present in a molar ratio of 1: 1 or in excess based on the compound of the formula (XIII), preferably in a 1.5-fold molar excess.
  • the reaction mixture Before the concentration, the reaction mixture can be purified by an aqueous basic purification known to the person skilled in the art.
  • an aqueous potassium carbonate solution is added to the reaction mixture, the organic phase is washed several times with water and the organic phase is dried with sodium sulfate.
  • An alternative and preferred purification can be achieved by precipitating the compound of the formula (XIV) as the oxalic acid salt.
  • the solvent of the organic phase is changed to methanol and heated to a temperature of 40.degree. C. to 80.degree. C., preferably 65.degree.
  • the mixture is stirred at a temperature of 40 ° C. to 65 ° C., preferably 50 ° C. to 55 ° C., and then to a temperature of 0 ° C. to 20 ° C. ° C, preferably 5 ° C to 10 ° C, cooled.
  • the precipitated solid is separated off and suspended in a mixture of water and an inert solvent which shows a phase separation with water, for example DCM, toluene or an ether, preferably DCM, and stirred.
  • an inert solvent which shows a phase separation with water, for example DCM, toluene or an ether, preferably DCM, and stirred.
  • a suitable base for example and preferably sodium hydroxide solution
  • the phases are separated and the organic phase is concentrated.
  • the mixture is concentrated at a temperature of 25 ° C. to 70 ° C., preferably 30 ° C. to 50 ° C., particularly preferably 35 ° C., preferably at reduced atmospheric pressure, and the compound of the formula (XIV) is obtained as an oil.
  • Another object of the present invention is the compound of the formula (XIV)
  • Another object of the present invention is the compound of the formula (XIV- 1) where R 2 denotes a silyl protective group, as well as its salts, solvates and solvates of the salts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIV- 1) whereby
  • R 2 denotes a silyl protective group, characterized in that the compound of the formula (XIII) is reacted with the corresponding silyl chloride in the presence of an amine base.
  • a “silyl protective group” is a silyl protective group known to the person skilled in the art, which is suitable for converting a reactive functional group into an unreactive form by means of an organosilicon compound.
  • the corresponding silyl chloride is that silyl chloride which is used to produce the respective silyl protective group.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIV-1), wherein the amine base is imidazole.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIV-1), where R 2 is selected from a group comprising trimethylsilyl, triethylsilyl, triisopropylsilyl, tert. -Butyldiphenylsilyl and /.-Butyldimcthylsilyl.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIV-1), where R 2 is tert. -Butyldimethylsilyl.
  • the present invention also provides a process for the preparation of the compound of the formula (XIV-1), the corresponding silyl chloride being selected from a group comprising trimethylsilyl chloride, triethylsilyl chloride, triisopropylsilyl chloride, tert. -Butyldiphenylsilylchloride and /tT/.-Butyldimethylsilylchlorid.
  • Another object of the present invention is a process for the preparation of the compound of formula (XIV-1), wherein the corresponding silyl chloride tert. -Butyldimethylsilyl chloride.
  • the present invention further relates to a process for the preparation of the compound of the formula (XIV-1), the amine base being pregiven in a molar ratio of 1.5: 1 or in excess based on the compound of the formula (XIII).
  • Process step 6B Alternatively, the compound of the formula (XIV) can be prepared in process step 6B (scheme 4) from 2- (4-cyanophenyl) ethyl-4-methylbenzenesulfonate of the formula (V) and 2- (2-aminoethyl) phenol of the formula (XVII) .
  • the compound of the formula (V) is dissolved in a suitable solvent, for example an ether, preferably DCM or THF, particularly preferably THF and 2- (2-aminoethyl) phenol of the formula (XVII), preferably in a ratio of 2: 1 or higher based on the compound of the formula (V) and triethylamine, preferably in a ratio of 3: 1 or higher based on the Compound of formula (V) is added.
  • a suitable solvent for example an ether, preferably DCM or THF, particularly preferably THF and 2- (2-aminoethyl) phenol of the formula (XVII), preferably in a ratio of 2: 1 or higher based on the compound of the formula (V) and triethylamine, preferably in a ratio of 3: 1 or higher based on the Compound of formula (V) is added.
