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

wherein R is aryl or heteroaryl and both aryl or heteroaryl are optionally substituted by

Ci-4-alkyl, halo-Ci-4-alkyl, Ci-4-alkoxy or halogen.

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).

A process for the preparation of chiral pyrollidine-2-yl- methanol derivatives of the formula I has been described in Soai et al.; J.Chem.Soc, Chem.Commun. 1986, 412-413. The three step process starts from S-proline and is characterized by the reduction of a chiral benzoyl pyrrolidine with various reducing agents which affords, depending on the reducing agent, erythro/threo mixtures of the chiral pyrollidine-2-yl-methanol.

There is a need for a scalable process which affords the desired chiral building block in good yields and high enantiomeric purity. Object of the invention accordingly was to overcome the flaws of the state of the art processes.

The object could be achieved with the new process as described below.

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

wherein R is aryl or heteroaryl and both aryl or heteroaryl are optionally substituted by Ci-4-alkyl, halo-Ci-4-alkyl, Ci-4-alkoxy or halogen; comprises the steps a) a pyrrolidine carboxylic acid derivative of formula II

wherein R is an amino protecting group is transformed with an Ν,Ο-dialkylhydroxylamine of the formula IV

wherein R ³ and R ⁴ independently of each other are Ci_ ₄ -alkyl into the carbamoyl pyrrolidine derivative of formula III

wherein R 2 is as above and R 3 and R 4 independently of each other are Ci_ ₄ -alkyl ; b) the carbamoyl pyrrolidine derivative of formula III is reacted with a Grignard reagent of the formula

wherein R is as above and Hal stands for a halogen atom to form the aroyl pyrrolidine derivative of formula IV

wherein R 1 and R 2 are as above and; c) the aroyl pyrrolidine derivative of formula IV is first freed from the amino protecting group R and subsequently hydrogenated in the presence of a hydrogenation catalyst to form the chiral pyrollidine-2-yl- methanol derivative of the formula I.

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

The term "chiral" signifies that the molecule can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure

diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. In a preferred embodiment of the invention the term "chiral" denotes optically pure enantiomers.

In the structural formulae presented herein a broken bond (a) denotes that the substituent is below the plane of the paper and a wedged bond (b) denotes that the substituent is above the plane of the paper.

The spiral bond (c) denotes both options i.e. either a broken bond (a) or a wedged bond

(b). The term "aryl" denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. Phenyl is the preferred aryl group.

The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl,

benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or

quinoxalinyl.

Preferably the term "heteroaryl" denotes a monovalent aromatic heterocyclic monocyclic ring system of 5 to 6 ring atoms comprising lto 3 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of preferred heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or isoxazolyl.

The term "optionally substituted" in connection with the term "aryl" or "heteroaryl" denotes that the aryl or heteroaryl group may be unsubstituted or substituted by one or more substituents, independently selected from Ci_ ₄ -alkyl, halo-Ci_ ₄ -alkyl, C- i_ ₄ -alkoxy or halogen, preferably from Ci_ ₄ -alkyl, halo-Ci_ ₄ -alkyl or C-i_ ₄ -alkoxy.

The term "C- _1-4 - alkyl" denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 4 carbon atoms. Examples of C- _1-4 - alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec -butyl, or tert-butyl. The term "C-i_ ₄ -alkoxy" denotes a group of the formula -O-R', wherein R' is a C- _1-4 - alkyl group. Examples of C-i_ ₄ -alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert- butoxy.

The term "halo", "halogen", and "halide" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo.

The term "halo-Ci_ ₄ -alkyl" denotes a C- _1-4 - alkyl group as defined above which carries one or more halogen substituents as defined above. Examples of halo-Ci_ ₄ -alkyl are chloromethyl, 2-chloroethyl, 3-chloropropyl, bromomethyl, 2-bromoethyl, 3-bromopropyl, 2,2-dichloroethyl, trichloromethyl or trichloroethyl.

In a preferred embodiment of the present invention R ¹ is aryl, preferably phenyl or naphthyl, more preferably phenyl unsubstituted or substituted by Ci_ ₄ -alkyl, halo-Ci_ ₄ -alkyl, C _1-4 - alkoxy or halogen.

In another preferred embodiment R ¹ is phenyl unsubstituted or substituted by one or more substituents selected from methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, fluoro, chloro, bromo, iodo, methoxy, ethoxy, isopropoxy or tert-butoxy.

Preferred examples for R ¹ are phenyl, naphthyl, p-tolyl, m-tolyl, 3,5-difluorophenyl, 3,4,5-trifluorophenyl or 3,5-dimethoxyphenyl.

Phenyl is the most preferred substituent for R ¹ .

The term "amino-protecting group" denotes groups intended to protect an amino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), Fmoc (9- Fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert- butoxycarbonyl (BOC), and trifluoroacetyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, "Protective Groups in Organic

Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. Preferred amino-protecting group is tert-butoxycarbonyl (BOC).

