ASYMMETRIC TRANSFER HYDROGENATION OF 2-ARYL SUBSTITUTED BICYCLIC PYRIDINE KETONES IN PRESENCE OF A CHIRAL RUTHENIUM CATALYST

Abstract

The invention relates to a process for preparing optically active 2-aryl substituted 6,7-dihydro-5H-cyclopenta[b]pyridin-7-ols comprising asymmetric transfer hydrogenation of the corresponding ketones in presence of a ruthenium catalyst comprising a chiral diamine or amino alcohol ligand.

Claims

1. A process for preparing a compound of formula (Ia) or (Ib), ##STR00031## where R.sup.1 and R.sup.2 are independently from one another selected from the group consisting of hydrogen and C.sub.1-C.sub.4-alkyl, each R.sup.3, if present, is independently selected from C.sub.1-C.sub.4-alkyl, and n is 0, 1, 2 or 3,  comprising asymmetric transfer hydrogenation of a ketone of formula (II) ##STR00032##  in which the substituents R.sup.1, R.sup.2, R.sup.3 and the integer n are as defined for the compound of formula (Ia) or (Ib), in presence of a chiral ruthenium catalyst and a polar solvent, wherein the ruthenium catalyst comprises a chiral amino alcohol ligand or a chiral diamine ligand.

2. The process according to claim 1, wherein the chiral ruthenium catalyst comprises a chiral ligand of formula (IIIa), (IIIb), (IVa) or (IVb) ##STR00033## where Y is NR.sup.7 or O, R.sup.4 is phenylsulphonyl, wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl and halogen, or R.sup.4 is 2-pyrrolidinylcarbonyl or 2-piperidinylcarbonyl, R.sup.5 and R.sup.6 together form a —(CH.sub.2).sub.3— or —(CH.sub.2).sub.4— group, or R.sup.5 and R.sup.6 are independently of one another selected from phenyl, which is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl, R.sup.7 is hydrogen, phenyl-(CH.sub.2).sub.3—, phenyl-(CH.sub.2).sub.4—, benzyloxymethyl, benzyloxyethyl or phenyl-(CH.sub.2).sub.2—O—CH.sub.2—, wherein the phenyl and benzyl groups are optionally substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl, R.sup.8 is C.sub.2-C.sub.6-alkyl and R.sup.9 is hydrogen, or  R.sup.8 and R.sup.9 are independently of one another selected from phenyl, which is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl, or R.sup.8 and R.sup.9 form together a group of formula ##STR00034##  wherein the bond marked with “*” is connected to the carbon bearing the hydroxyl group and the bond marked with “#” is connected to the carbon bearing the amino group, and wherein m is 0 or 1, x is 0, 1 or 2, and each R.sup.10, if present, is independently selected from C.sub.1-C.sub.4-alkyl.

3. The process according to claim 1, wherein the chiral ruthenium catalyst has formula (Va), (Vb), (VIa) or (VIb): ##STR00035## where Z is NR.sup.13 or O, R.sup.4 is phenylsulphonyl, wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl and halogen, or R.sup.4 is 2-pyrrolidinylcarbonyl, R.sup.5 and R.sup.6 together form a —(CH.sub.2).sub.4— group, or R.sup.5 and R.sup.6 are unsubstituted phenyl, each R.sup.11, if present, is independently selected from C.sub.1-C.sub.4-alkyl, R.sup.12 is C.sub.1-C.sub.4-alkyl or hydrogen and R.sup.13 is hydrogen, or R.sup.12 and R.sup.13 form together a —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —CH.sub.2—O—CH.sub.2—, *—(CH.sub.2).sub.2—O—CH.sub.2—# or *—(CH.sub.2)—O—(CH.sub.2).sub.2—# group, where the bond marked with “*” is bonded to the nitrogen and the bond marked with “#” is bonded to the phenyl ring, q is 0, 1, 2, 3, 4 or 5, X.sup.1 is chlorine or bromine, or X.sup.1 is BF.sub.4.sup.−, PF.sub.6.sup.− or SbF.sub.6.sup.−, in which case the Ru—X.sup.1 bond is of a coordinative or ionic nature and the Ru has a positive charge, R.sup.8 and R.sup.9 are unsubstituted phenyl, or R.sup.8 and R.sup.9 form together a group of formula ##STR00036##  wherein the bond identified by “*” is connected to the carbon bearing the hydroxyl group and the bond identified by “#” is connected to the carbon bearing the amino group,  each R.sup.14, if present, is independently selected from C.sub.1-C.sub.4-alkyl, p is 0, 1, 2, 3, 4, 5 or 6, and X.sup.2 is chlorine or bromine, or X.sup.2 is BF.sub.4.sup.−, PF.sub.6.sup.− or SbF.sub.6.sup.−, in which case the Ru—X.sup.2 bond is of a coordinative or ionic nature and the Ru has a positive charge.

