Patent Application
20240018076
The invention relates to a process for the preparation of the chiral triol of the formula I
Chiral triols are versatile building blocks for the preparation of various pharmaceutically active drug substances such as for instance for statin drugs (A. Lenhart, W. D. Chey “Adv. Nutr. 2017, 8(4), 587-596).
The object of the present invention was to provide a process which allows the preparation of the chiral triol in a scalable manner with high enantiomeric purity and yield.
The object could be reached with the process for the preparation of the chiral triol of formula I
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.
The term “chiral” denotes the ability of non-superimposability with the mirror image, while the term “achiral” refers to embodiments which are superimposable with their mirror image. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention.
The term “chiral” signifies that the molecule can exist in the form of optically pure enantiomers, mixtures of enantiomers, optically pure diastereoisomers or mixtures of diastereoisomers.
In a preferred embodiment of the invention the term “chiral” denotes optically pure enantiomers or optically pure diastereoisomers.
The term “stereoisomer” denotes a compound that possesses identical molecular connectivity and bond multiplicity, but which differs in the arrangement of its atoms in space.
The term “diastereomer” denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers may have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.
The term “enantiomers” denotes two stereoisomers of a compound which are non-superimposable mirror images of one another.
In the structural formula presented herein a dashed bond (a) denotes that the substituent is below the plane of the paper and a wedged bond (b) denotes that the substituent is above the plane of the paper.
The spiral bond (c) denotes both options i.e. either a dashed bond (a) or a wedged bond (b).
The term “C-1-8-alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 8 carbon atoms. Examples of C1-8-alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl, hexyl, heptyl or octyl with its isomers. Preferably the term denotes a C-1-6-alkyl group.
The term “C3-8-cycloalkyl” denotes a saturated carbocycle of 3 to 8 carbon atoms. Examples of C3-8-cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl with its isomers. Preferably the term encompasses C4-7-cycloalkyl, more preferably cyclpentyl and cyclohexyl.
The term “C-1-6-alkoxy” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms attached to an oxygen atom. Examples of C1-6-alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or pentoxy or hexoxy with its isomers. Preferably the term denotes a C-1-4-alkoxy group, more preferably the methoxy group.
The term “halogen” denotes fluoro, chloro, bromo, or iodo.
The term “C-1-8-halogenalkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 8 carbon atoms which is substituted by one or more halogen atoms. Preferably the term denotes C-1-4-halogenalkyl, more preferably a methyl group which is substituted with one or more halogen atoms such as trifluoromethyl.
The ketone of formula IIa may occur in the mesomeric structures outlined in the scheme below. For the sake of clarity the formula IIa is consistently used throughout this description.
The process of the present invention can be illustrated with the scheme 1 below
The embodiments a) to d) are preferred, more preferred are the embodiments a), b) and d) and embodiment d) is most preferred.
In a preferred embodiment of the present invention the chiral triol has the formula Ia
In a further preferred embodiment of the present invention the chiral triol has the formula Ib
Scheme 2 illustrates a preferred embodiment of the invention.
a) The Asymmetric Hydrogenation of the Ketone of Formula IIa in the Sole Presence of an Ir-SpiroPAP Catalyst
The iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) are of the formula IIIa or IIIb, or enantiomers thereof
In a preferred embodiment
In a further preferred embodiment
In a further preferred embodiment the iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) are selected from the compounds
In a further preferred embodiment the iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) is selected from the compound
Suitable catalysts are typically commercially available e.g. from Jiuzhou Pharma in China.
The asymmetric hydrogenation can be performed in the presence of suitable organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar, preferably of 30 bar to 70 bar and at a reaction temperature of 10° C. to 90° C., preferably of 20° C. to 40° C.
The organic solvent can be selected from aliphatic alcohols selected from methanol, ethanol, isopropanol, tert-amylalcohol, from halogen substituted alcohols like trifluoroethanol, from haloalkanes like dichloromethane, from ethers like tetrahydrofuran or dioxane or from aromatic solvents like toluene or mixtures thereof Also suited are mixtures of aliphatic alcohols such as methanol or ethanol with water or with dioxane. The preferred solvent is methanol or ethanol, even more preferred ethanol.
Suitable bases are inorganic bases selected from alkali or earth alkali-carbonates or—hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines. Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-Diazabicyclo(2.2.2)octane (DABCO) and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), most preferred is DBU.
