Acid addition salts of (s)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and (s)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine, specific polymorphs thereof and methods for their manufacture

1 . A method for the manufacture of a compound of Formula (VI) comprising the steps of:

a) reacting the compound of Formula (III),

wherein Y is selected from S or O; PG is an amine protecting group selected from fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl (CF 3 CO), benzyl (Bn) or 4-methoxybenzyl (PMB); trityl (Tr), or tosyl (Ts),

in a solvent with hydrogen gas (H 2 ) in the presence of a transition metal catalyst selected from palladium/charcoal (Pd/C), PtO 2 , a palladium complex, a rhodium complex, a ruthenium complex, or an iridium complex to obtain a racemic compound of Formula (IVa) or (IVb)

or, alternatively, reacting the compound of Formula (III) in a solvent, with a deprotection reagent to obtain a compound of Formula (IIIa)

b) reacting the compound of Formula (IVa), if formed in step a), in a solvent with a deprotection reagent to obtain a racemic compound of Formula (IVb),

or, alternatively, reacting the compound of Formula (IIIa), if formed in step a), in a solvent, with hydrogen gas (H 2 ) in the presence of a transition metal catalyst selected from palladium/charcoal (Pd/C), PtO 2 , a palladium complex, a rhodium complex, a ruthenium complex, or an iridium complex, to obtain a racemic compound of Formula (IVb)

c) reacting a compound of Formula (IVb) with a chiral acid in a solvent to obtain a compound of Formula (V) having an enantiomeric excess (ee) of at least 70%,

wherein X − is the conjugate base of the chiral acid,

and liberating the salt of Formula (V) to obtain the compound of Formula(S)-(IVb)

d) reacting the compound of Formula(S)-(IVb) in a solvent with succinic acid, L-tartaric acid, or HCl to obtain a crystalline compound of Formula (VI),

wherein

A − is selected from 3-carboxypropanoate, (2R,3R)-3-carboxy-2,3-dihydroxypropanoate or chloride (Cl − ).

2 . The method according to claim 1 , wherein the chiral acid in step c) is selected from (−)-O,O′-Di-p-toluoyl-L-tartaric acid or (−)-Di-p-anisoyl-L-tartaric acid.

3 . The method according to claim 1 , wherein the transition metal catalyst is palladium/charcoal (Pd/C).

4 . The method according to claim 1 , wherein the solvent in the hydrogenation, in step a) or b), comprises EtOAc.

5 . The method according to claim 1 , wherein the solvent, in the chiral resolution in step c) comprises THF, ACN, IPA, or MTBE and optionally further H 2 O as co-solvent.

6 . The method according to claim 5 , wherein the solvent comprises THF and H 2 O as co-solvent.

7 . A method for the manufacture of a compound of Formula (VI), comprising the steps of:

a) reacting the compound of Formula (III),

wherein Y is selected from S or O; PG is an amine protecting group selected from fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl (CF 3 CO), benzyl (Bn) or 4-methoxybenzyl (PMB); trityl (Tr), or tosyl (Ts),

in a solvent with hydrogen gas (H 2 ) in the presence of a transition metal catalyst, and a chiral ligand, wherein the transition metal catalyst is selected from a palladium complex, a rhodium complex, a ruthenium complex, or an iridium complex, to obtain a compound of Formula(S)-(IVa) or(S)-(IVb), having an enantiomeric excess (% ee) of at least 70%,

or reacting the compound of Formula (III) in a solvent, with a deprotection reagent to obtain a compound of Formula (IIIa)

b) reacting the compound of Formula(S)—(IVa), if formed in step a), in a solvent with a deprotection reagent to obtain a compound of Formula(S)-(IVb) having an enantiomeric excess (% ee) of at least 70%,

or alternatively, reacting the compound of Formula (IIIa), if formed in step a), in a solvent with hydrogen gas (H 2 ) in the presence of a transition metal catalyst and a chiral ligand, wherein the transition metal catalyst is selected from a palladium complex, a rhodium complex, a ruthenium complex, or an iridium complex, to obtain a compound of Formula(S)-(IVb), having an enantiomeric excess (% ee) of at least 70%,

c) reacting the compound of Formula(S)-(IVb) in a solvent with succinic acid, L-tartaric acid, or HCl to obtain a crystalline compound of Formula (VI),

wherein A − is selected from 3-carboxypropanoate, (2R,3R)-3-carboxy-2,3-dihydroxypropanoate or chloride (Cl − ).

8 . The method according to claim 1 , wherein the amine protecting group is tert-butyloxycarbonyl (Boc) and the deprotection reagent is an acid.

9 . The method according to claim 1 , wherein the solvent, in the deprotection in step a) or b), comprises EtOAc or 2-Me-THF.

10 . The method according to claim 7 , wherein the organic solvent in the asymmetric hydrogenation, in step a) or b), comprises EtOH.

11 . The method according to claim 1 , wherein the solvent, in the crystallization with succinic acid, L-tartaric acid, or HCl, comprises ACN, EtOH, or Acetone.