  • the reaction mixture is heated for several hours, preferably 20 to 60 hours, particularly preferably 46 hours, preferably at a temperature which corresponds to the
  • the solution can then be washed by known methods, for example and preferably by single or multiple washing with sodium bicarbonate and optionally further concentrated, for example and preferably at temperatures of 45 ° C. or less.
  • Imidazole is added to the resulting solution, preferably in a ratio of 2: 1 to 5: 1, preferably 3: 1 based on the compound of the formula (V), and preferably at a temperature of 20 to 35 ° C., particularly preferably boiling temperature, stirred until the reaction is complete.
  • aqueous basic purification known to the person skilled in the art can then take place.
  • the following process is preferably provided for this purpose: the reaction mixture is washed once or several times with water and the solvent is changed to methanol. At a temperature of 40 to 70 ° C., preferably 50 to 55 ° C., oxalic acid is added and stirred. After cooling to a temperature of 0 to 20 ° C., preferably 5 to 10 ° C., the solid is isolated and washed with methanol.
  • the residue is suspended in a mixture of DCM or toluene and water, preferably DCM and water, preferably in a volume ratio of 1: 1, and at a temperature of 15 to 40 ° C, preferably 25 to 35 ° C with a concentrated base, preferably sodium hydroxide solution, particularly preferably 45% strength sodium hydroxide solution, is added and a pH value between 10.5 and 12.5 is reached.
  • a concentrated base preferably sodium hydroxide solution, particularly preferably 45% strength sodium hydroxide solution
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIV- 1) whereby
  • R 2 denotes a silyl protective group, characterized in that the compounds of the formulas (XVI) and (V), (V), are coupled in a first step in the presence of an amine base, for example triethylamine, and the reaction product is reacted with the corresponding silyl chloride in a second step, likewise in the presence of an amine base.
  • an amine base for example triethylamine
  • the present invention further provides a process for the preparation of the compound of the formula (XIV-1) as described above, the amine base in the first step being triethylamine.
  • the present invention further provides a process for the preparation of the compound of the formula (XIV-1) as described above, the first step taking place in a suitable ether as solvent.
  • the present invention further provides a process for the preparation of the compound of the formula (XIV-1) as described above, the suitable ether being dichloromethane or tetrahydrofuran.
  • the present invention further provides a process for the preparation of the compound of the formula (XIV-1) as described above, the compound of the formula (XVI) in a ratio of 2: 1 or higher based on the compound of the formula (V) is used.
  • the present invention further provides a process for the preparation of the compound of the formula (XIV-1) as described above, wherein triethylamine is used in a ratio of 3: 1 or higher, based on the compound of the formula (V).
  • the present invention also provides a process for the preparation of the compound of the formula (XIV-1) as described above, the reaction being carried out in the first step for several hours, preferably 20 to 60 hours, particularly preferably 46 hours, at boiling temperature.
  • the present invention further provides a process for the preparation of the compound of the formula (XIV-1) as described above, the amine base in the second step being imidazole.
  • Another object of the present invention is a process for the preparation of the compound of formula (XIV-1) as described above, wherein the amine base in the second step in a ratio of 2: 1 to 5: 1, preferably 3: 1, based on the Compound of formula (V) is used.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XIV-1) as described above, wherein the second step takes place at a temperature of 20.degree. C. to 35.degree.
  • Example 7 For the preparation of (5S) -5 - ⁇ [2- (2 - ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ phenyl) ethyl] [2- (4-cyanophenyl) ethyl] amino ⁇ -5,6,7 , 8-tetrahydroquinoline-2-carbonitrile of the formula (XV) in process step 7 (scheme 3), (5R) -5-hydroxy-5,6,7,8-tetrahydroquinoline-2-carbonitrile of the formula (III) becomes a suitable one Given solvent. Suitable solvents are those which are liquid at the reaction temperatures, for example THF or DCM; DCM is preferably used. A suitable base is added to the solution.
  • Sterically hindered secondary amines or 2,6-disubstituted pyridines are suitable as bases.
  • Suitable sterically hindered secondary amines are, for example, diisopropylamine, 2,5-dimethylpiperidine or 2,2,5,5-tetramethylpiperidine, preferably diisopropylamine.
  • An excess of diisopropylamine is particularly preferred, very particularly preferably 3 eq.
