Process for preparation of [Ru (OAc) 2 (ligand)] catalysts

Abstract

The present invention includes a process for preparing a [Ru (OAc) 2 (ligand)] catalyst of formula I, # imgabs0 # wherein R1 is a C1-6 alkyl group, and R3 is hydrogen or a C1-6 alkyl group, and R4 is hydrogen or a C1-6-alkoxy group. The [Ru (OAc) 2 (ligand)] catalyst is a general hydrogenation catalyst.

Description

[0001] The present invention relates to a novel process for preparing a [Ru(OAc)2(ligand)] catalyst of formula I and its enantiomers

[0002]

[0003] Where R 1 C 1-6 Alkyl, and R 3 is hydrogen or C 1-6 Alkyl, and R 4 is hydrogen or C 1-6 -alkoxy.

[0004] The [Ru(OAc)2(ligand)] catalyst is a versatile hydrogenation catalyst which has been successfully applied on a commercial scale for the enantioselective hydrogenation of intermediates in the synthesis of pharmaceutically active compounds (European Patent Application EP 1127886A1).

[0005] The object of the present invention is to provide an alternative process for the large-scale production of [Ru(OAc)2(ligand)] catalysts with high purity and yield.

[0006] It was found that this object can be achieved using a process for preparing a [Ru(OAc)2(ligand)] catalyst of formula I

[0007]

[0008] Where R 1 C 1-6 Alkyl, and R 3 is hydrogen or C 1-6 Alkyl, and R 4 is hydrogen or C 1-6 -alkoxy, the method comprises reacting a phosphine precursor of formula II

[0009]

[0010] Where R 1 , R 3 and R 4 As mentioned above,

[0011] Use [Ru(OAc)2(p-isopropyltoluene)], where Ac represents acetyl,

[0012] The conversion is carried out in the presence of a non-polar solvent at a reaction temperature of 40°C to 110°C.

[0013] The following definitions are set forth herein to illustrate and define the meaning and scope of the various terms used to describe the present invention.

[0014] Terminology C 1-6-Alkyl represents a straight-chain or branched alkyl radical of 1 to 6 C atoms. Representative radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, pentyl and its isomers, and hexyl and its isomers.

[0015] Terminology C 1-6 -Alkoxy represents a straight-chain or branched alkyl radical of 1 to 6 C atoms which is attached to an oxygen atom. Representative radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, pentoxy and its isomers, and hexoxy and its isomers.

[0016] In a preferred embodiment, R 1 C 1-4 -alkyl, more preferably methyl, R 3 C 1-4 -alkyl, more preferably tert-butyl, and R 4 is hydrogen or C 1-4 -alkoxy, more preferably hydrogen or methoxy.

[0017] Phosphine precursor of formula II

[0018]

[0019] Where R 1 , R 3 and R 4 As mentioned above, is commercially available, for example from Solvias, SigmaAldrich or Strem.

[0020] Preferred starting materials are compounds

[0021] (R)-3,5-tBu-4-MeO-MeOBIPHEP (CAS#352655-61-9), a compound of formula II, wherein R 1 is methyl, R 3 is tert-butyl, and R 4 is methoxy, and or

[0022] (R)-3,5-tBu-MeOBIPHEP (CAS#192138-05-9), a compound of formula II, wherein R 1 is methyl, R 4 is hydrogen, and R 3 It is tert-butyl.

[0023] (R)-MeOBIPHEP (CAS#133545-16-1), a compound of formula II, wherein R 1 is methyl, R 4 and R 3 For hydrogen.

[0024] [Ru(OAc)2(p-isopropyltoluene)] is generally readily prepared from commercially available [RuCl2(p-isopropyltoluene)]2 (CAS#52462-29-0), similar to the literature ((a) MA Bennett et al. J. Chem. Soc. Dalton Trans. 1983, 1571-1581, b.) PHDixneuf et al., Green Chem. 2011, 13, 3075-3078), synthesized as described in Examples 1.1 and 1.2, respectively.

[0025] As mentioned above, the process is carried out in the presence of a non-polar solvent.

[0026] Suitable non-polar solvents may be selected from tetrahydrofuran, toluene, benzene, 1,4-dioxane, 2-methyltetrahydrofuran, but preferably 2-methyltetrahydrofuran is used.

[0027] The upper limit of the reaction temperature is usually determined by the boiling point of the selected non-polar solvent. For toluene, the upper limit of the reaction temperature is 110°C. The lower limit can be selected at 40°C.

[0028] For the preferred solvent 2-methyltetrahydrofuran, the reaction temperature is preferably selected between 40 and 80 °C, more preferably between 70 and 80 °C.

[0029] The reaction is usually carried out under an inert gas atmosphere. Argon is a commonly used inert gas.

