Process and intermediates for producing pridopidine

Abstract

According to the present disclosure, methods and intermediates for producing pridopidine are provided.

Description

[Technical field]

[0001] The present invention relates to processes and intermediates for the preparation of pridopidine. [Background technology]

[0002] Pridopidine, or 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, is a potent sigma-1 receptor (S1R) agonist in clinical development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Recent data, including in vivo PET imaging and in vitro binding assays in rats, indicate that pridopidine acts primarily through the sigma-1 receptor (S1R). Pridopidine has been shown to have 100-500 times higher binding affinity for S1R compared to dopamine D2 receptors (Sahlholm K, Arhem P, Fuxe K, et al. The dopamine 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 that is mainly present in the mitochondria-associated membrane (MAM) and controls various cellular processes such as calcium signaling, ion channel regulation, and endoplasmic reticulum (ER) stress response (Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca (2+) signaling and cell survival. Cell 2007; 3: 596-610).

[0003] Activation of S1R 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(Pt A):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 effects in several in vitro and in vivo 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(Pt A):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).

[0004] Methods for synthesizing pridopidine and pharma- ceutically acceptable salts thereof are disclosed in Patent Documents 1-3.

[0005] The present invention relates to processes and intermediates for the preparation of pridopidine. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Pat. No. 7,923,459 [Patent Document 2] U.S. Patent No. 10,047,049 [Patent Document 3] U.S. Patent No. 6,903,120 Summary of the Invention [Means for solving the problem]

[0007] In some embodiments, the present invention provides a compound I represented by the following formula (I): where A is -SMe or -SO2Me, and X - is an anion.

[0008] [ka]

[0009] In some embodiments, the present invention provides a method for preparing pridopidine, i.e., 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, represented by the following formula, or a pharma- ceutically acceptable salt thereof, from compound I above:

[0010] [ka]

[0011] In some embodiments, the compound I is represented by the following formula (1): - is an anion.

[0012] [ka]

[0013] In some embodiments, the compound I is represented by the following formula (2): - is an anion.

[0014] [ka] [Brief description of the drawings]

[0015] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of this specification. The invention, however, both as to organization and method of operation, together with its objects, features, and advantages, may best be understood by reading the following detailed description when read in conjunction with the accompanying drawings.

[0016] [Figure 1] FIG. 1 shows a synthetic scheme for the preparation of pridopidine (1) by a step of complete reduction of the pyridinium ring of the intermediate compound I, where A is SMe or SO2Me. [Diagram 2] FIG. 2 shows a synthetic scheme for the preparation of pridopidine (2) by stepwise reduction of the pyridinium ring of the intermediate compound I, where A is SMe or SO2Me. [Diagram 3] FIG. 3 shows a synthesis scheme of the production method (3) of compound I. [Figure 4] 4 shows a synthetic scheme for the preparation of pridopidine via an intermediate compound of formula I (compound 3) where A is a bromide and X is an anion, which is shown in Example 1. [Diagram 5] 5 shows a synthetic scheme for the preparation of pridopidine by complete reduction of the intermediate pyridinium ring of the compound of formula I (compound 2) where A is SO2Me and X- is an anion, which is shown in Example 2. [Figure 6] 6 shows a synthetic scheme for the preparation of pridopidine by stepwise reduction of the pyridinium ring of the intermediate of the compound of formula I (compound 2) where A is SO2Me and X- is I-. This preparation is shown in Example 3. [Figure 7]7 shows a synthetic scheme for the preparation of pridopidine by complete reduction of the intermediate pyridinium ring of the compound of formula I (compound 1) where A is SMe and X- is I-. This preparation is shown in Example 4. [Figure 8] Figure 8 shows a synthetic scheme for the preparation of pridopidine via an intermediate of the compound of formula I where A is SMe and X- is I- (compound 1). This intermediate is oxidized to SO2Me. When A is SO2Me and X- is -OH (compound 2), this is followed by complete reduction of the pyridinium ring. This preparation is shown in Example 5. [Figure 9] 9 shows a synthetic scheme for the preparation of pridopidine by stepwise reduction of the pyridinium ring of the intermediate compound of formula I, followed by reduction of the tetrahydropyridine ring, where A is SMe (compound 1), which is then oxidized to SO2Me. This preparation is shown in Example 6. [Figure 10] 10 shows a synthetic scheme for the preparation of pridopidine via an intermediate compound of formula I where A is a nitro group, which preparation is shown in Example 7. [Figure 11] 11 shows a synthetic scheme for the preparation of pridopidine via an intermediate compound of formula I where A is a protected amine, which preparation is shown in Example 8. [Figure 12] 12 shows a synthetic scheme for the preparation of pridopidine via the intermediate compound 9, which is shown in Example 9. [Figure 13] 13 shows a synthetic scheme for the preparation of pridopidine via the intermediate compound 10, which is shown in Example 10.

