Process and intermediates for preparation of pridopidine

Abstract

Provided herein are processes and intermediates for the preparation of pridopidine.

Description

Field of the Invention

[0001] The present invention relates to a process and intermediates for preparing pridopidine. Background of the Invention

[0003] Pridopidine, 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, is a potent sigma-1 receptor (S1R) agonist in clinical development for HD and ALS. Recent data, including in vitro binding assays and in vivo PET imaging in rats, indicate that pridopidine acts primarily via the sigma-1 receptor (S1R). Compared to dopamine D2 receptors, pridopidine exhibits a binding affinity for S1R that is between 100-fold and 500-fold higher [Sahlholm K, Arhem P, Fuxe K, et al., Thedopamine stabilizers ACR16 and (-) OSU6162 display nanomolar affinities at the sigma-1 receptor. Mol Psychiatry 2013; 18: 12-14.; Sahlholm K, Sijbesma JW, Maas B, et al., Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses. Psychopharmacology (Berl). 2015; 232(18): 3443-53]. S1R is an endoplasmic reticulum (ER) protein primarily located at the mitochondrion-associated membrane (MAM), where it regulates a variety of cellular processes, including calcium signaling, ion channel regulation, and ER stress response [Hayashi T, SuTP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+)signaling and cell survival. Cell 2007; 3:596-610].

[0004] S1R activation is known to promote neuroprotection by stimulating neuronal survival, repair, and plasticity [Ryskamp D, Wu J, Geva M, et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis. 2016; 97(PtA): 46-59.; Geva M, Kusko R, Soares H, et al. Pridopidine activates neuroprotective pathways impaired in Huntington disease. Hum Med Gen 2016; 25(18): 3975-3987]. Pridopidine exhibits neuroprotective properties in several in vivo and in vitro HD models mediated by S1R [Ryskamp D, Wu J, Geva M et al. The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis. 2016; 97(PtA): 46-59.; Nguyen L, Lucke-Wold BP, Mookerjee SA et al. Role of sigma-1 receptors in neurodegenerative diseases. J Pharm Sci 2015; 127: 17-29].

[0005] The synthesis process of pridopidine and its pharmaceutically acceptable salts is disclosed in US Pat. No. 7,923,459, US Pat. No. 10,047,049 and US Pat. No. 6,903,120.

[0006] The present invention relates to a process and intermediates for preparing pridopidine. SUMMARY OF THE INVENTION

[0008] In some embodiments, the present invention relates to compounds represented by the structure of Formula I:

[0009]

[0010] wherein A is -SMe or -SO2Me; and

[0011] X - It is an anion.

[0012] In some embodiments, the present invention relates to a method for preparing pridopidine (4-[3-(methyl-sulfonyl)phenyl]-1-propylpiperidine) from a compound of formula I and a process for preparing a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound of Formula I is represented by the structure of Compound 1:

[0014]

[0015] Where X - It is an anion.

[0016] In some embodiments, the compound of Formula I is represented by the structure of Compound 2:

[0017]

[0018] Where X - It is an anion. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. Figure 1 The invention, both as to its organization and its process of operation, together with its objects, features and advantages may be best understood by reference to the following detailed description when read in conjunction with the accompanying drawings:

[0021] Figure 1 A synthetic scheme for Process 1 for the preparation of pridopidine via a complete reduction step of the pyridinium ring of an intermediate of a compound of Formula I, wherein A is SMe or SO2Me, is presented.

[0022] Figure 2 A synthetic scheme for Process 2 is presented for the preparation of pridopidine by stepwise reduction of the pyridinium ring of an intermediate of a compound of Formula I, wherein A is SMe or SO2Me.

[0023] Figure 3 A synthetic scheme for Process 3 for the preparation of compounds of Formula I is presented.

[0024] Figure 4 A synthetic scheme for preparing pridopidine via an intermediate of a compound of formula I wherein A is a bromide and X is presented. - is an anion (compound 3). This process is illustrated in Example 1.

[0025] Figure 5A synthetic scheme for the preparation of pridopidine by complete reduction of the pyridinium ring of an intermediate of a compound of formula I wherein A is SO2Me and X - is an anion (compound 2). This process is illustrated in Example 2.

[0026] Figure 6 A synthetic scheme for the preparation of pridopidine by stepwise reduction of the pyridinium ring of an intermediate of a compound of formula I wherein A is SO2Me and X - isI - (Compound 2). This process is illustrated in Example 3.

[0027] Figure 7 A synthetic scheme for the preparation of pridopidine by complete reduction of the pyridinium ring of an intermediate of a compound of formula I wherein A is SMe and X is presented. - isI - (Compound 1). This process is illustrated in Example 4.

[0028] Figure 8 A synthetic scheme for preparing pridopidine via an intermediate of a compound of formula I wherein A is SMe and X - isI - (Compound 1), which is oxidized to SO2Me, wherein A is SO2Me and X - yes - OH (compound 2), followed by complete reduction of the pyridinium ring. This process is illustrated in Example 5.

[0029] Fig. 9 A synthetic scheme for preparing pridopidine by stepwise reduction of the pyridinium ring of an intermediate of a compound of formula I, wherein A is SMe (compound 1), SMe is oxidized to SO2Me, followed by reduction of the tetrahydropyridine ring. This process is illustrated in Example 6.

[0030] Fig.10 A synthetic scheme is presented for the preparation of pridopidine via an intermediate of a compound of Formula I, wherein A is nitro. This process is illustrated in Example 7.

[0031] Fig.11 A synthetic scheme is presented for the preparation of pridopidine via an intermediate of a compound of Formula I, wherein A is a protected amine. This process is illustrated in Example 8.

[0032] Fig.12 A synthetic scheme is presented for the preparation of pridopidine via the intermediate of compound 9. This process is illustrated in Example 9.

[0033] Fig.13 A synthetic scheme is presented for the preparation of pridopidine via the intermediate of compound 10. This process is illustrated in Example 10.

[0034] It will be understood that, for simplicity and clarity of illustration, the elements shown in the drawings are not necessarily drawn to scale. For example, for clarity, the size of some of the elements may be enlarged relative to other elements. In addition, reference numerals may be repeated in the drawings to indicate corresponding or similar elements where deemed appropriate.

[0035] Detailed description of the invention

[0036] In the following detailed description, many specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be appreciated by those skilled in the art that the present invention can be practiced without these specific details. In other cases, well-known processes, procedures and components are not described in detail to avoid obscuring the present invention.

[0037] In some embodiments, the present invention relates to 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine for preparing pridopidine:

[0038] and a pharmaceutically acceptable salt thereof, wherein the process comprises using a compound of formula I as an intermediate:

[0039]

[0040] in

[0041] A is halide, nitro, protected amine, -SMe or -SO2Me; and

[0042] X - It is an anion.

[0043] In some embodiments, the present invention relates to 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine for preparing pridopidine:

[0044] and a pharmaceutically acceptable salt thereof, wherein the process comprises using a compound of formula IV as an intermediate:

[0045]

[0046] in

[0047] R1 is H, propyl or a protecting group; and

[0048] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring,

[0049] wherein the ring is optionally substituted.

[0050] In some embodiments, the present invention relates to 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine for preparing pridopidine:

[0051] and a pharmaceutically acceptable salt thereof, wherein the process comprises using a compound of formula XIII as an intermediate:

[0052]

[0053] in

[0054] R1 is H, propyl or a protecting group.

[0055] In one embodiment, the present invention provides a process 1 for preparing pridopidine, the process comprising:

[0056] Reduction of the pyridinium group of the compound of formula I

[0057]

[0058] in

[0059] A is SMe or SO2Me, and X - is an anion,

[0060] To obtain compound 7:

[0061] or pridopidine;

[0062] Among them, compound 7 is further oxidized (-SMe is oxidized to -SO2Me) to obtain pridopidine.

[0063] In one embodiment, the present invention provides a process 1A for preparing pridopidine, comprising:

[0064] Oxidation of the compound of formula I:

[0065]

[0066] in,

[0067] A is SMe, and X - is an anion,

[0068] To obtain compound 2:

[0069] The pyridinium ring is subsequently reduced to afford pridopidine.

[0070] In one embodiment, the present invention provides a process 2 for preparing pridopidine, the process comprising:

[0071] Reduction of the pyridinium ring of the compound of formula I:

[0072]

[0073] Where A is SMe or SO2Me, and X - It is an anion;

[0074] To obtain compound 4,

[0075]

[0076] or compound 5

[0077]

[0078] wherein compound 5 is further reduced (reduction of the double bond) to obtain pridopidine; or

[0079] Compound 4 is further oxidized (-SMe is oxidized to -SO2Me) and then reduced (double bond) to obtain pridopidine; or alternatively, compound 4 is further reduced (double bond) and then oxidized (-SMe is oxidized to -SO2Me) to obtain pridopidine.

[0080] In another embodiment, pridopidine is prepared according to Example 3 and Figure 6 preparation.

[0081] In another embodiment, pridopidine is prepared according to Example 4 and Figure 7 preparation.

[0082] In one embodiment, the present invention provides process 3 for preparing a compound of formula I:

[0083]

[0084] Where A is a halide, nitro, protected amine, -SMe or -SO2Me, and X - It is an anion;

[0085] The process (process 3) comprises:

[0086] a) in the presence of a first palladium catalyst and a weak base, subjecting a compound of formula II to

[0087]

[0088] wherein A is a halide, nitro, a protected amine, -SMe or -SO2Me; and X1 is a halide;

[0089] and (pyridin-4-ylboronic acid) to obtain a compound of formula III:

[0090]

[0091] wherein A is halide, nitro, protected amine, -SMe or -SO2Me; and

[0092] b) reacting the compound of formula III with a propyl moiety to obtain the compound of formula I.

[0093] In another embodiment, the compound of formula I is Figure 3 Prepared as described in .

[0094] In another embodiment, when A is bromide, the compound of Formula I is Figure 4 Prepared as described.

[0095] In some embodiments, provided herein are processes for preparing pridopidine using a compound of Formula I as an intermediate, wherein A is a halide, nitro, a protected amine, -SMe or -SO2Me; and X - It is an anion.

[0096] In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is a halide; and X - is an anion. In another embodiment, the halide is bromide, chloride, fluoride or iodide. In another embodiment, A is bromide. In one embodiment, provided herein is a process for preparing pridopidine using a compound of Formula I as an intermediate, wherein A is a halide; and X - is an anion, wherein the process comprises a reaction between a compound of formula I and a SMe moiety (which will be further oxidized to SO2Me) or with a SO2Me moiety, and further reducing the pyridinium ring to obtain pridopidine. In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is a halide; and X - is an anion, wherein the process comprises reducing the pyridinium ring, followed by reacting the halide group with a SMe moiety (which will be further oxidized to SO2Me) or with a SO2Me moiety to obtain pridopidine. In another embodiment, the oxidation of SMe to SO2Me is performed before or after the reduction of the pyridinium ring. In another embodiment, provided herein is a method for Figure 4 The process for preparing Pridopidine was as presented in Example 1.

[0097] In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is nitro; and X - In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is nitro; and X - is an anion, wherein the process comprises reducing the pyridinium ring and the nitro group to an amine, and then converting the amine to a SMe group (which will be further oxidized to SO2Me) or a SO2Me group to obtain pridopidine. In another embodiment, the oxidation of SMe to SO2Me is performed before or after the reduction of the pyridinium ring. In another embodiment, provided herein is a method for Fig.10 The process for preparing Pridopidine was as presented in Example 7.

[0098] In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is a protected amine; and X - In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is a protected amine; and X - Is an anion, wherein the process comprises reducing the pyridinium ring, followed by removal of the protecting group and converting the amine into a SMe group (which will be further oxidized to SO2Me) or a SO2Me group to obtain pridopidine. In one embodiment, provided herein is a process for preparing pridopidine using a compound of formula I as an intermediate, wherein A is a protected amine; and X - is an anion, wherein the process comprises removing the protecting group and converting the amine into a SMe group (which will be further oxidized to SO2Me) or a SO2Me group, followed by reduction of the pyridinium ring to obtain pridopidine. In another embodiment, the oxidation of SMe to SO2Me is performed before or after the reduction of the pyridinium ring. In another embodiment, the protecting group of the amine is Boc, Cbz, benzyl, Fmoc and dibenzyl. In another embodiment, provided herein is a method for Fig.11 The process for preparing Pridopidine was as presented in Example 8.