  • Diisopropylamine based on the compound of the formula (X) was added. Surprisingly, better yields can be achieved with these compounds compared to sterically unhindered or tertiary amines. It was particularly surprising that the most advantageous yields are achieved through the use of diisopropylamine.
  • reaction mixture is cooled to a temperature between -90 ° C. and -50 ° C., preferably -78 ° C. and -65 ° C., and trifluoromethanesulfonic anhydride, preferably in excess, particularly preferably 1.5 eq. based on the compound of the formula (III), added and stirred. While maintaining the temperature range mentioned, 4- (2- ⁇ [2- (2- ⁇ [tert-)
  • the reaction mixture Before concentration, the reaction mixture can be purified by an aqueous acidic purification known to the person skilled in the art.
  • the reaction mixture is acidified with a mineral acid, preferably phosphoric acid or hydrochloric acid, particularly preferably hydrochloric acid, optionally washed with water, and the organic phase is isolated.
  • the mixture is concentrated at a temperature of 30.degree. C. to 80.degree. C., preferably 30.degree. C. to 60.degree. C., particularly preferably 40.degree. C., preferably at reduced atmospheric pressure, and the compound of the formula (XV) is obtained as an oil.
  • the oil obtained can optionally be filtered through silica gel.
  • the oil is dissolved in a suitable solvent, preferably DCM, filtered through silica gel and eluted with a suitable solvent, preferably a solvent mixture of ethyl acetate and n-hexane in a ratio of 1: 2 (ethyl acetate: n-hexane).
  • a suitable solvent preferably a solvent mixture of ethyl acetate and n-hexane in a ratio of 1: 2 (ethyl acetate: n-hexane).
  • Another object of the present invention is the compound of the formula (XV) as well as their salts, solvates and solvates of the salts.
  • Another object of the present invention is the compound of the formula (XV- 1)
  • R 2 denotes a silyl protective group, as well as its salts, solvates and solvates of the salts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XV-1)
  • R 2 denotes a silyl protective group, characterized in that at a temperature of -90 ° C to -50 ° C in a first step to the compound of the formula (III),
  • R 2 is a silyl protecting group, is reacted.
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, the sterically hindered secondary amine being selected from a list comprising diisopropylamine, 2,5-dimethylpiperidine and 2, 2.5, 5-tetramethylpiperidine.
  • the present invention also provides a process for the preparation of the compound of the formula (XV-1) as described above, the base being diisopropylamine.
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, the temperature being -78.degree. C. to -65.degree. C., preferably -76.degree.
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, the compound of the formula (III) being present in solution in tetrahydrofuran or dichloromethane, preferably dichloromethane.
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, wherein trifluoromethanesulfonic anhydride is added in a molar excess, preferably in a ratio of 1.5: 1 based on the compound of the formula (III)
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, the base being present in a molar excess, preferably in a ratio of 3: 1, based on the compound of the formula (III).
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, the compound of the formula (XIV-1) in a molar ratio of 1: 1 to 1.1: 1 based on the compound of the formula (III) is used.
  • the present invention further provides a process for the preparation of the compound of the formula (XV-1) as described above, the process taking place with the exclusion of water, preferably under a protective gas atmosphere, particularly preferably under argon gassing.
  • the compound of the formula (VI) can be extracted as a solid.
  • This solid can preferably be stirred in a mixture of water and dichloromethane, and the organic phase can be washed with water and concentrated.
  • the solid obtained can furthermore be dissolved in a mixture of methanol and water at reflux temperature and, surprisingly, can be obtained with a higher enantiomeric purity by cooling to room temperature without the addition of chiral reagents. This is particularly advantageous for the production of enantimerically pure active ingredient.
  • Another object of the present invention is the compound of the formula (XVI)
  • Another object of the present invention is a process for the preparation of the compound of the formula (XVI), characterized in that the compound of the formula (XV-1),
  • R 2 is a silyl protecting group, is reacted with a mineral acid.
  • the present invention further provides a process for the preparation of the compound of the formula (XVI) as described above, the mineral acid being hydrochloric acid, preferably 25% hydrochloric acid.
  • the present invention further provides a process for the preparation of the compound of the formula (XVI) as described above, the reaction taking place at a temperature of 10 ° C to 40 ° C, preferably 25 ° C.