[0017] It will be understood that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, dimensions of some elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals have been repeated among the figures to indicate corresponding or similar elements. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0019] In some embodiments, the present invention provides a method for preparing pridopidine, i.e., 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, represented by the formula:

[0020] [ka]

[0021] The present invention provides a method comprising the step of using a compound I represented by the following formula (I) as an intermediate:

[0022] [ka]

[0023] During the ceremony, A is a halide, a nitro group, a protected amine, -SMe, or -SOMe; X - is an anion.

[0024] In some embodiments, the present invention provides a method for preparing pridopidine, i.e., 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, represented by the formula:

[0025] [ka]

[0026] The present invention provides a method comprising the step of using a compound IV represented by the following formula (IV) as an intermediate:

[0027] [ka]

[0028] During the ceremony, R1 is H, propyl, or a protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0029] In some embodiments, the present invention provides a method for preparing pridopidine, i.e., 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, represented by the formula:

[0030] [ka]

[0031] The present invention provides a method comprising the step of using a compound (XIII) represented by the following formula (XIII) as an intermediate:

[0032] [ka]

[0033] During the ceremony, R1 is H, propyl, or a protecting group.

[0034] In one embodiment, the present invention provides a method for producing pridopidine (1), comprising the steps of: By reducing the pyridinium ring of compound I represented by the following formula (I),

[0035] [ka]

[0036] During the ceremony, A is -SMe or -SO2Me; X - is an anion.

[0037] obtaining compound 7 or pridopidine represented by the following formula (7);

[0038] [ka]

[0039] and oxidizing -SMe of compound 7 to -SO2Me to obtain pridopidine.

[0040] In one embodiment, the present invention provides a method for producing pridopidine (1A), comprising the steps of: Compound I represented by the following formula (I) is oxidized,

[0041] [ka]

[0042] During the ceremony, A is -SMe; X - is an anion.

[0043] The method includes the steps of obtaining compound 2 represented by the following formula (2) and then reducing the pyridinium ring to obtain pridopidine.

[0044] [ka]

[0045] In one embodiment, the present invention provides a method for producing pridopidine (2), comprising the steps of: By reducing the pyridinium ring of compound I represented by the following formula (I),

[0046] [ka]

[0047] During the ceremony, A is -SMe or -SO2Me; X - is an anion.

[0048] Obtaining a compound 4 represented by the following formula (4) or a compound 5 represented by the following formula (5);

[0049] [ka]

[0050] [ka]

[0051] reducing the double bond of compound 5 to give pridopidine, or oxidizing -SMe of compound 4 to -SOMe and then reducing the double bond to give pridopidine, or reducing the double bond of compound 4 and then oxidizing -SMe to -SOMe to give pridopidine.

[0052] In another embodiment, pridopidine is prepared as described in Example 3 and FIG.

[0053] In another embodiment, pridopidine is prepared as described in Example 4 and FIG.

[0054] In one embodiment, the present invention provides a method (3) for preparing compound I of formula (I), comprising the steps of:

[0055] [ka]

[0056] During the ceremony, A is a halide, a nitro group, a protected amine, -SMe, or -SOMe; X - is an anion.

[0057] (a) reacting a compound II represented by the following formula (II) (wherein A is a halide, a nitro group, a protected amine, -SMe, or -SOMe, and X1 is a halide) in the presence of a palladium catalyst and a weak base,

[0058] [ka]

[0059] Pyridine-4-boronic acid represented by the formula

[0060] [ka]

[0061] to obtain a compound III represented by formula (III) below, where A is a halide, a nitro group, a protected amine, -SMe, or -SOMe;

[0062] [ka]

[0063] (b) reacting compound III with a propyl moiety to obtain compound I.

[0064] In another embodiment, compound I of formula (I) is prepared as depicted in FIG.

[0065] In another embodiment, compound I of formula (I) is prepared as depicted in FIG. 4 when A is bromide.

[0066] In some embodiments, the present invention provides a method for producing pridopidine using compound I of formula (I) as an intermediate.

[0067] [ka]

[0068] During the ceremony, A is a halide, a nitro group, a protected amine, -SMe, or -SOMe; X - is an anion.

[0069] In one embodiment, the compound of formula I, where A is a halide and X - A method for preparing pridopidine using as an intermediate a compound represented by formula I, where A is a halide and X is an anion, is provided. In another embodiment, the halide is bromide, chloride, fluoride, or iodide. In another embodiment, A is bromide. In one embodiment, a compound represented by formula I, where A is a halide and X is an anion, is provided. -A method for preparing pridopidine using compound I as an intermediate is provided, comprising reacting compound I with a SMe moiety (which is further oxidized to SOMe) or a SOMe moiety, followed by reduction of the pyridinium ring to obtain pridopidine. In one embodiment, compound I of formula I, where A is a halide and X is an anion, is provided. - is an anion) as an intermediate to prepare pridopidine, comprising reducing the pyridinium ring and then reacting a halogenated group with an SMe moiety (which is further oxidized to SO2Me) or an 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, the present disclosure provides a method for preparing pridopidine as shown in Figure 4 and Example 1.