4. The process according to claim 2, wherein the chiral ruthenium catalyst comprises a chiral ligand of formula (IIIa), (IIIb), (IVa) or (IVb), where Y is NR.sup.7 or O, R.sup.4 is phenylsulphonyl, wherein the phenyl is unsubstituted or substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl and halogen, or R.sup.4 is (2S)-2-pyrrolidinylcarbonyl, R.sup.5 and R.sup.6 together form a —(CH.sub.2).sub.4— group, or R.sup.5 and R.sup.6 are unsubstituted phenyl, R.sup.7 is hydrogen, phenyl-(CH.sub.2).sub.3—, phenyl-(CH.sub.2).sub.4—, benzyloxymethyl, benzyloxyethyl or phenyl-(CH.sub.2).sub.2—O—CH.sub.2— group, wherein the phenyl and benzyl groups are optionally substituted with one or more substituents independently selected from C.sub.1-C.sub.4-alkyl, R.sup.8 and R.sup.9 are unsubstituted phenyl, or R.sup.8 and R.sup.9 form together a group of formula ##STR00037##  wherein the bond marked with “*” is connected to the carbon bearing the hydroxyl group and the bond marked with “#” is connected to the carbon bearing the amino group.

5. The process according to claim 2, wherein the chiral ruthenium catalyst comprises a chiral ligand of formula (IIIa) or (IIIb).

6. The process according to claim 1, wherein the compounds of formulae (Ia), (Ib) and (II) are compounds of formulae (Ia′), (Ib′) and (II′) ##STR00038## wherein R.sup.1, R.sup.3a and R.sup.3b are independently of one another selected from C.sub.1-C.sub.4-alkyl.

7. The process according to claim 6, wherein R.sup.1 is methyl, R.sup.3a is methyl, and R.sup.3b is ethyl.

8. The process according to claim 1, wherein the hydrogen source is selected from the group consisting of sodium formate, potassium formate, lithium formate, calcium formate, magnesium formate, formic acid/triethylamine, potassium tert-butylate/isopropanol, sodium tert-butylate/isopropanol and lithium tert-butylate/isopropanol.

9. The process according to claim 1, wherein the hydrogen source is sodium formate or formic acid/triethylamine.

10. The process according to claim 1, wherein the amount of ruthenium catalyst used is within a range of from 0.1 mol % to 5 mol %, based on amount of the compound of formula (II).

11. The process according to claim 1, wherein transfer hydrogenation is conducted at a temperature within a range of from 20° C. to 80° C.

12. The process according to claim 1, wherein the polar solvent is selected from the group consisting of dichloromethane, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, dimethylformamide, acetonitrile, methanol/water, ethanol/water, isopropanol/water, n-butanol/water, tetrahydrofuran/water, 2-methyl-tetrahydrofuran/water, dimethylformamide/water, acetonitrile/water, and mixtures thereof.

13. The process according to claim 3, wherein R.sup.12 is C.sub.1-C.sub.4-alkyl and Z is O or NH, and wherein the chiral ruthenium catalyst is formed in situ by mixing a dichloro (aromatic ligand)ruthenium (II) dimer precatalyst or a dibromo (aromatic ligand)ruthenium (II) dimer precatalyst with a chiral ligand of formula (IIIa′), (IIIb′), (IVa) or (IVb), ##STR00039## wherein R.sup.4, R.sup.5 and R.sup.6 are each as defined for the complexes of formulae (Va) and (Vb), Z is NH or O, R.sup.8 and R.sup.9 are each as defined for the complexes of formulae (VIa) and (VIb), and wherein the aromatic ligand of the precatalyst is selected from the group consisting of p-cymene and benzene, which is optionally substituted with one or more methyl groups, in an organic solvent.