  • the present invention further provides a process for the preparation of the compound of the formula (XVI) as described above, the reaction taking place in methanol.
  • the present invention further provides a process for the preparation of the compound of the formula (XVI) as described above, ammonia solution, preferably 30% ammonia solution, being added after the reaction and the compound of the formula (VI) as a solid is extracted.
  • ammonia solution preferably 30% ammonia solution
  • Formula (XVI) suspended in high concentration hydrochloric acid, preferably 25% strength hydrochloric acid, and stirred at a temperature of 90.degree. C. to 110.degree. C., preferably 103.degree. C., until conversion is complete.
  • the reaction product can be used directly in the next stage.
  • the reaction product is first cooled to a temperature of 15 ° C. to 50 ° C., preferably 40 ° C., the suspension is filtered and the filtrate is used in the next stage.
  • Another object of the present invention is the compound of the formula (IX) as well as their salts, solvates and solvates of the salts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (IX), characterized in that the compound of the formula (XVI), (XVI), is reacted with a mineral acid.
  • the present invention further provides a process for the preparation of the compound of the formula (IX) as described above, the mineral acid being hydrochloric acid, preferably 25% hydrochloric acid.
  • the present invention further provides a process for the preparation of the compound of the formula (IX) as described above, the reaction taking place at a temperature of 90.degree. C. to 110.degree. C., preferably 103.degree.
  • the compound of the formula (IX) can be selected from (5S) -5- ⁇ [2- (4-cyanophenyl) ethyl] [2- (2-methoxyphenyl) ethyl] amino ⁇ -5, 6,7,8-tetrahydroquinoline-2-carbonitrile of the formula (VIII) can be prepared.
  • the compound of the formula (VIII) is suspended with hydrobromic acid in high concentration, preferably 48% hydrobromic acid, and stirred at a temperature of 90 ° C. to 110 ° C., preferably 108 ° C., until conversion is complete.
  • the reaction product is then initially cooled to a temperature of 15 ° C.
  • Process 9B produces toxic methyl bromide, so the gases produced during the reaction must be collected in a gas scrubber.
  • the hydrobromic acid used as a starting material has strongly corrosive properties.
  • Another object of the present invention is a process for the preparation of the compound of the formula (IX), characterized in that the compound of the formula (VIII), is reacted with hydrobromic acid at a temperature of 90 ° C to 110 ° C.
  • the present invention further provides a process for the preparation of the compound of the formula (IX) as described above, using 48% strength hydrobromic acid.
  • the present invention further provides a process for the preparation of the compound of the formula (IX) as described above, the reaction taking place at a temperature of 108.degree.
  • Any aqueous proportions of solvent, for example contained in the precursor and formed during the reaction, are removed. This can be done, for example, by distillation with continuous addition of the organic solvent until the boiling point of the organic solvent is reached.
  • the steps described are preferably carried out under reduced atmospheric pressure.
  • the mixture is then cooled to a temperature of 10 ° C. to 30 ° C., preferably 22 ° C., and an aqueous basic purification is carried out.
  • it is filtered and the aqueous basic purification is carried out with the Liltrat.
  • Aqueous basic purifications are known to Lachmanns; for the aqueous basic purification, ethyl acetate and an aqueous base, preferably ammonia solution or potassium carbonate and water, are preferably added, stirred, and the aqueous phase is separated off and discarded.
  • ethyl acetate and an aqueous base preferably ammonia solution or potassium carbonate and water, are preferably added, stirred, and the aqueous phase is separated off and discarded.
  • water and sodium chloride are preferably added to the remaining organic phase, the mixture is stirred, and the aqueous phase is separated off and discarded.
  • water is preferably added to the remaining organic phase, stirred, and the aqueous phase is separated off and discarded.
  • the remaining organic phase is concentrated at a temperature of 30 ° C to 80 ° C, preferably 40 ° C to 70 ° C, particularly preferably 55 ° C, preferably at reduced atmospheric pressure, and the compound of the Lormel (X) obtained as oil.
  • the oil obtained is dissolved in DCM and methanol, filtered with silica gel and the filtrate obtained is again concentrated to an oil under the conditions described above.