The term "salt" in the context of the present invention denotes the salt generated upon removal of the amino-protecting group R , i.e. salts formed with a strong acid such as with hydrochloric acid or trifluoro acetic acid. The hydrochloride salt formed with hydrochloric acid is the preferred salt. In a preferred embodiment of the present invention the chiral pyrollidine-2-yl- methanol derivative of the formula I has the structure la. wherein R is as above.

In another preferred embodiment of the present invention the chiral pyrollidine-2-yl- methanol derivative of the formula I has the structure lb.

wherein R is as above.

Preferably, the substituent R ¹ stands for phenyl, optionally substituted by Ci-4-alkyl, C _1-4 - alkoxy or halogen, but particularly for unsubstituted phenyl.

Step a)

Step a) requires the transformation of a pyrrolidine carboxylic acid derivative of formula II with a Ν,Ο-dialkylhydroxylamine into the carbamoyl pyrrolidine derivative of formula III.

The pyrrolidine carboxylic acid derivatives of formula II are particularly used in their chiral form preferably as pure enantiomers.

The amino protecting group R can be selected from those mentioned above, but preferred are those which are cleavable under strong acidic conditions. Preferred amino protecting group is tert-butoxycarbonyl (BOC).

The Ν,Ο-dialkylamine has the formula IV

R ⁴ ONHR ³ P wherein R ³ and R ⁴ independently of each other are Ci-4-alkyl is usually applied in the form of a suitable salt such as the hydrochloride. In a preferred embodiment R ³ and R ⁴ are methyl.

The coupling as a rule takes place in the presence of a coupling agent, an amine base and an organic solvent at a reaction temperature between 0°C and 60°C.

The coupling agent can be selected from DCC (Ν,Ν'-dicyclohexylcarbodiimide) or EDC (N-(3-dimethylaminopropyl)-N -ethylcarbodiimide-hydrochloride) or TBTU (Ν,Ν,Ν',Ν'- tetramethyl-0-(benzotriazol-l-yl)uronium tetrafluoroborate, HBTU (2-(lH-benzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate) together with an additive selected from HOBt (1-hydroxybenztriazole), HOSu (N-hydroxysuccinimide) or HO At (l-hydroxy-7- azabenzotriazole and common combinations thereof such as TBTU/HOBt or HBTU/HOAt. A suitable alternative is n-propylphosphonic acid anhydride (T3P ^® ).

The amine base usually is a tertiary amine, like triethylamine or N-ethyldiisopropylamine, pyridine derivatives such as 2,4,6-collidine, DABCO (l,4-Diazabicyclo[2.2.2]octane) or N- methylmorpholine , but preferably N-methylmorpholine.

Preferably n-propylphosphonic acid anhydride (T3P ^® ) is used as coupling agent. The reaction expediently takes place in a polar aprotic solvent like acetonitrile, dimethyl sulfoxide or tetrahydrofuran or mixtures thereof.

The reaction temperature preferably is in the range of 10°C and 40°C, more preferably at 20°C to 30°C.

Isolation of the formed carbamoyl pyrrolidine derivative of formula III can happen by methods known to the skilled in the art such as by adding water and a weak acid and subsequent extraction with a suitable organic solvent like ethylacetate or toluene. Weak acids can be selected from an organic acid like citric acid or from diluted mineral acids like diluted hydrochloric-, sulfuric or phosphoric-acid. Evaporation of the organic solvent after extraction with a weak base as a rule provides the carbamoyl pyrrolidine derivative of formula III in a sufficient purity for the next step. Alternatively the pyrrolidine derivative of formula III can also be used as solutions in toluene or THF for the next step.

Preferred carbamoyl pyrrolidine derivatives have the formula Ilia or Illb

wherein R 2 , R 3 and R 4 are as above.

Even more preferred carbamoyl pyrrolidine derivatives have the formula IIIc or Hid

wherein R is as above.

In a still further preferred embodiment R is tert-butoxycarbonyl (BOC).

Step b)

Step b) requires the reaction of the carbamoyl pyrrolidine derivative of formula III with a Grignard reagent to form the aroyl pyrrolidine derivative of formula IV.

In view of the fact that initial step a) is preferably performed with a chiral starting compound the starting compound for step b) i.e. the carbamoyl pyrrolidine derivative of formula III is also particularly used in their chiral form preferably as pure enantiomer.

The Grignard reaction can be performed following methods well known to the skilled in the art.

The Grignard reagents of the formula R^gHal, wherein R ¹ is as above and Hal stands for a halogen atom are either commercially available or can alternatively readily be prepared as described e.g. by P. Knochel and co-workers in Angew. Chem. Int. Ed., 2004, 43, 3333-3336. In a preferred embodiment R ¹ is phenyl optionally substituted by Ci_ ₄ -alkyl, preferably methyl or ethyl, Ci_ ₄ -alkoxy, preferably methoxy or ethoxy or halogen, preferably fluorine. More preferably R ¹ is unsubstituted phenyl.

Hal preferably stands for chlorine or bromine. The most preferred Grignard reagent is PhenylMgBr.