[0030] Usually, a conversion rate of about 90% to 95% can be achieved after about 24h to 40h reaction time. 31 P-NMR detection.

[0031] The [Ru(OAc)2(ligand)] catalyst of formula I can be isolated from the reaction mixture by methods known to those skilled in the art, for example by removing the solvent and drying the catalyst under vacuum at room temperature.

[0032] In a preferred embodiment of the present invention, separation from the reaction mixture is via solvent interchange or solvent swap, wherein the non-polar solvent used in the reaction is replaced by an anti-solvent, ie, a solvent in which the catalyst is not soluble.

[0033] Suitable antisolvents can be selected from linear or branched C 5-10 The alkane is preferably selected from n-pentane, n-hexane or n-heptane, more preferably selected from n-hexane.

[0034] In the first step, the reaction mixture was concentrated under vacuum.

[0035] After this time, the antisolvent is added and the mixture is concentrated under vacuum, typically at room temperature.

[0036] Subsequently, further cycles consisting of anti-solvent addition and subsequent concentration can be performed until the non-polar solvent is completely removed.

[0037] Two cycles have been found to be sufficient to remove the preferred non-polar solvent 2-methyltetrahydrofuran.

[0038] Eventually, the catalyst precipitates and can be filtered off. The filter cake can then be dried under vacuum, typically at room temperature, after washing with an anti-solvent.

[0039] Using this preferred separation procedure, the [Ru(OAc)2(ligand)] catalyst of Formula I can be obtained with a yield of up to 77% and an extremely high purity of up to >99.5%, while the residual non-polar solvent is close to 0 wt%.

[0040] Examples

[0041] abbreviation:

[0042]

[0043]

[0044] Example 1

[0045] Synthesis of [Ru(OAc)2(p-isopropyltoluene)]

[0046] Example 1.1

[0047] Under argon atmosphere, a 2L round-bottom flask with an argon inlet on top and a Teflon-coated stirring bar was charged with [RuCl2(p-isopropyltoluene)]2 (82.5 g, 0.14 mol) and silver acetate (98.9 g, 0.59 mol). Toluene (750 mL) was added, and the resulting yellow-brown suspension was stirred at room temperature for 23 h (by 1H-NMR spectroscopy confirmed complete conversion). DCM (100 mL) was added and the suspension was filtered through a high porosity glass sinter filter (P3) covered with a 2 cm filter press flocculation pad (MN2101, Macherey-Nagel). The filter cake was rinsed with DCM (300 mL) and the combined filtrate was evaporated to dryness at 50 mbar / 45°C. The dark red residue was dissolved in DCM (150 mL) and filtered through a high porosity glass sinter filter (P3) covered with a 2 cm filter press flocculation pad. The filter cake was rinsed with DCM (75 mL). Hexane (100 mL) was added to the combined filtrate and the solution was concentrated to about half volume at 400 mbar / 35°C. Hexane (100 mL) was added and the solution was concentrated to about half volume at 400 mbar / 35°C. This operation was repeated once to remove residual DCM and the product was precipitated respectively. The resulting suspension was stirred at room temperature for 30 min and the pale yellow supernatant was removed by suction using a tube equipped with a candle filter. The crystalline residue was washed with hexane (600 mL) in 3 portions, each time removing the supernatant by suction using a tube equipped with a candle filter. The residue was dried overnight at 1 mbar / room temperature to give the title compound (86.7 g, 91%) as a yellow-brown powder.

[0048] Example 1.2

[0049] Under argon atmosphere, a 100 mL round-bottom flask with an argon inlet and a Teflon-coated stirring bar was charged with [RuCl2(p-isopropyltoluene)]2 (5.0 g, 8.2 mmol) and potassium acetate (4.0 g, 40.8 mmol). Toluene (50 mL) was added and the resulting red suspension was stirred at room temperature for 24 h (by 1 H-NMR spectrum confirmed complete conversion). DCM (20 mL) was added, and the suspension was filtered through a high porosity glass sinter filter (P3) covered with a 2 cm filter press flocculation pad (MN2101, Macherey-Nagel). The filter cake was rinsed with DCM (80 mL), and the combined filtrate was evaporated to dryness at 50 mbar / 50 ° C. MeTHF (25 mL) was added to the dark red residue, and the mixture was heated to 75 ° C for 15 min to give a dark red solution. After cooling to room temperature, the formed suspension was stirred in an ice bath for 30 min, and the crude product was filtered out on a high porosity glass sinter filter (P3). The filter cake was washed with cold MeTHF (5 mL) and dried overnight at 1 mbar / room temperature to give the title compound (5.0 g, 86%) as a yellow-brown powder.

