WO2021254896A1 - Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide activé par une réduction catalytique asymétrique par esters de hantzsch - Google Patents

Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide activé par une réduction catalytique asymétrique par esters de hantzsch Download PDF

Info

Publication number
WO2021254896A1
WO2021254896A1 PCT/EP2021/065751 EP2021065751W WO2021254896A1 WO 2021254896 A1 WO2021254896 A1 WO 2021254896A1 EP 2021065751 W EP2021065751 W EP 2021065751W WO 2021254896 A1 WO2021254896 A1 WO 2021254896A1
Authority
WO
WIPO (PCT)
Prior art keywords
hantzsch
naphthyridine
process according
ethoxy
reduction
Prior art date
Application number
PCT/EP2021/065751
Other languages
English (en)
Inventor
Johannes Platzek
Andreas LERCHEN
Varinder Aggarwal
Narasimhulu GANDHAMSETTY
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2021254896A1 publication Critical patent/WO2021254896A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for preparing (4S)-4-(4-Cyano-2-methoxyphenyl)-5- ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) by an asymmetric Hantzsch ester reduction of the racemic naphthyridine-precursor (II) hat exists as a mixture of atropisomers (IIa) and (IIb)
  • the present inventi on relates to a novel process for preparing (4R)-4-(4-Cyano-2-methoxyphenyl)-5- ethoxy-2,8-dimethyl
  • he present invention further provides a process for the synthesis of (Ib) as presented above, characterizedn that chiral phosphoric acid catalysts of general formulae (IIIa) is used, where R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted arene or polyarene, or a triphenylsilyl group in which phenyl and the substituted or unsubstituted arene or polyarene may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of (C 1 -C 4 )- alkyl, isopropyl, cyclohexyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )- alkylamino or di
  • the present invention further provides a process for the synthesis of (Ia) as presented above, characterizedn that chiral phosphoric acid catalysts of general formulae (IIIa) and (IIIb) are used, where R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted arene or olyarene, or a triphenylsilyl group in which phenyl and the substituted or unsubstituted arene or polyarene may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of (C 1 -C 4 )- alkyl, isopropyl, cyclohexyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )- alkylamino or di-(C 1 -C 4 )-alkylamino and fluorine.
  • R represents a substituted or unsubstitute
  • he present invention further provides a process for the synthesis of (Ib) as presented above, characterizedn that chiral phosphoric acid catalysts of general formulae (IIIa) is used, where R represents 9-anthracene, 2,4,6-(triisopropylphenyl), 3,5-bis(trifluoromethyl)phenyl, or a triphenylsilyl group.
  • the present invention further provides a process for the synthesis of (Ia) as presented above, characterized in that chiral phosphoric acid catalysts of general formulae (IIIb) is used, where R represents 9-anthracene, 2,4,6-(triisopropylphenyl), 3,5-bis(trifluoromethyl)phenyl, or a triphenylsilyl group.
  • chiral phosphoric acid catalysts of general formulae (IIIb) is used, where R represents 9-anthracene.
  • the present invention further provides a process for the synthesis of (Ia) as presented above, characterized in that chiral phosphoric acid catalysts of general formulae (IIIb) is used, where R represents 9-anthracene.
  • the formula is depicted below: he present invention further provides a process as presented above, characterized in that the Hantzsch ster of general formula (IV) is used, 1 n which R represents (C 1 -C 6 ) alkyl or benzyl.
  • he present invention further provides a process as presented above, characterized in that the Hantzsch ester of general formula (IV) is used, 1 in which R represents methyl, ethyl, n-propyl, isopropyl, tert-butyl, butyl or benzyl.
  • the present invention further provides a process as presented above, characterized in that the Hantzsch ester of general formula (IV) is used, 1 R n which R 1 represents methyl or ethyl.
  • Background Finerenone (Ia) acts as a non-steroidal antagonist of the mineralocorticoid receptor and may be used as an agent for prophylaxis and/or treatment of cardiovascular and renal disorders such as heart failure and diabetic nephropathy, for example.
  • This selector was prepared in a multi-stage process and then polymerized on special silica gel. Methanol/ethyl acetate served as eluent.
