PROCESS FOR THE PREPARATION OF CHIRAL PYROLLIDINE-2-YL- METHANOL DERIVATIVES

Abstract

The invention relates to a novel process for the preparation of a chiral pyrollidine-2-yl-methanol derivative or a salt thereof of the formula I

##STR00001##

wherein R.sup.1 is aryl or heteroaryl and both aryl or heteroaryl are optionally substituted by C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy or halogen. The chiral pyrollidine-2-yl-methanol derivatives of the formula I are versatile building blocks in the synthesis of pharmacologically active compounds, such as for the stereospecific synthesis of oligonucleotides carrying chiral phosphonate moieties (see e.g. Int. PCT Publication WO 2010/064146).

Claims

1. A process for the preparation of a chiral pyrollidine-2-yl-methanol derivative of formula I ##STR00041## or a salt thereof, wherein R.sup.1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy and halogen, said process comprising a) transforming a pyrrolidine carboxylic acid derivative of formula II ##STR00042## with an N,O-dialkylhydroxylamine of formula V
R.sup.4ONHR.sup.3V into the carbamoyl pyrrolidine derivative of formula III ##STR00043## wherein R.sup.2 is an amino protecting group; and R.sup.3 and R.sup.4 are each independently C.sub.1-4-alkyl; b) reacting the carbamoyl pyrrolidine derivative of formula III with a Grignard reagent of the formula
R.sup.1MgHal to form the aroyl pyrrolidine derivative of formula IV ##STR00044## wherein R.sup.1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy and halogen; Hal is halogen; and R.sup.2 is an amino protecting group; and c) removing the amino protecting group R.sup.2 from the aroyl pyrrolidine derivative of formula IV, and subsequently hydrogenating the aroyl pyrrolidine derivative in the presence of a hydrogenation catalyst to form the chiral pyrollidine-2-yl-methanol derivative of formula I.

2. The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative has the structure of formula Ia. ##STR00045## wherein R.sup.1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy and halogen.

3. The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative the structure of formula Ib. ##STR00046## wherein R.sup.1 is aryl or heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl, C.sub.1-4-alkoxy and halogen.

4. The process of claim 1, wherein R.sup.1 is aryl, optionally substituted with one or more substituents selected from the group consisting of C.sub.1-4-alkyl, halo-C.sub.1-4-alkyl and C.sub.1-4-alkoxy.

5. The process of claim 4, wherein R.sup.1 is phenyl.

6. The process of claim 1, wherein the transformation in step a) is performed in the presence of a coupling agent, an amine base and an organic solvent at a reaction temperature between 0 C. and 60 C.

7. The process of claim 6, wherein the coupling agent is selected from the group consisting of n-propylphosphonic acid anhydride (T3P), N,N-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide-hydrochloride (EDC), N,N,N,N-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU).

8. The process of claim 7, wherein the coupling agent is combined with an additive selected from the group consisting of 1-hydroxybenztriazole (HOBt), N-hydroxysuccinimide (HOSu), and 1-hydroxy-7-azabenzotriazole (HOAt) and combinations thereof.

9. The process of claim 6, wherein the amine base is a tertiary amine, and the organic solvent is a polar aprotic solvent.

10. The process of claim 1, wherein step b) is performed in an organic solvent at a reaction temperature between 10 C. and 50 C.

11. The process of claim 10, wherein the organic solvent is an ethereal or aromatic hydrocarbon solvent or mixtures thereof.

12. The process of claim 1, wherein the amino protecting group R.sup.2 is cleavable under acidic conditions.

13. The process of claim 1, wherein R.sup.2 is tert-butoxycarbonyl (BOC).

14. The process of claim 1, wherein removing the amino protecting group R.sup.2 from the aroyl pyrrolidine derivative of formula IV is performed with a strong acid.

15. The process of claim 14, wherein the strong acid is hydrochloric acid.

16. The process of claim 1, wherein the hydrogenation in step c) is performed in the presence of a hydrogenation catalyst comprising a platinum group metal selected from the group consisting of ruthenium, osmium, rhodium, iridium, palladium and platinum.

17. The process of claim 1, wherein the platinum group metal is palladium.

18. The process of claim 1, wherein the hydrogenation in step c) is performed in a polar protic solvent at a reaction temperature between 0 C. and 60 C. and a hydrogen pressure between 1 and 10 bar.

19. The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative is obtained in the form of its hydrochloride salt.

20. The process of claim 1, wherein the chiral pyrollidine-2-yl-methanol derivative is selected from the group consisting of ##STR00047##

Description

EXAMPLES

Abbreviations

[0095] rt=room temperature, T3P=propylphosphonic anhydride, EtOAc=ethyl acetate, NMM=4-methylmorpholine, ACN=acetonitrile, PhMgBr=phenylmagnesium bromide, THF=tetrahydrofuran, CPME=cyclopentyl methyl ether, n-PrOH=1-Propanol, i-PrOH=2-propanol, n-PrOAc=propyl acetate, TFA=trifluoroacetic acid

Example 1

Preparation of (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol Hydrochloride

[0096] Reaction Scheme:

##STR00012##

a) tert-Butyl (2S)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate

[0097] ##STR00013##

[0098] A 500-mL-round-bottomed flask equipped with an overhead stirrer was charged with (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (50 g, 232 mmol, Eq: 1) and N,O-dimethyl-hydroxylamine hydrochloride (27.2 g, 279 mmol, Eq: 1.2). Under an inert atmosphere the solids were suspended in acetonitrile (354 g, 450 ml, Eq: -) to give a light yellow suspension. N-methylmorpholine (70.5 g, 76.6 ml, 697 mmol, Eq: 3) was added dropwise over 40 min at rt. During the addition the reaction was kept a rt. To the resulting suspension 1-propanephosphonic anhydride in EtOAc (50%, 222 g, 205 ml, 348 mmol, Eq: 1.5) was added over 40 min keeping the reaction mixture at rt. After the addition the suspension was stirred for 2 h at rt, diluted with water (175 mL) and stirred for 30 min before citric acid (325 ml 1.6 M, 520 mmol) was added. The resulting clear yellow solution was extracted three times with EtOAc (500 mL each). The organic phases were washed twice with 5% NaHCO.sub.3 (625 mL each), followed by 10% NaCl solution (625 mL). The combined organic phases were concentrated under reduced pressure and the oily residue was suspended in toluene (500 mL), filtered and the clear solution was again concentrated under reduced pressure to give 56.3 g (94%) of tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]-pyrrolidine-1-carboxylate as a clear yellowish oil with a chemical purity of 95.0% (see GC method bellow) and enantiomeric excess >99.9% (see chiral HPLC method below).

[0099] 1H-NMR (600 MHz, CDCl.sub.3) ppm 4.59 (br s, 1H), 3.67-3.82 (m, 3H), 3.53-3.64 (m, 1H), 3.36-3.51 (m, 1H), 3.11-3.24; (m, 3H), 2.07-2.27 (m, 1H), 1.77-2.07 (m, 3H), 1.34-1.49 (m, 9H).

[0100] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 m; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up for 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL ACN. Retention time: 12.41 min tert-butyl (2S)-2-[methoxy(methyl)-carbamoyl]pyrrolidine-1-carboxylate.