A substrate to catalyst ratio can expediently be chosen in a range of 100 to 10,000, preferably in a range of 1000 to 5000.
The chiral triol of formula I can be separated from the reaction mixture by evaporation of the solvent. Subsequent crystallization in a suitable solvent, typically in ketones like methyl isobutyl ketone or esters like isopropyl acetate renders the chiral triol of formula I in good yields, high purity and high enantiomeric excess.
b) The Asymmetric Hydrogenation of the Ketone of Formula IIa in the Presence of an In Situ Formed Ir-SpiroPAP Catalyst.
In another embodiment the iridium spiro-pyridylamidophosphine catalyst (Ir-SpiroPAP catalyst) of formula IIIa or IIIb may be prepared in situ in the course of the asymmetric hydrogenation reaction by bringing together a suitable Iridium-pre catalyst complex with a spiro-pyridylamidophosphine ligand of the formula
Preferred Iridium-pre catalyst complex compound is [IrCl(COD)]2.
Usually the iridium-pre catalyst complex compound and the spiro-pyridylamidophosphine ligand are typically mixed in the presence of the organic solvent and the base mentioned under embodiment a).
The substrate to Iridium ratio as a rule is adjusted between 100 and 10000, preferably between 1000 and 5000. The substrate to ligand ratio as a rule is adjusted between 0.5 and 1.5, preferably between 0.9 and 1.1.
The asymmetric hydrogenation conditions and the isolation of the chiral triol of formula I can otherwise be chosen as for the process of embodiment a). Also the preferred embodiments outlined in embodiment a) apply likewise.
c) The Asymmetric Hydrogenation of the Ketone of Formula IIa to the Ketone of Formula IIb in the Sole Presence of an Ir-PEN Catalyst and the Subsequent Asymmetric Hydrogenation to the Chiral Triol of Formula I in the Presence of the Ir-SpiroPAP Catalyst.
The iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVa or IVb, or enantiomers thereof
In a further preferred embodiment the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVa, or enantiomers thereof, wherein,
In a further preferred embodiment the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are of the formula IVb, or enantiomers thereof, wherein,
In a further preferred embodiment the iridium-phenylendiamine catalyst (Ir-PEN catalyst) are selected from compounds of the formula IVc and IVd
The asymmetric hydrogenation for the formation of the ketone of formula IIb of can be performed in the presence of suitable organic solvent at a hydrogen pressure of 5 bar to 100 bar, preferably of 30 bar to 70 bar and at a reaction temperature of 10° C. to 90° C., preferably of 20° C. to 40° C.
The organic solvent can be selected from aliphatic alcohols selected from methanol, ethanol, isopropanol, tert-amylalcohol, from halogen substituted alcohols like trifluoroethanol, from haloalkanes like dichloromethane, from ethers like tetrahydrofuran or dioxane or from aromatic solvents like toluene or mixtures thereof. Also suited are mixtures of aliphatic alcohols such as methanol or ethanol with water or with dioxane. The preferred solvent is methanol or ethanol, even more preferred ethanol.
The reaction can be performed without the presence of a base.
However, bases are tolerated. Suitable bases are inorganic bases selected from alkali or earth alkali-carbonates or—hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines. Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-Diazabicyclo(2.2.2)octane (DABCO) and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), most preferred is DBU.
A substrate to catalyst ratio can expediently be chosen in a range of 100 to 10000, preferably in a range of 500 to 1000.
The ketone of formula IIb can be separated from the reaction mixture by evaporation of the solvent. Subsequent crystallization in a suitable solvent, typically in an aliphatic alcohol like i-propanol renders the ketone of formula IIb in good yields, high purity and high enantiomeric excess. Alternatively the ketone of formula IIb is not isolated and is further hydrogenated to the chiral triol of formula I in the presence of the Ir-SpiroPAP catalyst.
The subsequent asymmetric hydrogenation can take place in the same manner as described in embodiment a)
d) The Asymmetric Hydrogenation of the Ketone of Formula IIa in the Presence of a Mixture of an Ir-SpiroPAP Catalyst and an Ir-PEN Catalyst.
In this embodiment the asymmetric hydrogenation is performed in the presence of a mixture of the Ir-SpiroPAP catalyst and an Ir-PEN catalyst.