[0070] In one embodiment, the compound of formula I, where A is a nitro group and X - In one embodiment, a method for preparing pridopidine is provided using a compound represented by formula I, where A is a nitro group and X is an anion, as an intermediate. - is an anion) as an intermediate to prepare pridopidine, comprising reducing the pyridinium ring and nitro group to an amine and then converting the amine to an SMe group (which is further oxidized to SOMe) or to an SOMe group to obtain pridopidine. In another embodiment, the oxidation of SMe to SOMe is performed before or after the reduction of the pyridinium ring. In another embodiment, the present disclosure provides a method for preparing pridopidine as shown in FIG. 10 and Example 7.

[0071] In one embodiment, the compound of formula I, where A is a protected amine and X - In one embodiment, a method for preparing pridopidine is provided using a compound represented by formula I, where A is a protected amine and X is an anion, as an intermediate. -is an anion) as an intermediate to prepare pridopidine, comprising the steps of reducing the pyridinium ring, then removing the protecting group, and then converting the amine to a SMe group (which is further oxidized to SO2Me) or a SO2Me group to obtain pridopidine. In one embodiment, a compound I represented by formula I, where A is a protected amine and X - is an anion) as an intermediate to prepare pridopidine, comprising removing the protecting group and then converting the amine to an SMe group (which is further oxidized to SOMe) or to a SOMe group, followed by reduction of the pyridinium ring to obtain pridopidine. In another embodiment, the oxidation of SMe to SOMe is performed before or after reduction of the pyridinium ring. In another embodiment, the protecting group of the amine is Boc, Cbz, benzyl, Fmoc, or dibenzyl. In another embodiment, the present disclosure provides a method for preparing pridopidine as shown in FIG. 11 and Example 8.

[0072] In one embodiment, the present invention provides a method for producing pridopidine (4a), comprising the steps of: (a) reacting a compound IV represented by the following formula (IV) in the presence of a second palladium catalyst and a weak base:

[0073] [ka]

[0074] During the ceremony, R1 is H, propyl, or a protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0075] with 3-halothioanisole to obtain a compound V represented by the following formula (V) (wherein R1 is hydrogen or a protecting group):

[0076] [ka]

[0077] optionally reacting compound V with a propyl moiety when R1 of compound V is hydrogen (R1=H) to obtain a derivative of compound V (compound 4); optionally deprotecting the protecting group when R1 of compound V is a protecting group (R1=protecting group) and optionally reacting compound V with a propyl moiety to obtain a derivative of compound V (compound 4); (d) oxidizing compound V to obtain compound VI represented by the following formula (VI), wherein R1 is hydrogen or a protecting group:

[0078] [ka]

[0079] optionally reacting compound VI with a propyl moiety when R1 of compound VI is hydrogen (R1=H) to obtain a derivative of compound VI (compound 5); optionally deprotecting the protecting group when R1 of compound VI is a protecting group (R1=protecting group) and optionally reacting compound VI with a propyl moiety to obtain a derivative of compound VI (compound 5); (e) reducing compound VI to obtain pridopidine or compound VII represented by formula (VII) below, wherein R6 is H or a protecting group,

[0080] [ka]

[0081] and, if R6 of compound VII is hydrogen (R6=H), reacting compound VII with a propyl moiety to obtain pridopidine, and, if R6 of compound VII is a protecting group (R6=protecting group), optionally deprotecting the protecting group and optionally reacting compound VII with a propyl moiety to obtain pridopidine.

[0082] In one embodiment, the present invention provides a process for the preparation of pridopidine (4b), comprising the steps of: (a) reacting a compound VI represented by the following formula (VI) in the presence of a second palladium catalyst and a weak base:

[0083] [ka]

[0084] During the ceremony, R1 is H, propyl, or a protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0085] with 3-halothioanisole to obtain a compound VI represented by the following formula (VI) (wherein R1 is hydrogen or a protecting group):

[0086] [ka]

[0087] optionally reacting compound VI with a propyl moiety when R1 of compound VI is hydrogen (R1=H) to obtain the propyl derivative of compound VI (compound 5); and optionally deprotecting the protecting group when R1 of compound VI is a protecting group (R1=protecting group), and optionally reacting compound VI with a propyl moiety to obtain the propyl derivative of compound VI (compound 5); (b) reducing compound VI to obtain pridopidine or compound VII represented by the following formula (VII), wherein R6 is H or a protecting group:

[0088] [ka]

[0089] and if R6 of compound VII is hydrogen (R6=H), reacting compound VII with a propyl moiety to obtain pridopidine, and if R6 of compound VII is a protecting group (R6=protecting group), deprotecting the protecting group and reacting compound VII with a propyl moiety to obtain pridopidine.