  • a major disadvantage of this method was the very low loading, 30 mg per separation on a 500*63 mm chromatography column, such that there was a high need to find as effective a separation method as possible which allows separation of antipodes to be performed in the multi-ton range. It has been found, surprisingly, that the separation can also be performed on a readily commercially available phase. This takes the form of the phase Chiralpak AS-V, 20 ⁇ m.
  • the eluent used was a mixture of methanol/acetonitrile 60:40.
  • the chromatography may be carried out on a conventional chromatography column, but preferably the techniques known to those skilled in the art such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68) or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901) are used.
  • SMB simulated moving bed
  • Varicol Computer and Chemical Engineering 27 (2003) 1883-1901
  • the chiral phase is expensive and has only a limited life-time. Therefore, it needs be changed continuously in the on-going production process leading to a need for a second plant in order to guarantee a continuous work-flow which is very cost-intensive and thereby a huge disadvantage or this approach.
  • the recovery of solvents is a time-imiting step and requires huge and expensive thin-filter-evaporators, is associated with the consumption of huge amounts of energy and thereby costly.
  • WO2019/206909 describes the preparation of the enantiomer (Ia) by racemate resolution using chiral substituted tartaric acid esters using conventional pilot plant equipment (stirred vessel/isolation pparatuses) but still needs recycling of (Ib) and isomerization to (Ia) to be an efficient approach for the ynthesis of (Ia). or this reason, it was necessary to discover an alternative route to obtain Finerenone (Ia) in a direct symmetric fashion, so that the chiral separation of the racemate can be avoided. That would offer a emendous advantage, since (Ia) could be obtained in high yield and the time and resources intensive ecycling of (Ib) and isomerization to (Ia) could be avoided.
  • Finerenone (Ia) e.g. hydrogenation of naphthyridine- to dihydronaphthyridine moieties
  • the goal of the present finding was therefore the discovery of novel conditions, that enable the synthesis of Finerenone (Ia) in high yield and with high enantiomeric excess.
  • the presentnvention allows the selective synthesis of Finerenone (Ia) in high yield and high enantiomeric excess.
  • Detailed description he present invention describes the chiral reduction of a racemic mixture of the atropisomers of formulae IIa) and (IIb).
  • the present invention gives access to a novel and efficient protocol for the synthesis of (4S)-4-(4-Cyano- 2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), s well as for the synthesis of the corresponding enantiomer of formula (Ib), using an asymmetric Hantzsch ster reduction of the racemic naphthyridine-precursor of formula (IIa/IIb),
  • the no vel protocol of the present invention uses chiral phosphoric acid catalysts with the general formula (IIIa) and (IIIb),
  • R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted arene or polyarene, or a triphenylsilyl group, in which phenyl and the substituted or unsubstituted arene or polyarene may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of (C 1 -C 4 )- alkyl, isopropyl, cyclohexyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )- alkylamino or di-(C 1 -C 4 )-alkylamino and fluorine.
  • novel protocol of the present invention preferably uses chiral phosphoric acid catalysts with the eneral formula (IIIa), (IIIb) where R represents 9-anthracene, 2,4,6-(triisopropylphenyl), 3,5-bis(trifluoromethyl)phenyl, or a triphenylsilyl group.
  • the novel protocol of the present invention uses Hantzsch ester of general formula (IV), where R 1 represents (C 1 -C 6 ) alkyl or benzyl
  • the novel protocol of the present invention preferably uses Hantzsch ester of general formula (IV), • - where R 1 represents methyl, ethyl, n-propyl, isopropyl, butyl or benzyl.
  • he present invention gives access to a novel and efficient protocol for the synthesis of (4S)-4-(4-Cyano- -methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), using an asymmetric Hantzsch ester reduction in which racemic naphthyridine-precursor of formula (IIa/IIb),
  • R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted arene or polyarene, or a triphenylsilyl group, in which phenyl and the substituted or unsubstituted arene or polyarene may be substituted by 1 to 3 substituents selected independently of one another from the group consisting of (C 1 -C 4 )-alkyl, isopropyl, cyclohexyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, hydroxy, mono-(C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino and fluorine in the presence of Hantzsch ester of general formula (IV), w where R 1 represents (C 1 -C 6 ) alkyl or benzyl.