[0050] 1H-NMR (400MHz, CDCl3): δ (ppm) 5.80 (d, J = 5.9Hz, 2H), 5.58 (d, J = 6.2Hz, 2H), 2.86 (spt, J = 6.9Hz, 1H), 2.26 (s, 3H), 1.93 (s, 6H), 1.36 (d, J = 6.7Hz, 6H)

[0051] Example 2

[0052] Synthesis of [Ru(OAc)2((R)-3,5-tBu-4-MeO-MeOBIPHEP)]

[0053] Under argon atmosphere, a 250 mL Schlenk flask equipped with a reflux condenser, an argon inlet on top and a Teflon-coated magnetic stirring bar was charged with (R)-3,5-tBu-4-MeO-MeOBIPHEP (10.0 g, 8.68 mmol) and [Ru(OAc)2(p-isopropyltoluene)] (3.1 g, 8.68 mmol). MeTHF (80 mL) was added and the resulting brown suspension was stirred at 85°C (jacket temperature) for 40 h to achieve 91% conversion (via 31 P-NMR spectrum is determined). Make reaction mixture cool to room temperature, and be concentrated to the volume of 30mL to 40mL at 100mbar to 300mbar.Add hexane (40mL), the gained brown solution is cooled in an ice bath, and is filtered through the high porosity glass sinter filter (P3) covered with 2cm filter press flocculation pad (MN2101, Macherey-Nagel).Filter cake hexane (25mL) is rinsed, and the filtrate merged is concentrated to the volume of 30mL to 40mL at 100mbar to 300mbar / room temperature.Add another portion of hexane (40mL), and the gained solution is concentrated to the volume of 30mL to 40mL at 100mbar to 300mbar / room temperature, to remove residual MeTHF.Subsequently, add hexane (40mL), and the suspension formed is stirred at room temperature overnight, then cool in an ice bath, stir and reach 1h and filter out on high porosity glass sinter filter (P3). The filter cake was rinsed with hexane (20 mL) and dried at 0.05 to 0.1 mbar / room temperature for 4 h to afford the title compound (9.2 g, 77%) as an orange solid with a purity of >99% (by 31 P-NMR determination).

[0054] 31P-NMR (162 MHz, CDCl3): δ (ppm) 66.6 (s). Residual solvents: MeTHF (0.03 wt% (GC)), hexane (0.11 wt% (GC)), H2O (<0.1 wt% (Karl Fischer)).

[0055] Example 3

[0056] Synthesis of [Ru(OAc)2((R)-3,5-tBu-MeOBIPHEP)]

[0057] Under argon atmosphere, a 250 mL Schlenk flask equipped with a reflux condenser, an argon inlet on top and a Teflon-coated magnetic stirring bar was charged with (R)-3,5-tBu-MeOBIPHEP (10.0 g, 9.70 mmol) and [Ru(OAc)2(p-isopropyltoluene)] (3.8 g, 10.78 mmol). MeTHF (80 mL) was added and the resulting brown suspension was stirred at 85°C (jacket temperature) for 24 h to achieve 94% conversion (via 31 P-NMR spectrum confirmed). The reaction mixture was cooled to room temperature and concentrated to a volume of 30mL to 40mL at 100mbar to 300mbar. Hexane (40mL) was added, and the resulting solution was concentrated to a volume of 30mL to 40mL at 100mbar to 300mbar. This operation was repeated once to remove residual MeTHF. Subsequently, hexane (40mL) was added, and the solution was stirred overnight at room temperature. The reaction mixture was then heated to 40°C and filtered on a high porosity glass sintered filter (P3) with a 2cm filter press flocculation pad (MN2101, Macherey-Nagel). The filter cake was rinsed with hexane (30mL), and the combined filtrate was concentrated to a volume of 30mL at 100mbar to 300mbar / room temperature. The resulting dark brown suspension was heated to 60°C to provide a clear solution, which was then cooled to 0°C to 5°C. The formed precipitate was filtered off on a high porosity glass sinter filter (P3), the filter cake was washed with hexane (30 mL) and dried overnight at 0.05 to 0.1 mbar / room temperature to give the title compound (9.4 g, 70%) as a yellow solid with a purity of 98% (by 31 P-NMR confirmed), containing 2% (R)-3,5-tBu-MeOBIPHEP.

[0058] Optionally, the yellow solid can be recrystallized from hexane at 60°C (as described above) to give 31P-NMR pure (>99.5%) [Ru(OAc)2((R)-3,5-tBu-MeOBIPHEP)] (8.8 g, 65% overall yield).