12 . The method according to claim 11 , wherein the solvent comprises EtOH.

13 . The method according to claim 7 , wherein the chiral ligand is (R,R)-i-Pr-DuPhos.

14 . The method according to claim 7 , wherein transition metal catalyst is a rhodium complex.

15 . A crystalline compound of Formula (VI),

wherein

A − is 3-carboxypropanoate and the crystalline compound is the polymorph with the XRPD spectrum having 2θ peaks 4.077°, 8.108°, 11.991°, 12.156°, 13.893°, 15.876°, 16.218°, 16.412, 16.596°, 17.849°, 19.507°, 19.786°, 20.031°, 20.297°, 21.122°, 22.011°, 22.635°, 23.000°, 23.268°, 24.065°, 24.408°, 25.414°, 25.758°, 26.947°, 27.751°, 28.032°, 28.314°, 29.966°, 30.358°, 30.562°, 30.770°, 31.378°, 32.306°, 32.868°, 33.505°, 34.710°, 35.206°, 36.418°, 36.714°, 37.306°, 38.147°, 38.322°, 38.745°, when measured with a radiation wavelength of λ=1.5418 Å, or

A − is (2R,3R)-3-carboxy-2,3-dihydroxypropanoate and the crystalline compound is the polymorph with the XRPD spectrum having 2θ peaks 5.925°, 10.183°, 11.313°, 11.823°, 12.209°, 12.542°, 15.233°, 15.592°, 15.776°, 16.275°, 16.719°, 17.063°, 17.406°, 17.752°, 18.012°, 19.568°, 19.692°, 20.291°, 20.746°, 21.261°, 21.839°, 22.200°, 22.700°, 23.226°, 23.372°, 23.603°, 23.962°, 24.516°, 24.707°, 25.013°, 25.440°, 25.914°, 26.502°, 27.003°, 27.496°, 27.902°, 28.365°, 28.786°, 29.078°, 29.791°, 30.027°, 30.299°, 30.785°, 31.187°, 31.686°, 32.070°, 32.392°, 33.434°, 33.862°, 34.358°, 34.790°, 35.584°, 36.277°, 36.801°, 37.197°, 38.121° and 39.667°, when measured with a radiation wavelength of λ=1.5418 Å, or A − is selected as chloride (Cl − ) and the crystalline compound is the polymorph with the XRPD spectrum having 2θ peaks 7.457°, 9.185°, 10.899°, 11.738°, 12.604°, 14.956°, 17.706°, 18.215°, 18.382°, 19.307°, 19.902°, 20.442°, 20.956°, 21.850°, 22.449°, 23.781°, 24.007°, 24.357°, 24.752°, 25.327°, 25.557°, 26.064°, 27.377°, 27.702°, 28.340°, 28.557°, 29.144°, 29.366°, 29.915°, 30.164°, 30.669°, 30.975°, 32.213°, 32.725°, 33.018°, 33.742°, 34.605°, 35.012°, 35.618°, 36.883°, 37.131°, 37.250°, 37.772°, 38.358°, 38.626°, 39.140°, 39.869°, when measured with a radiation wavelength of λ=1.5418Å.

16 . The crystalline compound according to claim 15 , wherein A − is 3-carboxypropanoate and the salt is the polymorph with the XRPD spectrum having 2θ peaks 4.077°, 8.108°, 11.991°, 12.156°, 13.893°, 15.876°, 16.218°, 16.412, 16.596°, 17.849°, 19.507°, 19.786°, 20.031°, 20.297°, 21.122°, 22.011°, 22.635°, 23.000°, 23.268°, 24.065°, 24.408°, 25.414°, 25.758°, 26.947°, 27.751°, 28.032°, 28.314°, 29.966°, 30.358°, 30.562°, 30.770°, 31.378°, 32.306°, 32.868°, 33.505°, 34.710°, 35.206°, 36.418°, 36.714°, 37.306°, 38.147°, 38.322°, 38.745°, when measured with a radiation wavelength of λ=1.5418Å.

17 . An intermediate compound of Formula (III) or (IIIa),

wherein Y is selected from O or S, PG is selected from fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl (CF 3 CO), benzyl (Bn) or 4-methoxybenzyl (PMB); trityl (Tr), or tosyl (Ts).

18 . The intermediate compound according to claim 17 , wherein the amine protecting group is tert-butyloxycarbonyl (Boc).

19 . The intermediate compound according to claim 17 , wherein Y is O.

20 . A method of manufacturing a compound having the structure of Formula (IVa),

comprising a step of using the intermediate compound of claim 17 .

21 . The method according to claim 7 , wherein the amine protecting group is tert-butyloxycarbonyl (Boc) and the deprotection reagent is an acid.

22 . The method according to claim 7 , wherein the solvent, in the deprotection in step a) or b), comprises EtOAc or 2-Me-THF.

23 . The method according to claim 7 , wherein the solvent, in the crystallization with succinic acid, L-tartaric acid, or HCl, comprises ACN, EtOH, or Acetone.