Typically the Ir-PEN catalyst catalyzes the first step of the reaction i.e. the transformation to the ketone of formula IIb faster and with a higher chiral selectivity than the Ir-SpiroPAP catalyst.
Therefore, regarding catalyst concentration of the two catalysts a higher Ir-PEN catalyst concentration is as a rule applied.
The substrate to Ir-PEN catalyst ratio can therefore expediently be chosen in a range of 100 to 10000 preferably in a range of 500 to 1000.
The substrate to Ir-Spiro-PAP catalyst ratio can expediently be chosen in a range of 100 to 10000, preferably in a range of 2500 to 7500.
The asymmetric hydrogenation can be performed in the presence of suitable organic solvent and a base at a hydrogen pressure of 5 bar to 100 bar, preferably of 30 bar to 70 bar and at a reaction temperature of 10° C. to 90° C., preferably of 20° C. to 40° C.
The organic solvent can be selected from aliphatic alcohols selected from methanol, ethanol, isopropanol, tert-amylalcohol, from halogen substituted alcohols like trifluoroethanol, from haloalkanes like dichloromethane, from ethers like tetrahydrofuran or dioxane or from aromatic solvents like toluene or mixtures thereof. Also suited are mixtures of aliphatic alcohols such as methanol or ethanol with water or with dioxane. The preferred solvent is methanol or ethanol, even more preferred ethanol.
Suitable bases are inorganic bases selected from alkali or earth alkali-carbonates or—hydrogen carbonates or phosphates or hydrogenphosphates or dihydrogenphosphates or acetates or formates or organic bases selected from amines, alkali alcoholates or amidines. Organic bases are usually preferred. Typical representatives of organic bases are potassium tert-butylate or 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-Diazabicyclo(2.2.2)octane (DABCO) and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), most preferred is DBU.
The chiral triol of formula I can be separated from the reaction mixture by evaporation of the solvent. Subsequent crystallization in a suitable solvent, typically in ketones like methyl isobutyl ketone or esters like isopropyl acetate renders the chiral triol of formula I in good yields, high purity and high enantiomeric excess.
e) The Asymmetric Hydrogenation of Intermediate IIb, IIc or IId. In the Sole Presence of an Ir-SpiroPAP Catalyst
The intermediates IIb, IIc or IId typically need not to be isolated and can directly be converted to the desired chiral triol of formula I.
Intermediate IIb can be prepared and isolated in accordance with embodiment c).
Also intermediate IIc or IId can in principle be isolated by interrupting the hydrogenation at the appropriate stage and individually be subjected to the asymmetric hydrogenation with either the Ir-Spiro PAP catalyst alone or in the presence of a mixture of an Ir-SpiroPAP catalyst and an Ir-PEN catalyst. The reaction conditions as described in the previous embodiments can likewise be applied.
As outlined above the embodiments a) to d) are preferred, more preferred are the embodiments a), b) and d) and embodiment d) is most preferred.
Pre-Catalysts, Catalyst and Ligands:
627-630 and 6051-6056 were prepared according to T. Ohjuma et al. Organic Letters, 2007, 9, 2565. All other (pre-) catalysts and ligands were commercially available e.g. from Strem, Sigma Aldrich, Jiuzhou Pharma.
Analytical Methods
a) Achiral LC Method to Determine the Conversion and Purifies of 1, 3 and the Cis- and Trans-Isomers of 4-6
b) Chiral LC Method to Determine the Enantiomeric Purity of 3
c) Chiral LC Method to Determine the Enantiomeric Purifies of 3, 4, 5 and 6
1. Preparation of (R)-3 Via Asymmetric Hydrogenation of 1
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (20.0 g, 78.5 mmol), 630 (60.2 mg, 78.3×10−6 mol, S/C 1,000) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line, pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken after 1 h (50% conversion) and 2 h (>99.9% conversion) to follow the progress of the reaction. After a total reaction time of 2.5 h, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude (R)-3 (19.9 g) with 96.7 area-% purity and 94.3% ee. 0.9% of trans-4 was detected as major impurity (note: trans-4 demonstrated to have limited stability and converted during handling and storage gradually into trans-5).