[0099] In one embodiment, the present invention provides a process 4a for preparing pridopidine, wherein the process comprises:

[0100] (a) in the presence of a second palladium catalyst and a weak base, reacting a compound of formula IV

[0101]

[0102] wherein R1 is H, propyl or a protecting group; and

[0103] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring, wherein the ring is optionally substituted;

[0104] Reaction with 3-halothioanisole to obtain a compound of formula V

[0105]

[0106] wherein if R1 of the compound of formula V is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a derivative of formula V (compound 4); or if R1 of the compound of formula V is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a derivative of formula V (compound 4);

[0107] (d) oxidizing the compound of formula V to obtain the compound of formula VI:

[0108]

[0109] in

[0110] If R1 of the compound of formula V is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula V (compound 5); or if R1 of the compound of formula V is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula V (compound 5); and

[0111] (e) reducing the compound of formula V to obtain pridopidine or a compound of formula VII

[0112]

[0113] Wherein R6 is H or a protecting group;

[0114] Wherein if R6 of the compound of formula VII is hydrogen (R6=H), then the compound is reacted with a propyl moiety to obtain pridopidine; or if R6 of the compound of formula VII is a protecting group (R6=protecting group), then the compound is further deprotected and reacted with a propyl moiety to obtain pridopidine.

[0115] In one embodiment, the present invention provides a process 4b for preparing pridopidine, comprising:

[0116] (a) making a compound of formula IV:

[0117]

[0118] in

[0119] R1 is H, propyl or a protecting group; and

[0120] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring, wherein the ring is optionally substituted;

[0121] Reaction with 1-halogenated-3-(methylsulfonyl)benzene, a weak base and a second palladium catalyst to obtain a compound of formula VI

[0122]

[0123] wherein if R1 of the compound of formula VI is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula VI (Compound 5); or if R1 of the compound of formula VI is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula VI (Compound 5); and

[0124] (b) reducing the compound of formula VI to obtain pridopidine or a compound of formula VII:

[0125]

[0126] Wherein R6 is H or a protecting group;

[0127] Wherein if R6 of the compound of formula VII is hydrogen (R6=H), then the compound is reacted with a propyl moiety to obtain pridopidine; or if R6 of the compound of formula VII is a protecting group (R6=protecting group), then the compound is further deprotected and reacted with a propyl moiety to obtain pridopidine.

[0128] In one embodiment, the present invention provides a process 4c for preparing pridopidine, comprising:

[0129] (a) in the presence of a second palladium catalyst and a weak base, compound 10:

[0130]

[0131] Reaction with 3-haloanisole to obtain compound 4:

[0132]

[0133] (d) Oxidizing the -SMe of compound 4 to -SO2Me to obtain compound 5:

[0134] as well as

[0135] (e) Compound 5 is reduced to obtain pridopidine.

[0136] In one embodiment, the present invention provides a process 4d for preparing pridopidine, comprising:

[0137] (a) Compound 10

[0138]

[0139] Reaction with 1-halogeno-3-(methylsulfonyl)benzene, a weak base and a second palladium catalyst to obtain compound 5:

[0140] as well as

[0141] (b) Compound 5 is reduced to obtain pridopidine.

[0142] In one embodiment, the present invention provides a process 4e for preparing pridopidine, comprising:

[0143] (a) in the presence of a second palladium catalyst and a weak base, reacting a compound of formula IV:

[0144]

[0145] wherein R1 is H, propyl or an amine protecting group; and

[0146] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring, wherein the ring is optionally substituted;

[0147] Reaction with 3-halothioanisole to obtain a compound of formula V:

[0148]

[0149] wherein if R1 of the compound of formula V is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a derivative of formula V (compound 4); or if R1 of the compound of formula V is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a derivative of formula V (compound 4);

[0150] (c) reducing the compound of formula V to obtain the compound of formula XIV:

[0151]

[0152] wherein if R1 of the compound of formula XIV is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula XIV; or if R1 of the compound of formula XIV is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula XIV; and

[0153] (b) oxidizing the compound of formula XIV to obtain pridopidine or a compound of formula VII

[0154]

[0155] Wherein R6 is H or a protecting group;

[0156] in,

[0157] If R6 of the compound of formula VII is hydrogen (R6=H), then the compound is reacted with a propyl moiety to obtain pridopidine; or if R6 of the compound of formula VII is a protecting group (R6=protecting group), then the compound is further deprotected and reacted with a propyl moiety to obtain pridopidine.

[0158] In one embodiment, the present invention provides a process 5a for preparing pridopidine, comprising:

[0159] (a) making a compound of formula IV:

[0160]

[0161] in

[0162] R1 is H, propyl or a protecting group; and

[0163] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring, wherein the ring is optionally substituted;

[0164] With a compound of formula VIII:

[0165]

[0166] in

[0167] X1 and X2 are each independently halogen;

[0168] The reaction is carried out by Suzuki-Miyaura reaction to obtain the compound of formula IX:

[0169]

[0170] in

[0171] X1 is halogen; and

[0172] R1 is H, propyl or a protecting group,

[0173] wherein if R1 of the compound of formula IX is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula IX; or if R1 of the compound of formula IX is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula IX; and

[0174] (b) using 1,2-diaminocyclohexane (a mixture of cis and trans forms) as a catalyst, reacting a compound IX in which X1 is a halogen with sodium methanesulfinate and copper (II) trifluoromethanesulfonate by Ullmann reaction to obtain a sulfone, a compound of formula VI

[0175]

[0176] wherein if R1 of the compound of formula VI is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula VI (Compound 5); or if R1 of the compound of formula VI is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula VI (Compound 5); and

[0177] (c) reducing the compound of formula VI to obtain pridopidine or a compound of formula VII:

[0178]

[0179] Wherein R6 is H or a protecting group;

[0180] Wherein if R6 of the compound of formula VII is hydrogen (R6=H), then the compound is reacted with a propyl moiety to obtain pridopidine; or if R6 of the compound of formula VII is a protecting group (R6=protecting group), then the compound is further deprotected and reacted with a propyl moiety to obtain pridopidine.

[0181] In one embodiment, the present invention provides a process 5b for preparing pridopidine, comprising:

[0182] (a) Compound 10:

[0183]

[0184] With a compound of formula VIII:

[0185]

[0186] in

[0187] X1 and X2 are each independently halogen;

[0188] The reaction is carried out by Suzuki-Miyaura reaction to obtain the compound of formula XVII:

[0189]

[0190] in

[0191] X1 is halogen; and

[0192] (b) using 1,2-diaminocyclohexane (a mixture of cis and trans forms) as a catalyst, reacting a compound XVII wherein X1 is a halogen with sodium methanesulfinate and copper (II) trifluoromethanesulfonate by Ullmann reaction to obtain a sulfone, a compound of formula V,

[0193]

[0194] (c) reducing the compound of formula V to obtain pridopidine.

[0195] In one embodiment, the present invention provides process 6a for preparing a compound of formula IV:

[0196]

[0197] wherein R1 is H, propyl or a protecting group; and

[0198] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring, wherein the ring is optionally substituted;

[0199] The process comprises:

[0200] (a) making a compound of formula X:

[0201]

[0202] Reaction with a strong base which further reacts with the trifluoro moiety to obtain a compound of formula XI:

[0203]

[0204] wherein if R1 of the compound of formula XI is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of the compound of formula XI;

[0205] or if R1 of the compound of formula XI is a protecting group (R1 = protecting group), the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of the compound of formula XI; and

[0206] (b) reacting a compound of formula XI with diboron, a mild base and a second palladium catalyst to obtain a compound of formula IV;

[0207]

[0208] wherein if R1 of the compound of formula IV is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula IV;

[0209] Alternatively, if R1 of the compound of formula IV is a protecting group (R1 = protecting group), the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula IV.

[0210] In one embodiment, the present invention provides process 6b for preparing compound 10:

[0211]

[0212] The process comprises:

[0213] (b) making a compound of formula X:

[0214]

[0215] Reaction with a strong base which further reacts with the trifluoro moiety to obtain a compound of formula XI:

[0216]

[0217] wherein if R1 of the compound of formula XI is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of the compound of formula XI;

[0218] or if R1 of the compound of formula XI is a protecting group (R1 = protecting group), the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of the compound of formula XI; and

[0219] (b) reacting a compound of formula XI with diboron, a mild base and a second palladium catalyst to obtain compound 10 or a compound of formula XII;

[0220]

[0221] Wherein if R6 of the compound of formula XII is hydrogen (R6=H), then the compound is reacted with a propyl moiety to obtain compound 10;

[0222] Alternatively, if R6 of the compound of formula XII is a protecting group (R6=protecting group), the protecting group is deprotected and reacted with a propyl moiety to obtain compound 10.

[0223] In one embodiment, the present invention provides a process 7a for preparing pridopidine, wherein the process comprises:

[0224] (a) making a compound of formula XIII

[0225]

[0226] in

[0227] R1 is H, propyl or a protecting group;

[0228] Reaction with a strong base to obtain a compound of formula XIV:

[0229]

[0230] wherein if R1 of the compound of formula XIV is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula XIV; or if R1 of the compound of formula XIV is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula XIV; and

[0231] (c) oxidizing the compound of formula XIV to obtain pridopidine or a compound of formula XV:

[0232]

[0233] Wherein R6 is H or a protecting group;

[0234] Wherein if R6 of the compound of formula XV is hydrogen (R6=H), then the compound is reacted with a propyl moiety to obtain pridopidine; or if R6 of the compound of formula XV is a protecting group (R6=protecting group), then the compound is further deprotected and reacted with a propyl moiety to obtain pridopidine.

[0235] In another embodiment, the present invention provides a process 7b for preparing pridopidine, wherein the process comprises:

[0236] (a) Compound 9:

[0237]

[0238] Reaction with a strong base to obtain compound 7:

[0239] as well as

[0240] (c) Compound 7 is oxidized to obtain pridopidine.

[0241] In one embodiment, the present invention provides process 8a for preparing a compound of formula XIII:

[0242]

[0243] Wherein R1 is H, propyl or a protecting group;

[0244] The process comprises:

[0245] 2-(3-(methylthio)phenyl)acetonitrile is reacted with a compound of formula XVI:

[0246]

[0247] Wherein R1 is H, propyl or a protecting group;

[0248] reacting in the presence of a strong base to obtain a compound of formula XIII;

[0249] Wherein if R1 of the compound of formula XIII is hydrogen (R1=H), then the compound is optionally reacted with a propyl moiety to obtain a propyl derivative of formula XIII; or if R1 of the compound of formula XIII is a protecting group (R1=protecting group), then the protecting group is optionally deprotected and optionally reacted with a propyl moiety to obtain a propyl derivative of formula XIII.

[0250] In one embodiment, the present invention provides process 8b for preparing compound 9:

[0251]

[0252] The process comprises:

[0253] 2-(3-(methylthio)phenyl)acetonitrile and compound 11:

[0254]

[0255] Wherein Pr is propyl;

[0256] The reaction was carried out in the presence of a strong base to obtain compound 9.

[0257] In some embodiments, provided herein are compounds of Formula I and / or Compound 1 and / or Compound 2 and / or Compound 3, wherein the compound comprises an anion X- In one embodiment, the anion is a halide, a hydroxyl, and a sulfonate, such as a mesylate, a tosylate. In one embodiment, the anion is a halide. In one embodiment, the anion is an iodide. In one embodiment, the anion is a hydroxyl (OH) - In one embodiment, the anion is sulfonate (R-SO2 - ).

[0258] In some embodiments, provided herein is a process for preparing pridopidine, wherein the process is via an intermediate compound of the compound of formula I. The process includes commercially available relatively cheap (low-cost) starting materials, easily isolated solid pyridinium salts, and includes three main steps.

[0259] In some embodiments, process 1 comprises reducing the pyridinium group of the compound of formula I to obtain compound 7 or pridopidine, respectively, wherein A is SMe or SO2Me. In another embodiment, the reduction step of the pyridinium ring comprises reacting the compound of formula I with PtO2 and H2 (gas).