[0101] Chiral HPLC method: Column: Chiralpak IC-3, 1504.6 mm, 3 um, Nr. 188; Mobile phases, A: n-heptane, 80%, B: 0.1% TFA in n-heptane, 10%, C: Ethanol, 10%; Flow: 2.5 mL/min isocratic; Temp.: 40 C.; Starting Pressure: 186 bar; Inj. Vol.: 4.0 uL; UV 210 nm; Sample prep: 5 mg/ml Ethanol. Retention times: 2.82 min tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]-pyrrolidine-1-carboxylate, 3.26 min tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate.

b) tert-Butyl (2S)-2-benzoylpyrrolidine-1-carboxylate

[0102] ##STR00014##

[0103] A 500-mL-round-bottomed flask equipped with an overhead stirrer was charged with (S)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (26.18 g, 99.9 mmol, Eq: 1) in cyclopentyl methyl ether (100 mL). The clear solution was cooled to 0 C. and phenylmagnesium bromide (1.0M in THF, 150 ml, 150 mmol, Eq: 1.5) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown clear solution was stirred for 80 min at 0 C., then warmed to rt over 1 hr and stirred for 2 h and 20 min at rt. After 25 min at rt the clear solution became turbid.

[0104] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (200 mL, 1.6M, 230 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with heptane (100 mL). The organic layers were washed twice with 5% NaHCO.sub.3 (250 mL each) and 10% NaCl (200 mL), combined, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 24.6 g of a clear, dark yellow oil with a chemical purity of 79.8% (see GC method below).

[0105] The crude material was dissolved in a mixture of i-PrOH (100 mL) and water (100 mL) at 50 C. to give a yellow clear solution. The solution was cooled to 0 C. over 3 h, seeded at 40 C., 35 C., and 30 C. with 200 mg pure material. To the suspension at 0 C. water (85 mL) was added over 1 hr. After complete addition the yellow suspension was stirred for 1 hr at 0 C. The crystals (light yellow) were filtered, washed with a mixture of i-PrOH/water (3.5:6.5, 100 mL) and dried under reduced pressure. After drying for 14 h 19.7 g (71.6%) off-white crystals were obtained with a chemical purity of 99.4% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0106] 1H NMR (600 MHz, CHLOROFORM-d) ppm 7.89-8.11 (m, 2H), 7.42-7.67 (m, 3H), 5.12-5.47 (m, 1H), 3.39-3.79 (m, 2H), 2.21-2.49 (m, 1H), 1.81-2.03 (m, 3H), 1.46 (s, 9H);

[0107] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL ACN. Retention times: 12.41 min tert-butyl (2S)-2-[methoxy(methyl)-carbamoyl]pyrrolidine-1-carboxylate, 14.09 min tert-butyl (2S)-2-benzoylpyrrolidine-1-carboxylate

[0108] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.47 min tert-Butyl (2R)-2-benzoylpyrrolidine-1-carboxylate, 1.66 min tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate.

c) (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol Hydrochloride

[0109] ##STR00015##

[0110] A 350 mL-round-bottomed flask equipped with an overhead stirrer was charged with (S)-tert-butyl 2-benzoylpyrrolidine-1-carboxylate (28.5 g, 104 mmol, Eq: 1) in 1-propanol (114 g, 143 ml, Eq: -). The clear yellow solution was heated to 70 C. and then HCl 37% (15.3 g, 12.7 ml, 155 mmol, Eq: 1.5) was added dropwise over 15 min. The resulting dark yellow clear solution was stirred at 70 C. for 3 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (11 g, 14 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (10%, 1.81 g, 1.7 mmol, Eq: 0.02) was added. The autoclave was flushed with H.sub.2 three times, heated to 30 C. and under stirring the hydrogen pressure was increased to 5 bar. After 3 h the reaction mixture was cooled to rt and the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol (200 ml, Eq: -) The crude reaction mixture showed a mixture of desired (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol hydrochloride (94.8%), (S)-phenyl-[(2S)-pyrrolidin-2-yl]methanol hydrochloride (3.1%), (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride (1.0%), (2S)-2-benzylpyrrolidine (see chiral SFC method below).

[0111] The reaction mixture was concentrated under reduced pressure to 135 g at which point n-PrOAc (100 mL) was added. The resulting mixture was again concentrated under reduced pressure to 130 g at which point n-PrOAc (100 mL) was added. The resulting suspension was stirred for 2 h at rt, then cooled to 0 C. and stirred for 2 h. The suspension was filtered, and the crystalline white solid was washed with cold (0 C.) n-PrOAc (100 mL). After drying under reduced pressure at 50 C. for 14 h white crystals (18.1 g, 82%) with a chemical purity of 99.1% and an enantiomeric excess of >99% were obtained.

[0112] 1H NMR (600 MHz, DMSO-d6) ppm 8.74-9.85 (m, 1H), 7.48-7.49 (m, 1H), 7.21-7.46 (m, 2H), 6.09 (br d, J=3.5 Hz, 1H), 5.06 (br s, 1H), 3.61-3.79 (m, 1H), 3.07-3.20 (m, 1H), 1.68-1.97 (m, 1H), 1.52-1.65 (m, 1H). HRMS: (ESI-TOF) calculated for (C.sub.11H.sub.15NO): 177.1154, found: 177.1154.

[0113] Chiral SFC method: Chiralcel OZ-3, 1504.6 mm, Nr: 183; Mobile phases, A: CO.sub.2, 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol+0.2% iso-propyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50 C.; BPR: 130 bar; Inj. Vol.: 5.0 uL; UV 210 nm; Sample prep.: 2.0 mg/ml Ethanol. Retention times: 2.67 min (2R)-2-benzylpyrrolidine, 3.01 min (2S)-2-benzylpyrrolidine, 3.84 min (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol, 4.09 min phenyl-[(2R)-pyrrolidin-2-yl]methanone, 4.33 min phenyl-[(2S)-pyrrolidin-2-yl]methanone, 4.55 min (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 4.89 min (S)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 5.47 min (R)-phenyl-[(2R)-pyrrolidin-2-yl]methanol.

Purification of (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol Hydrochloride

[0114] A 30 L Reactor was charged with (S)-phenyl((R)-pyrrolidin-2-yl)methanol (1.16 kg, 5.44 mol) and acetonitrile (13.8 kg, 17.5 l, Eq: -). The resulting suspension was heated to 80 C. until a solution was obtained and the volume was reduced by 1 L via destillation. The clear yellow solution was cooled to 0 C. over 3 hr. The resulting suspension was stirred for an additional 1 hr at 0 C. and was then filtered. The white crystals where washed with cold (0 C.) acetonitrile (3.93 kg, 5 l, Eq: -) and dried under reduced pressure to give desired product (1057 g, 91%) with a chemical purity of >99% (see HPLC method bellow) and an enantiomeric excess of >99% (see chiral SFC method bellow)

[0115] HPLC method: Column: XBridge BEH Phenyl, 2.5 um, 1004.6 mm, Nr: 207; Solvent: A: H2O/ACN, 95/5: 80-45% in 4 min, hold for 1 min, B: ACN: 15-50% in 4 min, hold for 1 min, D: 100 mM Ammonium formate in H2O/ACN (95/5) @ pH9 with NH3: 5% isocratic; Temp: 50 C.; Flow: 1.5 ml/min; Inj. Vol.: 3.5 ul+wash, Starting pressure: 247 bar; Detector: 212 nm, BW: 8 nm, Ref: 360 nm, Ref BW: 50M; Sample Prep: 0.5 mg/ml in H2O/ACN (1/1; v/v)

[0116] Chiral SFC method: Chiralcel OZ-3, 1504.6 mm, Nr: 183; Mobile phases, A: CO.sub.2, 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol+0.2% iso-propyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50 C.; BPR: 130 bar; Inj. Vol.: 5.0 uL; UV 210 nm; Sample prep.: 2.0 mg/ml Ethanol. Retention times: 2.67 min (2R)-2-benzylpyrrolidine, 3.01 min (2S)-2-benzylpyrrolidine, 3.84 min (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol, 4.09 min phenyl-[(2R)-pyrrolidin-2-yl]methanone, 4.33 min phenyl-[(2S)-pyrrolidin-2-yl]methanone, 4.55 min (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 4.89 min (S)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 5.47 min (R)-phenyl-[(2R)-pyrrolidin-2-yl]methanol.