[0090] In one embodiment, the present invention provides a process for the preparation of pridopidine (4c), comprising the steps of: (a) reacting a compound (10) represented by the following formula (10) in the presence of a second palladium catalyst and a weak base:

[0091] [ka]

[0092] and reacting with 3-halothioanisole to obtain compound 4 represented by formula (4):

[0093] [ka]

[0094] (d) oxidizing -SMe of compound 4 to -SOMe to obtain compound 5 represented by the following formula (5):

[0095] [ka]

[0096] (e) reducing compound 5 to obtain pridopidine.

[0097] In one embodiment, the present invention provides a process for the preparation of pridopidine (4d), comprising the steps of: (a) reacting a compound (10) represented by the following formula (10) in the presence of a second palladium catalyst and a weak base:

[0098] [ka]

[0099] and 1-halo-3-(methylsulfonyl)benzene to obtain compound 5 represented by formula (5):

[0100] [ka]

[0101] (b) reducing compound 5 to obtain pridopidine.

[0102] In one embodiment, the present invention provides a process for the preparation of pridopidine (4e), comprising the steps of: (a) reacting a compound IV represented by the following formula (IV) in the presence of a second palladium catalyst and a weak base:

[0103] [ka]

[0104] During the ceremony, R1 is H, propyl, or an amine protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0105] with 3-halothioanisole to obtain a compound V represented by the following formula (V) (wherein R1 is hydrogen or a protecting group):

[0106] [ka]

[0107] optionally reacting compound V with a propyl moiety when R1 of compound V is hydrogen (R1=H) to obtain a propyl derivative of compound V (compound 4); optionally deprotecting the protecting group when R1 of compound V is a protecting group (R1=protecting group) and optionally reacting compound V with a propyl moiety to obtain a derivative of compound V (compound 4); (c) reducing compound V to obtain compound XIV represented by the following formula (XIV) (wherein R1 is H or a protecting group),

[0108] [ka]

[0109] When R1 of compound XIV is hydrogen (R1=H), compound XIV is optionally reacted with a propyl moiety to obtain a propyl derivative of compound XIV, when R1 of compound XIV is a protecting group (R1=protecting group), the protecting group is optionally deprotected and compound XIV is optionally reacted with a propyl moiety to obtain a propyl derivative of compound XIV; (b) oxidizing compound XIV to obtain compound VII represented by formula (VII) below, wherein R6 is H or a protecting group,

[0110] [ka]

[0111] and if R6 of compound VII is hydrogen (R6=H), reacting compound VII with a propyl moiety to obtain pridopidine, and if R6 of compound VII is a protecting group (R6=protecting group), deprotecting the protecting group and reacting compound VII with a propyl moiety to obtain pridopidine.

[0112] In one embodiment, the present invention provides a process for the preparation of pridopidine (5a), comprising the steps of: (a) Compound IV represented by the following formula (IV) is obtained by Suzuki-Miyaura reaction:

[0113] [ka]

[0114] During the ceremony, R1 is H, propyl, or an amine protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0115] With a compound VIII represented by the following formula (VIII) (wherein X1 and X2 are each independently halo),

[0116] [ka]

[0117] Obtaining a compound IX represented by the following formula (IX) (wherein X1 is halo and R1 is H, propyl, or an amine protecting group),

[0118] [ka]

[0119] optionally reacting compound IX with a propyl moiety when R1 of compound IX is hydrogen (R1=H) to obtain a propyl derivative of compound IX, and optionally deprotecting said protecting group when R1 of compound IX is a protecting group (R1=protecting group) and optionally reacting compound IX with a propyl moiety to obtain a propyl derivative of compound IX; (b) reacting compound IX, where X1 is halo, with sodium methylsulfinate and copper(II) trifluoromethanesulfonate via Ullmann reaction using 1,2-diaminocyclohexane (mixture of cis and trans) as catalyst to obtain compound VI, a sulfone of formula (VI) below, where R1 is H or a protecting group:

[0120] [ka]

[0121] optionally reacting compound VI with a propyl moiety when R1 of compound VI is hydrogen (R1=H) to obtain the propyl derivative of compound VI (compound 5); optionally deprotecting the protecting group when R1 of compound VI is a protecting group (R1=protecting group) and optionally reacting compound VI with a propyl moiety to obtain the propyl derivative of compound VI (compound 5); (c) reducing compound VI to obtain pridopidine or compound VII represented by formula (VII) below, wherein R6 is H or a protecting group,

[0122] [ka]

[0123] When R6 of compound VII is hydrogen (R6=H), optionally reacting compound VII with a propyl moiety to obtain pridopidine, and when R1 of compound VII is a protecting group (R6=protecting group), optionally deprotecting the protecting group and optionally reacting compound VII with a propyl moiety to obtain pridopidine.