The Grignard reaction is usually performed in an organic solvent, preferably an ethereal or aromatic hydrocarbon solvent or mixtures thereof. Typical ethereal solvent are

tetrahydrofuran, methyl-tetrahydrofuran or cyclopentyl methyl ether. A typical aromatic solvent is toluene. The reaction temperature is commonly selected between -10°C and 50°C, but typically lower temperatures between 0°C and 30°C are preferred.

Isolation of the aroyl pyrrolidine derivative of formula IV can happen following methods known to the skilled in the art, for instance by quenching the reaction mixture with a weak acid such as with an aqueous organic acid like citric acid or an aqueous mineral acid. Subsequent extraction of the biphasic mixture with a suitable organic solvent which can be selected from hydrocarbons like heptane, ethers like tetrahydrofuran or aromatic solvents like toluene and finally evaporation of the organic phase renders the crude aroyl pyrrolidine. Further purification can be reached by crystallization in a polar protic solvent like an aqueous i-propanol or n- propanol. In view of the preference to use chiral compounds the preferred aroyl pyrrolidine derivative have the formula IVa or IVb.

wherein R 1 and R 2 are as above. Step c) Step c) requires in a first step the removal of the amino protecting group R in the aroyl pyrrolidine derivative of the formula IV and in a second step the hydrogenation in the presence of a hydrogenation catalyst to form the chiral pyrollidine-2-yl- methanol derivative of the formula I.

The removal of amino protecting groups can be accomplished following methods known in literature and to the skilled in the art. The preferred amino protecting groups are those which are cleavable with a strong acid.

Suitable strong acids are mineral acids such as hydrochloric acid or a strong organic acid such as trifluoroacetic acid, however typically an aqueous hydrochloric acid having a HC1 concentration of 25% and more is used.

The reaction usually takes place in the presence of a protic solvent, for instance in lower alcohols like ethanol or n-propanol at elevated temperatures between 40°C to 80°C until no starting material can any longer be detected.

The reaction mixture can then, without isolation of the de-protected intermediate (which in case of HC1 is the hydrochloride salt of the de-protected aroyl pyrrolidine) be transferred to the hydrogenation reaction. The hydrogenation is performed in the presence of a hydrogenation catalyst, preferably consisting of a platin group metal selected from ruthenium, osmium, rhodium, iridium, palladium and platin, preferably from palladium.

The platinum metals are usually applied on an inert carrier, typically on carbon.

In a preferred embodiment palladium (Pd) on carbon, more preferably 2%wt.Pd to 20%wt. Pd, even more preferably 8%wt. to 12%wt. Pd on carbon is used.

The hydrogenation reaction expediently takes place in a polar protic solvent at a reaction temperature between 0°C and 60°C and a hydrogen pressure between 1 bar and 10 bar.

The polar protic solvent is preferably the same as used for the de-protection, i.e. a lower alcohol like ethanol or n-propanol. The reaction temperature preferably is maintained between 20°C and 40°C and the hydrogen pressure preferably is selected between 3 bar and 7 bar.

After completion of the reaction the catalyst is removed by filtration. The desired product can then be obtained by crystallization with a suitable solvent such as with n-propylacetate or i- propylacetate. Further purification can be reached by a recrystallization from a polar aprotic solvent, preferably from acetonitrile.

According to the preferred embodiment the chiral aroyl pyrrolidines of formula IVa or IVb are applied for step c). The desired pyrollidine-2-yl- methanol derivative of the formula I, particularly of formula la or lb can following the methods described above be obtained in high yields and an optical purity of greater 95% ee, preferably greater 99% ee.

The desired pyrollidine-2-yl- methanol derivative of the formula I, particularly of formula la or lb, are obtained in the form of the salt of the strong acid used for the de-protection of the preferred BOC-group as described above, preferably the hydrochloride salt.

Examples:

Abbreviations: rt = room temperature, T3P = propylphosphonic anhydride, EtOAc = ethyl acetate ,

NMM = 4-methylmorpholine, ACN = acetonitrile, PhMgBr = phenylmagnesium bromide, THF = tetrahydrofuran, CPME = cyclopentyl methyl ether, w-PrOH = 1-Propanol,

z ^' -PrOH = 2-propanol, w-PrOAc = propyl acetate, TFA = trifhioroacetic acid

Example 1:

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

Reaction Scheme:

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

A 500-mL-round-bottomed flask equipped with an overhead stirrer was charged with (S)-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (50 g, 232 mmol, Eq: 1) and iV,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% NaHC0 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-l-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). 1H-NMR (600 MHz, CDC1 ₃ ) δ ppm 4.59 (br s, 1 H), 3.67 - 3.82 (m, 3 H), 3.53 - 3.64 (m, 1 H), 3.36 - 3.51 (m, 1 H), 3.11 - 3.24; (m, 3 H), 2.07 - 2.27 (m, 1 H), 1.77 - 2.07 (m, 3 H), 1.34 - 1.49 (m, 9 H).

GC method: Column: HP-5, 30m x 0.32mm ID, 0.25μηι; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400 ml/min; H ₂ : 30ml/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.