  • chiral phosphoric acid catalysts with the general formula (IIIb), where R represents 9-anthracene, 2,4,6-(triisopropylphenyl), 3,5-bis(trifluoromethyl)phenyl, or a triphenylsilyl group are used. More preferably chiral phosphoric acid catalyst with the general formula (IIIb), where R represents 9-anthracene is used.
  • Hantzsch ester of general formula (IV), w where R 1 represents methyl, ethyl, n-propyl, isopropyl, butyl or benzyl is used. More preferably Hantzsch ester of general formula (IV), 0 o where R 1 represents methyl or ethyl is used.
  • Hantzsch ester of general formula (IV), 1 where R represents methyl or ethyl or tert-butyl is used.
  • articularyl preferred is a protocol for the synthesis of (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8- imethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), using an asymmetric Hantzsch ester reduction in which racemic naphthyridine-precursor of formula (IIa/IIb),
  • organic aprotic solvents examples include tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, toluene, chlorobenzene.
  • preferred solvents are tetrahydrofuran, 2-methyltetrahydrofuran, whereby tetrahydrofuran is especially preferred.
  • the Hantzsch reduction is performed in a solvent selected from dichlormethane (CH 2 Cl 2 ), 2-methyl tetrahydrofurane (2-MeTHF), acetonitrile (MeCN), 1,2- dichloroethane (DCE), diethylether (Et 2 O), trifluorotoluene (CF3-Ph), tetrahydrofurane and mixtureshereof.
  • a solvent selected from dichlormethane (CH 2 Cl 2 ), 2-methyl tetrahydrofurane (2-MeTHF), acetonitrile (MeCN), 1,2- dichloroethane (DCE), diethylether (Et 2 O), trifluorotoluene (CF3-Ph), tetrahydrofurane and mixtureshereof.
  • a solvent selected from dichlormethane (CH 2 Cl 2 ), 2-methyl tetrahydrofurane (2-MeTHF), acetonit
  • the temperature ranges are in between 20° C – 100 °C, preferentially 40° C – 100 °C.
  • the synthesis is performed at a temperature of 40 °C for 12 h-36 h, followed by increasing the temperature to 00 °C for 12 h-36 h.
  • Particular preference is given to performing the synthesis at a temperature of 40 °C or 24 h, followed by increasing the temperature to 100 °C for 24 h.
  • the synthesis is performed t a temperature of 100 °C for 24 h.
  • he reaction time is 12-60 hours, preferably 24-60 hours. Particular preference is given to 24-48 hours.
  • 10 equivalents of Hantzsch ester with the general structure (IV) are used, preferably 2-6 equivalents. articular preference is given to 2-4 equivalents.
  • he chiral phosphoric acid catalysts (IIIa and IIIb) can be used in a range of 0.5-7 mol%, preferentially .5-5 mol%. Particular preference is given to 5 mol%.
  • the Hantzsch esters used in the present invention are commercially available.
  • a further aspect of the present finding is the novel synthesis of the racemic mixture of atropisomers (IIa and IIb).
  • Racemic dihydropyridine (I) is oxidized to the naphthyridine product (IIa/IIb).
  • the oxidation is described in PCT Int. Appl. (2017), WO 2017032678 A1 20170302, PCT Int. Appl. (2017), WO 2017032627 A120170302.
  • a preferred medium for the oxidation is nitric acid.
  • he racemic compound (I) can be obtained via a condensation reaction using the amino alcohol (V) and cetoacetamide (VI).
  • the condensation reaction can be performed in solvents such as toluene, chlorobenzene, xylene, ethylbenzene, preferably in toluene.
  • the reaction is performed at temperatures of 80° C to 120 °C, preferably at 90° C to110 °C.
  • the reaction time is 12-36 hours, preferentially 20-30 hours.
  • the chiral or racemic phosphoric acid derivatives of the general structure (IIIa and IIIb) can be used as catalyst, preferentially diphenyl phosphate (DPP) is used. In case the chiral phosphoric acid derivatives are used as catalyst, some enantioenriched material of Ia or Ib might be obtained.
  • the amino alcohol (V) can be synthesized via deprotection of the protecting group of the compound (VII).
  • protecting group (PG) amino protecting groups known in the art can be employed; preferentially a Boc- (-COO(tert.-butyl)) or pivaloyl (-CO(tert-butyl)) protecting group is used, more preferably a ivaloyl protecting group is used.
  • the deprotection can be performed according to known procedures, for xamples, see Green’s Protecting groups in organic chemistry, A John Wiley & Sons, Inc.,Publication 007.
  • Compound of formula (VII) is synthesized by addition of an organometal-nucleophile that is generated byhe deprotonation of ethyl ether (VIII) in presence of a strong base to the aldehyde (IX):