[0124] In one embodiment, the present invention provides a process for the preparation of pridopidine (5b), comprising the steps of: (a) Compound 10 represented by the following formula (10) is produced by the Suzuki-Miyaura reaction:

[0125] [ka]

[0126] With a compound VIII represented by the following formula (VIII) (wherein X1 and X2 are each independently halo),

[0127] [ka]

[0128] Obtaining a compound XVII represented by the following formula (XVII) (wherein X1 is halo);

[0129] [ka]

[0130] (b) reacting compound XVII, where X1 is halo, with sodium methylsulfinate and copper(II) trifluoromethanesulfonate via Ullmann reaction using 1,2-diaminocyclohexane (mixture of cis and trans) as catalyst to obtain compound V, sulfone, represented by formula (V):

[0131] [ka]

[0132] (c) reducing compound V to obtain pridopidine.

[0133] In one embodiment, the present invention provides a method (6a) for preparing a compound VI represented by the following formula (VI):

[0134] [ka]

[0135] During the ceremony, R1 is H, propyl, or an amine protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0136] (a) A compound X represented by the following formula (X):

[0137] [ka]

[0138] reacting with a strong base followed by further reaction with a trifluoro moiety to obtain a compound XI represented by formula (XI) below, wherein R1 is hydrogen or a protecting group:

[0139] [ka]

[0140] if R1 of compound XI is hydrogen (R1=H), optionally reacting compound XI with a propyl moiety to obtain a propyl derivative of compound XI, if R1 of compound XI is a protecting group (R1=protecting group), optionally deprotecting the protecting group, and optionally reacting compound XI with a propyl moiety to obtain a propyl derivative of compound XI; (b) reacting compound XI with diborane, a mild base, and a second palladium catalyst to obtain compound IV represented by formula (IV) below, wherein R6 is H or a protecting group:

[0141] [ka]

[0142] When R1 of compound IV is hydrogen (R1=H), optionally reacting compound IV with a propyl moiety to obtain a propyl derivative of compound IV, and when R1 of compound IV is a protecting group (R1=protecting group), optionally deprotecting the protecting group and optionally reacting compound IV with a propyl moiety to obtain a propyl derivative of compound IV.

[0143] In one embodiment, the present invention provides a method (6b) for producing compound 10 represented by the following formula (10):

[0144] [ka]

[0145] (a) A compound X represented by the following formula (X):

[0146] [ka]

[0147] reacting with a strong base followed by further reaction with a trifluoro moiety to obtain a compound XI represented by formula (XI) below, wherein R1 is hydrogen or a protecting group:

[0148] [ka]

[0149] if R1 of compound XI is hydrogen (R1=H), optionally reacting compound XI with a propyl moiety to obtain a propyl derivative of compound XI, if R1 of compound XI is a protecting group (R1=protecting group), optionally deprotecting the protecting group, and optionally reacting compound XI with a propyl moiety to obtain a propyl derivative of compound XI; (b) reacting compound XI with diborane, a mild base, and a second palladium catalyst to obtain compound 10 or compound XII represented by the following formula (XII) (wherein R6 is H or a protecting group):

[0150] [ka]

[0151] and optionally reacting compound XII with a propyl moiety to obtain compound 10 when R6 of compound XII is hydrogen (R6=H), and optionally deprotecting the protecting group when R6 of compound XII is a protecting group (R6=protecting group), and optionally reacting compound XII with a propyl moiety to obtain compound 10.

[0152] In one embodiment, the present invention provides a method for preparing pridopidine (7a), comprising the steps of: (a) A compound XIII represented by the following formula (XIII) (wherein R1 is H, propyl, or a protecting group)

[0153] [ka]

[0154] reacting with a strong base to obtain a compound XIV represented by the following formula (XIV) (wherein R1 is hydrogen or a protecting group):

[0155] [ka]

[0156] optionally reacting compound XIV with a propyl moiety when R1 of compound XIV is hydrogen (R1=H) to obtain a propyl derivative of compound XIV, and optionally deprotecting the protecting group when R1 of compound XIV is a protecting group (R1=protecting group) and optionally reacting compound XIV with a propyl moiety to obtain a propyl derivative of compound XIV; (c) oxidizing compound XIV to obtain pridopidine or compound XV represented by the following formula (XV), wherein R6 is hydrogen or a protecting group:

[0157] [ka]

[0158] When R6 of compound XV is hydrogen (R6=H), optionally reacting compound XV with a propyl moiety to obtain pridopidine, and when R6 of compound XV is a protecting group (R6=protecting group), deprotecting the protecting group and reacting compound XV with a propyl moiety to obtain pridopidine.

[0159] In another embodiment, the present invention provides a process for the preparation of pridopidine (7a), comprising the steps of: (a) Compound 9 represented by the following formula (9):

[0160] [ka]

[0161] reacting with a strong base to obtain compound 7 represented by formula (7) below;

[0162] [ka]

[0163] (c) oxidizing compound 7 to obtain pridopidine.

[0164] In one embodiment, the present invention provides a method (8a) for preparing a compound XIII represented by the following formula (XIII), in which R1 is H, propyl, or a protecting group:

[0165] [ka]

[0166] reacting 2-(3-(methylthio)phenyl)acetonitrile with a compound XVI represented by the following formula (XVI) (wherein R1 is H, propyl, or a protecting group) in the presence of a strong base to obtain a compound XIII,

[0167] [ka]

[0168] and optionally reacting compound XIII with a propyl moiety when R1 of compound XIII is hydrogen (R1=H) to obtain a propyl derivative of compound XIII, and when R1 of compound XIII is a protecting group (R1=protecting group), deprotecting the protecting group and reacting with a propyl moiety to obtain a propyl derivative of compound XIII.