[0260] In some embodiments, the processes provided herein include an oxidation step of oxidizing a -SMe group to a -SO2Me group (see, e.g., Process 1, Process 2, Process 4a, Process 4c, Process 4e, Process 7a, and Process 7b, Figure 2 , Figure 7 , Figure 8 , Fig. 9 , Fig.10 , Fig.11 , Fig.12 ). In one embodiment, the oxidation step comprises reacting with an oxidant. In another embodiment, the oxidant comprises a tungsten catalytic oxidant. In another embodiment, the oxidant comprises a tungsten catalytic oxidant and a peroxide. In another embodiment, the oxidation step comprises reacting with a peroxide. In another embodiment, the oxidation step comprises reacting with a peroxide and Na2WO4. In another embodiment, the oxidation step comprises reacting with a tungsten catalytic oxidant at a pH of less than 2 in the presence of a peroxide oxidant. In another embodiment, the oxidation step comprises reacting with a tungsten catalytic oxidant at a temperature range of 40°C to 60°C in the presence of a peroxide oxidant. In another embodiment, the tungsten catalytic oxidant is sodium tungstate. In another embodiment, the peroxide is sodium peroxide.

[0261] In some embodiments, the processes provided herein include a partial reduction step of the pyridinium group to obtain an olefinic piperidine ring as presented below (see, e.g., Process 2, Figure 2 , Figure 4 , Figure 6 , Fig. 9 ):

[0262] In another embodiment, the reduction step of the pyridinium group comprises reacting the compound of Formula I with a hydrogen source. In another embodiment, the hydrogen source used to reduce the pyridinium group is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or H2 (gas).

[0263] In some embodiments, the processes provided herein include a reduction step of an olefin-piperidine ring to a saturated piperidine ring (see, e.g., Process 2, Process 4a, Process 4b, Process 4c, Process 4d, and Process 4e, Figure 2 , Figure 4 , Figure 6 , Fig. 9 , Fig.13 ), including a reduction step for reducing the double bond to obtain a piperidine ring as presented below:

[0264] In one embodiment, the reduction step includes reacting with a hydrogen source for reducing double bonds to obtain a piperidine ring. In another embodiment, the reduction step for reducing double bonds to obtain a piperidine ring includes reacting with a hydrogen source and a catalyst. In another embodiment, the reduction step for reducing double bonds to obtain a piperidine ring is catalytic hydrogenation in an aqueous solution with an alcohol in the presence of a hydrogen source and a second palladium catalyst, a platinum catalyst or a rhodium catalyst. In another embodiment, non-limiting examples of alcohol include methanol, ethanol, propanol, isopropanol and the like. In another embodiment, the third palladium catalyst is 10% carbon-supported palladium, 5% carbon-supported palladium, 5% alumina-supported Pd.

[0265] In another embodiment, the rhodium catalyst is 5% rhodium on carbon. In another embodiment, the platinum catalyst is platinum dioxide.

[0266] In another embodiment, for process 2, process 4a, process 4b, process 4c, process 4d and process 4e or Figure 2 , Figure 4 , Figure 6 , Fig. 9 and Fig.13 The hydrogen source for the reduction step in the step comprises the use of hydrogen, formic acid or formate; each is a separate embodiment according to the present invention. In another embodiment, the hydrogen source for the reduction step is ammonium formate. In another embodiment, the reduction step is carried out with H2, Pd(OH)2 / C.

[0267] In some embodiments, process 3 comprises a reaction between a compound of formula II and pyridin-4-ylboronic acid in the presence of a first palladium catalyst to obtain a compound of formula III. In another embodiment, the palladium catalyst comprises tetrakis(triphenylphosphine)palladium(0) (Pd(Ph3P)4), palladium(II) acetate (Pd(OAc)2), bis(triphenylphosphine)palladium chloride (Pd(Ph3P)2Cl2) or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(Cl2)dppf).

[0268] In some embodiments, process 3, process 4a, process 4b, process 4c, process 4d and process 4e include steps for preparing compounds of formula III, formula V, formula VI, and compound 4 and compound 5, and utilize a weak base. In another embodiment, the weak base includes potassium phosphate, sodium bicarbonate, potassium carbonate, pyridine or any combination thereof, each of which is a separate embodiment according to the present invention.

[0269] In another embodiment, the weak base of process 3 for preparing the compound of formula III comprises sodium ethoxide and cesium carbonate or any combination thereof. In another embodiment, the weak base of process 3 for preparing the compound of formula III comprises potassium carbonate, potassium phosphate, sodium bicarbonate, sodium ethoxide and cesium carbonate or any combination thereof.

[0270] In some embodiments, the processes provided herein utilize a "propyl moiety" (see, e.g., Process 3, Process 4a, Process 4b, Process 4e, Process 7a, and Process 8a and Figure 7-Figure 11 ). In other embodiments, the "propyl moiety" refers to propionaldehyde or a propyl group substituted by a leaving group. In other embodiments, the "propyl moiety" refers to a propyl group substituted by a leaving group. Non-limiting examples of propyl moieties include propyl bromide, propyl chloride, propyl iodide, propyl methanesulfonate, propyl p-toluenesulfonate, or propyl benzenesulfonate. In some embodiments, the "propyl moiety" is propionaldehyde. In another embodiment, if the propyl moiety is propionaldehyde, the reaction is carried out by "reductive amination" and a reducing agent is added.

[0271] In another embodiment, the reducing agent is selected from a hydrogen source. In another embodiment, the hydrogen source comprises NaCNBH3, NaBH4, NaBH(OAc)3, H2(gas).

[0272] In some embodiments, the processes provided herein utilize a second palladium catalyst to prepare compounds of formula V, formula VI and compound 4, compound 5 and compound 10, and compounds of formula IV and formula XII (see, for example, catalysts (see, for example, process 4a, process 4b, process 4c, process 4d, process 4e, process 6a and process 6b). In another embodiment, the second palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4.

[0273] In some embodiments, the processes provided herein utilize a "deprotection step" (see, for example, process 4a, process 4b, process 5a, process 6a, process 6b, process 7a, and process 8a, or when the protected amine in the compound of formula I is deprotected). The deprotection step refers to deprotecting the protecting group. In one embodiment, the deprotection step is carried out under acidic conditions, alkaline conditions, or by catalytic hydrogenation, depending on the protecting group. In another embodiment, trifluoroacetic acid, methanesulfonic acid, trimethylsilyl chloride, or hydrochloric acid is used to complete the deprotection of the Boc group. In another embodiment, a base such as ammonia, piperidine, or morpholine is used to complete the deprotection of the Fmoc group. In another embodiment, the deprotection of the benzyl group is completed by catalytic hydrogenation. In another embodiment, the deprotection step includes any known procedure for removing the protecting group, and is included in those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference in their entirety.

[0274] In some embodiments, process 4a, process 4c and process 4e include steps for preparing a compound of formula V and utilize 3-halothioanisole. In another embodiment, 3-halothioanisole includes 3-bromothioanisole, 3-chlorothioanisole, 3-iodothioanisole; each is a separate embodiment according to the present invention.

[0275] In some embodiments, process 6a and process 6b for preparing compounds of formula IV and formula XII include the use of a mild base. In another embodiment, the mild base includes potassium acetate, potassium carbonate, sodium carbonate, sodium methoxide, potassium methoxide, potassium phenoxide, cesium carbonate, sodium acetate, tributylamine, triethylamine, DBU, cesium fluoride, or any combination thereof. In another embodiment, the mild base is potassium acetate. In another embodiment, the mild base is pyridine.

[0276] In another embodiment, the mild base used in Process 6a and Process 6b for preparing compounds of Formula IV and Formula XII comprises a weak base as described herein.

[0277] In some embodiments, process 6a, process 6b, process 7a, process 7b, process 8a and process 8b utilize a strong base to prepare compounds of formula XI, formula XIV, formula XIII, and compound 7 and compound 9; each is a separate embodiment according to the present invention. In one embodiment, the strong base comprises sodium hydroxide, lithium bis(trimethylsilyl)amide, potassium hydroxide, sodium amide or a combination thereof; each is a separate embodiment according to the present invention.

[0278] In some embodiments, process 4b utilizes 1-halo-3-(methylsulfonyl)benzene to obtain a compound of formula VI from a compound of formula IV. In other embodiments, 1-halo-3-(methylsulfonyl)benzene includes 1-bromo-3-(methylsulfonyl)benzene, 1-chloro-3-(methylsulfonyl)benzene, or 1-iodo-3-(methylsulfonyl)benzene.

[0279] In some embodiments, process 6a and process 6b utilize diboron to prepare compounds of formula IV and formula XII. In another embodiment, diboron is bis(catecholic acid)diboron, bis(neopentanoic acid)diboron, 2,2'-bis-1,3,2,-dioxaborane, bis(hexene glycolic acid)diboron, bis(diethyl-D-tartrate glycolic acid)diboron, bis(N,N,N',N'-tetramethyl-L-tartrate amide glycolic acid)diboron or bis(pinacolyl)diboron. In another embodiment, diboron is bis(pinacolyl)diboron; each is a separate embodiment according to the present invention.

[0280] In some embodiments, Process 6a and Process 6d utilize a trifluoro moiety to prepare a compound of Formula XI. In another embodiment, the source of the trifluoro moiety is 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethanesulfonic anhydride, or trimethylsilyl trifluoromethanesulfonate.

[0281] In some embodiments, R1 of the compound of Formula IV, V, VI, IX, X, XI, XIII, XIV or XVI is propyl; each is a separate embodiment according to the present invention.

[0282] In some embodiments, R1 of the compound of Formula IV, Formula V, Formula VI, Formula IX, Formula X, Formula XI, Formula XIII, Formula XIV or Formula XVI is hydrogen; each is a separate embodiment according to the present invention. In some embodiments, R1 of the compound of Formula IV, Formula V, Formula VI, Formula IX, Formula X, Formula XI, Formula XIII, Formula XIV or Formula XVI is a protecting group; each is a separate embodiment according to the present invention.

[0283] In some embodiments, R6 of the compound of Formula VII, Formula XII or Formula XV is hydrogen. In another embodiment, R6 of the compound of Formula VII, Formula XII or Formula XV is a protecting group.

[0284] In some embodiments, the protecting group of the compound of formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV or formula XVI includes t-Boc (tert-butyloxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl), Bn (benzyl), Bz (benzoyl), Ts (toluenesulfonyl) or carbamate group; each is a separate embodiment according to the present invention. In another embodiment, the protecting group of the compound of formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV or formula XVI is benzyl; each is a separate embodiment according to the present invention. In another embodiment, the protecting group of the compound of formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV or formula XVI is t-Boc; each is a separate embodiment according to the present invention. In another embodiment, the protecting group of the compound of formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV or formula XVI is Fmoc; each is a separate embodiment according to the present invention. In another embodiment, the protecting group of the compound of formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV or formula XVI is Cbz; each is a separate embodiment according to the present invention. In another embodiment, the protecting group of the compound of formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV, formula XV or formula XVI is tosyl; each is a separate embodiment according to the present invention. In another embodiment, the protecting group of the compound of Formula IV, V, VI, VII, IX, X, XI, XII, XIII, XIV, XV or XVI includes any amine protecting group known in the art, and includes those described in detail in Protecting Groups in Organic Synthesis, TW Green and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety.

[0285] In some embodiments, R2 of the compound of formula IV is an alkyl group. In some embodiments, R3 of the compound of formula IV is an alkyl group. In one embodiment, R2 and R3 of the compound of formula IV together form a 5-8 membered ring, wherein the ring is optionally substituted. In another embodiment, R2 and R3 of the compound of formula IV together form a 5-8 membered ring, wherein the ring comprises OBO as shown below:

[0286]

[0287] wherein the ring is optionally substituted. In another embodiment, R2 and R3 of the compound of formula IV together form a substituted or unsubstituted 5-8 membered ring or a substituted or unsubstituted fused 5-8 membered ring. In another embodiment, R2 and R3 of the compound of formula IV together form a substituted or unsubstituted 5-8 membered ring, wherein in addition to the OBO atoms, the ring includes N (nitrogen), O (oxygen) or both. In another embodiment, the N in the ring is optionally replaced by R A In another embodiment, R2 and R3 of the compound of Formula IV together form a substituted or unsubstituted fused 5-8 membered ring, wherein in addition to the OBO atoms, the ring also includes N (nitrogen), O (oxygen), or both. In another embodiment, the N contained in the fused ring is optionally replaced by R A In another embodiment, R A It is alkyl, heteroalkyl, aryl, heteroaryl, alkoxy, acyl, each of which is a separate embodiment according to the present invention. In another embodiment, the substituent includes one or more groups, such as alkyl, ester, acylamino, halogen, hydroxyl, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclic radical, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxyl, carbamoyl, formamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio or alkylsulfonyl group, each of which is a separate embodiment according to the present invention. Any substituent can be unsubstituted or further substituted by any of these substituents mentioned above.