14. The process according to claim 1, wherein the product of formula (Ia) or (Ib) or a mixture thereof is purified by forming a crystalline addition salt with camphor sulfonic acid.

15. The process according to claim 1, wherein the ketone of formula (II) is obtained from a racemic mixture of the compounds of formulae (Ia) and (Ib) ##STR00040## wherein the substituents R.sup.1, R.sup.2, R.sup.3 and the integer n are each as defined for the compound of formula (II), by oxidation using TEMPO, a TEMPO derivative or a TEMPO analogue, a hypochlorite salt and optionally a bromide salt.

Description

EXAMPLES

Preparation of the Starting Material (II′-1) by TEMPO-Mediated Oxidation of (Ia′-1)/(Ib′-1)

[0174] ##STR00015##

Example 1

[0175] A racemic mixture of compounds (Ia′-1) and (Ib′-1) (93.3% w/w, 1421.5 g, 4489 mmol), TEMPO (35 g, 224 mmol), potassium bromide (53 g, 449 mmol), tetrabutylammonium bromide (72 g, 224 mmol), dichloromethane (6.8 L) and saturated sodium bicarbonate solution (made with 4.5 L of water) were placed in a reactor. The beige colored mixture was cooled down to 0° C. and a mixture of sodium hypochlorite solution (13.4% w/w, total amount needed: 3530 g, 5454 mmol, 1.215 equiv) and saturated sodium bicarbonate solution (total amount needed: 3.81 kg) was added at 0° C. (±4° C.) under temperature control until in-process control (HPLC@220 nm) showed complete conversion of starting material. The reaction mixture was transferred into a stirring vessel and was diluted with water (2.8 L). The aqueous phase was separated and re-extracted with dichloromethane (5.6 L). The combined organic layers were washed with water (5.6 L) and filtered through a sodium sulfate plug (1 kg), which was rinsed with dichloromethane (2.8 L). 10 L of solvent were distilled off (40° C.) and 6 L of heptane were added. Again 4.5 L of solvent were distilled off and replaced by heptane. 1 L of heptane was distilled off and the solution was seeded by adding 2 g of compound (II′-1) to initiate crystallization. The suspension was concentrated at 45° C. to a total mass of 8 kg, cooled down and rotated at 0-5° C. for 3 hours. The solid was filtered off and washed with cold heptane (5 L, 0-5° C.). The solid was dried under vacuum at 40-45° C.

[0176] Mass: 1273 g (97% of theory); Appearance: beige solid; HPLC (220 nm): ≥99% area; Assay (1H-NMR, DMSO-d6, TMB as Standard): 96%. Yield (mass yield x assay): 93% of compound (II′-1).

Example 2

[0177] A racemic mixture of compounds (Ia′-1) and (Ib′-1) (0.13 g, 0.44 mmol), 4-hydroxy-TEMPO (3.8 mg, 0.022 mmol), potassium bromide (15 mg, 0.044 mol), tetrabutylammonium bromide (7.1 mg, 0.022 mmol), dichloromethane (2.6 mL) and saturated sodium bicarbonate solution (1.3 mL) were placed in a vial under inert atmosphere (N.sub.2). The beige colored mixture was cooled down to 0° C. and a mixture of sodium hypochlorite solution (10-14% w/w, 0.7 mL) and saturated sodium bicarbonate solution (0.9 mL) was added dropwise at 0° C. (±4° C.) during 5 min. After 20 min stirring at this temperature, in-process control (HPLC@220 nm) showed complete conversion of starting material and 82.9% a/a of compound (II′-1).

Example 3

[0178] A racemic mixture of compounds (Ia′-1) and (Ib′-1) (0.13 g, 0.44 mmol), silica-supported TEMPO (0.35 mmol TEMPO per gramm of material, 63 mg, 0.022 mmol), potassium bromide (15 mg, 0.044 mol), tetrabutylammonium bromide (7.1 mg, 0.022 mmol), dichloromethane (2.6 mL) and saturated sodium bicarbonate solution (1.3 mL) were placed in a vial under inert atmosphere (N.sub.2). The beige colored mixture was cooled down to 0° C. and a mixture of sodium hypochlorite solution (10-14% w/w, 0.7 mL) and saturated sodium bicarbonate solution (0.9 mL) was added dropwise at 0° C. (±4° C.) during 5 min. After 20 min stirring at this temperature, in-process control (HPLC@220 nm) showed complete conversion of starting material and 96.6% a/a of compound (II′-1).