[0169] In one embodiment, the present invention provides a method for producing a compound 9 represented by the following formula (9):

[0170] [ka]

[0171] The method includes reacting 2-(3-(methylthio)phenyl)acetonitrile with compound 11 (wherein Pr is propyl) represented by formula (11) below in the presence of a strong base to obtain compound 9.

[0172] [ka]

[0173] In some embodiments, according to the present disclosure, Compound I, Compound 1, Compound 2, and / or Compound 3 are provided comprising an anion X - In one embodiment, the anion is a halide, such as mesylate, tosylate, hydroxyl, and sulfonate. 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 - ).

[0174] In some embodiments, the present disclosure provides a method for producing pridopidine via an intermediate compound of compound I. The disclosed method for producing pridopidine uses commercially available, relatively inexpensive (low-cost) starting materials and a solid pyridinium salt that can be easily isolated, and includes three major steps.

[0175] In some embodiments, the disclosed method of preparation 1 comprises reducing the pyridinium ring of compound I, where A is SMe or SO2Me, to obtain compound 7 or pridopidine. In another embodiment, reducing the pyridinium ring comprises reacting compound I with PtO2 and H2 (gas).

[0176] In some embodiments, the disclosed manufacturing methods include an oxidation step in which -SMe groups are oxidized to -SO2Me groups (see, e.g., manufacturing methods 1, 2, 4a, 4c, 4e, 7a, and 7b, and Figures 2, 7, 8, 9, 10, 11, and 12). In one embodiment, the oxidation step includes reaction with an oxidizing agent. In another embodiment, the oxidizing agent includes a tungsten-catalyzed oxidizing agent. In another embodiment, the oxidizing agent includes a tungsten-catalyzed oxidizing agent and a peroxide. In another embodiment, the oxidation step includes reaction with a peroxide. In another embodiment, the oxidation step includes reaction with a peroxide and Na2WO4. In another embodiment, the oxidation step includes reaction with a tungsten-catalyzed oxidizing agent in the presence of a peroxide oxidizing agent at a pH below 2. In another embodiment, the oxidation step includes reaction with a tungsten-catalyzed oxidizing agent in the presence of a peroxide oxidizing agent at a temperature range of 40°C to 60°C. In another embodiment, the tungsten-catalyzed oxidizing agent is sodium tungstate. In another embodiment, the peroxide is sodium peroxide.

[0177] In some embodiments, the preparation methods of the present disclosure include a step of partial reduction of the pyridinium ring to provide an alkene piperidine ring, as shown below (see, e.g., Preparation 2 and Figures 2, 4, 6, and 9).

[0178] [ka]

[0179] In another embodiment, the step of reducing the pyridinium ring comprises reacting compound I with a hydrogen source. In another embodiment, the hydrogen source used to reduce the pyridinium ring is sodium borohydride, sodium cyanoborohydride, sodium borohydride triacetoxide, or H2 (gas).

[0180] In some embodiments, the preparation methods of the present disclosure include a reduction step in which an alkene piperidine ring is reduced to a saturated piperidine ring, as shown below, where the double bond is reduced to give the piperidine ring (see, e.g., Preparations 2, 4a, 4b, 4c, 4d, and 4e, and Figures 2, 4, 6, 9, and 13).

[0181] [ka]

[0182] In one embodiment, the reduction step comprises reducing the double bond to give a piperidine ring by reaction with a hydrogen source. In another embodiment, the reduction step comprises reducing the double bond to give a piperidine ring by reaction with a hydrogen source and a catalyst. In another embodiment, the reduction step of reducing the double bond to give a piperidine ring is catalytic hydrogenation in an aqueous solution containing an alcohol in the presence of a hydrogen source and a second palladium, platinum, or rhodium catalyst. In another embodiment, non-limiting examples of alcohols include methanol, ethanol, propanol, isopropanol, and the like. In another embodiment, the second palladium catalyst is 10% palladium on carbon, 5% palladium on carbon, or 5% palladium on alumina.

[0183] In another embodiment, the rhodium catalyst is 5% rhodium on carbon, hi another embodiment, the platinum catalyst is platinum dioxide.

[0184] In another embodiment, the hydrogen source used in the reduction step of the disclosed methods 2, 4a, 4b, 4c, 4d, and 4e, or of Figures 2, 4, 6, 9, and 13, includes hydrogen gas, formic acid, or formate salts. Each is a separate embodiment of the present invention. In another embodiment, the hydrogen source used in the reduction step is ammonium formate. In another embodiment, the reduction step is performed using H2 or Pd(OH)2 / C.