Next, crude (R)-3 (5.00 g) was dissolved in iPr2O (25 mL) at 60° C. The clear solution was allowed to cool to 0° C. within 6 h and stirred at this temperature for another 1.5 h. The formed white crystals were filtered, washed with 9 mL of ice cold iPr2O and dried for 1 h at 40° C. under vacuum (10 mbar) to afforded pure (R)-3 (4.15 g, 82% yield) with 99.9 area-% purity and 99.6% ee.
Analytical Data for 3
LC-MS ESI (m/z): 256.0 [M+]
1H-NMR (CDCl3, 600 MHz): δ ppm 7.89 (d, J=8.8 Hz, 2H), 7.41-7.50 (m, 3H), 4.65 (td, J=5.8, 3.8 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 3.46-3.53 (m, 1H), 3.38-3.45 (m, 1H), 3.27 (d, J=5.6 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H)
Analytical Data for Trans-4
GC-MS ESI (m/z): 258.0 [M+]
1H NMR (DMSO-D6, 600 MHz): δ ppm 7.35-7.38 (m, 2H), 7.32-7.35 (m, 2H), 5.44 (br s, 2H), 4.73 (br d, J=9.6 Hz, 1H), 4.25 (br d, J=8.6 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 1.53-1.78 (m, 1H), 1.45-1.99 (m, 1H), 1.17 (t, J=7.1 Hz, 3H)
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (20.0 g, 78.5 mmol), 629 (48.4 mg, 78.3×10−6 mol, S/C 1,000) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line, pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. A reaction sample was taken after 3.5 h (98% conversion) to follow the progress of the reaction. After a total reaction time of 4 h, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude (R)-3 (20.0 g) with 94 area-% purity and 94.5% ee. 1.3% of trans-4 was detected as major impurity. Next, crude (R)-3 (20.0 g) was dissolved in iPr2O (200 mL) at 40° C. The clear solution was then allowed to cool to 0° C. within 6 h and stirred at this temperature for another 1.5 h. The formed white crystals were filtered, washed with 45 mL of ice cold iPr2O and dried for 1 h at 40° C. under vacuum (10 mbar) to afforded 15.62 g of pure (R)-3 (15.62 g, 78% yield) with 99.2 area-% purity and 99.8% ee.
In analogy to Example 1.1, 1 (0.5 g, 1.96 mmol) was hydrogenated for 20 h in EtOH (5 mL) and the presence of the catalysts as listed in Table 1 at 30° C. and an initial hydrogen pressure of 70 bar H2.
In analogy to Example 1.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 2 h in EtOH (5 mL) and the presence of the catalysts as listed in Table 2 at 30° C. and an initial hydrogen pressure of 70 bar H2.
In analogy to Example 1.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 2 h in EtOH (5 mL) at 30° C. in the presence of the catalysts (S/C 1,000) and initial hydrogen pressures as listed in Table 3.
In analogy to Example 1.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 2 h in EtOH (5 mL) at 30° C. and an initial hydrogen pressures of 70 bar in the presence of various amounts of catalysts and DBU as base as listed in Table 4.
2. Preparation of (R,R)-6 Via Asymmetric Hydrogenation of 1
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (10.0 g, 39.3 mmol), 680 (38.4 mg, 39.3×10−6 mol, S/C 1,000), DBU (597.8 mg, 3.93 mmol, S/B 10) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was run at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude 6 (9.0 g) with 98.4 area-% purity (DBU not integrated) and a trans cis ratio of 7.7. (R,R)-6 was obtained with 98.8% ee.
Analytical Data for Cis-5
GC-MS ESI (m/z): 212.0 [M+]
1H-NMR (DMSO-D6, 600 MHz): δ 7.47-7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 2H), 6.02 (br s, 1H), 5.40 (dd, J=10.8, 5.4 Hz, 1H), 4.62 (dd, J=10.7, 8.6 Hz, 1H), 2.89 (ddd, J=12.2, 8.2, 5.4 Hz, 1H), 1.93 (dt, J=12.1, 11.0 Hz, 1H)
Analytical Data for Trans-5
GC-MS ESI (m/z): 212.0 [M+]
1H-NMR (DMSO-D6, 600 MHz): δ 7.47 (d, J=8.7 Hz, 2H), 7.40-7.42 (m, 2H), 6.18 (br d, J=5.2 Hz, 1H), 5.68 (t, J=6.7 Hz, 1H), 4.38 (dt, J=7.0, 4.9 Hz, 1H), 2.44-2.48 (m, 1H), 2.36-2.42 (m, 1H)
Analytical Data for Trans-6
GC-MS ESI (m/z): 216.0 [M+]
1H NMR (400 MHz, DMSO) δ 7.40-7.31 (m, 4H), 5.23 (d, J=4.9 Hz, 1H), 4.75 (dd, J=9.9, 4.8 Hz, 1H), 4.50 (dd, J=6.5, 5.5 Hz, 2H), 3.68-3.67 (m, 1H), 3.30-3.24 (m, 2H), 1.67-1.61 (m, 1H), 1.44-1.39 (m, 1H).