Example 4

[0179] A racemic mixture of compounds (Ia′-1) and (Ib′-1) (0.13 g, 0.44 mmol), polystyrene-supported TEMPO (1 mmol TEMPO per gramm of material, 22 mg, 0.022 mmol), potassium bromide (15 mg, 0.044 mol), tetrabutylammonium bromide (7.1 mg, 0.022 mmol), dichloromethane (2.6 mL) and saturated sodium bicarbonate solution (1.3 mL) were placed in a vial under inert atmosphere (N.sub.2). The beige colored mixture was cooled down to 0° C. and a mixture of sodium hypochlorite solution (10-14% w/w, 0.7 mL) and saturated sodium bicarbonate solution (0.9 mL) was added dropwise at 0° C. (±4° C.) during 5 min. After 20 min stirring at this temperature, in-process control (HPLC@220 nm) showed complete conversion of starting material and 90.4% a/a of compound (II′-1).

Asymmetric Transferhydrogenation

[0180] Reactions were performed in glass vessels of appropriate dimensions. Unless stated otherwise, reaction mixtures were analyzed without workup via HPLC (Chiralpak IC column, heptane/ethanol gradient (with 0.02% of diethylamine as stabilizing additive), 1 mL/min).

Preparation of Chiral Ruthenium Catalysts

[0181] ##STR00016## ##STR00017## ##STR00018##

[0182] The catalysts used in examples 5-14 were preformed prior to reaction by dissolving a ruthenium (II) catalyst precursor ([RuCl.sub.2(p-cymene)].sub.2 or [RuCl.sub.2(hexamethylbenzene].sub.2, 1.0 equiv.) in DCE at 60° C., adding the ligand given in table 1 (1.2 equiv.) and stirring of the solution for 1 h at 60° C., followed by evaporation of DCE.

[0183] The following catalysts are commercially available and were used as purchased in examples 15-34:

##STR00019##

Transfer Hydrogenation Reaction

[0184] ##STR00020##

[0185] Under an inert gas atmosphere, one well of a 96 well-plate autoclave was filled with 9.7 mg of ketone starting material (II′-1) (33 μmol, 1 equiv), reductant (see table 1; NaCO.sub.2H: 2.5 equiv.; HCO.sub.2H/NEt.sub.3: 2.7 equiv./0.6 equiv., respectively), 0.66 μmol of catalyst (2 mol %, see table 1) in the respective solvent mixture (see table 1, starting material concentration is 0.13 M). The autoclave was closed and heated to 35° C. and the reaction mixture was shaken at that temperature for 17 h. Chromatographic analysis of the cooled and de-pressurized reaction mixture showed the % a/a HPLC conversion rates of starting material (II′-1) to the reduced alcohol product (Ia′-1) or (Ib′-1). The % a/a HPLC conversion rates and enantioselectivities are depicted in table 1 below.