Example 2

Preparation of (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0117] Reaction Scheme:

##STR00016##

a) tert-Butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate

[0118] ##STR00017##

[0119] A 30-L reactor was charged with (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2300 g, 10.7 mol, Eq: 1) and N, O-dimethylhydroxylamine hydrochloride (1.09 kg, 11.1 mol, Eq: 1.04). Under an inert atmosphere the solids were suspended in acetonitrile (16.2 kg, 20.6 l, Eq: -) to give a light yellow suspension. N-methylmorpholine (3.24 kg, 3.52 l, 32.1 mol, Eq: 3) was added dropwise over 15 min at rt. During the addition the reaction was kept a rt. The resulting suspension was stirred for 40 min at rt, before 1-propanephosphonic anhydride in EtOAc (50%, 7.48 kg, 6.93 l, 11.8 mol, Eq: 1.1) was added at rt C. over 70 min keeping the reaction mixture at rt. After the addition the suspension was stirred for 2 h at rt and then concentrated at 60 C. under reduced pressure to a total volume of 18 L. The solvent was replaced under reduced pressure with toluene under a constant volume. Toluene (7.71 kg, 9 l, Eq: -) was added to further dilute the suspension before it was filtered and to the resulting clear solution was washed with a solution of citric acid monohydrate (1.84 kg, 8.76 mol, Eq: 0.819) in water (7.36 l, Eq: -), followed by a solution of NaHCO.sub.3 (460 g, 5.48 mol, Eq: 0.512) in water (8.62 L), followed by a solution of NaCl (920 g) in water (8.24 L). Then the organic phase was separated. The aqueous phases were re-extracted with toluene (8.65 kg) and the organic phases were combined, concentrated at 50 C. under reduced pressure to 6 L, filtered and washed with toluene to a give a solution of tert-Butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate (2510 g, 91%) in toluene (3200 g).

[0120] To toluene solution was used in the next step without further purification. Analytical data was generated by concentration of an aliquot of the solution under reduced pressure and analyzing the oily residue which yielded a clear yellowish oil with a chemical purity of 98.8% (see HPLC method bellow) and enantiomeric excess >99% (see chiral HPLC method below).

[0121] 1H NMR (600 MHz, CDCl.sub.3) ppm 4.59-4.75 (m, 1H), 3.68-3.85 (m, 3H), 3.35-3.63 (m, 2H), 3.21 (s, 3H), 1.85-2.29 (m, 2H), 1.82-2.06 (m, 2H), 1.38-1.49 (m, 9H).

[0122] HPLC method. Column: XBridge BEH C8, 2.5 um, 1004.6 mm, Nr: 182; Mobile phases: A: H.sub.2O/ACN, 95/5: 80-10% in 6 min, hold for 1 min, B: ACN, 10-80% in 6 min, hold for 1 min, C: H.sub.2O+0.5% TFA: 10% isocratic; Flow: 1.5 ml/min; Temp.: 45 C.; Inj. Volume: 2 ul; UV: 200 nm (BW: 8 nm), Ref: 360 nm (BW: 100 nm); Sample prep: 2 mg/mL H.sub.2O/ACN, 1/1 Chiral HPLC method: Column: Chiralpak IC-3, 1504.6 mm, 3 um, Nr. 188; Mobile phases, A: n-heptane, 80%, B: 0.1% TFA in n-heptane, 10%, C: Ethanol, 10%; Flow: 2.5 mL/min isocratic; Temp.: 40 C.; Starting Pressure: 186 bar; Inj. Vol.: 4.0 uL; UV 210 nm; Sample prep: 5 mg/ml Ethanol. Retention times: 2.82 min tert-butyl (2S)-2-[methoxy-(methyl)carbamoyl]pyrrolidine-1-carboxylate, 3.26 min tert-butyl (2R)-2-[methoxy-(methyl)carbamoyl]pyrrolidine-1-carboxylate.

b) tert-Butyl (2R)-2-benzoylpyrrolidine-1-carboxylate

[0123] ##STR00018##

[0124] A 30-L reactor was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2382 g, 9.22 mol, Eq: 1) in toluene (3200 g). Toluene was added (4.35 kg, 5 L), the clear solution was cooled to rt and phenylmagnesium bromide (15% in THF, 17 kg, 17.3 L, 14.1 mol, Eq: 1.53) was added over 60 min maintaining the temperature at rt. The initially clear yellow solution turns brownish over the course of the reaction. After 4 h at rt, the reaction mixture is cooled to 5 C. and added to a solution of citric acid monohydrate (2.1 kg, 10.9 mol, Eq: 1.19) in water (10 L) at 5 C. under stirring over the course of 30 min. The organic phase was separated and washed twice a solution of NaHCO.sub.3 in water (5%, 10 L) followed by a solution of NaCl in water (5%, 10 L). The organic phase was again separated and concentrated under reduced pressure to give a red oil (3.16 kg), which was re-dissolved in toluene (4.33 kg, 5 l, Eq: -), filtered and the resulting solution was diluted with n-propanol (8 kg, 10 l, Eq: -). The solution was filtered over activated charcoal and washed with additional n-propanol (2.4 kg, 3 L, Eq: -) and again concentrated under reduced pressure at 50 C. and the residue redissolved in n-propanol (4.4 kg, 5.5 L, Eq: -). To the clear red solution at 35 C. water (5.5 kg, 5.5 L, Eq: -) was added over 30 min and the resulting solution was seeded with pure tert-Butyl (2R)-2-benzoylpyrrolidine-1-carboxylate. After the crystallisation started additional water (22 kg, 22 L, Eq: -) was added. The resulting suspension was stirred at rt for 30 min and then cooled to 5 C. and stirred for 5 h. The crystalline solid was filtered of and the reactor and the solids were washed with a solution of n-propanol (0.5 L) and water (3.0 L). The solid was dissolved in n-propanol (4 kg, 5 L) and concentrated under reduced pressure at 50 C. to remove residual water, the resulting solid was again dissolved in n-propanol (4 kg, 5 L) and concentrated under reduced pressure at 50 C. to give an orange, crystalline solid (1.90 kg, 75%) with a purify of 99.2% (see GC method below) and enantiomeric excess of >99% (see chiral SFC method)

[0125] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL ACN. Retention times: 12.41 min tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate, 14.09 min tert-butyl (2S)-2-benzoylpyrrolidine-1-carboxylate.

[0126] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.47 min tert-Butyl (2R)-2-benzoylpyrrolidine-1-carboxylate, 1.66 min tert-butyl (2S)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate.

c) (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0127] ##STR00019##

[0128] A 4500 mL-round-bottomed flask equipped with an overhead stirrer was charged with (R)-tert-butyl 2-benzoylpyrrolidine-1-carboxylate (476 g, 1.73 mol, Eq: 1) in 1-propanol (1.84 kg, 2.3 l, Eq: -). The clear yellow solution was heated to 60 C. and then HCl 37% (261 g, 221 ml, 2.65 mol, Eq: 1.53) was added dropwise over 15 min. The resulting dark yellow clear solution was stirred at 60 C. for 3 hr and then heated to 70 C. and stirred for another 3 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (110 g, 140 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (10%, 18.3 g, 17.2 mmol, Eq: 0.01) was added. The autoclave was flushed with H.sub.2 three times, heated to 25 C. and under stirring the hydrogen pressure was increased to 5 bar. After 3 h the reaction mixture was cooled to rt and the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol (500 ml, Eq: -). The crude reaction mixture showed the desired (S)-phenyl-[(RS)-pyrrolidin-2-yl]methanol hydrochloride in 97.3% purity (see chiral SFC method below).