13C NMR (101 MHz, DMSO) δ 146.6, 131.3, 128.4, 127.9, 68.7, 68.6, 66.8, 44.3.
Analytical Data for Cis-6
GC-MS ESI (m/z): 216.0 [M+]
1H-NMR (CDCl3, 600 MHz): δ ppm 7.31-7.34 (m, 2H), 7.32 (s, 2H), 4.98 (dd, J=9.9, 2.5 Hz, 1H), 4.04 (br d, J=2.4 Hz, 1H), 3.45-3.70 (m, 2H), 2.76 (s, 1H), 1.65-1.95 (m, 2H), 1.08 (s, 2H).
13C-NMR (CDCl3, 151 MHz) δ 142.7, 133.3, 128.7, 127.1, 73.82, 72.3, 66.7, 41.6.
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (10.0 g, 39.3 mmol), 601 (29.4 mg, 19.6×10−6 mol, S/Ir 1,000), 1508 (13.2 mg, 39.3×10−6 mol, S/L 1,000), DBU (597.8 mg, 3.93 mmol, S/B 10) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude 6 (9.1 g) with 96.5 area-% purity (DBU not integrated) and a trans/cis ratio of 8.3. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: trans-5 (0.8%)
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (10.0 g, 39.3 mmol), 601, 29.4 mg, 19.6×10−6 mol, S/Ir 1,000), 1508 (13.2 mg, 39.3×10−6 mol, S/L 1,000), KOtBu (437.6 mg, 3.93 mmol, S/B 10) and EtOH (200 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 42 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude 6 (9.0 g) with 84.2 area-% purity and a trans/cis ratio of 8.0. (R,R)-6 was obtained with 98.6% ee.
Specified impurity: trans-5 (0.9%)
In analogy to Example 2.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 20 h in EtOH (5 mL) at 30° C. and an initial hydrogen pressure of 70 bar in the presence KOtBu (4.9×10−5 mol, S/B 20) and of the catalysts (S/C 1,000) as listed in Table 5.
In analogy to Example 2.2, 1 (0.25 g, 0.98 mmol) was hydrogenated for 20 h in EtOH (5 mL) at 30° C. and an initial hydrogen pressure of 70 bar in the presence of 1508 (0.98×10−6 mol, S/L 1,000), the presence or absence of DBU (0.98×10−4 mol, S/B 10) and the presence of a pre-catalyst (S/Ir 1,000) as listed in Table 6.
In analogy to Example 2.1, 1 (0.10 g, 0.39 mmol or 0.25 g, 0.98 mmol) was hydrogenated for 20 h in EtOH (2 mL for 0.10 g scale experiments, resp. 4 mL for 0.25 g experiments) at 30° C. and an initial hydrogen pressure of 70 bar in the presence of 680 (9.8×10−7 mol, S/C 1,000), the presence of a base (S/B 10) as listed in Table 7.
In analogy to Example 2.1, 1 (0.25 g, 0.98 mmol) was hydrogenated for 20 h at 30° C. and an initial hydrogen pressure of 70 bar in the presence of 680 (either 0.98×10−6 mol, S/C 1,000 or 0.20×10−6 mol, S/C 5,000), the presence of KOtBu (0.98 mmol, S/B 10) and a solvent or solvent mixtures (5 mL) as listed in Table 8.