  • An advantage of this process is that water that is present or that arises during the reaction can be removed very effectively from the reaction mixture by aceotropic distillation and thus the reaction time can be shortened until complete conversion is achieved.
  • butanol is distinguished by the fact that it removes considerably more water from the reaction mixture compared to other solvents such as acetonitrile, based on the amount of solvent distilled off. This has a beneficial effect on the duration of the distillation. On an industrial scale, the shorter distillation time results in lower operating costs, apparatus occupancy times and lower energy costs.
  • the solvent that is used for the aceotropic distillation is also the reagent for the formation of the butyl ester, which makes the use of a further solvent superfluous.
  • Another advantage of the process is that the end of the reaction when the conversion is complete is indicated without further analytical investigations by the internal temperature being reached at the boiling point of the butanol under the selected distillation conditions (distillation pressure). This is a considerable advantage, especially on an industrial scale.
  • Another object of the present invention is the compound of the formula (X) (X), as well as their salts, solvates and solvates of the salts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (X), characterized in that the compound of the formula (IX), is reacted with n-butanol in the presence of a mineral acid.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, using n-butanol.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the mineral acid being hydrochloric acid.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the reaction taking place at the boiling point.
  • Process step 10B
  • butyl (5S) -5 - ( ⁇ 2- [4- (butoxycarbonyl) phenyl] ethyl ⁇ [2- (2-hydroxyphenyl) ethyl] amino) -5,6,7,8-tetrahydroquinoline-2-carboxylate of the formula (X) can be obtained from the compounds of the formula (III) and formula (XIV) without isolation of intermediates (process step 10B - scheme 4).
  • process steps 7, 8, 9A and 10A are carried out one after the other, with the respective products of the process steps being obtained as oils and being used directly in the respective next stage.
  • Another object of the present invention is a process for the preparation of the compound of the formula (X), characterized in that in a first step at a temperature of -90 ° C to -50 ° C to give the compound of the formula (III),
  • R 2 denotes a silyl protective group, is reacted, in a third step the reaction product is reacted with hydrochloric acid and in a fourth step the reaction product is reacted with butanol in the presence of a mineral acid.
  • Another object of the present invention is a process for the preparation of the compound of the formula (X) as described above, wherein the sterically hindered secondary amine is selected from a list comprising diisopropylamine, 2,5-dimethylpiperidine and 2,2,5,5- Tetramethylpiperidine.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the base being diisopropylamine.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the temperature in the first and second step being -78 ° C to -65 ° C, preferably -76 ° C.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the compound of the formula (III) being present in solution in tetrahydrofuran or dichloromethane, preferably dichloromethane.
  • the present invention also provides a process for the preparation of the compound of the formula (X) as described above, wherein trifluoromethanesulfonic anhydride is added in a molar excess, preferably in a ratio of 1.5: 1 based on the compound of the formula (III).
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the base being present in a molar excess, preferably in a ratio of 3: 1, based on the compound of the formula (III).
  • Another object of the present invention is a process for the preparation of the compound of the formula (X) as described above, wherein the compound of the formula (XIV-1) in a molar ratio of 1: 1 to 1.1: 1 based on the compound of formula (III) is used.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the process taking place with the exclusion of water, preferably under a protective gas atmosphere, particularly preferably under argon gassing.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the butanol used being n-butanol.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the mineral acid being hydrochloric acid.
  • the present invention further provides a process for the preparation of the compound of the formula (X) as described above, the reaction taking place in the third at a temperature of 90 ° C. to 110 ° C., preferably 103 ° C., and the reaction in the fourth Step takes place at boiling temperature.
  • the solution is 4- (bromomethyl) -3-chloro-4 '- (trifluoromethyl) [biphenyl] of the formula (XI), preferably in an amount of 1 eq to 2 eq, particularly preferably 1.2 eq, based on the compound of the formula (X).
  • An additive selected from a list containing alkali carbonate, for example sodium carbonate, potassium carbonate or cesium carbonate or alkali hydroxides, for example sodium hydroxide or potassium hydroxide, or tetraalkylammonium carbonate, for example tetramethyl, tetraethyl, tetrapropyl or tetrabutylammonium carbonate, is added to the solution,
  • Benzyltrimethyl-, benzyltriethyl-, benzyltripropyl- or benzyltributylammonium carbonate are added, preferably cesium carbonate is used.