[0129] The reaction mixture was concentrated under reduced pressure at 60 C. to 1.5 L at which point crystallization of the product already started subsequently the solvent was exchanged with n-PrOAc maintaining a constant volume at 60 C. For the solvent exchange n-PrOAc (8.01 kg, 9 l, Eq: -) was used. The resulting mixture was cooled to rt and stirred for 1 hr at rt. The suspension was filtered, and the crystalline solid was washed with n-PrOAc (623 g, 700 ml, Eq:). After drying under reduced pressure at 50 C. for 14 h yellow crystals (335 g, 91%) with a chemical purity of 98% (see HPLC method below) and an enantiomeric excess of 99% (see chiral SFC method bellow) were obtained.

[0130] 1H NMR (600 MHz, DMSO-d6) ppm 9.40-9.52 (m, 1H), 8.68-8.80 (m, 1H), 7.40-7.43 (m, 2H), 7.36-7.40 (m, 2H), 7.27-7.32 (m, 1H), 6.04-6.12 (m, 1H), 5.01-5.06 (m, 1H), 3.66-3.74 (m, 1H), 3.08-3.19 (m, 2H), 1.54-1.94 (m, 4H)

[0131] HPLC method: Column: XBridge BEH Phenyl, 2.5 um, 1004.6 mm, Nr: 207; Solvent: A: H2O/ACN, 95/5: 80-45% in 4 min, hold for 1 min, B: ACN: 15-50% in 4 min, hold for 1 min, D: 100 mM Ammonium formate in H2O/ACN (95/5) @ pH9 with NH3: 5% isocratic; Temp: 50 C.; Flow: 1.5 ml/min; Inj. Vol.: 3.5 ul+wash, Starting pressure: 247 bar; Detector: 212 nm, BW: 8 nm, Ref: 360 nm, Ref BW: 50M; Sample Prep: 0.5 mg/ml in H2O/ACN (1/1; v/v)

[0132] Chiral SFC method: Chiralcel OZ-3, 1504.6 mm, Nr: 183; Mobile phases, A: CO.sub.2, 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol+0.2% iso-propyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50 C.; BPR: 130 bar; Inj. Vol.: 5.0 uL; UV 210 nm; Sample prep.: 2.0 mg/ml Ethanol. Retention times: 2.67 min (2R)-2-benzylpyrrolidine, 3.01 min (2S)-2-benzylpyrrolidine, 3.84 min (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol, 4.09 min phenyl-[(2R)-pyrrolidin-2-yl]methanone, 4.33 min phenyl-[(2S)-pyrrolidin-2-yl]methanone, 4.55 min (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 4.89 min (S)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 5.47 min (R)-phenyl-[(2R)-pyrrolidin-2-yl]methanol.

Purification of (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0133] A 30 L Reactor was charged with (S)-phenyl((R)-pyrrolidin-2-yl)methanol (1.32 kg, 6.16 mol) with the above mentioned chemical purity of 98% and an enantiomeric excess of 99% and acetonitrile (15.7 kg, 20 l, Eq: -). The resulting suspension was heated to 80 C. until a solution was obtained and the volume was reduced by 1.5 L via destillation. The clear yellow solution was cooled to 0 C. over 3 hr. The resulting suspension was stirred for an additional 1 hr at 0 C. and was then filtered. The white crystals where washed with cold (0 C.) acetonitrile (3.93 kg, 5 l, Eq: -) and dried under reduced pressure to give desired product (1202 g, 91%) with a chemical purity of >99% (see HPLC method bellow) and an enantiomeric excess of >99% (see chiral SFC method bellow)

[0134] 1H NMR (600 MHz, DMSO-d6) ppm 9.42 (br s, 1H), 8.71 (br s, 1H), 7.22-7.46 (m, 5H), 6.09 (br dJ,=3.1 Hz, 1H), 5.03 (br s, 1H), 3.64-3.78 (m, 1H), 3.06-3.21 (m, 2H), 2.04-2.12 (m, 1H), 1.70-1.99 (m, 3H), 1.52-1.64 (m, 1H)

[0135] HRMS: (ESI-TOF) calculated for (C.sub.11H.sub.15NO): 177.1154, found: 177.1161.

[0136] HPLC method: Column: XBridge BEH Phenyl, 2.5 um, 1004.6 mm, Nr: 207; Solvent: A: H2O/ACN, 95/5: 80-45% in 4 min, hold for 1 min, B: ACN: 15-50% in 4 min, hold for 1 min, D: 100 mM Ammonium formate in H2O/ACN (95/5) @ pH9 with NH3: 5% isocratic; Temp: 50 C.; Flow: 1.5 ml/min; Inj. Vol.: 3.5 ul+wash, Starting pressure: 247 bar; Detector: 212 nm, BW: 8 nm, Ref: 360 nm, Ref BW: 50M; Sample Prep: 0.5 mg/ml in H2O/ACN (1/1; v/v)

[0137] Chiral SFC method: Chiralcel OZ-3, 1504.6 mm, Nr: 183; Mobile phases, A: CO.sub.2, 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol+0.2% iso-propyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50 C.; BPR: 130 bar; Inj. Vol.: 5.0 uL; UV 210 nm; Sample prep.: 2.0 mg/ml Ethanol. Retention times: 2.67 min (2R)-2-benzylpyrrolidine, 3.01 min (2S)-2-benzylpyrrolidine, 3.84 min (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol, 4.09 min phenyl-[(2R)-pyrrolidin-2-yl]methanone, 4.33 min phenyl-[(2S)-pyrrolidin-2-yl]methanone, 4.55 min (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 4.89 min (S)-phenyl-[(2S)-pyrrolidin-2-yl]methanol, 5.47 min (R)-phenyl-[(2R)-pyrrolidin-2-yl]methanol.

Example 3

Preparation of (S)-p-tolyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0138] Reaction Scheme:

##STR00020##

a) tert-butyl (2R)-2-(4-methylbenzoyl)pyrrolidine-1-carboxylate

[0139] ##STR00021##

[0140] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.5 g, 9 mmol, Eq: 1) in cyclopentyl methyl ether (3 mL). The yellow solution was cooled to 0 C. p-Tolylmagnesium bromide (1M in THF, 18 ml, 18 mmol, Eq: 2) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown-yellow clear solution was stirred for 80 min at 0 C., then warmed to rt over 1 hr and stirred for 3 hr at rt.

[0141] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (25 mL, 1.6M, 40 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with cyclopentyl methyl ether (10 mL). The organic layers were washed with 5% NaHCO.sub.3 (25 mL) and 10% NaCl (20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 1.8 g of a clear, orange viscous oil with a chemical purity of 68.9% (see HPLC method below)

[0142] The crude material was dissolved in a mixture of i-PrOH/water (1:1, 12 mL) at 60 C. to give an orange clear solution. The solution was cooled to rt over 1 hr and started to crystallize at 30 C. The suspension was cooled to 0 C. and stirred for 2 hr. The crystals were filtered, washed with a mixture of i-PrOH/water (1:1, 5 mL) and dried under reduced pressure. After drying 0.75 g (28.8%) pink crystals were obtained with a chemical purity of 97.5% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0143] 1H NMR (600 MHz, CDCl.sub.3) ppm 7.70-8.04 (m, 1H), 5.08-5.36 (m, 1H), 3.34-3.72 (m, 2H), 2.37-2.46 (m, 2H), 2.23-2.34 (m, 1H), 1.84-1.97 (m, 1H), 1.82-1.97 (m, 1H), 1.15-1.54 (m, 7H)

[0144] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 5.79 min tert-butyl (2R)-2-(4-methylbenzoyl)pyrrolidine-1-carboxylate

[0145] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 14.64 min tert-butyl (2R)-2-(4-methylbenzoyl)pyrrolidine-1-carboxylate

[0146] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.49 min tert-butyl (2R)-2-(4-methylbenzoyl)pyrrolidine-1-carboxylate, 1.72 min tert-butyl (2S)-2-(4-methylbenzoyl)pyrrolidine-1-carboxylate

b) (S)-p-tolyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0147] ##STR00022##