TABLE-US-00002 TABLE 1 Catalyst Product Conversion Precursor.sup.1)/ (major (% a/a % Ex. Catalyst.sup.2) Ligand Solvent Reductant enantiomer) HPLC) ee  5 [RuCl.sub.2(p-cymene)].sub.2 [00021] iPrOH; H.sub.2O HCO.sub.2Na (Ib′-1) 79.9 56.4  6 [RuCl.sub.2(p-cymene)].sub.2 [00022] DMF; H.sub.2O HCO.sub.2Na (Ib′-1) 43.9 80.3  7 [RuCl.sub.2(p-cymene)].sub.2 [00023] .sup.iPrOH; H.sub.2O HCO.sub.2Na (Ia′-1) 100 92.3  8 [RuCl.sub.2(hexa- methylbenzene)].sub.2 [00024] MeTHF; H.sub.2O HCO.sub.2Na (Ib′-1) 100 97.9  9 [RuCl.sub.2(p-cymene)].sub.2 [00025] MeCN; H.sub.2O HCO.sub.2Na (Ib′-1) 100 96.1 10 [RuCl.sub.2(p-cymene)].sub.2 [00026] DMF HCO.sub.2H; NEt.sub.3 (Ib′-1) 86.9 89.1 11 [RuCl.sub.2(p-cymene)].sub.2 [00027] DMF; H.sub.2O HCO.sub.2Na (Ib′-1) 100 96.8 12 [RuCl.sub.2(p-cymene)].sub.2 [00028] MeTHF; H.sub.2O HCO.sub.2Na (Ia′-1) 97.2 84 13 [RuCl.sub.2(hexa- methylbenzene)].sub.2 [00029] MeCN; H.sub.2O HCO.sub.2Na (Ib′-1) 98.4 30.4 14 [RuCl.sub.2(p-cymene)].sub.2 [00030] EtOH; H.sub.2O HCO.sub.2Na (Ib′-1) 21.8 16.7 15 (Va-1) — EtOH HCO.sub.2H; (Ia′-1) 100 97.5 NEt.sub.3 16 (Va-1) — DMF; HCO.sub.2Na (Ia′-1) 98.9 95.9 H.sub.2O 17 (Va-1) — MeTHF HCO.sub.2H; (Ia′-1) 83.0 93.6 NEt.sub.3 18 (Va-1) — MeCN; HCO.sub.2Na (Ia′-1) 99.1 97.3 H.sub.2O 19 (Vb-2) — EtOH HCO.sub.2H; (Ib′-1) 100 97.1 NEt.sub.3 20 (Vb-2) — DMF; HCO.sub.2Na (Ib′-1) 100 94.5 H.sub.2O 21 (Vb-2) — MeTHF HCO.sub.2H; (Ib′-1) 100 95.5 NEt.sub.3 22 (Vb-2) — MeCN; HCO.sub.2Na (Ib′-1) 100 96.9 H.sub.2O 23 (Va-3) — EtOH HCO.sub.2H; (Ia′-1) 100 92.1 NEt.sub.3 24 (Va-3) — DMF; HCO.sub.2Na (Ia′-1) 98.5 98.5 H.sub.2O 25 (Va-3) — MeTHF HCO.sub.2H; (Ia′-1) 96.6 91.6 NEt.sub.3 26 (Va-3) — MeCN; HCO.sub.2Na (Ia′-1) 100 98.7 H.sub.2O 27 (Vb-4) — EtOH HCO.sub.2H; (Ib′-1) 100 96.2 NEt.sub.3 28 (Vb-4) — MeTHF HCO.sub.2H; (Ib′-1) 100 96.6 NEt.sub.3 29 (Vb-4) — DMF; HCO.sub.2Na (Ib′-1) 98.2 96.3 H.sub.2O 30 (Va-5) — EtOH HCO.sub.2H; (Ia′-1) 100 94.1 NEt.sub.3 31 (Va-5) — MeTHF HCO.sub.2H; (Ia′-1) 100 91.9 NEt.sub.3 32 (Va-5) — DMF; HCO.sub.2Na (Ia′-1) 98.9 96.7 H.sub.2O .sup.1): The catalysts used in examples 5-12 are complexes of the formula (Va), (Vb) or (VIa). These catalysts were preformed prior to the reaction from the catalyst precursors and ligands given in the table according to the method described above. The catalysts used in examples 13 and 14 were prepared accordingly. 2): The catalysts used in examples 15-32 are commercially available and were employed as purchased.

Example 33

[0186] All solvents and solutions for the reaction and work-up procedure were degassed with argon before use. Ketone starting material (II′-1) (9.4 g, 32 mmol) and ethanol (70 ml) were placed in a 50 ml three necked round bottom flask under argon atmosphere. Argon was bubbled through the suspension for 15 minutes before catalyst (Va-3) (2 mol %, 379 mg, 0.64 mmol) was added. A solution of sodium formate (24 g, 352 mmol) in water (94 ml) was added. The reaction was stirred at 35° C. (bath temperature) overnight (16 h). In a separation funnel, the oily upper layer was separated and the aqueous phase was extracted with heptane (50 ml). The combined upper layers were diluted with heptane (25 ml) and washed with water (50 ml). The separated aqueous phase was re-extracted with heptane (40 ml). The combined organic phases were washed with water (50 ml) and brine (aqueous, 30%, 30 ml).