[0185] In some embodiments, the disclosed method 3 comprises reacting compound II with pyridin-4-ylboronic acid in the presence of a first palladium catalyst to obtain compound 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).

[0186] In some embodiments, the disclosed methods of preparation 3, 4a, 4b, 4c, 4d, and 4e include steps for preparing Compound III, Compound V, Compound VI, Compound 4, and Compound 5, and use a weak base. In another embodiment, the weak base includes potassium phosphate, sodium bicarbonate, potassium carbonate, pyridine, or any combination thereof. Each is a separate embodiment of the present invention.

[0187] In another embodiment, the weak base used in method 3 for producing compound III comprises sodium ethoxide, cesium carbonate, or any combination thereof. In another embodiment, the weak base used in method 3 for producing compound III comprises potassium carbonate, potassium phosphate, sodium bicarbonate, sodium ethoxide, cesium carbonate, or any combination thereof.

[0188] In some embodiments, the manufacturing methods of the present disclosure use a "propyl moiety" (see, e.g., manufacturing methods 3, 4a, 4b, 4e, 7a, and 8a, and Figures 7-11). In other embodiments, the "propyl moiety" refers to a propyl group substituted with a propionaldehyde or a leaving group. In another embodiment, the "propyl moiety" refers to a propyl group substituted with 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, when the propyl moiety is propionaldehyde, the reaction is carried out by "reductive amination" and a reducing agent is added.

[0189] In another embodiment, the reducing agent is selected from a hydrogen source, hi another embodiment, the hydrogen source comprises NaCNBH3, NaBH4, NaBH(OAc)3, or H2 (gas).

[0190] In some embodiments, the disclosed manufacturing methods for producing Compound V, Compound VI, Compound 4, Compound 5, Compound 10, Compound IV, and Compound XII use a second palladium catalyst (see, for example, Manufacturing Methods 4a, 4b, 4c, 4d, 4e, 6a, and 6b). In another embodiment, the second palladium catalyst comprises 1,1'bis(diphenylphosphino)fersen-palladium dichloride, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Pd XPhos G2), or tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3))4.

[0191] In some embodiments, the manufacturing method of the present disclosure uses a "deprotection step" (see, for example, manufacturing methods 4a, 4b, 5a, 6a, 6b, 7a, and 8a, or when deprotecting a protected amine in compound I). The deprotection step refers to the deprotection of a protecting group. In one embodiment, the deprotection step is carried out under acidic conditions, basic conditions, or by catalytic hydrogenation, depending on the protecting group. In another embodiment, the deprotection of a Boc group is carried out using trifluoroacetic acid, methanesulfonic acid, trimethylsilyl chloride, or hydrochloric acid. In another embodiment, the deprotection of an Fmoc group is carried out using a base such as ammonia, piperidine, or morpholine. In another embodiment, the deprotection of a benzyl group is carried out by catalytic hydrogenation. In another embodiment, the deprotection step comprises known procedures for removing protecting groups, as described in detail, for example, in "Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999," which is incorporated herein by reference in its entirety.

[0192] In some embodiments, preparation methods 4a, 4c, and 4e of the present disclosure include a step for preparing compound V using a 3-halothioanisole. In another embodiment, the 3-halothioanisole comprises 3-bromothioanisole, 3-chlorothioanisole, or 3-iodothioanisole. Each is a separate embodiment of the present invention.

[0193] In some embodiments, methods 6a and 6b for preparing compound IV and compound XII include the use of a medium base. In another embodiment, the medium 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 medium base is potassium acetate. In another embodiment, the medium base is pyridine.

[0194] In another embodiment, the medium base of methods 6a and 6b for preparing compound IV and compound XII comprises a weak base as described herein.

[0195] In some embodiments, processes 6a, 6b, 7a, 7b, 8a, and 8b of the present disclosure use a strong base to prepare compound XI, compound XIV, compound XIII, compound 7, and compound 9. Each is a separate embodiment of the present invention. In one embodiment, the strong base comprises sodium hydroxide, lithium bis(trimethylsilyl)amide, potassium hydroxide, sodium amide, or any combination thereof. Each is a separate embodiment of the present invention.

[0196] In some embodiments, the disclosed process 4b uses 1-halo-3-(methylsulfonyl)benzene to obtain compound VI from compound IV. In other embodiments, the 1-halo-3-(methylsulfonyl)benzene comprises 1-bromo-3-(methylsulfonyl)benzene, 1-chloro-3-(methylsulfonyl)benzene, or 1-iodo-3-(methylsulfonyl)benzene.

[0197] In some embodiments, the disclosed methods of preparation 6a and 6b use diborane to prepare compound IV and compound XII. In another embodiment, the diborane is bis(catecholato)diborane, bis(neopentylglycolato)diborane, 2,2'-bi-1,3,2,-dioxaborinane, bis(hexenyleneglycolato)dibis(diethyl-D-tartrate glycolato)diborane, bis(N,N,N',N'-tetramethyl-L-tartrate amido glycolato)diborane, or bis(pinacolato)diborane. In another embodiment, the diborane is bis(pinacolato)diborane. Each is a separate embodiment of the present invention.