  • the bases for the deprotonation can be n-butyllithium or sec-butyllithium, preferentially n-butyllithium is used. It has been found that TMEDA can be added as an additional base.
  • the reaction can be performed in THF, diethylether, 2-methyl-THF or mixtures of THF and diethylether. The reaction is performed at lower temperatures, preferentially at -50 °C to -78°C.
  • Compound of formula (VIII) is synthesized by introducing a suitable protecting group (PG) at the amine- moiety of the amine of formula (X):
  • the introduction of the amine protecting groups can be conducted via procedures according to Green‘ Protecting groups in organic chemistry, A John Wiley & Sons, Inc.,Publication 2007.
  • pivalate is used as protecting group
  • compound (X) is treated with pivaloyl chloride and triethylamine in dichloromethane to give the compound of formula (VIII).
  • Aldehyde (IX) is commercially available and known in the literature (WO 2016/016287 A1 expample 3).
  • Compound (X) is synthesized via alkylation/aromatization of the pyridone (XI).
  • the ketone (XII) can be synthesized by oxidation of the alcohol (VII) followed by deprotection of the protecting group.
  • the oxidation can be performed according to reported methodologies such as Swern- Oxidation, Oppenauer-Oxidation, Chrom(IV)salt-Oxidation etc. (e.g. Organikum, VEB-Verlag Berlin).
  • the ketone (VII) can be synthesized using Mangenese dioxide.
  • Another pathway could behat compound (VII) can be deprotonated by a strong base and then converted with an activated acid X in which X represents Cl, Br, Imidazole or a Weinreb-amide (-N(OMe)Me).
  • Suitable bases for deprotonation are n-butyllithium or sec-butyllithium, preferentially n-butyllithium. Addition of TMEDA as additional base can be advantageous.
  • the reaction can be performed in THF, diethylether, 2-methyl-THF or mixtures of THF and diethylether. The reaction can be performed at low temperatures, preferentially at -50 to -78°C.
  • the activated acid derivatives (XIII) will be synthesized starting from the carboxylic acid according to common procedures.
  • the solvent will be emoved under reduced pressure or destilled. Toluene will be preferentially used as denatured solvent. he solvent will be reduced to a 3- to 5-times lower volume and then the product can crystallize. It will e cooled to 0 °C and then the crystals can be isolated and dried in vacuo at 40-50 °C.
  • the yields are in eneral >90% from theory.
  • the obtained chemical purity is 99.8% and the content ⁇ 100% is in accordance with the ICH-guidelines for trade products. Traces of remaining solvent (in this case ethanol) are lower 0.02%.
  • the optical purity is >>99%ee.
  • he present invention further provides methods for preparing the racemic mixture of atropisomers (IIa nd IIb) said methods comprising the step of alkylation/aromatization of the pyridone (XI), ) H using ethyl iodide and silver carbonate in toluene, hereby giving pyridine of formula (X), H which is converted to the compound of formula (VIII) by introduction of a suitable amino protection group, which is deprotonated in a suitable solvent in the presence of a strong base and then allowed to react with ldehyde (IX) if applicable in the presence of TMEDA with aldehyde (IX), H o give the compound of formula (VII), which after removal of the protecting group gives the compound of formula (V), which is allowed to react with acetoacetamide of formula (VI), in a suitable solvent in the presence of a suitable catalyst at temperatures of 80°C to 120°C, thereby giving the racemic compound of formula (I), which is oxid
  • Anhydrous solvents were either dried using an Anhydrous Engineering alumina column drying system (THF, toluene, dichloromethane) or obtained as Acroseal bottles and used directly. All other employed solvents were reagent grade solvents and were used directly. Petroleum ether refers to the fraction collected between 40° C – 60 °C. Reactions requiring anhydrous conditions (where specified) were onducted under a Nitrogen / Argon atmosphere using standard Schlenk techniques unless otherwise tated. All reagents were purchased from commercial sources and used as received, unless otherwise tated. Flash column chromatography was carried out using Aldrich silica gel (40-63 ⁇ m).
  • Chiral supercritical fluid chromatography was performed on a Waters TharSFC system using a Chiralpak® IB column (4.6 ⁇ 250 mm ⁇ 5 ⁇ m) at an oven temperature of 40 °C and was monitored using a diode array detector (DAD).