Purification by Silica Plug Filtration

[0187] A column was filled with silica gel 60 (Fluka 89943, 50 g) as slurry in heptane. The organic layer from the extraction was directly applied on the column and eluted with a gradient from heptane (100%) to heptane/MeTHF 3/1 (v/v). Product fractions were evaporated in vacuum yielding 9.3 g of beige/brown solid (Assay: 96% w/w, 94% yield, 97% ee).

Example 34

[0188] The reaction was performed under inert gas atmosphere. All solvents and solutions for the reaction and work-up procedure were degassed with argon prior to use. Compound (II′-1) (1230 g, 4025 mmol) and catalyst (Va-3) (54 g, 80 mmol) were placed in 20-L round bottom flask under inert gas atmosphere (Argon). Acetonitrile (4 L) was added and the mixture was mixed (30° C.) to get a brownish to red solution (Solution 1). Sodium formate (1369 g, 20.1 mol) was dissolved in degassed water (7 L). The solution was three times evacuated and flushed with argon (Solution 2). Solution 1 was placed in a reactor (flask rinsed with 0.5 L of acetonitrile) followed by Solution 2 (flask rinsed with 1 L of water).

[0189] The mixture was heated up to 35° C. within about 45 minutes and stirred at this temperature for one hour. Process control showed full conversion of the starting material (II′-1). The reaction mixture was cooled down to 25° C. and transferred into a separation vessel and the phases were separated. The aqueous layer was re-extracted with Heptane (3.7 L). The mixed organic phases (biphasic mixture) was washed with 2×1.85 L half saturated aqueous sodium bicarbonate, followed by 1.85 L of saturated aqueous sodium bicarbonate solution. The organic layer was filtered over a sodium sulfate plug (800 g) and rinsed with heptane (2×1 L). The solvent was evaporated under vacuum (45° C.) giving 1260 g of a brownish to violet resin.

[0190] Analytics: HPLC achiral (220 nm): 97.6% area, HPLC chiral (220 nm): ee 99.7%. The chemical yield was determined after purification via salt-formation and freebasing (cf. example 35).

Camphersulfonic Acid Salt Formation

Example 35

[0191] Crude (Ia′-1) (from example 34, 1321 g) was dissolved in MeTHF (7 L) at 50° C. A solution of (1S)-(+)-10-camphor sulfonic acid (981 g, 4221 mmol) in MeTHF (4 L) was added continuously at 50° C. within 20 minutes; the solution was seeded while adding. After complete addition, the formed suspension was stirred for additional 30 minutes at 50° C. and then cooled down to 20° C. within 1 hour. The solid was filtered off, washed with MeTHF (2×1 L) and dried under vacuum at 45° C.

[0192] Yield: 1947 g (87% of theory) white solid, HPLC (220 nm): ≥99% area

[0193] 1945 g of this material was dissolved in MeTHF (13 L) and water (5 L). 1.65 L of aqueous, saturated Na.sub.2CO.sub.3-solution was added to increase to pH to 10). The phases were separated, and the organic layer was washed with water (3.3 L) and brine (30%, 1.6 L). The organic layer was filtered over a sodium sulfate plug (1 kg) and rinsed with MeTHF (1.5 L). The solvent was evaporated in vacuum (45° C.). The residue was co-evaporated with heptane (3×1.3 L).

[0194] Yield: 1087 g (beige solid). Analytics: 99.7% qNMR (DMSO-d6, internal standard: trimethoxybenzene); 99.7% ee (Chiralpak IC column, heptane/ethanol gradient (with 0.02% of diethylamine as stabilizing additive), 1 mL/min, 220 nm). Purity corrected yield: 87% over 3 steps (transferhydrogenation (example 34), salt-formation, freebasing).

Example 36

[0195] The reaction was performed under inert gas atmosphere. All solvents and solutions for the reaction and work-up procedure were degassed with nitrogen prior to use. Compound (II′-1) (177 g, 589 mmol) and catalyst (Va-3) (1.92 g, 2.95 mmol, 0.5 mol %) were placed in a round bottom flask under inert gas atmosphere (Argon). Acetonitrile (646 mL) was added and the mixture was mixed to get a brownish to red solution (Solution 1). Sodium formate (200.4 g, 2947 mmol) was dissolved in degassed water (1.15 L). The solution was further degassed by bubbling through nitrogen for 1 h (Solution 2). Solution 2 was placed in a reactor followed by Solution 1.