Chiral HPLC method: Column: Chiralpak IC-3, 150 x 4.6mm, 3um, Nr. 188; Mobile phases, A: w-heptane, 80%, B: 0.1% TFA in w-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-l- carboxylate, 3.26 min tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-l-carboxylate. b) tert-Butyl (2S)-2-benzoylpyrrolidine-l-carboxylate

A 500-mL-round-bottomed flask equipped with an overhead stirrer was charged with (S)-tert- butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-l-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 lhr and stirred for 2 h and 20 min at rt. After 25 min at rt the clear solution became turbid.

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% NaHC0 ₃ (250 mL each) and 10% NaCl (200 mL), combined, dried over Na ₂ S0 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)

The crude material was dissolved in a mixture of z ^' -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 lhr. After complete addition the yellow suspension was stirred for lhr at 0°C. The crystals (light yellow) were filtered, washed with a mixture of -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).

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

GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H2); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l-carboxylate, 14.09 min tert-butyl (2S)-2-benzoylpyrrolidine-l- carboxylate Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l-carboxylate, 1.66 min tert-butyl (2S)-2-[methoxy- (methyl)carbamoyl]pyrrolidine- 1 -carboxylate. c) (R)-phenyl-[(2S)-pyrrolidin-2-yl]methanol hydrochloride

A 350mL-round-bottomed flask equipped with an overhead stirrer was charged with (S)-tert- butyl 2-benzoylpyrrolidine-l-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 HC1 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 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).

The reaction mixture was concentrated under reduced pressure to 135 g at which point w-PrOAc (100 mL) was added. The resulting mixture was again concentrated under reduced pressure to 130 g at which point w-PrOAc (100 mL) was added. The resulting suspension was stirred for 2 h at rt, then cooled to 0 °C and stirred for 2h. The suspension was filtered, and the crystalline white solid was washed with cold (0 °C) w-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.

1H NMR (600 MHz, DMSO-d6) δ ppm 8.74 - 9.85 (m, 1 H), 7.48 - 7.49 (m, 1 H), 7.21 - 7.46 (m, 2 H), 6.09 (br d,J=3.5 Hz, 1 H), 5.06 (br s, 1 H), 3.61 - 3.79 (m, 1 H), 3.07 - 3.20 (m, 1 H), 1.68 - 1.97 (m, 1 H), 1.52 - 1.65 (m, 1 H). HRMS: (ESI-TOF) calculated for (C _n H ₁₅ NO): 177.1154, found: 177.1154. Chiral SFC method: Chiralcel OZ-3, 150x4.6mm, Nr: 183; Mobile phases, A: C0 ₂ , 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol + 0.2% zsopropyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50°C; BPR: 130bar; 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

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 1, Eq: -). The resulting suspension was heated to 80 °C until a solution was obtained and the volume was reduced by 1 L via destination. 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 1, 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)

HPLC method: Column: XBridge BEH Phenyl, 2.5um, 100x4.6mm, Nr: 207;Solvent: A:

H20/ACN, 95/5: 80-45% in 4min, hold for lmin, B: ACN: 15-50% in 4min, hold for lmin, D: lOOmM Ammonium formate in H20/ACN (95/5) @ pH9 with NH3: 5% isocratic; Temp: 50°C; Flow : 1.5 ml/min; Inj. Vol.: 3.5 ul + wash, Starting pressure: 247bar; Detector: 212nm, BW: 8nm, Ref: 360nm, Ref BW: 50M; Sample Prep: 0.5mg/ml in H20/ACN (1/1; v/v)

Chiral SFC method: Chiralcel OZ-3, 150x4.6mm, Nr: 183; Mobile phases, A: C0 ₂ , 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol + 0.2% zsopropyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50°C; BPR: 130bar; 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 Reaction scheme:

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

A 30-L reactor was charged with (R)-l-(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 1, Eq: -) to give a light yellow suspension. N-methylmorpholine (3.24 kg, 3.52 1, 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 1, 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 1, 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 1, Eq: -), followed by a solution of NaHC0 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-l-carboxylate (2510 g, 91%) in toluene (3200 g). 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).

1H NMR (600 MHz, CDC1 ₃ )5 ppm 4.59 - 4.75 (m, 1 H), 3.68 - 3.85 (m, 3 H), 3.35 - 3.63 (m, 2 H), 3.21 (s, 3 H), 1.85 - 2.29 (m, 2 H), 1.82 - 2.06 (m, 2 H), 1.38 - 1.49 (m, 9 H).