  • Chiral supercritical fluid chromatography was performed on an Agilent 1290 Infinity chiral SFC using a Chiralpak® IB column (4.6 ⁇ 250 mm ⁇ 5 ⁇ m) or a Chiralpak® IC column (4.6 ⁇ 250 mm ⁇ 5 ⁇ m) at an oven temperature of 40 °C and was monitored using a diode array detector (DAD).
  • Example 1a 2-ethoxy-5-methylpyridin-4-amine (X) -amino-5-methylpyridin-2(1H)-one (XI) (124,1 mg, 1.00 mmol, 1.00 equiv) and Ag 2 CO 3 (607 mg, .20 mmol, 2.20 equiv) were submitted to a flame-dried Young-type pressure tube equipped with a stirring ar. After 3 vacuum/nitrogen cycles toluene (3.3 mL) was added, followed by ethyl iodide (161 ⁇ L, 2.00 mmol, 2.00 equiv). The resulting suspension was heated to 110 °C for 16 hours in an oil bath.
  • IR (film) ⁇ max/cm –1 : 3463, 3343, 3216, 2978, 1634, 1613, 1568, 1498, 1460, 1424, 1387, 1226, 1183, 1041, 1010, 836.
  • 2-ethoxy-5-methylpyridin-4-amine ((X), 5.02 g, 33.0 mmol, 1.00 equiv) and triethylamine (6.67 g, 66.0 mmol, 2.00 equiv) in dichloromethane (25 mL) was added a solution of pivaloyl chloride (6.0 g, 49.5 mmol, 1.50 equiv) in dichloromethane (6 mL) dropwise while stirring. Then, the reaction mixture was allowed to warm up to room temperature.
  • Example 1d 4-((4-Amino-2-ethoxy-5-methylpyridin-3-yl)(hydroxy)methyl)-3-methoxybenzonitrile (V) N-(3-[(4-Cyano-2-methoxyphenyl)](hydroxy-methyl)-2-ethoxy-5-methylpyridin-4-yl)pivalamide ((VII), 2.38 g, 6.00 mmol) was dissolved in 1,4-dioxane (36.0 mL) and water (36.0 mL). Concentrated hydrochloric acid (24.0 mL) was added dropwise simultaneously to the stirred solution.
  • Example 1e 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide (IIa, IIb) -[(4-Amino-2-ethoxy-5-methylpyridin-3-yl) hydroxymethyl]-3-methoxybenzonitrile (V) (31.3 mg, .10 mmol; 1.00 equiv), acetoacetamide ((VI), 30.3 mg, 0.30 mmol; 3.00 equiv), DPP catalyst (5 mg, 0 mol%) and flame dried 4 ⁇ molecular sieves (90.0 mg/0.10 mmol) were loaded into an oven dried microwave vial and suspended in anhydrous toluene (1.00 mL) under an argon atmosphere.
  • V 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3
  • the vial was losed with a sealed cap.
  • the reaction mixture was stirred at 110 °C for 24 hours and the reaction progress was monitored by TLC (hexane/ethyl acetate; 2:8). Then, the reaction mixture was cooled down to 0 °C nd diluted with n-butanol (1.5 mL). Then, concentrated nitric acid (90%, 0.07 mL, 0.15 mmol, .50 equiv) was slowly added and the mixture was heated to react at 100 °C. After 3 hours, the reaction mixture was cooled down to 0 °C and quenched with saturated aqueous sodium bicarbonate solution (1 mL).
  • reaction mixture was extracted with ethyl acetate (3x 3 mL).
  • the combined organic layers were dried over magnesium sulphate, evaporated under reduced pressure, and purified by column hromatography on silica gel (50:50; hexane/ethyl acetate) to give the racemic mixture (IIa, IIb) (21.4 mg, 7%) as a pale yellow solid.
  • Rf 0.27 (pentane/ethyl acetate, 50:50).
  • IR (film) ⁇ max /cm –1 : 3336, 3181, 2980, 2231, 1668, 1602, 1568, 1508, 1480, 1440, 1406, 1383, 1326, 1307, 1195, 1120, 1034, 927, 853, 813.
  • Example 2 General procedure for the catalyst reaction: 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide (IIa,IIb), 37.6 mg, 0.1 mmol, 1.00 equiv), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (Hantzsch ethylester (IV), 50.7 mg, 0.2 mmol, 2.00 equiv) and the chiral phosphoric acid catalyst IIIa or IIIb (5 mol%) were added in a flame-dried Young-type pressure tube equipped with a stirring bar.
  • Example 3 Effect of varying solvents and temperature 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,6-naphthyridine-3-carboxamide ((IIa, IIb), 37.6 mg, 0.1 mmol, 1.00 equiv), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (Hantzsch ethylester (IV),50.7 mg, 0.2 mmol, 2.00 equiv) and the chiral phosphoric acid catalyst ((R)-IIIa4) (3.5 mg, 5 mol%) were added in a flame-dried Young-type pressure tube equipped with a stirring bar.
  • R (film) ⁇ max/cm –1 : 3456, 3343, 2977, 2927, 2858, 2229, 1663, 1570, 1490, 1445, 1381, 1334, 1268, 137, 1034, 925, 826.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation de (4S)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide par une réduction asymétrique par esters de Hantzsch de 4-(4-cyano-2-méthoxyphényle)-5-éthoxy-2,8-diméthyl-1,6-naphtyridine-3-carboxamide racémique.
PCT/EP2021/065751 2020-06-16 2021-06-11 Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide activé par une réduction catalytique asymétrique par esters de hantzsch WO2021254896A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20180267 2020-06-16
EP20180267.5 2020-06-16