[0059] 31 P-NMR (162MHz, CDCl3): δ (ppm) 67.5 (s). Residual solvent: MeTHF (0.00wt% (GC)), hexane (1.15wt% (GC)), H2O (<0.1wt% (Karl Fischer))

[0060] Example 4

[0061] Synthesis of [Ru(OAc)2((R)-MeOBIPHEP)]

[0062] Under argon atmosphere, a 100 mL Schlenk flask equipped with a reflux condenser, an argon inlet on top and a Teflon-coated magnetic stirring bar was charged with (R)-MeOBIPHEP (5.0 g, 8.58 mmol) and [Ru(OAc)2(p-isopropyltoluene)] (3.0 g, 8.58 mmol). MeTHF (40 mL) was added and the resulting brown suspension was stirred at 85°C (jacket temperature) for 20 h to achieve >99.5% conversion (via 31 P-NMR spectrum confirmed). The reaction mixture was cooled to room temperature and concentrated to a volume of 35 mL at 100 mbar to 300 mbar. The solution was filtered on a high porosity glass sintered filter (P3) with a 1.5 cm filter press flocculation pad (MN2101, Macherey-Nagel). The filter cake was rinsed with MeTHF (15 mL). Hexane (40 mL) was added to the combined filtrate, and the resulting dark suspension was cooled in an ice bath and stirred for 1 h. The solid was filtered off on a high porosity glass sintered filter (P3), the filter cake was washed with ice-cold MeTHF (40 mL) and dried at 0.05 mbar to 0.1 mbar / room temperature for 72 h to give the title compound (4.2 g, 61%) as a yellow solid with a purity of> 99.5% (by 31 P-NMR determination)

[0063] 31 P-NMR (162 MHz, CDCl3): δ (ppm) 63.4 (s). Residual solvents: MeTHF (0.03 wt% (GC)), hexane (0.11 wt% (GC)), H2O (0.3 wt% (Karl Fischer)).

[0064] Examples 5.1-5.3

[0065] Synthesis of [Ru(OAc)2((R)-3,5-tBu-4-MeO-MeOBIPHEP)]

[0066] Analogously to Example 2, (R)-3,5-tBu-4-MeO-MeOBIPHEP (500 mg, 0.434 mmol) and [Ru(OAc)2(p-isopropyltoluene)] (153 mg, 0.434 mmol) were dissolved in 4 ml of DCM or MeTHF, and the resulting suspension was stirred at the temperature described in Table 1. To determine the conversion at different time points, the reaction mixture was sampled and quenched by 31 P-NMR spectroscopy was used for analysis.

[0067] Table 1

[0068]

[0069] 1 Jacket temperature

[0070] Examples 6.1-6.3

[0071] Synthesis of [Ru(OAc)2((R)-MeOBIPHEP)]

[0072] Analogously to Example 4, (R)-MeOBIPHEP (250 mg, 0.429 mmol) and [Ru(OAc)2(p-isopropyltoluene)] (151 mg, 0.429 mmol) were dissolved in 4 ml of DCM or MeTHF and the resulting suspension was stirred at the temperature described in Table 2. To determine the conversion at different time points, the reaction mixture was sampled and quenched by 31 P-NMR spectroscopy was used for analysis.

[0073] Table 2

[0074]

[0075] 1 Jacket temperature

Claims

1. A method for preparing a [Ru(OAc)2(ligand)] catalyst of formula I and its enantiomers, Where R 1 C 1-6 Alkyl, and R 3 is hydrogen or C 1-6 Alkyl, and R 4 is hydrogen or C 1-6 - alkoxy, The method comprises treating a phosphine precursor of formula II Where R 1 , R 3 and R 4 As mentioned above, Use [Ru(OAc)2(p-isopropyltoluene)], where Ac represents acetyl, The conversion is carried out in the presence of a non-polar solvent at a reaction temperature of 40°C to 110°C.

2. The method according to claim 1, wherein R 1 It is methyl.

3. The method according to claim 1 or 2, wherein R 3 C 1-4 -alkyl, preferably tert-butyl.

4. The method according to any one of claims 1 to 3, wherein R 4 is hydrogen or C 1-4 - alkoxy, preferably hydrogen or methoxy.

5. The process according to any one of claims 1 to 4, wherein the non-polar solvent is selected from tetrahydrofuran, toluene, benzene, 1,4-dioxane and 2-methyltetrahydrofuran, preferably from 2-methyltetrahydrofuran.

6. The process according to any one of claims 1 to 5, wherein the reaction temperature is selected between 40°C and 110°C.

7. The process according to any one of claims 1 to 6, wherein the reaction is carried out under an inert gas atmosphere.

8. A process according to any one of claims 1 to 7, wherein the [Ru(OAc)2(ligand)] catalyst of formula I is separated from the reaction mixture via solvent exchange, wherein the non-polar solvent used in the reaction is replaced by an anti-solvent.

9. The method according to claim 8, wherein the anti-solvent is selected from a linear or branched C 5-10 The alkane is preferably selected from n-pentane, n-hexane or n-heptane.

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