HPLC method. Column: XBridge BEH C8, 2.5um, 100x4.6mm, Nr: 182; Mobile phases: A: H ₂ 0/ACN, 95/5: 80-10% in 6min, hold for lmin, B: ACN, 10-80% in 6min, hold for lmin, C: H ₂ 0 + 0.5% TFA: 10% isocratic; Flow: 1.5ml/min; Temp.: 45°C; Inj.Volume: 2ul; UV: 200nm (BW: 8nm), Ref: 360nm (BW: lOOnm); Sample prep: 2mg/mL H ₂ 0/ACN, 1/1 Chiral HPLC method: Column: Chiralpak IC-3, 150 x 4.6mm, 3um, Nr. 188; Mobile phases, A: w-heptane, 80%, B: 0.1% TFA in w-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-l- carboxylate, 3.26 min tert-butyl (2R)-2-[methoxy(methyl)carbamoyl]pyrrolidine-l-carboxylate. b) tert-Butyl (2R)-2-benzoylpyrrolidine-l-carboxylate

A 30-L reactor was charged with (R) -tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-l- 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 NaHC0 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 1, Eq: -), filtered and the resulting solution was diluted with n-propanol

(8 kg, 10 1, 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-l-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 purifty of 99.2% (see GC method below) and enantiomeric excess of >99% (see chiral SFC method)

GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H2); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l-carboxylate, 14.09 min tert-butyl (2S)-2-benzoylpyrrolidine-l- carboxylate.

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR:

130bar; 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-l-carboxylate, 1.66 min tert-butyl (2S)-2-[methoxy- (methyl)carbamoyl]pyrrolidine- 1 -carboxylate. c) (S)-phenyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

A 4500mL-round-bottomed flask equipped with an overhead stirrer was charged with (R)-tert- butyl 2-benzoylpyrrolidine-l-carboxylate (476 g, 1.73 mol, Eq: 1) in 1-propanol (1.84 kg, 2.3 1, Eq: -). The clear yellow solution was heated to 60 °C and then HC1 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 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). The reaction mixture was concentrated under reduced pressure at 60 °C to 1.5 L at which point crysalization of the product already started subsequently the solvent was exchanged with n- PrOAc maintaining a constant volumeat 60 °C. For the solvent exchange w-PrOAc (8.01 kg, 9 1, Eq: -) was used. The resulting mixture was cooled to rt and stirred for 1 hr at rt. The suspension was filtered, and the crystaline solid was washed with w-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.

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

HPLC method: Column: XBridge BEH Phenyl, 2.5um, 100x4.6mm, Nr: 207;Solvent: A:

H20/ACN, 95/5: 80-45% in 4min, hold for lmin, B: ACN: 15-50% in 4min, hold for lmin, D: lOOmM Ammonium formate in H20/ACN (95/5) @ pH9 with NH3: 5% isocratic; Temp: 50°C; Flow : 1.5 ml/min; Inj. Vol.: 3.5 ul + wash, Starting pressure: 247bar; Detector: 212nm, BW: 8nm, Ref: 360nm, Ref BW: 50M; Sample Prep: 0.5mg/ml in H20/ACN (1/1 ; v/v)

Chiral SFC method: Chiralcel OZ-3, 150x4.6mm, Nr: 183; Mobile phases, A: C0 ₂ , 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol + 0.2% zsopropyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50°C; BPR: 130bar; 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

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 1, Eq: -). The resulting suspension was heated to 80 °C until a solution was obtained and the volume was reduced by 1.5 L via destination. 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 1, 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) 1H NMR (600 MHz, DMSO-d6) δ ppm 9.42 (br s, 1 H), 8.71 (br s, 1 H), 7.22 - 7.46 (m, 5 H), 6.09 (br dJ,=3.1 Hz, 1 H), 5.03 (br s, 1 H), 3.64 - 3.78 (m, 1 H), 3.06 - 3.21 (m, 2 H), 2.04 - 2.12 (m, 1 H), 1.70 - 1.99 (m, 3 H), 1.52 - 1.64 (m, 1 H)

HRMS: (ESI-TOF) calculated for (C _n H ₁₅ NO): 177.1154, found: 177.1161.

HPLC method: Column: XBridge BEH Phenyl, 2.5um, 100x4.6mm, Nr: 207;Solvent: A:

H20/ACN, 95/5: 80-45% in 4min, hold for lmin, B: ACN: 15-50% in 4min, hold for lmin, D: lOOmM Ammonium formate in H20/ACN (95/5) @ pH9 with NH3: 5% isocratic; Temp: 50°C; Flow : 1.5 ml/min; Inj. Vol.: 3.5 ul + wash, Starting pressure: 247bar; Detector: 212nm, BW: 8nm, Ref: 360nm, Ref BW: 50M; Sample Prep: 0.5mg/ml in H20/ACN (1/1; v/v)

Chiral SFC method: Chiralcel OZ-3, 150x4.6mm, Nr: 183; Mobile phases, A: C0 ₂ , 90-60% in 8.8 min, hold for 0.5 min, B: Ethanol + 0.2% zsopropyl amine, 10-40% in 8.8 min, hold for 0.5 min; Flow: 3 ml/min; Temp: 50°C; BPR: 130bar; 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.

Reaction scheme:

A 100-mL-foiir-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- l - carboxylate (2.5 g, 9 mmol, Eq: I ) in cyclopentyl methyl ether (3 mL), The yellow solution was cooled to 0 °C. p-Tolylmagnesium bromide ( I M in THF, 1 8 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 3hr at rt.