Publications (1)

Publication Number Publication Date
WO2021254896A1 true WO2021254896A1 (fr) 2021-12-23

Family

ID=71105229

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/065751 WO2021254896A1 (fr) 2020-06-16 2021-06-11 Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide activé par une réduction catalytique asymétrique par esters de hantzsch

Country Status (3)

Country Link
AR (1) AR122634A1 (fr)
TW (1) TW202214624A (fr)
WO (1) WO2021254896A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104306A2 (fr) 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
WO2016016287A1 (fr) 2014-08-01 2016-02-04 Bayer Pharma Aktiengesellschaft Procédé pour fabriquer du (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide et le purifier en vue de l'utiliser en tant que principe actif pharmaceutique
WO2017032678A1 (fr) 2015-08-21 2017-03-02 Bayer Pharma Aktiengesellschaft Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et de récupération de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide au moyen de méthodes électrochimiques
WO2017032627A1 (fr) 2015-08-21 2017-03-02 Bayer Pharma Aktiengesellschaft Procédé de préparation de métabolites de (4s) et (4r)- 4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et leur utilisation
WO2019206909A1 (fr) 2018-04-24 2019-10-31 Bayer Aktiengesellschaft Procédé de fabrication de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide par résolution racémique au moyen d'esters d'acide tartrique diastéréoisomères