[0288] In another embodiment, R2 and R3 of the compound of formula IV together form a 5-membered ring substituted with 1-4 methyl groups. In another embodiment, R2 and R3 of the compound of formula IV together form pinacol borate. Non-limiting examples of R2 and R3 forming a ring containing OBO are presented below:

[0289]

[0290] In some embodiments, X1 of the compound of formula II is a halide. In another embodiment, X1 of the compound of formula II is Br. In another embodiment, X1 of the compound of formula II is I. In another embodiment, X1 of the compound of formula II is Cl. In another embodiment, X1 of the compound of formula II is F.

[0291] In some embodiments, X1 of the compound of formula VIII, formula IX or formula XVII is a halide. In another embodiment, X1 of the compound of formula VIII, formula IX or formula XVII is Br. In another embodiment, X1 of the compound of formula VIII, formula IX or formula XVII is I. In another embodiment, X1 of the compound of formula VIII, formula IX or formula XVII is Cl. In another embodiment, X1 of the compound of formula VIII, formula IX or formula XVII is F.

[0292] In some embodiments, X2 of the compound of formula VIII is a halide. In another embodiment, X2 of the compound of formula VIII is Br. In another embodiment, X2 of the compound of formula VIII is I. In another embodiment, X2 of the compound of formula VIII is Cl. In another embodiment, X2 of the compound of formula VIII is F.

[0293] As used herein, unless otherwise indicated, the term "alkyl" as used herein alone or as part of another group refers to a straight or branched chain alkyl group containing up to about 24 carbons. In one embodiment, the alkyl group includes C1-C3 carbons. In one embodiment, the alkyl group includes C1-C4 carbons. In one embodiment, the alkyl group includes C1-C5 carbons. In another embodiment, the alkyl group includes C1-C6 carbons. In another embodiment, the alkyl group includes C1-C8 carbons. In another embodiment, the alkyl group includes C1-C 10 In another embodiment, the alkyl group includes C1-C 12 In another embodiment, the branched alkyl group is an alkyl group substituted with an alkyl side chain of 1 to 5 carbons. In one embodiment, the alkyl group can be unsubstituted. In another embodiment, the alkyl group can be substituted with halogen, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio and / or thioalkyl.

[0294] The term "aryl" used herein alone or as part of another group refers to an aromatic ring system containing from 5 to 14 ring carbon atoms. The aryl ring can be monocyclic, bicyclic, tricyclic and the like. Non-limiting examples of aryl groups are phenyl; naphthyl, including 1-naphthyl and 2-naphthyl; and similar groups. The aryl group can be unsubstituted or substituted by one or more groups such as halogen, hydroxyl, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxyl, carbamoyl, formamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio or alkylsulfonyl groups. Any substituent may be unsubstituted or further substituted with any of these above-mentioned substituents.

[0295] The term "protecting group" refers to an amine protecting group. In another embodiment, the amine protecting group refers to any known amine protecting group, such as Boc, Fmoc, Cbz.

[0296] The term "SMe moiety" refers to a SMe base salt, such as Me-S-Na, Me-SK, Me-S-Li.

[0297] The term "SO2Me moiety" refers to an alkali metal SO2 salt, such as S(O)(ONa)Me, S(O)(OLi)Me, S(O)(OK)Me. In some embodiments, a Cu catalyst is required to convert Ph-Br to Ph-SO2Me via the Ullman reaction.

[0298] The term "pharmaceutically acceptable salt" refers to a salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid phosphate, sulfate, bisulfate, formate, gluconate, glucuronate, sucrose, isonicotinate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, gentisate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, bitartrate and toluene p-sulfonate and pamoate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoate)). Each represents a separate embodiment of the present invention. In another embodiment, pridopidine is in the form of HCl.

[0299] In one embodiment, the present invention provides a compound of formula I:

[0300]

[0301] Where A is a halide, nitro, protected amine, SO2Me or SMe, and X - In one embodiment, the present invention provides a compound of formula I:

[0302]

[0303] Where A is SO2Me or SMe.

[0304] In one embodiment, the present invention provides Compound 1:

[0305]

[0306] Where X - It is an anion.

[0307] In one embodiment, the present invention provides Compound 2:

[0308]

[0309] Where X - It is an anion.

[0310] In one embodiment, the present invention provides compound 3:

[0311]

[0312] Where X - It is an anion.

[0313] In one embodiment, the present invention provides a compound of formula IV:

[0314]

[0315] in

[0316] R1 is H, propyl or a protecting group; and

[0317] R2 and R3 are each independently an alkyl group or R2 and R3 together form a 5-8 membered ring, wherein the ring is optionally substituted.

[0318] In one embodiment, the present invention provides compound 10:

[0319]

[0320] In one embodiment, the present invention provides a compound of formula XIII:

[0321]

[0322] in

[0323] R1 is H, propyl or a protecting group.

[0324] In one embodiment, the present invention provides compound 9:

[0325]

[0326] In some embodiments, the present invention provides a process for preparing pridopidine using at least one of Compound 1, Compound 2, Compound 9, Compound 10, a compound of Formula I, a compound of Formula IV, or a compound of Formula XIII.

[0327] The following non-limiting examples are presented to more fully illustrate certain embodiments of the present invention. However, they should never be interpreted as limiting the wide scope of the present invention. Those skilled in the art can easily envision many changes and modifications of the principles disclosed herein without departing from the scope of the present invention. Example

[0328] Example 1: Process for preparing Pridopidine

[0329]

[0330] 4-(3-Bromophenyl)pyridine

[0331] A clear solution of pyridin-4-ylboronic acid (5.00 g, 40.7 mmol), 1,3-dibromobenzene (14.4 g, 7.37 mL, 1.5 eq., 61.0 mmol), PdCl2(dppf) (1.49 g, 0.05 eq., 2.03 mmol) and Na2CO3 (12.9 g, 61.0 mL, 2 moles, 3 eq., 122 mmol) in 1,2-dimethoxyethane (125 mL) was degassed with N2 for 15 minutes and then heated to 85 °C for 3 hours. EtOAc (400 mL) and water (200 mL) were added. The reaction mixture was filtered through a bed of celite and the phases were separated. The organic phase was washed with water (2×200 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica; heptane / EtOAc): fraction 1 (tubes 67-95) was concentrated in vacuo to give 4-(3-bromophenyl)pyridine (5.31 g, 22.7 mmol, 55.8%).

[0332]

[0333] 4-(3-Bromophenyl)-1-propylpyridin-1-ium iodide

[0334] 1-Iodopropane (290 mg, 167 μL, 2.50 equiv, 1.71 mmol) was added to a solution of 4-(3-bromophenyl)pyridine (160 mg, 683 μmol) in acetonitrile (3 mL). The reaction mixture was heated to 85 °C overnight. Volatiles were removed in vacuo to give 4-(3-bromophenyl)-1-propylpyridin-1-ium iodide (260 mg, 643 μmol, yield = quantitative).

[0335]

[0336] 4-(3-Bromophenyl)-1-propylpiperidine.

[0337] PtO2 (33.2mg, 0.17 equivalent, 146μmol) is added to the clear brown solution of 4-(3-bromophenyl)-1-propylpyridin-1-ium iodide (348mg, 861μmol) in MeOH (5mL). The reaction mixture is stirred at room temperature for 2 nights under 5 bar hydrogen pressure. The material is diluted with MeOH and filtered through a diatomaceous earth layer. The filter cake is washed with MeOH. The filtrate merged is concentrated in a vacuum to obtain 276mg (HI salt). The material is dissolved in EtOAc (20mL) and saturated NaHCO3 aqueous solution (20mL). Separate each layer, and wash the organic layer with saturated NaHCO3 aqueous solution (20mL). The aqueous phase merged is extracted with EtOAc (20mL). The organic phase merged is dried over Na2SO4 and concentrated in a vacuum to obtain 190mg (free alkali). This material was purified by column chromatography (silica; 0-5% 7N NH3 in MeOH in DCM): fractions 1 (tubes 8-25) were concentrated to give 4-(3-bromophenyl)-1-propylpiperidine (164 mg, 581 μmol, yield = 67.5%).

[0338]

[0339] Pridopidine via 4-(3-bromophenyl)-1-propylpiperidine (8).

[0340] A mixture of 4-(3-bromophenyl)-1-propylpiperidine (164 mg, 581 μmol), sodium methanesulfinate (89.0 mg, 1.5 eq., 872 μmol), copper (II) trifluoromethanesulfonate (21.0 mg, 0.1 eq., 58.1 μmol) and 1,2-diaminocyclohexane (cis and trans mixture) (26.5 mg, 28.3 μL, 0.4 eq., 232 μmol) in DMSO (3 mL) was deoxygenated and purged with nitrogen, and then stirred at 190 ° C overnight for 6 hours. EtOAc (50 mL) and water (50 mL) were added. The layers were separated. The organic phase was washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica; 0-10% MeOH in DCM): fraction 1 (tubes 15-20) was concentrated in vacuo to give 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (25 mg, 89 μmol, yield = 15%).

[0341] Example 2: Process for preparing Pridopidine Figure 5 ]

[0342] Step 1: Suzuki coupling

[0343]

[0344] To a solution of 3-bromophenylmethylsulfone (3.0 g, 12.76 mmol, 1.0 eq) in 1,4-dioxane (60 mL) and water (6 mL) was added pyridine-4-boronic acid (1.88 g, 15.31 mmol, 1.2 eq) and Cs2CO3 (12.47 g, 38.28 mmol, 3.0 eq) and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (740 mg, 0.64 mmol, 0.05 eq) was added and the mixture was stirred at 80°C overnight. After this time, the mixture was cooled to room temperature and purified by The mixture was filtered through a pad of 4-nitropropene, washed with DCM and concentrated under reduced pressure. The residue was taken up in DCM, washed with water (3x), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica column chromatography (DCM: acetone 100: 0 -> 80: 20) to give 3.03 g (yield = quantitative) of 4- (3-methylsulfonylphenyl) pyridine as a brown oil with an LCMS purity of 99%. LCMS (ESI): Exact mass of C12H11NO2S: 233.29; [M+H] + =233.60 Actual measured value.

[0345] 1H NMR (300MHz, DMSO-d6) δ8.72(d,J=1.6Hz,2H),8.29(t,J=1.6Hz,1H),8.17(d,J=7. 9Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.87-7.75 (m, 3H), 7.67-7.50 (m, 2H), 3.33 (s, 3H).

[0346] Step 2: N-propylation

[0347]

[0348] 4- (3- methanesulfonylphenyl) pyridine (560mg, 2.43mmol, 1.0 equivalent) is dissolved in ACN (10mL) and placed in an ice-cooled bath. 1- iodopropane (474 ​​μL, 4.86mmol, 2.0 equivalent) is added dropwise and the reaction mixture is heated to 70 ° C overnight. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (x3). The combined organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The solid obtained is refluxed with EtOAc (10mL) for 1h, cooled to room temperature, washed with EtOAc and dried under reduced pressure to obtain 800mg (yield = 81%) of 4- (3- methanesulfonylphenyl) -1- propylpyridine iodide as a brown solid with 100% LCMS purity. LCMS (ESI): Exact mass of C15H18NO2S: 276.37; [M+H] + =276.60 Actual measured value.

[0349] 1 H NMR (300MHz, DMSO-d6) δ9.21(d,J=6.9Hz,2H),8.66(d,J=6.9Hz,2H),8.54(s,1H),8.42(d,J=8.0Hz,1H),8.18(d,J= 8.0Hz, 1H), 7.93 (t, J = 7.9Hz, 1H), 4.60 (t, J = 7.2Hz, 2H), 3.36 (s, 3H), 1.98 (h, J = 7.3Hz, 2H), 0.92 (t, J = 7.4Hz, 3H).

[0350] Step 3: Hydrogenation

[0351]

[0352] To a solution of 4-(3-methylsulfonylphenyl)-1-propylpyridinium iodide (800 mg, 1.98 mmol, 1.0 eq.) in methanol (20.0 mL) was added PtO2 (90 mg, 0.4 mmol, 0.2 eq.) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred overnight under a hydrogen atmosphere (balloon). After reaching completion, the mixture was passed through The mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of 4- (3- (methylsulfonyl) phenyl) -1-propylpiperidine and the solvent was removed under reduced pressure. DCM (10 mL) and 2M NaOH solution (10 mL) were added and the mixture was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was washed with DCM (2x). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give 635 mg (yield = quantitative) of 4- (3- (methylsulfonyl) phenyl) -1-propylpiperidine with 100% LCMS purity, which was purified during the formation of the HCl salt in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.; [M+H] + =281.65 measured value.