[0148] A 25 mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R)-tert-butyl 2-(4-methylbenzoyl)pyrrolidine-1-carboxylate (1.2 g, 4.15 mmol, Eq: 1) in 1-propanol (4.8 g, 6 ml, Eq: -). The clear light brown solution was heated to 70 C. and then hydrochloric acid 25% (720 mg, 600 l, 4.93 mmol, Eq: 1.19) was added dropwise over 1 min. The resulting dark brown solution was stirred at 70 C. for 6 hr. More hydrochloric acid 25% (490 mg, 408 l, 3.36 mmol, Eq: 0.81) was added dropwise and the solution was stirred at 70 C. for further 2 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (3.2 g, 4 ml) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 11 mg, 5.18 mol, Eq: 0.00125) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 10 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0149] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (15 mL) was added. The resulting mixture was again concentrated under reduced pressure to a viscous oil at which point more n-PrOAc (10 mL) was added. The resulting suspension was stirred for 1 h at rt, then cooled to 0 C. and stirred for 2.5 hr. The suspension was filtered, and the crystalline white solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure white crystals (0.73 g, 76.5%) with a chemical purity of 99.0% (see SFC method below) and an enantiomeric purity of 98.9% (see chiral SFC method below) were obtained.

[0150] 1H NMR (600 MHz, DMSO-d6) ppm 8.39-9.59 (m, 2H), 7.23-7.35 (m, 2H), 7.12-7.21 (m, 2H), 5.94-6.10 (m, 1H), 4.91-5.04 (m, 1H), 3.61-3.72 (m, 1H), 3.06-3.20 (m, 2H), 2.29 (s, 3H), 1.53-1.95 (m, 4H)

[0151] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 3.74 min (S)-p-tolyl-[(2R)-pyrrolidin-2-yl]methanol

[0152] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 4.26 min (S)-p-tolyl-[(2R)-pyrrolidin-2-yl]methanol.

Example 4

Preparation of (S)-m-tolyl-[(2R)-pyrrolidin-2-yl]methanol;hydrochloride

[0153] Reaction Scheme:

##STR00023##

a) tert-butyl (2R)-2-(3-methylbenzoyl)pyrrolidine-1-carboxylate

[0154] ##STR00024##

[0155] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.5 g, 9 mmol, Eq: 1) in toluene (15 mL). The light yellow solution was cooled to 0 C. m-tolylmagnesium bromide (1 M in THF, 13.1 ml, 13.1 mmol, Eq: 1.45) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown clear solution was stirred for 80 min at 0 C., then warmed to rt over 1 hr and stirred for 3 h at rt. The solution was re-cooled to 0 C. and more m-tolylmagnesium bromide (1M in THF, 1.8 ml, 1.8 mmol, Eq: 0.2) was added dropwise over 15 min maintaining the temperature at 0 C., then stirred for 1 h at rt.

[0156] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (25 mL, 1.6M, 40 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with toluene (10 mL). The organic layers were washed with 5% NaHCO.sub.3 (25 mL) and 10% NaCl (20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 1.93 g of a red solid with a chemical purity of 66.4% (see HPLC method below)

[0157] The crude material was dissolved in a mixture of i-PrOH/water (1:1, 16 mL) at 60 C. to give a red clear solution. The solution was cooled to rt over 1.5 h and started to crystallize at 30 C. The light red/pink suspension was cooled to 0 C. and stirred for 1 hr. The crystals were filtered, washed with a mixture of i-PrOH/water (1:1, 5 mL) and dried under reduced pressure. After drying 1.30 g (49.9%) light pink crystals were obtained with a chemical purity of 97.1% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0158] 1H NMR (600 MHz, CHLOROFORM-d) ppm 7.75-7.83 (m, 1H), 7.70-7.83 (m, 1H), 7.33-7.39 (m, 1H), 7.31-7.43 (m, 1H), 5.31-5.36 (m, 1H), 5.17-5.23 (m, 1H), 3.60-3.73 (m, 1H), 3.44-3.59 (m, 1H), 2.37-2.46 (m, 3H), 2.23-2.36 (m, 1H), 1.85-2.01 (m, 3H), 1.44-1.51 (m, 4H), 1.28 (s, 5H)

[0159] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 5.78 min tert-butyl (2R)-2-(3-methylbenzoyl)pyrrolidine-1-carboxylate

[0160] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 14.50 min tert-butyl (2R)-2-(3-methylbenzoyl)pyrrolidine-1-carboxylate

[0161] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.33 min tert-butyl (2R)-2-(3-methylbenzoyl)pyrrolidine-1-carboxylate, 1.49 min tert-butyl (2S)-2-(3-methylbenzoyl)pyrrolidine-1-carboxylate

b) (S)-m-tolyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0162] ##STR00025##

[0163] A 25 mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R)-tert-butyl 2-(3-methylbenzoyl)pyrrolidine-1-carboxylate (1 g, 3.46 mmol, Eq: 1) in 1-propanol (4 g, 5 ml, Eq: -). The clear solution was heated to 70 C. and then hydrochloric acid 25% (756 mg, 630 l, 5.18 mmol, Eq: 1.5) was added dropwise over 1 min. The clear solution was stirred at 70 C. for 3 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (4 g, 5 ml) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 18.3 mg, 8.65 mol, Eq: 0.0025) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 3 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0164] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (15 mL) was added. The resulting mixture was again concentrated and suspended in n-PrOAc (15 mL), the resulting suspension was again concentrated under reduced pressure. To the residue n-PrOAc (10 mL) was added. The resulting suspension was stirred for 30 min at rt, then cooled to 0 C. and stirred for 2 hr. The suspension was filtered, and the crystalline white solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure white crystals (0.68 g, 84.1%) with a chemical purity of 97.4% (see SFC method below) and an enantiomeric purity of >99.9% (see chiral SFC method below) were obtained.

[0165] 1H NMR (600 MHz, DMSO-d6) ppm 9.16-9.67 (m, 1H), 8.37-8.88 (m, 1H), 7.24-7.28 (m, 1H), 7.21 (s, 1H), 7.19 (dJ,=7.7 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 5.89-6.16 (m, 1H), 4.99 (br d, J=3.3 Hz, 1H), 3.63-3.74 (m, 1H), 3.08-3.21 (m, 2H), 2.32 (s, 3H), 1.56-1.93 (m, 4H).

[0166] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 3.65 min (S)-m-tolyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

[0167] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 3.92 min (S)-m-tolyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride.

Example 5

Preparation of (S)-(4-tert-butylphenyl)-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0168] Reaction Scheme:

##STR00026##

a) tert-butyl (2R)-2-(4-tert-butylbenzoyl)pyrrolidine-1-carboxylate

[0169] ##STR00027##

[0170] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (4 g, 15.1 mmol, Eq: 1) in toluene (5 mL). The light yellow solution was cooled to 0 C. (4-(tert-Butyl)phenyl)magnesium bromide (0.5M in 2-MeTHF, 60.5 ml, 30.3 mmol, Eq: 2) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light orange clear solution was stirred for 60 min at 0 C., then warmed to rt and stirred for 17 hr at rt.