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104306A2 (fr) 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Amides de 4-aryl-1,4-dihydro-1,6-naphthyridine substitués et utilisation de ceux-ci
WO2016016287A1 (fr) 2014-08-01 2016-02-04 Bayer Pharma Aktiengesellschaft Procédé pour fabriquer du (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide et le purifier en vue de l'utiliser en tant que principe actif pharmaceutique
WO2017032678A1 (fr) 2015-08-21 2017-03-02 Bayer Pharma Aktiengesellschaft Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et de récupération de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide au moyen de méthodes électrochimiques
WO2017032627A1 (fr) 2015-08-21 2017-03-02 Bayer Pharma Aktiengesellschaft Procédé de préparation de métabolites de (4s) et (4r)- 4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide et leur utilisation
WO2019206909A1 (fr) 2018-04-24 2019-10-31 Bayer Aktiengesellschaft Procédé de fabrication de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide par résolution racémique au moyen d'esters d'acide tartrique diastéréoisomères

Non-Patent Citations (30)

* Cited by examiner, † Cited by third party
Title
A. AILLERIEV. LEMAU DE TALANCEA. MONCOMBLET. BOUSQUETL. PELINSKI, ORG. LETT., vol. 16, 2014, pages 2982 - 2985
ALEXANDRE AILLERIE ET AL: "Enantioselective Organocatalytic Partial Transfer Hydrogenation of Lactone-Fused Quinolines", ORGANIC LETTERS, vol. 16, no. 11, 22 May 2014 (2014-05-22), US, pages 2982 - 2985, XP055736043, ISSN: 1523-7060, DOI: 10.1021/ol5011196 *
ANGEW. CHEM., vol. 117, 2005, pages 7590 - 7593
ANGEW. CHEM., vol. 118, 2006, pages 3765 - 3768
ANGEW. CHEM., vol. 119, 2007, pages 4646 - 4649
ANGEW. CHEM., vol. 124, 2012, pages 7394 - 7398
ANGEW. CHEM., vol. 128, 2016, pages 9941 - 9946
CHEMMEDCHEM, vol. 7, 2012, pages 1385
COMPUTERS AND CHEMICAL ENGINEERING, vol. 27, 2003, pages 1883 - 1901
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, vol. 2016, no. 32, 2016, pages 5365 - 5376
F. REZGUIP. MANGENEYA. ALEXAKIS, TETRAHEDRON LETT., vol. 40, 1999, pages 6241 - 6244
G. PAREDESM. MAZOTTI, JOURNAL OF CHROMATOGRAPHY A, vol. 1142, 2007, pages 56 - 68
LEI REN ET AL: "Step-Economical Synthesis of Tetrahydroquinolines by Asymmetric Relay Catalytic Friedländer Condensation/Transfer Hydrogenation", ANGEWANDTE CHEMIE, vol. 51, no. 3, 14 December 2011 (2011-12-14), DE, pages 771 - 774, XP055736038, ISSN: 1433-7851, DOI: 10.1002/anie.201106808 *
M. KRETZSCHMART. HODIKC. SCHNEIDER, ANGEW. CHEM. INT. ED., vol. 55, 2016, pages 9788 - 9792
M. RUEPINGA. P. ANTONCHICK, ANGEW. CHEM. INT. ED., vol. 46, 2007, pages 4562 - 4565
M. RUEPINGA. P. ANTONCHICKT. THEISSMANN, ANGEW. CHEM. INT. ED., vol. 45, 2006, pages 3683 - 3686
M. RUEPINGE. SUGIONOC. AZAPT. THEISSMANNM. BOLTE, ORG. LETT., vol. 7, 2005, pages 3781 - 3783
M. RUEPINGJ. DUFOURF. R. SCHOEPKE, GREEN CHEM., vol. 13, 2011, pages 1084 - 1105
M. RUEPINGT. THEISSMANNS. RAJAJ. W. BATS, ADV. SYNTH. CATAL., vol. 350, 2008, pages 1001 - 1006
R. I. STORERD. E. CARRERAY. NID. W. C. MACMILLAN, J. AM. CHEM. SOC., vol. 128, 2006, pages 84 - 86
S. HOFFMANNA. M. SEAYADB. LIST, ANGEW. CHEM. INT. ED., vol. 44, 2005, pages 7424 - 7427
SYNLETT, vol. 6, 2008, pages 883 - 885
SYNTHESIS, 1984, pages 765
SYNTHESIS, vol. 8, 2007, pages 1214 - 1224
T. HODIKC. SCHNEIDER, ORG. BIOMOL. CHEM., vol. 15, 2017, pages 3706 - 3716
TETRAHEDRON ASYMMETRY, vol. 13, no. 3, 2002, pages 227 - 232
TETRAHEDRON LETTERS, vol. 27, no. 49, 1986, pages 5997 - 6000
X. ZHANGX. SONGH. LIS. ZHANGX. CHENX. YUW. WANG, ANGEW. CHEM. INT. ED., vol. 51, 2012, pages 7282 - 7286
Y. LEES. HEOS.-G. KIM, ADV. SYNTH. CATAL., vol. 357, 2015, pages 1545 - 1550
Y. LEES.-G. KIM, J. ORG. CHEM., vol. 79, 2014, pages 8234 - 8243