  • the addition is given in a molar excess, preferably 2 eq to 4 eq, particularly preferably 2 eq, based on the compound of the formula (X). It is stirred until conversion to the compound of the formula (XII) is complete.
  • a further amount of the additive, preferably cesium carbonate can preferably be added to the reaction mixture and stirred again.
  • the resulting suspension is filtered. Before discarding the filter residue, it is preferably washed with acetonitrile.
  • the compound of the formula (XII) can be isolated as an oil.
  • the filtrate is concentrated to an oil at a temperature of 15 ° C. to 60 ° C., preferably 30 ° C. to 50 ° C., particularly preferably 40 ° C.
  • the concentration takes place preferably under reduced atmospheric pressure.
  • Another object of the present invention is the compound of the formula (XII) as well as their salts, solvates and solvates of the salts.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XII- 1) whereby R 3 and R 4 are independently Ci-C4-alkyl, characterized in that the compound of the formula (Xl), where R 3 and R 4 independently of one another are Ci-C t -alkyl, in the presence of an alkali metal carbonate, alkali metal hydroxide or tetraalkylammonium carbonate with the compound of the formula (XI), is implemented.
  • Another object of the present invention is a process for the preparation of the compound of the formula (XII) (XII), characterized in that the compound of the formula (X), in the presence of an alkali metal carbonate, alkali metal hydroxide or tetraalkylammonium carbonate with the compound of the formula (XI), is implemented.
  • the present invention also provides a process for the preparation of the compound of the formula (XII-1) as described above, using a suitable ether, acetone or acetonitrile, preferably acetonitrile, as the solvent.
  • the present invention also provides a process for the preparation of the compound of the formula (XII-1) as described above, using an alkali metal carbonate selected from a list comprising sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
  • an alkali metal carbonate selected from a list comprising sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
  • the present invention further provides a process for the preparation of the compound of the formula (XII-1) as described above, using an alkali metal hydroxide selected from a list comprising sodium hydroxide and potassium hydroxide.
  • the present invention further provides a process for the preparation of the compound of the formula (XII-1) as described above, using a tetraalkylammonium carbonate.
  • the present invention also provides a process for the preparation of the compound of the formula (XII-1) as described above, the alkali metal carbonate, alkali metal hydroxide or tetraalkylammonium carbonate in a molar excess, preferably in a molar ratio of 2: 1 to 4: 1 based on the compound of the formula (X), particularly preferably in a molar ratio of 2: 1, based on the compound of the formula (X).
  • the present invention further provides a process for the preparation of the compound of the formula (XII-1) as described above, the compound of the formula (XI) preferably in a molar ratio of 1: 1 to 2: 1 based on the compound of the formula ( X), particularly preferably in a molar ratio of 1.2: 1, based on the compound of the formula (X).
  • the compound of the formula (I) can be prepared from the compound of the formula (XII) or (XII-A) by a method of ester cleavage known to the person skilled in the art.
  • ester cleavage can take place analogously to the method described under Example 23 from WO 2014/012934.
  • LiHMDS lithium bis (trimethylsilyl) amide min minute (s)
  • InstrumentMS Waters (Micromass) QM; HPLC instrument: Agilent 1100 series; Column: AgientZORBAX Extend-C18 3.0x50mm 3.5-Micron; Eluent A: 1 1 water + 0.01 mol ammonium carbonate, eluent B: 1 1 acetonitrile; Gradient: 0.0 min 98% A - 0.2 min 98% A - 3.0 min 5% A - 4.5 min 5% A; Oven: 40 ° C; Flow rate: 1.75 ml / min; UV detection: 210 nm
  • Device type MS Waters Synapt G2S
  • Device type UPLC Waters Acquity I-CLASS
  • Eluent A 1 1 water + 0.01% formic acid
  • Eluent B 1 1 acetonitrile + 0.01% formic acid
  • Oven 50 ° C
  • Flow rate 1.20 ml / min
  • UV detection 210 nm
  • the solids from two batches were stirred with 15 L of water for 30 minutes, the solid was filtered off with suction, washed with 7.5 L of water and the process was repeated.