[0171] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (30 mL, 1.6M, 48 mmol). The resulting biphasic mixture was allowed to separate and the organic, orange clear solution was separated and the aqueous layer was extracted with toluene (15 mL). The organic layers were washed with 5% NaHCO.sub.3 (60 mL) and 10% NaCl (50 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 5.91 g of an orange solid with a chemical purity of 67.8% (see HPLC method below)

[0172] The crude material was dissolved in a mixture of i-PrOH/water (1:1, 42 mL) at 70 C. to give an orange clear solution. The solution was cooled to rt over 30 min and started to crystallize at 30 C. The suspension was stirred for 2.5 hr at rt. The crystals (off-white) were filtered, washed with a mixture of i-PrOH/water (1:1, 5 mL) and dried under reduced pressure. After drying 3.0 g (47.9%) off-white crystals were obtained with a chemical purity of 80.7% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0173] 1H NMR (600 MHz, CHLOROFORM-d) ppm 7.84-7.97 (m, 2H), 7.44-7.50 (m, 2H), 5.13-5.36 (m, 1H), 3.40-3.78 (m, 2H), 2.24-2.35 (m, 1H), 1.97 (br s, 2H), 1.85-1.97 (m, 1H), 1.44-1.48 (m, 4H), 1.32-1.35 (m, 9H), 1.27 (s, 4H), 1.25-1.28 (m, 1H)

[0174] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 6.76 min tert-butyl (2R)-2-(4-tert-butylbenzoyl)pyrrolidine-1-carboxylate

[0175] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 15.64 min tert-butyl (2R)-2-(4-tert-butylbenzoyl)pyrrolidine-1-carboxylate

[0176] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.53 min tert-butyl (2R)-2-(4-tert-butylbenzoyl)pyrrolidine-1-carboxylate, 1.63 min tert-butyl (2S)-2-(4-tert-butylbenzoyl)pyrrolidine-1-carboxylate

b) (S)-(4-tert-butylphenyl)-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0177] ##STR00028##

[0178] A 25 mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R)-tert-butyl 2-(4-(tert-butyl)benzoyl)pyrrolidine-1-carboxylate (1.5 g, 3.62 mmol, Eq: 1) in 1-propanol (6 g, 7.5 ml, Eq: -). The clear light brown solution was heated to 70 C. and then hydrochloric acid 25% (628 mg, 524 l, 4.31 mmol, Eq: 1.19) was added dropwise over 1 min. The brown solution was stirred at 70 C. for 6 hr. More hydrochloric acid 25% (428 mg, 356 l, 2.93 mmol, Eq: 0.81) was added dropwise and the solution was stirred at 70 C. for another 2 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (4 g, 5 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 9.57 mg, 4.52 mol, Eq: 0.00125) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 16 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0179] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (15 mL) was added. The resulting mixture was again concentrated under reduced pressure. n-PrOAc (10 mL) was added and the resulting suspension was stirred for 1 h at rt, then cooled to 0 C. and stirred for 2.5 hr. The suspension was filtered, and the crystalline off-white solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure off-white crystals (0.31 g, 31.0%) with a chemical purity of 97.5% (see SFC method below) and an enantiomeric purity of >99.9% (see chiral SFC method below) were obtained.

[0180] 1H NMR (600 MHz, DMSO-d6) ppm 8.51-9.55 (m, 2H), 7.37-7.41 (m, 2H), 7.30-7.35 (m, 2H), 5.93-6.06 (m, 1H), 4.94-5.01 (m, 1H), 3.68 (br d, J=4.1 Hz, 1H), 3.08-3.20 (m, 2H), 1.56-1.97 (m, 4H), 1.26-1.29 (m, 9H)

[0181] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 3.56 min (S)-(4-tert-butylphenyl)-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

[0182] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 4.11 min (S)-(4-tert-butylphenyl)-[(2R)-pyrrolidin-2-yl]methanol hydrochloride.

Example 6

Preparation of (S)-2-naphthyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0183] Reaction Scheme:

##STR00029##

a) tert-butyl (2R)-2-(naphthalene-2-carbonyl)pyrrolidine-1-carboxylate

[0184] ##STR00030##

[0185] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (3 g, 11.3 mmol, Eq: 1) in toluene (4 mL). The light yellow solution was cooled to 0 C. Naphthalen-2-ylmagnesium bromide (0.5M in THF, 45.4 ml, 22.7 mmol, Eq: 2) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown clear solution was stirred for 1 hr at 0 C., then warmed to rt and stirred for 16 hr at rt. The solution became turbid.

[0186] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (25 mL, 1.6M, 40 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with toluene (15 mL). The organic layers were washed with 5% NaHCO.sub.3 (45 mL) and 10% NaCl (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 4.65 g of an orange solid with a chemical purity of 45.7% (see HPLC method below)

[0187] The crude material was dissolved in a mixture of i-PrOH/water (1:1, 36 mL) at 80 C. to give an orange clear solution. The solution was cooled to rt over 30 min and started to crystallize. The suspension was cooled to 0 C. and stirred for 2 hr. The crystals were filtered and dried under reduced pressure. After drying 2.1 g brown crystals were obtained with a chemical purity of 55.3% (see HPLC method below). The brown crystals were further purified via flash chromatography (SiO.sub.2, 40 g, EtOAc:Heptane 1:9 to 1:1). After drying for 2 hr under reduced pressure, 1.63 g (42.6%) light brown solid was obtained with a chemical purity of 94.6% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0188] 1H NMR (600 MHz, CHLOROFORM-d) ppm 8.46-8.55 (m, 1H), 5.37 (dd, J=9.0, 3.8 Hz, 1H), 3.43-3.83 (m, 2H), 2.31-2.46 (m, 1H), 1.93-2.04 (m, 1H), 1.90-2.04 (m, 2H), 1.20-1.51 (m, 9H)

[0189] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 5.5 min tert-butyl (2R)-2-(naphthalene-2-carbonyl)pyrrolidine-1-carboxylate.

[0190] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 17.26 min tert-butyl (2R)-2-(naphthalene-2-carbonyl)pyrrolidine-1-carboxylate.

[0191] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 2.12 min tert-butyl (2R)-2-(naphthalene-2-carbonyl)pyrrolidine-1-carboxylate, 5.53 min tert-butyl (2S)-2-(naphthalene-2-carbonyl)pyrrolidine-1-carboxylate.

b) (S)-2-naphthyl-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0192] ##STR00031##

[0193] A 25 mL 3-necked flask equipped with a magnetic stirrer and a reflux condenser was charged with (R)-tert-butyl 2-(2-naphthoyl)pyrrolidine-1-carboxylate (0.8 g, 2.37 mmol, Eq: 1) in 1-propanol (3.2 g, 4 ml, Eq: -). The clear yellow solution was heated to 70 C. and then hydrochloric acid 25% (519 mg, 433 l, 3.56 mmol, Eq: 1.5) was added dropwise over 1 min. The clear light yellow solution was stirred at 70 C. for 3.5 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (3.2 g, 4 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 12.5 mg, 5.93 mol, Eq: 0.0025) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 10 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0194] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (15 mL) was added. The resulting mixture was again concentrated under reduced pressure. n-PrOAc (15 mL) was added and the resulting suspension was stirred for 30 min at rt, then cooled to 0 C. and stirred for 2 hr. The suspension was filtered, and the crystalline light brown solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure light brown crystals (0.55 g, 83.9%) with a chemical purity of 95.4% (see SFC method below) and an enantiomeric purity of 95.0% (see chiral SFC method below) were obtained.

[0195] 1H NMR (600 MHz, DMSO-d6) ppm 8.52-9.62 (m, 2H), 7.83-8.01 (m, 4H), 7.42-7.62 (m, 3H), 6.25 (br dJ,=3.3 Hz, 1H), 5.19 (br s, 1H), 3.82 (br d, J=4.2 Hz, 1H), 3.04-3.25 (m, 2H), 1.45-1.97 (m, 4H)

[0196] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 4.60 min (S)-2-naphthyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

[0197] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 5.30 min (S)-2-naphthyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride.

Example 7

Preparation of (S)-(3,5-difluorophenyl)-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0198] Reaction Scheme:

##STR00032##

a) tert-butyl (2R)-2-(3,5-difluorobenzoyl)pyrrolidine-1-carboxylate

[0199] ##STR00033##

[0200] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.2 g, 7.92 mmol, Eq: 1) in cyclopentyl methyl ether (3 mL). The light yellow solution was cooled to 0 C. (3,5-Difluorophenyl)magnesium bromide (0.5 M in 2-MeTHF, 31.7 ml, 15.8 mmol, Eq: 2) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown-yellow clear solution was stirred for 80 min at 0 C., then warmed to rt over 1 h and stirred for 19 h at rt. After 19 h at rt the clear solution became turbid.