[0353] Step 4: HCl Salt Formation

[0354]

[0355] 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine (558 mg, 1.98 mmol, 1.0 eq) was dissolved in PrOH (6.0 mL) and 6N HCl (400 μl, 2.38 mmol, 1.2 eq) in iPrOH was added dropwise. The reaction mixture was stirred at 80 °C for 2 h and at room temperature overnight. The precipitate was filtered off, washed with iPrOH and dried under reduced pressure to give 492 mg (yield = 88%) of 4-(3-methylsulfonylphenyl)pyridine hydrochloride as a light yellow solid with an LCMS purity of 100%. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =281.65 measured value.

[0356] HPLC purity: 99.89% (@268 nm)

[0357] 1 H NMR (300 MHz, methanol-d4) δ 7.88-7.79 (m, 2H), 7.69-7.55 (m, 2H), 3.74-3.63 (m, 2H), 3.20-2.98 (m, 8H), 2.24-1.94 (m, 4H), 1.90-1.71 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).

[0358] Example 3: Process for preparing Pridopidine Figure 6 ]

[0359] Compound 2 was prepared as described in Example 2.

[0360] Reduction with sodium borohydride

[0361]

[0362] 4-(3-Methylsulfonylphenyl)-1-propylpyridinium iodide (1.0 g, 3.62 mmol, 1.0 eq) was dissolved in methanol (10.0 mL) and water (20.0 mL), and the solution was placed in an ice-cooled bath. NaBH4 (821 mg, 21.71 mmol, 6 eq) was added and the reaction mixture was allowed to stand at ambient temperature for 2 h. Afterwards, the mixture was quenched with 1 N HCl solution and extracted with DCM (x3). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give 726 mg (yield = 66%) of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine with an LCMS purity of 93%, which was used as is in the next step. LCMS (ESI): Exact mass of C15H21NO2S: 279.40; [M+H] + =279.60 Actual measured value.

[0363] 1 H NMR (300 MHz, DMSO-d6) δ7.92-7.89 (m, 1H), 7.80 (d, J = 1.7 Hz,1H),7.77(s,1H),7.61(t,1H),6.37-6.30(m,1H),3.23(s,3H),3.09(q,J=3.0Hz,2H),2.69 -2.58(m,2H),2.56-2.51(m,2H),2.41-2.30(m,2H),1.58-1.43(m,2H),0.88(t,J=7.4Hz,3H).

[0364] Step 4. Hydrogenation reaction

[0365]

[0366] To a solution of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (616 mg, 2.20 mmol, 1.0 eq.) in methanol (30.0 mL) was added Pd(OH)2 / C (20% wt. loading, 50% wet, 62 mg, 0.4 mmol, 0.2 eq.) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred under a hydrogen atmosphere (balloon) overnight. Upon completion, the mixture was passed through The mixture was stirred for 30 minutes at room temperature. The mixture was filtered through a pad of 4- (3- (methylsulfonyl) phenyl) -1-propylpiperidine (100 mg, 1 mmol / l) and the solvent was removed under reduced pressure. DCM (10 mL) and 2M NaOH solution (10 mL) were added and the mixture was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was extracted with DCM (2x). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give 548 mg (yield = 88%) of 4- (3- (methylsulfonyl) phenyl) -1-propylpiperidine with a LCMS purity of 100%, which was purified during the formation of the HCl salt in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =281.65 measured value.

[0367] 1 H NMR (300MHz, DMSO-d6) δ7.83-7.70(m,2H),7.67-7.52(m,2H),3.21(s,3H),3.02-2.90(m,2H),2.71-2.54(m,1H),2. 30-2.20(m,2H),2.02-1.91(m,2H),1.83-1.72(m,2H),1.71-1.60(m,2H),1.54-1.37(m,2H),0.87(t,J=7.4Hz,3H).

[0368] Step 5: HCl Salt Formation

[0369]

[0370] 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine (548 mg, 1.94 mmol, 1.0 eq) was dissolved in iPrOH (6.0 mL) and then 6N HCl (653 μl, 3.89 mmol, 2 eq) in iPrOH was added dropwise. The reaction mixture was stirred at 80 °C for 2 h and at room temperature overnight. The precipitate was filtered off, washed with iPrOH and dried under reduced pressure to give 170 mg (yield = 30%) of 4-(3-methylsulfonylphenyl)pyridine hydrochloride as a light yellow solid with 100% LCMS purity. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H]+ =281.65 measured value.

[0371] HPLC purity: 99.89% (@268nm).

[0372] 1 H NMR (300 MHz, methanol-d4) δ 7.95-7.81 (m, 2H), 7.76-7.56 (m, 2H), 3.80-3.61 (m, 2H), 3.25-3.01 (m, 8H), 2.29-1.98 (m, 4H), 1.94-1.75 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

[0373] Example 4: Process for preparing Pridopidine Figure 7 ]

[0374] Step 1: Suzuki coupling

[0375]

[0376] To a solution of 1-bromo-3-(methylsulfanyl)benzene (5.0 g, 24.61 mmol, 1.0 eq) in 1,4-dioxane (200 mL) and water (20 mL) was added pyridine-4-boronic acid (3.93 g, 32.00 mmol, 1.3 eq) and Cs2CO3 (24.06 g, 73.85 mmol, 3.0 eq) and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (2.84 g, 2.46 mmol, 0.1 eq) was added and the mixture was stirred at 80°C overnight. After this time, the mixture was cooled to room temperature and purified by The mixture was filtered through a pad of 4-[3-(methylsulfanyl)phenyl]pyridine, washed with DCM and concentrated under reduced pressure. The residue was taken up in DCM, washed with water (3x), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica column chromatography (DCM: acetone 100: 0-> 80: 20) to give 3.0 g (yield = 48%) of 4-[3-(methylsulfanyl)phenyl]pyridine as a brown oil with an LCMS purity of 96%. LCMS (ESI): Exact mass of C12H11NS: 201.29; [M+H] + =202.05 measured value.

[0377] 1H NMR (300MHz, DMSO-d6) δ8.68-8.59(m,2H),7.76-7.69(m,2H),7.62(t,J=1.7Hz,1H ),7.55(d,J=7.7Hz,1H),7.45(t,J=7.7Hz,1H),7.36(d,J=7.9Hz,1H),2.55(s,3H).

[0378] Step 2: N-alkylation

[0379]

[0380] 4-[3-(Methylsulfanyl)phenyl]pyridine (3.0 g, 14.9 mmol, 1.0 equiv) was dissolved in ACN (60 mL) and placed in an ice-cooled bath. 1-Iodopropane (2.91 mL, 29.80 mmol, 2.0 equiv) was added dropwise and the reaction mixture was heated to 70 °C overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (x3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained solid was refluxed with EtOAc (10 mL) for 1 h, cooled to room temperature, washed with EtOAc and dried under reduced pressure to obtain 5.0 g (yield = 86%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide as a brown solid with a LCMS purity of 95%. LCMS (ESI): Exact mass of C15H18NS: 244.12; [M] + =243.80 Actual measured value.

[0381] 1 H NMR(300MHz,DMSO-d6)δ9.16-9.06(m,2H),8.61-8.51(m,2H),7.91-7.77(m,2H),7.62 -7.48(m,2H),4.56(t,J=7.3Hz,2H),2.59(s,3H),1.98(h,J=7.3Hz,2H),0.91(t,J=7.3Hz,3H).

[0382] Step 3: Hydrogenation

[0383]

[0384] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide (1.0 g, 4.09 mmol, 1.0 eq) in methanol (50 mL) was added PtO (186 mg, 0.81 mmol, 0.2 eq) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred under a hydrogen atmosphere (balloon) at 40° C. for 7 days.

[0385] After completion is reached, the mixture is passed through The mixture was stirred at room temperature for 30 minutes. The mixture was filtered through a pad of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (292 mg, yield = 25%). DCM (20 mL) and 2M NaOH solution (20 mL) were added and the mixture was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was washed with DCM (2x). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (ACN: water 40: 60) to give 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine with a LCMS purity of 90% (292 mg, yield = 25%). LCMS (ESI): Exact mass of C15H23NS: 249.16; [M+H] + =250.10 Actual measured value.

[0386] 1 H NMR(300MHz,DMSO-d6)δ7.38-7.31(m,2H),7.28-7.20(m,2H),3.61-3.51(m,2H),3.14-2.94(m,4H),2.89- 2.74(m,1H),2.47(s,3H),2.10-1.96(m,2H),1.95-1.76(m,2H),1.77-1.59(m,2H),0.93(t,J=7.4Hz,3H).

[0387] Step 4: Oxidation

[0388]

[0389] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (292 mg, 1.17 mmol, 1.0 eq) in water (14.6 mL) was added 96% H2SO4 (770 μL, 14.48 mmol, 12.37 eq) followed by sodium tungstate dihydrate (27 mg, 0.08 mmol, 0.07 eq) and 30% H2O2 (90 μL, 2.92 mmol, 2.50 eq). The reaction mixture was stirred at 55°C for 2 h, after which time it was cooled to 10°C and toluene (50 mL) was added followed by NaOH solution. The aqueous layer was extracted with toluene (3x). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure to give 124 mg (yield = 30%) of 4-(3-methylsulfonylphenyl)-1-propylpiperidine as a brown solid with 62% LCMS purity, which was purified during HCl salt formation in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.10 Actual measured value.

[0390] Step 5: HCl Salt Formation

[0391]

[0392] 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine (124 mg, 0.44 mmol, 1.0 eq) was dissolved in iPrOH (3.0 mL) and then 6N HCl (147 μl, 0.88 mmol, 1.2 eq) in iPrOH was added dropwise. The reaction mixture was stirred at 80 °C for 2 h and at room temperature overnight. The precipitate was filtered off, washed with iPrOH and dried under reduced pressure to give 13 mg (yield = 9%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a light yellow solid with 100% LCMS purity. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =281.65 measured value.

[0393] HPLC purity: 97.06% (@268nm).

[0394] 1 H NMR (300 MHz, methanol-d4) δ 7.92-7.83 (m, 2H), 7.72-7.58 (m, 2H), 3.75-3.61 (m, 2H), 3.20-3.01 (m, 8H), 2.25-1.93 (m, 4H), 1.88-1.77 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

[0395] Example 5: Process for preparing Pridopidine Figure 8 ]

[0396] According to Example 4 ( Figure 7 Compound 1 is prepared by using steps 1 and 2 in the above method.

[0397] Step 3: Oxidation

[0398]

[0399] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide (1.0 g, 4.09 mmol, 1.0 eq) in water (50 mL) was added 96% H2SO4 (2.69 mL, 50.61 mmol, 12.37 eq) followed by sodium tungstate dihydrate (94 mg, 0.286 mmol, 0.07 eq) and 30% H2O2 (313 μL, 10.23 mmol, 2.50 eq). The reaction mixture was stirred at 55°C for 2 h, after which time it was cooled to 10°C and toluene (50 mL) was added followed by the NaOH solution. The aqueous layer was extracted with toluene (3x). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure to give 630 mg (yield = 50%) of 4-(3-methylsulfonylphenyl)-1-propylpyridin-1-ium hydroxide as a yellow oil with 96% LCMS purity. LCMS (ESI): Exact mass of C15H18NO2S: 276.11; [M+H] + =277.35 measured value. 1 H NMR (300MHz, DMSO-d6) δ9.46-9.05(m,2H),8.84-7.51(m,6H),4.71-4.50(m,2H),3.36(s,3H),2.07-1.86(m,2H),1.03-0.82(m,3H).

[0400] Step 4: Hydrogenation

[0401]

[0402] To a solution of 4-(3-methylsulfonylphenyl)-1-propylpyridin-1-ium hydroxide (630 mg, 2.15 mmol, 1.0 eq.) in methanol (31 mL) was added PtO2 (117 mg, 0.516 mmol, 0.2 eq.) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred under a hydrogen atmosphere (balloon) overnight. After reaching completion, the mixture was passed through The mixture was filtered through a pad of 4- (3-methylsulfonylphenyl) -1-propylpiperidine and the solvent was removed under reduced pressure. DCM (20 mL) and 2M NaOH solution (20 mL) were added and the mixture was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was washed with DCM (2x). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give 512 mg (yield = 85%) of 4- (3-methylsulfonylphenyl) -1-propylpiperidine with a LCMS purity of 100%, which was purified during the formation of the HCl salt in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.10 Actual measured value.