  • the moist product was stirred with 7.5 L ethyl acetate for 1.5 h at 50 ° C, cooled to 22 ° C, stirred for 1 h at 22 ° C, filtered off, washed with 5 L ethyl acetate and at 40 ° C in a vacuum drying cabinet to 2, 13 kg dried.
  • the dry product was stirred in 2.2 L ethyl acetate and 5.38 L hydrochloric acid (15%), filtered off with suction, washed with 2.15 L water and dried at 40 ° C. in a vacuum drying cabinet to give 1.63 kg hydrochloride.
  • the hydrochloride was dissolved in 8.25 L dichloromethane and 8.25 L water, a pH of 13 to 14 was set with 45% sodium hydroxide solution, the phases were separated and the organic phase was washed with 2.75 L water. The organic phase was concentrated in vacuo at 40 ° C., 3 L dichloromethane were added and the mixture was concentrated again to give 1.44 kg oil.
  • a 30 L stainless steel reactor was charged with 1.0 kg of 5-oxo-5,6,7,8-tetrahydroquinoline-2-carbonitrile and 10.0 L of ethyl acetate. 1.175 kg of triethylamine were metered in at 20 ° C. over the course of 15 minutes. 18.5 g of ruthenium-p-cumene-R, R-TsDPEN (CAS number: 192139-92-7) are added to the solution at 20.degree. 1.337 kg of formic acid were metered into the solution at 0 ° C. to 5 ° C. over the course of 1 h (evolution of gas). The reaction was stirred at an internal temperature of 40 ° C. for 4 h.
  • the reaction monitoring showed complete conversion already after 2 h at 40 ° C. (laboratory HPLC).
  • the reaction mixture was cooled to 20 ° C. and stirred overnight at 20 ° C. for degassing.
  • the reaction mixture was mixed with 4.1 L of ethyl acetate and 4.1 L of 1N hydrochloric acid and stirred for a further 15 min.
  • the phases were separated. About 13.9 L of a dark brown, organic upper phase are obtained.
  • the product-containing upper phase was mixed with 13.9 L n-heptane.
  • a vacuum approximately 8 mbar, jacket temperature approx. 40 ° C.
  • the mixture was concentrated within approx. 2.5 h until approx. 17.6 L of distillate were reached.
  • Inoculated product and further cooled to room temperature.
  • the solid was filtered off with suction, washed with 300 ml of ethanol and dried in a vacuum drying cabinet at 25 ° C. in a stream of nitrogen.
  • the resulting solid was filtered off with suction, washed with 530 mL dichloromethane, stirred with 800 mL dichloromethane and filtered off with suction.
  • the moist product was dissolved in 835 ml of tetrahydrofuran and, with cooling, 526 ml (2.33 mol) of saturated (360 g / L) potassium-sodium tartrate solution were added.
  • the two-phase mixture was filtered off with suction, the solid was stirred with 1 L of ethyl acetate and filtered off with suction.
  • the purified solid was suspended in 835 ml of tetrahydrofuran and stirred for 30 min with 526 ml (2.33 mol) of saturated (360 g / L) potassium-sodium tartrate solution.
  • the solid was filtered off with suction from the product-containing filtrate and washed with 200 mL tetrahydrofuran.
  • the product-containing filtrates were combined and the organic phase was separated off and concentrated.
  • the residue was dissolved in 835 mL dichloromethane, washed with 31 mL aq. Ammonia solution (27%) made alkaline and washed three times with 309 mL of water each time.
  • the combined aqueous phases were washed with 155 mL dichloromethane and the combined organic phases were concentrated to an oil.
  • the reaction mixture was slowly cooled to 5-10 ° C. and stirred for a further 1-2 hours.
  • the solid was then filtered off, washed with methanol (2 x 20 ml).
  • the filter residue was then suspended in DCM / water (137 ml each) and stirred at 25-35 ° C. for several hours.
  • 45% NaOH (4.5 mL) was added in order to achieve a pH of 10.5 - 12.5.
  • a further 70 ml of water were added and the phases were separated.
  • the organic phase was concentrated in vacuo.
  • the residue obtained corresponds to the target substance (6.78g, 37%).