Also Published As

Publication number Publication date
TW202214624A (zh) 2022-04-16
AR122634A1 (es) 2022-09-28

Similar Documents

Publication Publication Date Title
Meyers et al. Asymmetric tandem addition to chiral 1-and 2-substituted naphthalenes. Application to the synthesis of (+)-phyltetralin
Mahmud et al. An intramolecular azomethine ylide–alkene cycloaddition approach to pyrrolo [3, 2-c] quinolines-synthesis of a C2-truncated martinelline model
CN109265475B (zh) 一种多取代芳基乙烯硼酸频哪醇酯衍生物的制备方法
EP1466905B1 (fr) Production d'ester d'acide oxoheptonoique optiquement actif
Xue et al. Iron-catalyzed radical cascade cyclization of oxime esters with isocyanides: synthesis of 1-cyanoalkyl isoquinolines and 6-cyanoalkyl phenanthridines
Pinto et al. Selective conjugate addition of nitromethane to enoates derived from D-mannitol and L-tartaric acid
CN112851744A (zh) 一种28-高芸苔素内酯的合成方法
CN111574444A (zh) 一种贝达喹啉的制备方法
JPH11501313A (ja) スピロ縮合アゼチジノンの触媒エナンチオ選択的合成
CN114716361A (zh) 一种合成手性螺环茚酮-吡咯类化合物的方法
WO2021254896A1 (fr) Procédé de préparation de (4s)-4-(4-cyano-2-méthoxyphényl)-5-éthoxy-2,8-diméthyl-1,4-dihydro-1,6-naphtyridine-3-carboxamide activé par une réduction catalytique asymétrique par esters de hantzsch
WO2024017221A1 (fr) PROCÉDÉ DE SYNTHÈSE D'UNE α-AZIDO CÉTONE CONTENANT UN STÉRÉOCENTRE TERTIAIRE
JPH11171861A (ja) ドネペジルの製造法
Yuan et al. A new and efficient asymmetric synthesis of 1‐amino‐1‐alkylphosphonic acids
Pan et al. Chiral Guanidine Catalyzed Annulation to the Core Structure of (‐)‐Huperzine A
CN107513056B (zh) 一种含四氢呋喃基团的喹啉类化合物的合成方法
CN115010753A (zh) 一种水相中制备磷酸化偕二氟二烯烃化合物的方法
CN110437277B (zh) 一种磷酸烯基酯类化合物的合成方法
CN111793017B (zh) 一种内酰胺化合物的制备方法
US6255540B1 (en) Methods for producing two-substituted glycerols having various levels of protection
CN114057717B (zh) 一种喹啉取代的双噁唑啉配体、其合成方法及其应用
WO2024040754A1 (fr) Procédé de synthèse de cis-2-méthyl-7-octadécène et de cis-7,8-époxy-2-méthyloctadécane
CN111393437B (zh) 三取代吲嗪类化合物及其制备方法
Inoue et al. Catalytic asymmetric intramolecular cyclopropanation of α-diazo-α-phosphoryl acetate
Matsumura et al. LITHIUM 1, 8-DIAZABICYCLO [5.4. 0] UNDEC-7-EN-6-IDE AS A NOVEL CARBON DIOXIDE CARRIER

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21731182

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21731182

Country of ref document: EP

Kind code of ref document: A1