[0403] Step 5: HCl Salt Formation

[0404]

[0405] 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine (512 mg, 1.81 mmol, 1.0 eq) was dissolved in iPrOH (5.0 mL) and 6N HCl (606 μl, 3.63 mmol, 2.0 eq) in iPrOH was added dropwise. The reaction mixture was stirred at 80 °C for 2 h and at room temperature overnight. The precipitate was filtered off, washed with iPrOH and dried under reduced pressure to give 50 mg (yield = 9%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a light yellow solid with 100% LCMS purity. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =281.65 measured value.

[0406] HPLC purity: 92.58% (@268nm).

[0407] 1 H NMR (300 MHz, methanol-d4) δ 7.92-7.81 (m, 2H), 7.74-7.57 (m, 2H), 3.78-3.61 (m, 2H), 3.22-3.01 (m, 8H), 2.25-1.97 (m, 4H), 1.92-1.76 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

[0408] Example 6: Process for preparing Pridopidine Fig. 9 ]

[0409] According to Example 4 ( Figure 7 Compound 1 is prepared by using steps 1 and 2 in the above method.

[0410] Step 3: Reduction with sodium borohydride

[0411]

[0412] 4-[3-(Methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide (800 mg, 3.27 mmol, 1.0 eq) was dissolved in methanol (8.0 mL) and water (16.0 mL), and the solution was placed in an ice-cooled bath. NaBH4 (743 mg, 19.64 mmol, 6 eq) was added and the reaction mixture was allowed to stand at ambient temperature for 2 h. Afterwards, the mixture was quenched with 1 N HCl solution and extracted with DCM (x3). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. The crude material was purified by flash column chromatography (DCM:MeOH, 9:1) to give 240 mg (yield = 28%) of 4-[3-(methylsulfanyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine with 95% LCMS purity. LCMS (ESI): Exact mass of C15H21NS: 247.14; [M+H] + =248.05 measured value.

[0413] 1 H NMR (300 MHz, DMSO-d6) δ 7.39-7.18 (m, 4H), 6.23 (s, 1H), 3.98-3.75 (m, 2H), 3.17-3.06 (m, 2H), 2.83-2.70 (m, 2H), 2.51 (s, 3H), 1.79-1.61 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). *2H overlapped with DMSO

[0414] Step 4: Oxidation

[0415]

[0416] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (240 mg, 0.97 mmol, 1.0 eq)) in water (12.0 mL) was added 96% H2SO4 (1.17 mL, 12.0 mmol, 12.37 eq) followed by sodium tungstate dihydrate (22 mg, 0.068 mmol, 0.07 eq) and 30% H2O2 (74 μL, 10.23 mmol, 2.42 eq). The reaction mixture was stirred at 55°C for 2 h, after which time it was cooled to 10°C and toluene (50 mL) was added followed by NaOH solution. The aqueous layer was extracted with toluene (3x). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure to give 162 mg (yield = 58%) of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine as a yellow oil with 97% LCMS purity. LCMS (ESI): Exact mass of C15H21NO2S: 279.13; [M+H] + =280.05 measured value.

[0417] 1 H NMR (300 MHz, DMSO-d6) δ 7.95-7.87 (m, 1H), 7.83-7.73 (m, 2H), 7.66-7.55 (m, 1H), 6.36-6.28 (m, 1H), 3.23 (s, 3H), 3.14-3.06 (m, 2H), 2.68-2.59 (m, 2H), 2.41-2.30 (m, 2H), 1.58-1.43 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). *2H overlapped with DMSO

[0418] Step 5: Hydrogenation

[0419]

[0420] To a solution of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (162 mg, 0.580 mmol, 1.0 eq.) in methanol (8 mL) was added Pd(OH)2 / C (20% wt. loading, 50% wet, 16 mg, 0.012 mmol, 0.02 eq.) under a gentle stream of argon and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred under a hydrogen atmosphere (balloon) overnight. After reaching completion, the mixture was passed through The mixture was filtered through a pad of 4- (3-methylsulfonylphenyl) -1-propylpiperidine and the solvent was removed under reduced pressure. DCM (20 mL) and 2M NaOH solution (20 mL) were added and the mixture was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was washed with DCM (2x). The organic phases were combined, dried over sodium sulfate, filtered and evaporated to give 88 mg (yield = 54%) of 4- (3-methylsulfonylphenyl) -1-propylpiperidine with a LCMS purity of 100%, which was purified during the formation of the HCl salt in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.10 Actual measured value.

[0421] Step 6: HCl Salt Formation

[0422]

[0423] 4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine (88 mg, 0.313 mmol, 1.0 equiv) was dissolved in iPrOH (4 mL) and 6N HCl (114 μl, 0.62 mmol, 2.0 equiv) in iPrOH was added dropwise. The reaction mixture was stirred at 80 °C for 2 h and at room temperature overnight. The precipitate was filtered off, washed with iPrOH and dried under reduced pressure to give 43 mg (yield = 48%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a light yellow solid with 100% LCMS purity. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =281.65 measured value.

[0424] HPLC purity: 95.37% (@268nm).

[0425] 1 H NMR (300 MHz, methanol-d4) δ 7.92-7.83 (m, 2H), 7.70-7.58 (m, 2H), 3.78-3.66 (m, 2H), 3.22-3.02 (m, 8H), 2.25-1.94 (m, 4H), 1.91-1.74 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

[0426] Example 7: Process for preparing Pridopidine Fig.10 ]

[0427] Step 1: Suzuki coupling

[0428]

[0429] To a solution of 1-bromo-3-nitrobenzene (2.0 g, 9.90 mmol, 1.0 eq.) in 1,4-dioxane (40 mL) and water (4 mL) was added pyridine-4-boronic acid (1.58 g, 12.87 mmol, 1.3 eq.) and Cs2CO3 (9.68 g, 29.70 mmol, 3.0 eq.), and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (1.14 g, 0.99 mmol, 0.1 eq.) was added and the mixture was stirred at 80°C overnight. After cooling to room temperature, it was passed through The mixture was filtered through a pad of 4-nitrophenyl-1-nitropropene, washed with DCM and concentrated under reduced pressure. The residue was taken up in DCM, washed with water (3x), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (DCM: MeOH 100:0->90:10) to give 1.4 g (yield = 72%) of 4-(3-nitrophenyl)pyridine as a brown solid with a LCMS purity of 100%. LCMS (ESI): Exact mass of C11H8N2O2: 200.2; [M+H] + =201.0 measured value.

[0430] 1 H NMR (300 MHz, methanol-d4) δ 8.68 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 1.8 Hz, 1H), 8.61 (t, J = 2.1 Hz, 1H), 8.39-8.31 (m, 1H), 8.23-8.14 (m, 1H), 7.85-7.74 (m, 3H).

[0431] Step 2: N-propylation

[0432]

[0433] 4- (3- nitrophenyl) pyridine (1.3g, 6.49mmol, 1.0 equivalent) is dissolved in ACN (26mL) and placed in an ice-cooled bath. 1- iodopropane (1.27mL, 12.99mmol, 2.0 equivalent) is added dropwise and the reaction mixture is heated to 70 ° C overnight. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (x3). The combined organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The solid obtained is refluxed with EtOAc (30mL) for 1h, cooled to room temperature, washed with EtOAc and dried under reduced pressure to obtain 2.16g (yield = 89%) of 4- (3- nitrophenyl) -1- propylpyridinium -1- ium iodide as a yellow solid with 100% LCMS purity. LCMS (ESI): Exact mass of C14H15N2O2: 243.29; [M]+ =242.85 measured value.

[0434] 1 H NMR (300 MHz, methanol-d4) δ 9.15-9.08 (m, 2H), 8.90-8.84 (m, 1H), 8.58-8.50 (m, 3H), 8.46-8.38 (m, 1H), 7.93 (t, J = 8.1 Hz, 1H), 4.67 (t, J = 7.4 Hz, 2H), 2.13 (h, J = 7.4 Hz, 2H), 1.08 (t, J = 7.4 Hz, 3H).

[0435] Step 3: Hydrogenation

[0436]

[0437] To a solution of 4-(3-nitrophenyl)-1-propylpyridin-1-ium iodide (1.0 g, 2.70 mmol, 1.0 eq.) in methanol (40.0 mL) was added PtO2 (307 mg, 1.35 mmol, 0.5 eq.) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred under a hydrogen atmosphere (balloon) overnight. After reaching completion, the mixture was passed through The mixture was filtered through a pad of 4% paraffin wax and the solvent was removed under reduced pressure. DCM (30 mL) and 2M NaOH solution (30 mL) were added and the mixture was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was washed with DCM (2x). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in methanol, 4N HCl in dioxane was added, and the solution was evaporated under reduced pressure to give 1.05 g (yield = quantitative) of 3-(1-propylpiperidin-4-yl)aniline dihydrochloride with a LCMS purity of 100%. LCMS (ESI): Exact mass of C14H22N2: 218.34; [M+H] + =219.10 measured value.

[0438] 1 H NMR (300 MHz, methanol-d4) δ 7.04 (t, J = 7.7 Hz, 1H), 6.66-6.55 (m, 3H), 3.44-3.34 (m, 2H), 2.84-2.75 (m, 2H), 2.76-2.54 (m, 3H), 2.01-1.84 (m, 4H), 1.78-1.65 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).

[0439] Step 4: Sandmeyer reaction

[0440]

[0441] 3-(1-propylpiperidin-4-yl)aniline dihydrochloride (445mg, 1.53mmol, 1.0 equivalent) was dissolved in ice-cold AcOH (13mL) and cooled to 0°C in an ice bath. A solution of o-phenylenedisulfonyl imide (536mg, 2.45mmol, 1.2 equivalent) in ice-cold AcOH (7mL) was added over a period of 10min, keeping the temperature below 5°C. The reaction mixture was stirred at 0°C for 10min, and then isoamyl nitrite (302μL, 2.24mmol, 1.1 equivalent) was added dropwise over a period of 10min. The solution was stirred at 0°C for 20min, and diethyl ether was added to precipitate the compound as an orange solid, which was filtered, washed with diethyl ether and dried under reduced pressure at room temperature. At 0 ° C, 3- (1-propylpiperidin-4-yl) benzene-1-diazonium o-benzenedisulfonimide (914 mg, 2.04 mmol, 1.0 equiv) was added once to a solution of sodium thiomethoxide (160 mg, 2.28 mmol, 1.12 equiv) in MeOH (20 mL). The reaction mixture was stirred for 1 h, keeping the temperature below 5 ° C, then it was quenched with water (50 mL) and extracted with DCM (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (DCM: MeOH 100: 0-> 85: 15) and then purified by pTLC (CHCl3: iPrOH, 9: 1) to give 161 mg (yield = 30%) of 4- [3- (methylsulfanyl) phenyl] -1-propylpiperidine as a yellow solid with a LCMS purity of 71%. LCMS (ESI): Exact mass of C15H23NS: 249.42; [M] + =250.10 Actual measured value.

[0442] 1 H NMR(300MHz,DMSO-d6)δ7.32-7.15(m,2H),7.13-6.95(m,2H),2.99-2.89(m,2H),2.46(s,3H),2. 30-2.16(m,2H),2.01-1.82(m,2H),1.81-1.53(m,5H),1.52-1.34(m,2H),0.86(t,J=7.4Hz,3H).

[0443] Step 5: Oxidation

[0444]

[0445] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (140 mg, 0.56 mmol, 1.0 equiv) in water (7 mL) was added 96% H2SO4 (370 μL, 6.94 mmol, 12.37 equiv) followed by sodium tungstate dihydrate (13 mg, 0.04 mmol, 0.07 equiv) and 30% H2O2 solution (144 μL, 1.40 mmol, 2.50 equiv). The reaction mixture was stirred at 55°C for 2 h, after which time it was cooled to 10°C and toluene (50 mL) was added followed by NaOH solution. The aqueous layer was extracted with toluene (3x). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure. The crude material was purified by pTLC (DCM:MeOH 9:1) to give 27 mg (yield = 17%) of 4-(3-methylsulfonylphenyl)-1-propylpiperidine as a yellow solid with 56% LCMS purity, which was purified during HCl salt formation in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.00 Actual measured value.