In analogy to Example 2.1, 1 (0.20 g, 0.79 mmol) was hydrogenated for 20 h in EtOH (5 mL) the presence of 680 (either 0.79×10−6 mol, S/C 9,000 or 0.16×10−6 mol S/C 5,000), the presence of various amounts of KOtBu, different temperatures and initial hydrogen pressures all as listed in Table 9.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 629 (1.21 mg, 1.96×10−6 mol, S/C 2,000), 680 (1.92 mg, 1.96×10−6 mol, S/C 2,000), DBU (59.8 mg, 3.93×10−4 mol, S/B 10) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 10) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 629 (2.42 mg, 3.93×10−6 mol, S/C 1,000), 680 (0.77 mg, 0.79×10−6 mol, S/C 5,000), DBU (30.0 mg, 1.97×10−4 mol, S/B 20) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 11) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 629 (2.42 mg, 3.93×10−6 mol, S/C 1,000), 680 (0.77 mg, 0.79×10−6 mol, S/C 5,000), DBU (5.98 mg, 3.93×10−5 mol, S/B 100) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 12) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.93×10−6 mol, S/C 1,000) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 30 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 30 bar for 4 h. Afterward the pressure was released to 1-2 bar and the autoclave returned to the glove box where under argon atmosphere it was opened and charged with 680 (0.77 mg, 0.79×10−6 mol, S/C 5,000), DBU (30.0 mg, 1.97×10−4 mol, S/B 20). The autoclave was sealed again and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. The reaction was continued for 18 h at to 70 bar and heated to 30° C. Reaction samples were taken at different time points (see Table 13) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.93×10−6 mol, S/C 1,000), 680 (0.77 mg, 0.79×10−6 mol, S/C 5,000), DBU (12.0 mg, 7.86×10−5 mmol, S/B 50) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 30 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 30 bar for 4 h. Afterward the pressure was increased to 70 bar and the reaction carried out for additional 19 h. Reaction samples were taken at different time points (see Table 14) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.93×10−6 mol, S/C 1,000), 680 (0.77 mg, 0.79×10−6 mol, S/C 5,000), DBU (12.0 mg, 7.86×10−5 mmol, S/B 50) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar for 23 h. Reaction samples were taken at different time points (see Table 15) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 180 mL autoclave was charged with 1 (1.00 g, 3.93 mmol), 630 (3.00 mg, 3.93×10−6 mol, S/C 1,000), 680 (0.77 mg, 0.79×10−6 mol, S/C 5,000), DBU (30.0 mg, 1.97×10−4 mol, S/B 20) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar for 23 h. Reaction samples were taken at different time points (see Table 16) to follow the progress of the reaction.
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (15.0 g, 59 mmol), 630 (45.1 mg, 5.9×10−5 mol, S/C 1,000), 680 (11.5 mg, 1.2×10−5 mol, S/C 5,000), DBU (179.3 mg, 1.2 mmol, S/B 50) and EtOH (300 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 17) to follow the progress of the reaction. After a total reaction time of 48 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (200 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to afford crude 6 (12.1 g—a higher yield would be achievable when omitting IPC sampling) with 99.4 area-% purity and a trans cis ratio of 15. (R,R)-6 was obtained with >99.9% ee.
Specified impurities: cis-6 (6.1%), trans-4 (0.2%), trans-5 (0.1%)
Next, crude (R,R)-6 (12.1 g) was suspended in iPrOAc (100 mL) and the slurry stirred for 2 h at 50° C. The suspension was cooled to 0° C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (60 ml) in 3 portions to afford after drying (25° C., 10 mbar) pure 6 (9.8 g, 77% yield) with 99.5 area-% purity and a trans cis ratio of 104. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (0.95%)
Subsequently, (R,R)-6 (9.8 g) from above was dissolved in iPrOAc (78 ml) at 90° C. The colorless solution was cooled to 25° C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25° C. for 2 h and cooled to 0° C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25° C., 10 mbar) off-white, crystalline 6 (9.0 g, 71% yield—a higher yield would be achievable when omitting IPC sampling during the hydrogenation run) with >99.9 area-% purity and a trans cis ratio of 713. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (0.14%)
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (15.0 g, 59 mmol), 630 (45.1 mg, 5.9×10−5 mol, S/C 1,000), 680 (11.5 mg, 1.2×10−5 mol, S/C 5,000), DBU (179.3 mg, 1.2 mmol, S/B 50) and EtOH (300 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 18) to follow the progress of the reaction. After a total reaction time of 23 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (200 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to afford crude 6 (12.4 g—a higher yield would be achievable when omitting IPC sampling) with 98.7 area-% purity and a trans/cis ratio of 14. (R,R)-6 was obtained with >99.9% ee.