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% NaHCOj (25 mL) and 10% NaCl (20 mL), dried over NaaSOj, 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)

The crude material was dissolved in a mixture of /-PrOH/water ( l : l , 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 /-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). 1H NMR (600 MHz, CDC1 ₃ ) δ ppm 7.70 - 8.04 (m, 1 H), 5.08 - 5.36 (m, 1 H), 3.34 - 3.72 (m, 2 H), 2.37 - 2.46 (m, 2 H), 2.23 - 2.34 (m, 1 H), 1.84 - 1.97 (m, 1 H), 1.82 - 1.97 (m, 1 H), 1.15 - 1.54 (m, 7 H)

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6min, hold 2min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; 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-l-carboxylate, 5.79 min tert-butyl (2R)-2-(4- methylbenzoyl)pyrrolidine- 1 -carboxylate

GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 14.64 min tert-butyl (2R)-2-(4- methylbenzoyl)pyrrolidine- 1 -carboxylate

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l -carboxylate, 1.72 min tert-butyl (2S)-2-(4- methylbenzoyl)pyrrolidine- 1 -carboxylate b) (S)-p-tolyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

A 25mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R) -tert-butyl 2-(4-methylbenzoyl)pyrrolidine-l -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 μΐ, 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 μΐ, 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 μιηοΐ, Eq:

0.00125) was added. The autoclave was flushed with H 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.

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 crystaline 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.

1H NMR (600 MHz, DMSO-d6) δ ppm 8.39 - 9.59 (m, 2 H), 7.23 - 7.35 (m, 2 H), 7.12 - 7.21 (m, 2 H), 5.94 - 6.10 (m, 1 H), 4.91 - 5.04 (m, 1 H), 3.61 - 3.72 (m, 1 H), 3.06 - 3.20 (m, 2 H), 2.29 (s, 3 H), 1.53 - 1.95 (m, 4 H) SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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

Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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-toly]-[(2R)-pyrro]idin-2-yl]methano!;hydrochloride

Reaction scheme:

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)carbarnoyl)pyrrolidine- l - carboxylate (2.5 g, 9 mmo!, 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 ( 1 M in THF, 1 .8 ml, 1 .8 mmo!, Eq: 0.2) was added dropwise over 1 5 min maintaining the temperature at 0 °C, then stirred for 1 h at rt.

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% NaHCOj (25 mL) and 10% NaC! (20 mL), dried over NajSOj, filtered and evaporated under reduced pressure to give 1 .93 g of a red soiid with a chemical purity of 66.4% (see HPLC method below)

The crude material was dissolved in a mixture of /-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 crystall ize 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 /-PrOH/water ( 1 : 1 , 5mL) 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).

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

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6 min, hold 2 min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; Sample Preparation: 2-3 drops reaction mixture quenched with 2ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2- (methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate, 5.78 min tert-butyl (2R)-2-(3- methylbenzoyl)pyrrolidine- 1 -carboxylate

GC method: Column: HP-5, 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 14.50 min tert-butyl (2R)-2-(3- methylbenzoyl)pyrrolidine- 1 -carboxylate

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l -carboxylate, 1.49 min tert-butyl (2S)-2-(3- methylbenzoyl)pyrrolidine- 1 -carboxylate b) (S)-m-tolyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride A 25mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R) -tert-butyl 2-(3-methylbenzoyl)pyrrolidine-l -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 μΐ, 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 μιηοΐ, Eq: 0.0025) was added. The autoclave was flushed with H 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. 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 w-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 crystaline white solid was washed with cold (0 °C) w-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.

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

SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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 Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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.

Reaction scheme:

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(methyi)carbamoy l)pyrrolidine- 1 - carboxylate (4 g, 15. 1 mmol, Eq: S ) in toluene (5 mL). The light yellow solution was cooled to 0 °C. (4-(tert-Buty!)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 rain at 0 °C, then warmed to rt and stirred for 17hr at rt.

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% NaHCOj (60 mL) and 10% NaCl {50 mL), dried over Na ₂ S0 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)

The crude material was dissolved in a mixture of / ^' -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 / ^' -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 chirai SFC method below). 1H NMR (600 MHz, CHLOROFORM-J) δ ppm 7.84 - 7.97 (m, 2 H), 7.44 - 7.50 (m, 2 H), 5.13 - 5.36 (m, 1 H), 3.40 - 3.78 (m, 2 H), 2.24- 2.35 (m, 1 H), 1.97 (br s, 2 H), 1.85 - 1.97 (m, 1 H), 1.44 - 1.48 (m, 4 H), 1.32 - 1.35 (m, 9 H), 1.27 (s, 4 H), 1.25 - 1.28 (m, 1 H)

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6min, hold 2min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; Sample Preparation: 2-3 drops reactionmixture quenched with 2ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2- (methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate, 6.76 min tert-butyl (2R)-2-(4-tert- butylbenzoyl)pyrrolidine- 1 -carboxylate

GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 15.64 min tert-butyl (2R)-2-(4-tert- butylbenzoyl)pyrrolidine- 1 -carboxylate

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l -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

A 25mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R) -tert-butyl 2-(4-(tert-butyl)benzoyl)pyrrolidine-l-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 μΐ, 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 μΐ, 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 μιηοΐ, Eq: 0.00125) was added. The autoclave was flushed with H 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.