[0446] Step 6: HCl Salt Formation

[0447]

[0448] 4-(3-methylsulfonylphenyl)-1-propylpiperidine (26 mg, 0.09 mmol, 1.0 equiv) was dissolved in iPrOH (300 μL), heated until 70 ° C and added 6N HCl (19 μL, 0.11 mmol, 1.2 equiv) in iPrOH. The mixture was heated to 80 ° C and stirred for 10 mm. After this time, it was cooled to 65 ° C, seeded with pure 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride, and cooled to room temperature to precipitate the product. The white solid was filtered off, washed with iPrOH and dried under reduced pressure to obtain 11 mg (yield = 37%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a white solid with a LCMS purity of 100%. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.05 measured value.

[0449] HPLC purity: 99.32% (@268nm)

[0450] 1H NMR (300 MHz, methanol d4) δ 7.92-7.84 (m, 2H), 7.74-7.59 (m, 2H), 3.76-3.61 (m, 2H), 3.23-2.99 (m, 8H), 2.28-1.94 (m, 4H), 1.89-1.74 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

[0451] Example 8: Process for preparing Pridopidine Fig.11 ]

[0452] Step 1: Suzuki coupling

[0453]

[0454] To a solution of tert-butyl N-(3-bromophenyl)carbamate (3.5 g, 12.86 mmol, 1.0 eq) in 1,4-dioxane (140 mL) and water (14 mL) was added pyridine-4-boronic acid (2.05 g, 16.71 mmol, 1.2 eq) and Cs2CO3 (12.57 g, 38.58 mmol, 3.0 eq) and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.1 eq) was added and the mixture was stirred at 80 °C overnight. After this time, the mixture was cooled to room temperature and purified by The mixture was filtered through a pad of 4-nitropropene, washed with DCM and concentrated under reduced pressure. The residue was taken up in DCM, washed with water (3x), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica column chromatography (DCM: MeOH 100: 0-> 85: 15) to give 3.1 g (yield = quantitative) of tert-butyl N-[3-(pyridin-4-yl)phenyl]carbamate as a brown solid with a LCMS purity of 100%. LCMS (ESI): Exact mass of C16H18N2O2: 270.14; [M+H] + =270.60 Actual measured value.

[0455] 1 H NMR (300MHz, DMSO-d6) δ9.51(s,1H),8.68-8.59(m,2H),7.94-7.87(m,1H),7.67-7.58(m,2H),7.55-7.48(m,1H),7.47-7.36(m,2H),1.49(s,9H).

[0456] Step 2: N-propylation

[0457]

[0458] N-[3-(pyridin-4-yl)phenyl]carbamic acid tert-butyl ester (3.0g, 11.08mmol, 1.0 equivalent) is dissolved in ACN (60mL) and placed in an ice-cooled bath. 1-Iodopropane (4.32mL, 44.39mmol, 4.0 equivalent) is added dropwise and the reaction mixture is heated to 70°C overnight. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (x3). The combined organic layer is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained solid is refluxed with EtOAc (10mL) for 1h, cooled to room temperature, washed with EtOAc and dried under reduced pressure to obtain 3.5g (yield = 72%) of 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridin-1-ium iodide as a yellow solid with 100% LCMS purity. LCMS (ESI): Exact mass of C19H25N2O2: 313.19; [M+H] + =313.9 measured value.

[0459] 1 H NMR(300MHz,DMSO-d6)δ9.66(s,1H),9.15-9.05(m,2H),8.41-8.34(m,2H),8.17-8.12(m,1H),7. 72-7.47(m,3H),4.57(t,J=7.3Hz,2H),1.96(h,J=7.3Hz,2H),1.50(s,9H),0.92(t,J=7.4Hz,3H).

[0460] Step 3: Hydrogenation

[0461]

[0462] To a solution of 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridin-1-ium iodide (1.0 g, 2.27 mmol, 1.0 eq) in methanol (50 mL) was added PtO2 (362 mg, 1.59 mmol, 0.7 eq) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred at 40° C. overnight under a hydrogen atmosphere (balloon). After reaching completion, the mixture was stirred by The mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure to give 1.1 g (yield = quantitative) of tert-butyl N-[3-(1-propylpiperidin-4-yl)phenyl]carbamate with 100% LCMS purity. LCMS (ESI): Exact mass of C19H30N2O2: 318.23; [M+H] + =319.15 measured value.

[0463] 1 H NMR (300 MHz, methanol-d4) δ 7.43 (s, 1H), 7.24-7.12 (m, 2H), 6.95-6.82 (m, 1H), 3.63-3.50 (m, 2H), 3.07-2.92 (m, 4H), 2.90-2.75 (m, 1H), 2.16-1.87 (m, 4H), 1.85-1.67 (m, 2H), 1.51 (s, 9H), 1.02 (t, J = 7.3 Hz, 3H).

[0464] Step 3.1: Reduction with NaBH4

[0465]

[0466] A solution of 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridin-1-ium iodide (1.0g, 2.27mmol, 1.0 equivalent) was dissolved in methanol (10mL) and water (20mL) and placed in an ice-cooled bath. NaBH4(724mg, 19.14mmol, 8.4 equivalents) was added and the reaction mixture was left to stand for 2h. Afterwards, the mixture was quenched with 1N HCl solution and extracted with DCM (x3). The organic phases were merged, dried over sodium sulfate, filtered and evaporated to obtain 815mg (yield=quantitative) of 91% LCMS purity of N-[3-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl]t-butyl carbamate, which was used as is in the next step. LCMS (ESI): Exact mass of C19H28N2O2: 316.22; [M+H] + =316.65 measured value.

[0467] 1 H NMR (300 MHz, methanol-d4) δ 7.60 (s, 1H), 7.31-7.19 (m, 2H), 7.14-7.04 (m, 1H), 6.17-6.11 (m, 1H), 3.72-3.65 (m, 2H), 3.30-3.26 (m, 2H), 3.01-2.90 (m, 2H), 2.85-2.69 (m, 2H), 1.87-1.68 (m, 2H), 1.52 (s, 9H), 1.03 (t, J = 7.4 Hz, 3H).

[0468] Step 3.2: Hydrogenation

[0469]

[0470] To a solution of tert-butyl N-[3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]carbamate (800 mg, 3.23 mmol, 1.0 eq.) in methanol (80 mL) was added 10% Pd / C (60%-65% wet, 229 mg, 1.13 mmol, 0.35 eq.) under a gentle stream of argon, and the reaction mixture was evacuated and backfilled with hydrogen three times. It was then stirred at 40° C. under a hydrogen atmosphere (balloon) overnight. After reaching completion, the mixture was stirred by The mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure to give 470 mg (yield = 45%) of tert-butyl N-[3-(1-propylpiperidin-4-yl)phenyl]carbamate with 100% LCMS purity. LCMS (ESI): Exact mass of C19H30N2O2: 318.23; [M+H] + =319.15 measured value.

[0471] 1 H NMR (300 MHz, methanol-d4) δ 7.44 (s, 1H), 7.27-7.12 (m, 2H), 7.00-6.82 (m, 1H), 3.66-3.48 (m, 2H), 3.12-2.93 (m, 4H), 2.93-2.72 (m, 1H), 2.18-1.88 (m, 4H), 1.87-1.67 (m, 2H), 1.52 (s, 9H), 1.04 (t, J = 7.4 Hz, 3H).

[0472] Step 4: BOC-deprotection

[0473]

[0474] Tert-butyl N-[3-(1-propylpiperidin-4-yl)phenyl]carbamate (470 mg, 1.47 mmol, 1.0 eq) was dissolved in dioxane (36 mL). 4N HCl in dioxane (10.4 mL, 43.71 mmol, 29.7 eq) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The solution was concentrated under reduced pressure to give 416 mg (yield = 97%) of 3-(1-propylpiperidin-4-yl)aniline dihydrochloride as a brown solid with 100% LCMS purity. LCMS (ESI): Exact mass for C14H22N2: 218.18; [M+H] + =218.75 measured value.

[0475] 1H NMR (300 MHz, methanol-d4) δ 7.53 (t, J = 7.8 Hz, 1H), 7.49-7.41 (m, 1H), 7.39-7.34 (m, 1H), 7.33-7.27 (m, 1H), 3.77-3.65 (m, 2H), 3.23-2.96 (m, 5H), 2.25-1.98 (m, 4H), 1.94-1.69 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H).

[0476] Step 5: Sandmeyer Reaction

[0477]

[0478] 3-(1-propylpiperidin-4-yl)aniline dihydrochloride (445mg, 1.53mmol, 1.0 equivalent) was dissolved in ice-cold AcOH (13mL) and cooled to 0°C in an ice bath. A solution of o-phenylenedisulfonyl imide (536mg, 2.45mmol, 1.2 equivalent) in ice-cold AcOH (7mL) was added over a period of 10min, keeping the temperature below 5°C. The reaction mixture was stirred at 0°C for 10min, and then isoamyl nitrite (302μL, 2.24mmol, 1.1 equivalent) was added dropwise over a period of 10min. The solution was stirred at 0°C for 20min, and diethyl ether was added to precipitate the compound as an orange solid, which was filtered, washed with diethyl ether and dried under reduced pressure at room temperature. At 0 ° C, 3- (1-propylpiperidin-4-yl) benzene-1-diazonium o-benzenedisulfonimide (914 mg, 2.04 mmol, 1.0 equiv) was added once to a solution of sodium thiomethoxide (160 mg, 2.28 mmol, 1.12 equiv) in MeOH (20 mL). The reaction mixture was stirred for 1 h, keeping the temperature below 5 ° C, then it was quenched with water (50 mL) and extracted with DCM (3x). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (DCM: MeOH 100: 0-> 85: 15) and then purified by pTLC (CHCl3: iPrOH, 9: 1) to obtain 161 mg (Y = 30%) of 4- [3- (methylsulfanyl) phenyl] -1-propylpiperidine as a yellow solid with a LCMS purity of 71%. LCMS (ESI): Exact mass of C15H23NS: 249.42; [M] + =250.10 Actual measured value.

[0479] 1H NMR(300MHz,DMSO-d6)δ7.32-7.15(m,2H),7.13-6.95(m,2H),2.99-2.89(m,2H),2.46(s,3H),2. 30-2.16(m,2H),2.01-1.82(m,2H),1.81-1.53(m,5H),1.52-1.34(m,2H),0.86(t,J=7.4Hz,3H).

[0480] Step 6: Oxidation

[0481]

[0482] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (140 mg, 0.56 mmol, 1.0 equiv) in water (7 mL) was added 96% H2SO4 (370 μL, 6.94 mmol, 12.37 equiv) followed by sodium tungstate dihydrate (13 mg, 0.04 mmol, 0.07 equiv) and 30% H2O2 solution (144 μL, 1.40 mmol, 2.50 equiv). The reaction mixture was stirred at 55°C for 2 h, after which time it was cooled to 10°C and toluene (50 mL) was added followed by NaOH solution. The aqueous layer was extracted with toluene (3x). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure. The crude material was purified by pTLC (DCM: MeOH 9: 1) to give 27 mg (Y = 17%) of 4-(3-methylsulfonylphenyl)-1-propylpiperidine as a yellow solid with an LCMS purity of 56%, which was purified during HCl salt formation in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H]+ = 282.00 found.

[0483] Example 9: Process for preparing Pridopidine Fig.12 ]

[0484] Step 1: Cyclization reaction

[0485]

[0486] A solution of (3-methylsulfanyl-phenyl)-acetonitrile (2.0 g, 12.3 mmol, 1.0 equiv) in DMSO (16 mL) was treated in batches with sodium hydride (60% dispersion, mineral oil, 1.47 g, 36.8 mmol, 3.0 equiv). The resulting suspension was stirred at room temperature for 30 minutes. After this time, N,N-bis(2-chloroethyl)propan-1-amine hydrochloride (2.97 g, 13.5 mmol, 1.1 equiv) was added slowly over 5 minutes, and the suspension was heated at 65 °C for 1 h. After completion, the reaction was diluted with water and extracted with ethyl acetate (3x). The combined extracts were washed with water (5x), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3.44 g (yield = 94%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine-4-carbonitrile as a brown oil with 92% purity. LCMS (ESI): Exact mass of C16H22N2S: 274.15; [M+H] + =275.05 measured value.

[0487] 1 H NMR (300 MHz, methanol-d4) δ 7.47-7.41 (m, 2H), 7.32-7.27 (m, 2H), 3.12-3.04 (m, 2H), 2.49-2.40 (m, 7H), 2.15-2.07 (m, 4H), 1.57 (m, 2H), 0.95 (t, 3H).