Specified impurities: cis-6 (6.5%), trans-4 (0.2%), trans-5 (0.4%)
Next, crude (R,R)-6 (12.4 g) was suspended in DCM (100 mL) and the slurry stirred for 2 h at 50° C. The suspension was cooled to 0° C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold DCM (60 ml) in 3 portions to afford after drying (25° C., 10 mbar) pure 6 (11.0 g, 91% yield) with 99.8 area-% purity and a trans/cis ratio of 65. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (1.52%)
Subsequently, (R,R)-6 (11.0 g) from above was dissolved in iPrOAc (88 ml) at 90° C. The colorless solution was cooled to 25° C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25° C. for 2 h and cooled to 0° C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25° C., 10 mbar) off white, crystalline 6 (9.0 g, 75% yield—a higher yield would be achievable when omitting IPC sampling during the hydrogenation run) with >99.9 area-% purity and a trans/cis ratio of 713. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (0.14%)
In a glove box under argon atmosphere, a 380 mL autoclave was charged with 1 (15.0 g, 59 mmol), 630 (45.1 mg, 5.9×10−5 mol, S/C 1,000), 680 (11.5 mg, 1.2×10−5 mol, S/C 5,000), DBU (179.3 mg, 1.2 mmol, S/B 50) and EtOH (300 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 23 h (>99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (200 mL) from the autoclave into a 500 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to afford crude 6 (13.2 g) with 99.4 area-% purity and a trans cis ratio of 18. (R,R)-6 was obtained with >99.9% ee.
Specified impurities: cis-6 (5.1%), trans-5 (0.3%)
Next, crude (R,R)-6 (13.2 g) was suspended in iPrOAc (106 mL) and the slurry stirred for 2 h at 50° C. The suspension was cooled to 0° C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (60 ml) in 3 portions to afford after drying (25° C., 10 mbar) pure 6 (10.6 g, 83% yield) with 99.8 area-% purity and a trans cis ratio of 91. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (1.1%)
Subsequently, (R,R)-6 (10.6 g) from above was dissolved in iPrOAc (85 ml) at 90° C. The colorless solution was cooled to 25° C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25° C. for 2 h and cooled to 0° C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (30 ml) in 2 portions to afford after drying (25° C., 10 mbar) off-white, crystalline 6 (9.8 g, 77% yield) with >99.9 area-% purity and a trans cis ratio of 249. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (0.41%)
Analytical Data for Trans-6
GC-MS ESI (m/z): 216.0 [M+]
NMR (400 MHz, DMSO) δ 7.27-7.42 (m, 4H), 5.21 (d, J=4.8 Hz, 1H), 4.69-4.82 (m, 1H), 4.48 (br d, J=4.6 Hz, 2H), 3.62-3.75 (m, 1H), 3.20-3.31 (m, 2H), 1.59-1.73 (m, 1H), 1.42 (ddd, J=13.9, 9.5, 2.2 Hz, 1H).
3. Preparation of (R,R)-6 Via Asymmetric Hydrogenation of (R)-3
In a glove box under argon atmosphere, a 185 mL autoclave was charged with (R)-3 (1.00 g, 3.91 mmol, quality: 99.9% ee, 99.8 area-% purity), 680 (3.83 mg, 3.91×10−6 mol, S/C 1,000) and DBU (59.5 mg, 3.91×10−4 mol, S/B 10) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. Reaction samples were taken at different time points (see Table 19) to follow the progress of the reaction.
In analogy to Example 3.1, 3 (0.25 g, 0.98 mmol) was hydrogenated in the presence of 680 (0.19 mg, 0.20×10−6 mol, S/C 5,000) for 23 h in EtOH (4 mL) at 30° C. and the presence of DBU as base in amounts as listed in Table 20.
In a glove box under argon atmosphere, a 185 mL autoclave was charged with (R)-3 (6.0 g, 23.0 mmol, quality: 99.9% ee, 99.8 area-% purity) 680 (22.9 mg, 2.3×10−5 mol, S/C 1,000) and DBU (71.2 mg, 4.7×10−4 mol, S/B 50) and EtOH (120 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 23 h (99.9% conversion), the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (20 mL) from the autoclave into a 250 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude (R,R)-6 (5.2 g) with 98.7 area-% purity and a trans/cis ratio of 28. (R,R)-6 was obtained with >99.9% ee.