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. w-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 crystaline off-white solid was washed with cold (0 °C) w-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.

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

SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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

Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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

Reaction scheme:

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

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-l- 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.

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% NaHC0 ₃ (45 mL) and 10% NaCl (30 mL), dried over Na ₂ S0 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)

The crude material was dissolved in a mixture of /-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 (Si0 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).

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

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6min, hold 2min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; Sample Preparation: 2-3 drops reactionmixture quenched with 2ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2- (methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate, 5.5 min tert-butyl (2R)-2-(naphthalene- 2-carbonyl)pyrrolidine- 1 -carboxylate.

GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H2); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 17.26 min tert-butyl (2R)-2- (naphthalene-2-carbonyl)pyrrolidine- 1 -carboxylate.

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l -carboxylate, 5.53 min tert-butyl (2S)-2- (naphthalene-2-carbonyl)pyrrolidine- 1 -carboxylate. b) (S)-2-naphthyl-[(2R)-pyrrolidin-2-yl]methanol hydrochloride

A 25mL 3-necked flask equipped with a magnetic stirrer and a reflux condenser was charged with (R)-tert-butyl 2-(2-naphthoyl)pyrrolidine-l-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 μΐ, 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 μιηοΐ, Eq: 0.0025) was added. The autoclave was flushed with H 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.

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. w-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 crystaline light brown solid was washed with cold (0 °C) w-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.

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

SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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 Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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.

Reaction scheme;

a) tert-butyl (2R)-2-(3,5-difluorobenzoy!)pyrrolidine-l-carboxylate

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)pyrroiidine- l - carboxy!ate (2.2 g, 7.92 mmol, Eq: 1 ) in cyciopentyl methyl ether (3 mL). The light yellow solution was cooled to 0 ^C C. (3,5-Difluorophenyl)magnesium bromide (0.5 M in 2-MeTHF, 3 1 .7 ml, 1 5.8 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 I h and stirred for ! 9h at rt. After I9h at rt the clear solution became turbid.

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 cyciopentyl methyl ether ( 10 mL). The organic layers were washed twice with 5% NaHCOj (25 mL) and 10% NaCI {20 mL), dried over Na?SO,|, 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)

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 ( l : l , 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).

1H NMR (600 MHz, CDCL3)5 ppm 7.40 - 7.54 (m, 2 H), 6.95 - 7.10 (m, 1 H), 4.95 - 5.24 (m, 1 H), 3.36 - 3.69 (m, 2 H), 2.14 - 2.38 (m, 1H), 1.79 - 2.03 (m, 2 H), 1.78 - 2.02 (m, 1 H), 1.16 - 1.52 (m, 9 H)

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6min, hold 2min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; Sample Preparation: 2-3 drops reactionmixture quenched with 2ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2- (methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate, 5.92 min tert-butyl (2R)-2-(3,5- difluorobenzoyl)pyrrolidine- 1 -carboxylate

GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 13.47 min tert-butyl (2R)-2-(3,5- difluorobenzoyl)pyrrolidine- 1 -carboxylate Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l-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

A 25mL 3-necked flask equipped with a magnetic stirrer and a reflux condenser was charged with (R)-tert-butyl 2-(3,5-difluorobenzoyl)pyrrolidine-l-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 μΐ, 4.68 mmol, Eq: 1.5) was added dropwise over 1 min. 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 μιηοΐ, Eq: 0.0025) was added. The autoclave was flushed with H 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.

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 crystaline 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.

1H NMR (600 MHz, DMSO-d6) δ ppm 9.22 - 9.50 (m, 1 H), 8.72 - 9.04 (m, 1 H), 7.15 - 7.21 (m, 1 H), 7.14 - 7.18 (m, 2 H), 6.11 - 6.46 (m, 1 H), 5.07 (br s, 1 H), 3.69 - 3.80 (m, 1 H), 3.10 - 3.21 (m, 2 H), 1.87 - 1.97 (m, 1 H), 1.73 - 1.84 (m, 1 H), 1.73 - 1.84 (m, 1 H), 1.62 - 1.71 (m, 1 H), 0.80 - 0.85 (m, 1 H) SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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

Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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.

Reaction scheme:

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 (methy I )carbamoy I )py rro I id i ne- 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 3hr at rt.