[0196] The mixture was heated up to 35° C. within about 35 minutes and stirred at this temperature overnight. Process control showed full conversion of the starting material (II′-1). The reaction mixture was cooled down to 25° C. and transferred into a separation vessel and the phases were separated. From the organic layer, most of the acetonitrile is removed under reduced pressure (150-100 mbar) and a jacket temperature of 40° C. The aqueous layer was re-extracted with xylene (233 g). The xylene layer is added to the distillation sump of the acetonitrile layer. Again, vacuum is applied (100 mbar, 50° C. jacket temperature), removing residues of acetonitrile, water, and part of the xylene (distillate amount: 233 g). A solution of (1S)-(+)-10-camphor sulfonic acid (136 g, 585 mmol) in MeTHF (420 g) was added continuously at 50° C. within 30 minutes. The mixture is kept at that temperature for 50 min, cooled to 10° C. within 2 h and then kept at 10° C. for a further 2 h. The mixture is filtered and washed twice with 226 g of MeTHF each. The filter cake is dried under vacuum at 30° C. yielding 288 g of Camphersulfonic acid salt in ≥99% a/a purity (92% yield (uncorrected) over two steps) and with an ee of 99.4%.

Example 37 (Freebasing)

[0197] 124 g of Camphersulfonic acid salt was dissolved in toluene (428 g), MeTHF, (48 g) and water (425 g) together with 2 g of sodium hydrogen carbonate. 49.3 g of 20% w/w aqueous sodium hydroxide solution were added dropwise to increase the pH to 10. The mixture was heated to 40-50° C., filtered clear, and the phases were separated. The organic layer was washed at 40-50° C. with a 5% w/w aqueous solution of sodium hydrogen carbonate (210 mL) and then evaporated to dryness to yield 70.5 g of Ia′-1 as a beige solid (99% yield, purity: 98% w/w.; 99.4% ee (Chiralpak IC column, heptane/ethanol gradient (with 0.02% of diethylamine as stabilizing additive), 1 mL/min, 220 nm). Alternatively, the distillation can be stopped before completion to obtain Ia′-1 as a 50% w/w solution in toluene.

Example 38

[0198] The reaction was performed under inert gas atmosphere. All solvents and solutions for the reaction and work-up procedure were degassed with nitrogen prior to use. Compound (II′-1) (93.9% purity, 78.5 g, 251 mmol) and catalyst (Va-3) (0.817 g, 1.25 mmol, 0.5 mol %) were placed in a round bottom flask under inert gas atmosphere (nitrogen). Acetonitrile (302 mL) was added and the mixture was mixed for 3 h under a constant flow of nitrogen to get a brownish to red solution (Solution 1). Sodium formate (85.4 g, 1256 mmol) was dissolved in degassed water (537 mL). The solution was further degassed by bubbling through nitrogen (Solution 2). Solution 2 was placed in a reactor followed by Solution 1.

[0199] The mixture was heated up to 35° C. within about 35 minutes and stirred for 6 h. Process control showed full conversion of the starting material (II′-1). The reaction mixture was cooled down to 25° C. and transferred into a separation vessel and the phases were separated. From the organic layer, most of the acetonitrile is removed under reduced pressure (150-100 mbar) and a jacket temperature of 40° C. The aqueous layer was re-extracted with xylene (162 g). The xylene layer is added to the distillation sump of the acetonitrile layer. Again, vacuum is applied (100-40 mbar, 50° C. jacket temperature), removing residues of acetonitrile, water, and part of the xylene (distillate amount: 139 g). At 50° C., 1 g of seed crystals are added. Then a solution of (1S)-(+)-10-camphor sulfonic acid (58.3 g, 251 mmol) in MeTHF (241 g) is added continuously within 30 minutes at 50° C. under fast stirring. The mixture is kept at that temperature for 30 min, cooled to 10° C. within 2 h and then kept at 10° C. overnight. The mixture is filtered and washed twice with 100 g of MTBE each. The filter cake is dried under vacuum at 30° C. yielding 122 g of Camphersulfonic acid salt (89% yield over two steps) in 97.1% w/w assay purity and with an ee of 99.4%.