Specified impurities: cis-6 (3.40%), 3 (0.10%)
Next, crude (R,R)-6 (5.2 g) was suspended in iPrOAc (52 mL) and the slurry stirred for 2 h at 50° C. The suspension was cooled to 0° C. and stirred at this temperature for 1 h, filtered and the filter cake washed with ice-cold iPrOAc (30 ml) in 3 portions to afford after drying (25° C., 10 mbar) pure 6 (4.1 g, 81% yield) with 99.5 area-% purity and a trans/cis ratio of 125. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (0.79%)
Subsequently, (R,R)-6 (4.1 g) from above was dissolved in iPrOAc (34 ml) at 90° C. The colorless solution was cooled to 25° C. within 2 h whereby the product started to crystallize. The formed suspension was kept at 25° C. for 2 h and cooled to 0° C. within 30 min. The crystals were filtered and washed with ice-cold iPrOAc (14 ml) in 2 portions to afford after drying (25° C., 10 mbar) off white, crystalline 6 (3.7 g, 73% yield) with >99.9 area-% purity and a trans/cis ratio of 586. (R,R)-6 was obtained with >99.9% ee.
Specified impurity: cis-6 (0.17%)
4. Preparation of (R,R)-6 Via Asymmetric Hydrogenation of (R,R)-5
In a glove box under argon atmosphere, a 185 mL autoclave was charged with (R,R)-5 (1.00 g, 4.71 mmol; quality: 99.9% ee, 99.9 area-% purity), 680 (4.62 mg, 4.71×10−6 mol, S/C 1,000), DBU (71.7 mg, 4.71×10−4 mol, S/B 10) and EtOH (20 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. A reaction sample was taken at different time points (see Table 21) to follow the progress of the reaction.
In analogy to Example 4.1, (R,R)-5 (0.25 g, 1.18 mmol; quality: 99.9% ee, 99.9 area-% purity) was hydrogenated in the presence of 680 (0.23 mg, 2.36×10−7 mol, S/C 5,000) and DBU (9.0 mg, 0.59×10−4 mol, S/B 20) in EtOH (5 mL) to yield after 20 h at 30° C. and an initial hydrogen pressure of 70 bar crude (R,R)-6 with 96.7% purity and >99.9% ee (99% conversion; trans cis ratio >100)
5. Preparation of (R,R)-8 Via Asymmetric Hydrogenation of 7
In a glove box under argon atmosphere, a 35 mL autoclave was charged with 7 (250 mg, 1.1 mmol), 680 (1.1 mg, 1.1×10−6 mol, S/C 1,000), KOtBu (12.1 mg, 1.1×10−4 mol, S/B 10) and EtOH (5 mL). The autoclave was sealed and removed from the glove box, connected to a hydrogen line and pressurized with hydrogen gas to 70 bar and heated to 30° C. Under stirring, the hydrogenation was ran at a constant hydrogen pressure of 70 bar. After a total reaction time of 20 h, the autoclave was vented and allowed to cool to room temperature. The reaction mixture was transferred with aid of EtOH (5 mL) from the autoclave into a 50 mL round bottomed flask and the orange reaction solution rotatory evaporated at 40° C./10 mbar to constant weight to yield crude trans-8 (presumable major enantiomer: (R,R)-8, 245 mg) with >95% LC/MS purity.
Analytical Data for Trans-8
GC-MS ESI (m/z): 182.1 [M+]
1H-NMR (CDCl3, 600 MHz): δ ppm 7.30-7.42 (m, 1H), 7.28-7.42 (m, 3H), 5.03 (br d, J=3.8 Hz, 1H), 3.98 (br s, 1H), 3.44-3.64 (m, 2H), 3.03-3.44 (m, 2H), 2.38-2.86 (m, 1H), 1.72-2.03 (m, 3H)
13C-NMR (CDCl3, 151 MHz): δ ppm 144.2, 128.5, 127.5, 125.5, 71.4, 69.4, 66.8, 41.0 ppm
| Number | Date | Country | Kind |
|---|---|---|---|
| 21151758.6 | Jan 2021 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/EP2022/050575 | Jan 2022 | US |
| Child | 18351377 | US |