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% NaHC0 ₃ (60 mL) and 10% NaCI (40 mL), dried over Na ₂ SOj, 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)

The crude material was purified via flash chromatography (Si<¾, 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). 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 7.02 - 7.15 (m, 2 H), 6.61 - 6.69 (m, 1 H), 5.08 - 5.29 (m, 1 H), 3.79 - 3.86 (m, 6 H), 3.41- 3.70 (m, 2 H), 1.22 - 1.48 (m, 9 H)

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6min, hold 2min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; Sample Preparation: 2-3 drops reaction mixture quenched with 2ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2- (methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate, 5.64 min tert-butyl (2R)-2-(3,5- dimethoxybenzoyl)pyrrolidine- 1 -carboxylate GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 16.16 min tert-butyl (2R)-2-(3,5- dimethoxybenzoyl)pyrrolidine- 1 -carboxylate

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l-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

A 25mL 3-necked flask equipped with a magnetic stirrer and reflux condenser was charged with (R) -tert-butyl 2-(3,5-dimethoxybenzoyl)pyrrolidine-l-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 μΐ, 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 μιηοΐ, Eq: 0.0025) was added. The autoclave was flushed with H 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.

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 crystaline 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.

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

SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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 Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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.

Reaction scheme:

S O

A 100-inL-four-necked flask equipped with a magnetic stirrer, argon inlet, thermometer and a syringe pump was charged with (R)-tert-butyl 2-(methoxy(methy l)carbamoy Opyrrolidine- 1 - carboxylate (2.5 g, 9.46 mmol, Eq: l ) in toluene (3 mL). The light yellow solution was cooled to 0 °C. (3,4,5-trifluorophenyl)inagnesiuni bromide (0.5M in 2-MeTHF, 37.8 ml, 1 8.9 mmol, Eq: 2) 15 was added dropwise over 30 min maintaining the temperature at 0 °C. The resulting Sight brown clear solution was stirred for 60 min at 0 °C, then warmed to rt over i hr and stirred for 19 hr at rt. The brown solution became turbid.

The reaction mixture was cooled to 0 ^C 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 0 solution was separated and the aqueous layer was extracted with toluene ( i 0 mL). The organic layers were washed with 5% NaHCO, (30 mL) and 10% NaCl (30 mL), dried over Na ₂ S0 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)

The crude material was purified via flash chromatography (SiOj, 80 g, EtOAc: Heptane 1 :9 to 5 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). 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 7.63 (dt,J=16.0, 7.1 Hz, 2 H), 4.89 - 5.31 (m, 1 H), 3.42 - 3.74 (m, 2 H), 2.22 - 2.39 (m, 1H), 1.81 - 2.01 (m, 3 H), 1.18 - 1.49 (m, 9 H)

HPLC method: Column: Waters XBridge C8 2.5um, 4.6x100mm Columen XP (PN: 186006051); Mobile phases, A: H ₂ 0 95:5 ACN = 80-10% in 6min, hold 2min, B: ACN = 10-80% in 6min, hold 2min, C: Wasser + 0.5% TFA = 10% isocratic; Flow: 1.500mL/min; Temp.: 45°C; DAD: 210nm (BW: 4nm), Inj Volume : 2.000 μΐ; Sample Preparation: 2-3 drops reactionmixture quenched with 2ml MeOH/water and filtrated. Retention times: 3.9 min (R)-tert-butyl 2- (methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate, 6.15 min tert-butyl (2R)-2-(3,4,5- trifluorobenzoyl)pyrrolidine- 1 -carboxylate GC method: Column: HP-5 , 30m x 0.32mm ID, 0.25um; 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.: Ιμΐ; Pressure: 44kPa, (H ₂ ); Flow: 2.7 ml/min; Average Velocity: 50cm/sec; FID: Air: 400ml/min; H ₂ : 30ml/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-l -carboxylate, 13.47 min tert-butyl (2R)-2-(3,4,5- trifluorobenzoyl)pyrrolidine- 1 -carboxylate

Chiral SFC method: Column: Chiralpak AD-3, 3um, 4.6mmx250mm, Nr.890; Mobile phases, A: C0 ₂ , 85%, B: MeOH + 0.2% TFA, 15%; Flow: 3.0 mL/min isocratic; Temp: 40°C, BPR: 130bar; 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-l-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

A 25mL 3-necked flask equipped with a magnetic stirrer and cooler was charged with (R)-tert- butyl 2-(3,4,5-trifluorobenzoyl)pyrrolidine-l-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 μΐ, 5.27 mmol, Eq: 1.5) was added dropwise over 1 min. 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 μιηοΐ, Eq: 0.0025) was added. The autoclave was flushed with H 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.

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. w-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 crystaline white solid was washed with cold (0 °C) w-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.

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

SFC method: Acquity UPC2 Torus DEA, 3um, 4.6mmxl00mm, Nr. 122; Mobile phases, A: C0 ₂ , 97%-65% in 6 min, B: EtOH + 0.2% IP Am, 3-35% in 6 min; Flow: 2.5 mL/min; Temp: 50°C, BPR: lOObar; 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

Chiral SFC method: Column: Chiralcel OZ-3, 3um, 4.6mmxl50mm, Nr. 183; Mobile phases, A: C0 ₂ , 90%-60% in 8.8 min, hold for 0.5 min, B: EtOH + 0.2% IP Am, 10-40% in 8.8 min. hold for 0.5 min; Flow: 3.0 mL/min; Temp: 50°C, BPR: 220bar; 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