[0488] Step 2: Hydrolysis-decarboxylation

[0489]

[0490] 4-[3-(Methylsulfanyl)phenyl]-1-propylpiperidine-4-carbonitrile (2.9 g, 10.6 mmol, 1.0 equiv) was dissolved in DMSO (58 mL) and potassium hydroxide (5.93 g, 105.7 mmol, 10.0 equiv) was added in portions. The reaction mixture was heated to 160 ° C and stirred for 72 h. After cooling to room temperature, the reaction mixture was quenched with water and extracted with DCM (3x). The combined extracts were washed with water (5x), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified using flash column chromatography (DCM: DCM / MeOH 9: 1 + 1% NH3) to give 223 mg (yield = 8%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine as a brown solid with a LCMS purity of 98%. LCMS (ESI): Exact mass of C15H23NS: 249.16; [M+H] + =250.10 Actual measured value.

[0491] 1 H NMR (300 MHz, methanol-d4) δ 7.23-7.15 (m, 4H), 3.13 (d, 2H), 2.47-2.40 (m, 5H), 2.26-2.14 (m, 2H), 1.90-1.53 ​​(m, 7H), 0.95 (t, J = 7.4 Hz, 3H).

[0492] Note: During process optimization, the reaction was successfully run at 50 mg scale to afford 41 mg (yield = 91%) of product with 80% LCMS purity.

[0493] Step 3: Oxidation

[0494]

[0495] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (200 mg, 0.80 mmol, 1.0 equiv) in water (10 mL) was added 96% H2SO4 (528 μL, 9.9 mmol, 12.37 equiv) followed by sodium tungstate dihydrate (20 mg, 0.10 mmol, 0.07 equiv) and 30% H2O2 (200 μL, 2.0 mmol, 2.50 equiv). The reaction mixture was stirred at 55°C for 2 h. After this time, the mixture was cooled to 10°C and toluene was added followed by NaOH solution until the pH was ~12. The aqueous layer was extracted with toluene (3x). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure to give 192 mg (yield = 85%) of 4-(3-methylsulfonylphenyl)-1-propylpiperidine as a brown oil with 92% LCMS purity, which was purified during HCl salt formation in the next step. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.05 measured value.

[0496] Step 4: Salt Formation

[0497]

[0498] 4-(3-methylsulfonylphenyl)-1-propylpiperidine (192mg, 0.68mmol, 1.0 equivalent) is absorbed in iPrOH (2.1mL), heated until 70°C and 6N HCl (136μL, 0.82mmol, 1.2 equivalent) in iPrOH is added. The mixture is heated to 80°C and stirred for 10min. After this time, it is cooled to 65°C and inoculated with pure 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride and cooled to room temperature. After cooling the solution, a white precipitate is formed, which is washed with iPrOH and dried to obtain 73mg (yield = 34%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a white solid with 100% LCMS purity. LCMS (ESI): Exact mass of C15H23NO2S: 281.14; [M+H] + =282.10 Actual measured value.

[0499] HPLC purity: 94.40% (@268nm)

[0500] 1 H NMR (300 MHz, methanol-d4) δ 8.00-7.90 (m, 2H), 7.62-7.53 (m, 2H), 3.78-3.66 (m, 2H), 3.23-3.00 (m, 8H), 2.23-1.95 (m, 4H), 1.94-1.75 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).

[0501] Example 10: Process for preparing Pridopidine Fig.13 ]

[0502] Step 1. Triflate formation

[0503]

[0504] 1-Propyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate

[0505] The clear brown solution of 1-propylpiperidin-4-one (506mg, 3.58mmol) in THF (2.5mL) was cooled to -75°C. LiHMDS (779mg, 4.66mL, 1M, 1.3 equivalents, 4.66mmol) was added dropwise, keeping the temperature below -70°C. The reaction mixture was stirred at -75°C for 30min. NFSI (1.41g, 1.1 equivalents, 3.94mmol) was added in batches. After addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (5mL). The reaction mixture was cooled using an ice bath. Saturated NH4Cl aqueous solution (5mL) was added dropwise. Each phase was separated, and the organic phase was washed with NH4Cl aqueous solution (5mL) and water (5mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to obtain 1.84g. The material was purified by column chromatography (silica; 0-3% 7N NH3 in MeOH in DCM): fraction 3 (tubes 37-43) was concentrated in vacuo to give 1-propyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (626 mg, 2.29 mmol, yield = 63.9%) as a light yellow oil.

[0506] Step 2: Formation of boronate ester

[0507]

[0508] 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (Compound 10)

[0509] A suspension of 1-propyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.95 g, 7.14 mmol), KOAc (2.10 g, 3 eq., 21.4 mmol) and B2Pin2 (2.17 g, 1.2 eq., 8.56 mmol) in 1,4-dioxane (22 mL) was stirred at room temperature. PdCl2(dppf) (261 mg, 0.05 eq., 357 μmol) was added and the reaction mixture was degassed with N2 for 15 min. The reaction mixture was then heated to 80 °C for 2.5 hours. The reaction mixture was filtered through a bed of celite. The filter cake was washed with 1,4-dioxane. The combined filtrates were concentrated in vacuo to give crude 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (4.25 g, 6.1 mmol, yield = 85%, 36% purity based on H-Q NMR). This material was used as is without further purification.

[0510] Step 3: Suzuki Miyaura Reaction

[0511]

[0512] 4-(3-Bromophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (Compound 6)

[0513] 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (615mg, 36%Wt, 881μmol) was dissolved in 1,2-dimethoxyethane (10mL). 1,3-dibromobenzene (1.04g, 533μL, 5 equivalents, 4.41mmol) was added, followed by Na2CO3 (280mg, 1.32mL, 2 moles, 3 equivalents, 2.64mmol) and PdCl2(dppf) (32.2mg, 0.05 equivalents, 44.1μmol). The reaction mixture was degassed with N2 for 15 minutes and stirred at 80°C for 3 hours. EtOAc (100mL) and water (50mL) were added. The mixture was filtered through a diatomaceous earth layer. The phases were separated and the organic phase was washed with water (2×50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give 1 g of crude product. The crude product was purified by column chromatography (silica; 0-3% 7N NH3 in MeOH in DCM): fraction 3 (tubes 21-34) was concentrated in vacuo to give 4-(3-bromophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (95 mg, 0.34 mmol, yield = 38%).

[0514] The chemistry of converting the olefin bromine intermediate to pridopidine is similar to that described above in Example 1. The double bond of compound 6 is first reduced to obtain compound 8, which is further converted to pridopidine.

[0515] Example 11: Process for preparing Pridopidine

[0516]

[0517] The boronate ester (Compound 10) was synthesized as described in Example 10 and further reacted with 1-bromo-3-(methylsulfonyl)benzene to give Compound 5. The double bond of Compound 5 was reduced to Pridopidine as described in Step 5 of Example 6.

[0518] Step 1: Suzuki coupling

[0519] To a solution of 1-bromo-3-(methylsulfonyl)benzene (0.415 g, 1.76 mmol, 1.0 eq) in 1,4-dioxane (5 mL) and water (1 mL) was added N-propyl-2H-pyridine-4-boronic acid pinacol ester (0.53 g, 2.11 mmol, 1.2 eq) and potassium acetate (0.52 g, 5.28 mmol, 3.0 eq) and the reaction mixture was purged with argon for 15 min. Pd(dppf)Cl2 (66 mg, 0.09 mmol, 0.05 eq) was added and the mixture was stirred at 80 °C overnight. After this time, the mixture was cooled to room temperature and purified by The residue was taken up in DCM, washed with water (3x), the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.18 g (yield = 37%) of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine as an oil after chromatographic purification. LCMS (ESI): Exact mass of C15H21NO2S: 279.13; [M+H] + =280.05 measured value.

[0520] Step 2: Reduction with formic acid

[0521] To a cold solution of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (1 g, 3.58 mmol, 1 eq) in 2.5 volumes of water was added formic acid (0.264 g, 5.73 mmol, 1.6 eq) and 0.1% (w / w) of 10% Pd / C. The reaction was heated to 30°C for about 4-5 hours. The mixture was filtered to remove the catalyst, the filtrate was added to toluene and the mixture was basified with a dilute NaOH solution. The lower aqueous phase was separated and the toluene phase was washed several times with 5 volumes of water to remove residual NaOH. Toluene was distilled off under vacuum and 4 volumes of n-heptane were added to the residue to form a slurry which was cooled to 0°C. The solid material formed was collected by filtration and dried under vacuum at 40°C. 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine was obtained with a yield of 85%.

[0522] Although certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will now occur to those of ordinary skill in the art. It will be understood, therefore, that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. A compound represented by the structure of Formula I: Where A is -SMe or -SO 2 Me; and X - It is an anion.

2. The compound according to claim 1, represented by the structure of compound 1:

3. The compound according to claim 1, represented by the structure of compound 2:

4. A process for preparing pridopidine, wherein the process is via an intermediate compound according to any one of claims 1 to 3.

5. The process according to claim 4, wherein the process comprises reducing the pyridinium ring of compound 1, followed by oxidation of -SMe to -SO 2 Me to get Pridopidine.

6. The process according to claim 4, wherein the process comprises oxidizing -SMe of compound 1 to -SO 2 Me, followed by reduction of the pyridinium ring to afford pridopidine.

7. The process according to claim 4, wherein the process comprises reducing the pyridinium ring of compound 2 to obtain pridopidine.

8. A process for preparing pridopidine, wherein the process (process 1) include: Reduction of the pyridinium group of the compound of formula I Where A is SMe or SO 2 Me, and X - It is an anion To obtain compound 7 or pridopidine; Among them, compound 7 was further oxidized (-SMe was oxidized to -SO) 2 Me) to obtain pridopidine.

9. The process according to any one of claims 5 to 8, wherein the reduction of the pyridinium ring comprises reacting with PtO 2 and H 2 (Gas) reaction.

10. A process for preparing pridopidine, wherein the process (process 2) include: Reduction of the pyridinium group of the compound of formula I: Where A is SMe or SO 2 Me, and X - It is an anion; To obtain compound 4, or compound 5 wherein compound 5 is further reduced (reduction of the double bond) to obtain pridopidine; or Compound 4 is further oxidized (-SMe is oxidized to -SO 2 Me), and then reduced (double bond) to obtain pridopidine; or alternatively, compound 4 is further reduced (double bond) and then oxidized (-SMe is oxidized to -SO 2 Me) to obtain pridopidine.

11. The process according to claim 10, wherein the reducing agent used to reduce the pyridinium ring of the compound of formula I to obtain compound 4 or compound 5 comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or H in the presence of a Pd / C catalyst. 2 (gas).

12. The process of claim 10, wherein reducing the double bond to obtain the piperidine ring comprises reaction with a hydrogen source and a catalyst, wherein the catalyst comprises a second palladium catalyst, a platinum catalyst, or a ruthenium catalyst.

13. The process of claim 12, wherein the hydrogen source comprises hydrogen gas, formic acid or a formate salt.

14. The process of claim 10, wherein the formate salt is ammonium formate.

15. A process according to claim 8 or claim 10, wherein -SMe is oxidized to -SO 2 Me includes reaction with a tungsten catalytic oxidant, a peroxide, or a combination thereof.

16. The process of claim 15, wherein the tungsten catalytic oxidant is sodium tungstate.

17. The process of claim 15, wherein the peroxide is sodium peroxide.

18. A process for preparing a compound of formula I: Where A is SMe or SO 2 Me, and X - It is an anion; The process (process 3) include: a) in the presence of a palladium catalyst and a weak base, reacting a compound of formula II Where A is SMe or SO 2 Me; and X 1 It is a halide; and (pyridin-4-ylboronic acid) to obtain a compound of formula III: as well as b) reacting the compound of formula III with a propyl moiety to obtain the compound of formula I.

19. The process of claim 18, wherein the weak base comprises potassium carbonate, potassium phosphate, sodium bicarbonate, sodium ethoxide, and cesium carbonate, or any combination thereof.

20. The process of claim 18, wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium(0) (Pd(Ph 3 P) 4 ), palladium(II) acetate (Pd(OAc) 2 ), bis(triphenylphosphine)palladium chloride (Pd(Ph 3 P) 2 Cl 2 ) or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (Pd(Cl 2 )dppf).

21. The process of claim 15, wherein the propyl moiety is 1-iodopropane.

22. A process for preparing pridopidine using an intermediate of a compound of formula I, Where A is SMe or SO 2 Me, and X - It is an anion; The intermediate of the compound of formula I is prepared according to any one of claims 18-21.

23. A process for the preparation of pridopidine according to any one of claims 4 to 17, wherein the compound of formula I is prepared according to any one of claims 18-21.

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