[0201] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (25 mL, 1.6M, 40 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with cyclopentyl methyl ether (10 mL). The organic layers were washed twice with 5% NaHCO.sub.3 (25 mL) and 10% NaCl (20 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 1.93 g of a clear, yellow oil with a chemical purity of 40.7% (see HPLC method below)

[0202] The crude material was dissolved in a mixture of i-PrOH/water (1:1, 6 mL) at 60 C. to give a yellow clear solution. The solution was cooled to rt over 30 min and started to crystallize at 30 C. The yellow suspension was cooled to 0 C. and stirred for 1 hr. The crystals were filtered, washed with a mixture of i-PrOH/water (1:1, 2 mL) and dried under reduced pressure. After drying 1.22 g (24%) light yellow crystals were obtained with a chemical purity of 98.8% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0203] 1H NMR (600 MHz, CDCL3) ppm 7.40-7.54 (m, 2H), 6.95-7.10 (m, 1H), 4.95-5.24 (m, 1H), 3.36-3.69 (m, 2H), 2.14-2.38 (m, 1H), 1.79-2.03 (m, 2H), 1.78-2.02 (m, 1H), 1.16-1.52 (m, 9H)

[0204] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 5.92 min tert-butyl (2R)-2-(3,5-difluorobenzoyl)pyrrolidine-1-carboxylate GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 13.47 min tert-butyl (2R)-2-(3,5-difluorobenzoyl)pyrrolidine-1-carboxylate

[0205] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.17 min tert-butyl (2R)-2-(3,5-difluorobenzoyl)pyrrolidine-1-carboxylate, 1.64 min tert-butyl (2S)-2-(3,5-difluorobenzoyl)pyrrolidine-1-carboxylate.

b) (S)-(3,5-difluorophenyl)-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0206] ##STR00034##

[0207] A 25 mL 3-necked flask equipped with a magnetic stirrer and a reflux condenser was charged with (R)-tert-butyl 2-(3,5-difluorobenzoyl)pyrrolidine-1-carboxylate (1 g, 3.12 mmol, Eq: 1) in 1-propanol (4 g, 5 ml, Eq: -). The clear solution was heated to 70 C. and then hydrochloric acid 25% (683 mg, 569 l, 4.68 mmol, Eq: 1.5) was added dropwise over 1 min.

[0208] The clear light yellow solution was stirred at 70 C. for 4 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (4 g, 5 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 16.5 mg, 7.8 mol, Eq: 0.0025) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 96 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0209] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (10 mL) was added. The resulting mixture was again concentrated under reduced pressure. n-PrOAc (10 mL) was added and the resulting suspension was stirred for 30 min at rt, then cooled to 0 C. and stirred for 2 hr. The suspension was filtered, and the crystalline white solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure white crystals (360 mg, 44.5%) with a chemical purity of 96.4% (see SFC method below) and an enantiomeric purity of >99.9% (see chiral SFC method below) were obtained.

[0210] 1H NMR (600 MHz, DMSO-d6) ppm 9.22-9.50 (m, 1H), 8.72-9.04 (m, 1H), 7.15-7.21 (m, 1H), 7.14-7.18 (m, 2H), 6.11-6.46 (m, 1H), 5.07 (br s, 1H), 3.69-3.80 (m, 1H), 3.10-3.21 (m, 2H), 1.87-1.97 (m, 1H), 1.73-1.84 (m, 1H), 1.73-1.84 (m, 1H), 1.62-1.71 (m, 1H), 0.80-0.85 (m, 1H)

[0211] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 3.63 min (S)-(3,5-difluorophenyl)-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

[0212] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 2.30 min (S)-(3,5-difluorophenyl)-[(2R)-pyrrolidin-2-yl]methanol hydrochloride.

Example 8

Preparation of (S)-(3,5-dimethoxyphenyl)-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0213] Reaction Scheme:

##STR00035##

a) tert-butyl (2R)-2-(3,5-dimethoxybenzoyl)pyrrolidine-1-carboxylate

[0214] ##STR00036##

[0215] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, a thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (4 g, 15.1 mmol, Eq: 1) in toluene (5 mL). The light yellow solution was cooled to 0 C. (3,5-Dimethoxyphenyl) magnesium bromide (0.5M in THF, 60.5 ml, 30.3 mmol, Eq: 2) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown clear solution was stirred for 60 min at 0 C., then warmed to rt and stirred for 3 hr at rt.

[0216] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (30 mL, 1.6M, 48 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with toluene (15 mL). The organic layers were washed with 5% NaHCO.sub.3 (60 mL) and 10% NaCl (40 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 5.74 g of an orange oil with a chemical purity of 46.0% (see HPLC method below)

[0217] The crude material was purified via flash chromatography (SiO.sub.2, 80 g, EtOAc:Heptane 1:9 to 1:1). After drying under reduced pressure, 2.56 g (46.8%) of a light yellow viscous oil was obtained with a chemical purity of 95.1% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0218] 1H NMR (600 MHz, CHLOROFORM-d) ppm 7.02-7.15 (m, 2H), 6.61-6.69 (m, 1H), 5.08-5.29 (m, 1H), 3.79-3.86 (m, 6H), 3.41-3.70 (m, 2H), 1.22-1.48 (m, 9H)

[0219] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 5.64 min tert-butyl (2R)-2-(3,5-dimethoxybenzoyl)pyrrolidine-1-carboxylate

[0220] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 16.16 min tert-butyl (2R)-2-(3,5-dimethoxybenzoyl)pyrrolidine-1-carboxylate

[0221] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.40 min tert-butyl (2R)-2-(3,5-dimethoxybenzoyl)pyrrolidine-1-carboxylate, 2.27 min tert-butyl (2S)-2-(3,5-dimethoxybenzoyl)pyrrolidine-1-carboxylate

b) (S)-(3,5-dimethoxyphenyl)-[(2R)-pyrrolidin-2-yl]methanol Hydrochloride

[0222] ##STR00037##

[0223] A 25 mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R)-tert-butyl 2-(3,5-dimethoxybenzoyl)pyrrolidine-1-carboxylate (1.2 g, 3.5 mmol, Eq: 1) in 1-propanol (4.8 g, 6 ml, Eq: -). The clear solution was heated to 70 C. and then hydrochloric acid 25% (765 mg, 637 l, 5.24 mmol, Eq: 1.5) was added dropwise over 1 min. The clear solution was stirred at 70 C. for 3.5 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (3.2 g, 4 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 18.5 mg, 8.75 mol, Eq: 0.0025) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 72 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0224] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (15 mL) was added. The resulting mixture was again concentrated under reduced pressure. n-PrOAc (15 mL) was added and the resulting suspension was stirred for 30 min at rt, then cooled to 0 C. and stirred for 2 hr. The suspension was filtered, and the crystalline white solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure white crystals (0.82 g, 85.1%) with a chemical purity of 99.4% (see SFC method below) and an enantiomeric purity of 99.3% (see chiral SFC method below) were obtained.

[0225] 1H NMR (600 MHz, DMSO-d6) ppm 8.51-9.45 (m, 2H), 6.58 (d, J=2.3 Hz, 2H), 6.36-6.45 (m, 1H), 5.97-6.12 (m, 1H), 4.82-5.01 (m, 1H), 3.74 (s, 6H), 3.64-3.72 (m, 1H), 3.05-3.19 (m, 2H), 1.60-1.96 (m, 4H)

[0226] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 3.87 min (S)-(3,5-dimethoxyphenyl)-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

[0227] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 4.17 min (S)-(3,5-dimethoxyphenyl)-[(2R)-pyrrolidin-2-yl]methanol hydrochloride.