  • Example 7 (5S) -5 - ⁇ [2- (2 - ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ phenyl) ethyl] [2- (4-cyanophenyl) ethyl] amino ⁇ -5,6,7, 8-tetrahydroquinoline-2-carbonitrile
  • Butyl (dimethyl) silyl] oxy ⁇ phenyl) ethyl] amino ⁇ ethyl) benzonitrile (Example 6) in 100 ml of dichloromethane at -75 ° C to -72 ° C, rinsed with 20 ml of dichloromethane and stirred for 2 h. 9.93 g (86.1 mmol) of 85% strength phosphoric acid were added to the reaction mixture, and the reaction mixture was washed twice with 500 ml of water each time. The combined aqueous phases were washed with 300 ml of dichloromethane and the combined organic phases were concentrated on a rotary evaporator at 40 ° C. in vacuo to give an oil (96.6 g).
  • the oil was dissolved in 50 ml of dichloromethane, filtered through 150 g of silica gel and the product was eluted with 800 ml of ethyl acetate / n-hexane in a ratio of 1: 2.
  • the product solution was concentrated on a rotary evaporator at 40 ° C. in vacuo to give an oil (79.3 g).
  • the product was dissolved in 50 ml of dichloromethane and filtered through 150 g of silica gel and eluted with 750 ml of ethyl acetate / n-hexane in a ratio of 1: 2.
  • the eluate was concentrated on a rotary evaporator at 35 ° C to give 48.2 g of crude product.
  • the solid residue was in 480 ml of deionized water and 250 ml of dichloromethane were stirred at RT for 30 min, the lower organic phase was washed with 450 ml of water and concentrated to 27.9 g at 35 ° C. on a rotary evaporator.
  • Method B In a 6 L flask with gas scrubber (filling: 600 g ethanolamine, 1200 g sodium hydroxide solution 5%, 1200 g isopropanol and approx. 0.5 g bromothymol blue) were 332.5 g (0.76 mol) (5S) - 5 - ⁇ [2- (4-Cyanophenyl) ethyl] [2- (2-methoxyphenyl) ethyl] amino ⁇ -5,6,7,8-tetrahydroquinoline-2-carbonitrile (Example 4) in 3210 g (2, 15 ml) 48% hydrobromic acid heated to 108 ° C and stirred for 24 h. The solution was cooled to 25 ° C. and washed twice with 650 ml of dichloromethane each time. The lower aqueous product phase was used in the next stage (Example 10). A sample was purified for analytical purposes.
  • the oil was dissolved in 500 ml of dichloromethane and filtered with a further 8 L of dichloromethane and then 2 L of methanol through a filter covered with 1 kg of silica gel.
  • the product solution was concentrated on a rotary evaporator to give 337.8 g of oil.
  • a sample was purified for analytical purposes.
  • Men at Ti 40 ° C cooled and stirred for 14 hours.
  • Another n-butanol (800 mL) was added and the mixture was concentrated to Ti men 102 ° C under the same conditions.
  • Ethyl acetate (800 ml), deionized water (400 ml) and potassium carbonate (44 g) were added and the mixture was stirred for a further 10 min. The phases were allowed to settle and the aqueous phase was separated off (is discarded). To the org.

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EP21724712.1A 2020-05-20 2021-05-14 Verfahren zur herstellung von butyl-(5s)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chlor-4'-(trifluormethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydrochinolin-2-carboxylat Pending EP4153569A1 (de)

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EP20175721 2020-05-20
PCT/EP2021/062837 WO2021233783A1 (de) 2020-05-20 2021-05-14 Verfahren zur herstellung von butyl-(5s)-5-({2-[4-(butoxycarbonyl)phenyl]ethyl}[2-(2-{[3-chlor-4'-(trifluormethyl)[biphenyl]-4-yl]methoxy}phenyl)ethyl]amino)-5,6,7,8-tetrahydrochinolin-2-carboxylat

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AR128147A1 (es) 2021-12-29 2024-03-27 Bayer Ag Procedimiento para la preparación del ácido (5s)-[2-(4-carboxifenil)etil][2-(2-[3-cloro-4’-(trifluorometil)bifenil-4-il]metoxifenil)etil]amino-5,6,7,8-tetrahidroquinolina-2-carboxílico y sus formas cristalinas para su uso como compuesto farmacéuticamente activo

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