Example 9

Preparation of (S)-[(2R)-pyrrolidin-2-yl]-(3,4,5-trifluorophenyl)methanol Hydrochloride

[0228] Reaction Scheme:

##STR00038##

a) tert-butyl (2R)-2-(3,4,5-trifluorobenzoyl)pyrrolidine-1-carboxylate

[0229] ##STR00039##

[0230] A 100-mL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.5 g, 9.46 mmol, Eq: 1) in toluene (3 mL). The light yellow solution was cooled 10 to 0 C. (3,4,5-trifluorophenyl)magnesium bromide (0.5M in 2-MeTHF, 37.8 ml, 18.9 mmol, Eq: 2) was added dropwise over 30 min maintaining the temperature at 0 C. The resulting light brown clear solution was stirred for 60 min at 0 C., then warmed to rt over 1 hr and stirred for 19 hr at rt. The brown solution became turbid.

[0231] The reaction mixture was cooled to 0 C. and carefully quenched with citric acid (25 mL, 1.6M, 40 mmol). The resulting biphasic mixture was allowed to separate and the organic, yellow clear solution was separated and the aqueous layer was extracted with toluene (10 mL). The organic layers were washed with 5% NaHCO.sub.3 (30 mL) and 10% NaCl (30 mL), dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to give 2.78 g of a yellow oil with a chemical purity of 50.0% (see HPLC method below)

[0232] The crude material was purified via flash chromatography (SiO.sub.2, 80 g, EtOAc:Heptane 1:9 to 1:1). After drying under reduced pressure, 1.66 g (51.4%) of colourless viscous oil was obtained with a chemical purity of 96.5% (see GC method below) and an enantiomeric excess of >99.9% (see chiral SFC method below).

[0233] 1H NMR (600 MHz, CHLOROFORM-d) ppm 7.63 (dt, J=16.0, 7.1 Hz, 2H), 4.89-5.31 (m, 1H), 3.42-3.74 (m, 2H), 2.22-2.39 (m, 1H), 1.81-2.01 (m, 3H), 1.18-1.49 (m, 9H)

[0234] HPLC method: Column: Waters XBridge C8 2.5 um, 4.6100 mm Columen XP (PN:186006051); Mobile phases, A: H.sub.2O 95:5 ACN=80-10% in 6 min, hold 2 min, B: ACN=10-80% in 6 min, hold 2 min, C: Wasser+0.5% TFA=10% isocratic; Flow: 1.500 mL/min; Temp.: 45 C.; DAD: 210 nm (BW: 4 nm), Inj Volume: 2.000 l; Sample Preparation: 2-3 drops reaction mixture quenched with 2 ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 6.15 min tert-butyl (2R)-2-(3,4,5-trifluorobenzoyl)pyrrolidine-1-carboxylate

[0235] GC method: Column: HP-5, 30 m0.32 mm ID, 0.25 um; Temp: 50 C. to 150 C., 10 C./min, 150 C. to 250 C., 20 C./min, at 250 C. hold up 3 min; Injector: 200 C.; Detector: 280 C.; Inj. Vol.: 1 l; Pressure: 44 kPa, (H.sub.2); Flow: 2.7 ml/min; Average Velocity: 50 cm/sec; FID: Air: 400 ml/min; H.sub.2: 30 ml/min; Makeup Flow: 30 ml/min; Split ratio: 5:1; Split flow 13.5 ml/min; Sample Preparation: 1.0 mg/mL EtOAc. Retention times: 12.41 min (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate, 13.47 min tert-butyl (2R)-2-(3,4,5-trifluorobenzoyl)pyrrolidine-1-carboxylate

[0236] Chiral SFC method: Column: Chiralpak AD-3, 3 um, 4.6 mm250 mm, Nr. 890; Mobile phases, A: CO.sub.2, 85%, B: MeOH+0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40 C., BPR: 130 bar; Inj. Vol.: 3.0 uL; UV 240 nm, Sample prep.: 1.5 mg/ml methanol. Retention times: 1.17 min tert-butyl (2R)-2-(3,4,5-trifluorobenzoyl)pyrrolidine-1-carboxylate, 1.42 min tert-butyl (2S)-2-(3,4,5-trifluorobenzoyl)pyrrolidine-1-carboxylate7

b) (S)-[(2R)-pyrrolidin-2-yl]-(3,4,5-trifluorophenyl)methanol Hydrochloride

[0237] ##STR00040##

[0238] A 25 mL 3-necked flask equipped with a magnetic stirrer and cooler was charged with (R)-tert-butyl 2-(3,4,5-trifluorobenzoyl)pyrrolidine-1-carboxylate (1.2 g, 3.52 mmol, Eq: 1) in 1-propanol (4.8 g, 6 ml, Eq: -). The clear light yellow solution was heated to 70 C. and then hydrochloric acid 25% (769 mg, 641 l, 5.27 mmol, Eq: 1.5) was added dropwise over 1 min.

[0239] The clear light yellow solution was stirred at 70 C. for 4 hr at which point complete disappearance of the starting material was observed. The reaction mixture was cooled to rt and transferred to an autoclave, the flask was rinsed with additional 1-propanol (4.8 g, 6 ml, Eq: -) and this solution was also transferred to the autoclave. After establishing an atmosphere of argon Palladium on Carbon (5.031%, 18.6 mg, 8.8 mol, Eq: 0.0025) was added. The autoclave was flushed with H.sub.2 and under stirring the hydrogen pressure was increased to 5 bar at 22 C. After 20 hr the autoclave was ventilated. The reaction mixture was filtered and the filter cake washed with 1-propanol.

[0240] The reaction mixture was concentrated under reduced pressure to a viscous oil at which point n-PrOAc (15 mL) was added. The resulting mixture was again concentrated under reduced pressure. n-PrOAc (10 mL) was added and the resulting suspension was stirred for 30 min at rt, then cooled to 0 C. and stirred for 2.5 hr. The suspension was filtered, and the crystalline white solid was washed with cold (0 C.) n-PrOAc (5 mL). After drying under reduced pressure white crystals (70 mg, 6.65%) with a chemical purity of 89.5% (see SFC method below) and an enantiomeric purity of 94.2% (see chiral SFC method below) were obtained.

[0241] 1H NMR (600 MHz, DMSO-d6) ppm 9.17-9.43 (m, 1H), 8.75-8.96 (m, 1H), 7.34-7.41 (m, 2H), 6.28-6.49 (m, 1H), 4.94-5.10 (m, 1H), 3.65-3.77 (m, 1H), 3.10-3.22 (m, 2H), 1.89-1.95 (m, 1H), 1.73-1.81 (m, 1H), 1.73-1.80 (m, 1H), 1.68 (dq, J=11.5, 7.5 Hz, 1H)

[0242] SFC method: Acquity UPC2 Torus DEA, 3 um, 4.6 mm100 mm, Nr. 122; Mobile phases, A: CO.sub.2, 97%-65% in 6 min, B: EtOH+0.2% IPAm, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50 C., BPR: 100 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml EtOH. Retention time: 3.76 min (S)-[(2R)-pyrrolidin-2-yl]-(3,4,5-trifluorophenyl)methanol hydrochloride

[0243] Chiral SFC method: Column: Chiralcel OZ-3, 3 um, 4.6 mm150 mm, Nr. 183; Mobile phases, A: CO.sub.2, 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH+0.2% IPAm, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50 C., BPR: 220 bar; Inj. Vol.: 3.0 uL; UV 210 nm, Sample prep.: 2 mg/ml methanol. Retention time: 2.11 min (S)-[(2R)-pyrrolidin-2-yl]-(3,4,5-trifluorophenyl)methanol hydrochloride