[0198] In some embodiments, preparation methods 6a and 6d of the present disclosure use a trifluoro moiety to prepare compound XI. In another embodiment, the trifluoro moiety is 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethylsulfonic anhydride, or trimethylsilyltrifluoromethanesulfonate.

[0199] In some embodiments, R of Compound IV, Compound V, Compound VI, Compound IX, Compound X, Compound XI, Compound XIII, Compound XIV, or Compound XVI is propyl. Each is a separate embodiment of the present invention.

[0200] In some embodiments, R1 of Compound IV, Compound V, Compound VI, Compound IX, Compound X, Compound XI, Compound XIII, Compound XIV, or Compound XVI is hydrogen. Each is a separate embodiment of the present invention. In some embodiments, R1 of Compound IV, Compound V, Compound VI, Compound IX, Compound X, Compound XI, Compound XIII, Compound XIV, or Compound XVI is a protecting group. Each is a separate embodiment of the present invention.

[0201] In some embodiments, R6 of Compound VII, Compound XII, or Compound XV is hydrogen. In other embodiments, R6 of Compound VII, Compound XII, or Compound XV is a protecting group.

[0202] In some embodiments, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI comprises a t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl), Bn (benzyl), Bz (benzoyl), Ts (tosyl), or carbamate group, each of which is a separate embodiment of the present invention. In another embodiment, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI is benzyl, each of which is a separate embodiment of the present invention. In another embodiment, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI is t-Boc, each of which is a separate embodiment of the present invention. In another embodiment, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI is Fmoc, each of which is a separate embodiment of the present invention. In another embodiment, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI is Cbz, each of which is a separate embodiment of the present invention. In another embodiment, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI is Tosyl, each of which is a separate embodiment of the present invention.In another embodiment, the protecting group of Compound IV, Compound V, Compound VI, Compound VII, Compound IX, Compound X, Compound XI, Compound XII, Compound XIII, Compound XIV, Compound XV, or Compound XVI includes any amine protecting group known in the art, such as those described in detail in, for example, "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.

[0203] In some embodiments, R2 of compound IV is an alkyl group. In some embodiments, R3 of compound IV is an alkyl group. In one embodiment, R2 and R3 of compound IV are combined to form a 5-8 membered ring, which is optionally substituted. In another embodiment, R2 and R3 of compound IV are combined to form a 5-8 membered ring, which includes OBO as shown below, which is optionally substituted.

[0204] [ka]

[0205] In another embodiment, R2 and R3 of compound IV are combined to 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 compound IV are combined to form a substituted or unsubstituted 5-8 membered ring, which includes, in addition to the OBO atom, N (nitrogen), O (oxygen), or both. In another embodiment, the N in the ring is optionally selected from R A In another embodiment, R2 and R3 of compound IV are combined to form a substituted or unsubstituted fused 5-8 membered ring that contains, in addition to the OBO atom, N (nitrogen), O (oxygen), or both. In another embodiment, the N in the fused ring is optionally substituted with R A In another embodiment, R Ais alkyl, heteroalkyl, aryl, heteroaryl, alkoxy, or acyl, each of which is a separate embodiment of the present invention. In another embodiment, the substituents are one or more groups selected from the group consisting of alkyl, ester, amido, halogen, hydroxy, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxamido, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, and alkylsulfonyl groups, each of which is a separate embodiment of the present invention. Any of the substituents may be unsubstituted or further substituted with any of the above substituents.

[0206] In another embodiment, R2 and R3 of compound IV combine to form a 5-membered ring substituted with 1-4 methyl groups. In another embodiment, R2 and R3 of compound IV combine to form a pinacol boronic ester. Non-limiting examples of R2 and R3 forming a ring containing OBO are shown below.

[0207] [ka]

[0208] In some embodiments, X1 of compound II is a halide. In another embodiment, X1 of compound II is Br. In another embodiment, X1 of compound II is I. In another embodiment, X1 of compound II is Cl. In another embodiment, X1 of compound II is F.

[0209] In some embodiments, X1 of the compound VIII, compound IX, or compound XVII is a halide. In another embodiment, X1 of the compound VIII, compound IX, or compound XVII is Br. In another embodiment, X1 of the compound VIII, compound IX, or compound XVII is I. In another embodiment, X1 of the compound VIII, compound IX, or compound XVII is Cl. In another embodiment, X1 of the compound VIII, compound IX, or compound XVII is F.

[0210] In some embodiments, X2 in compound VIII is a halide. In another embodiment, X2 in compound VIII is Br. In another embodiment, X2 in compound VIII is I. In another embodiment, X2 in compound VIII is Cl. In another embodiment, X2 in compound VIII is F.

[0211] As used herein, the term "alkyl," used alone or as part of another group, refers to a straight or branched chain alkyl group having up to about 24 carbon atoms, unless otherwise specified. In one embodiment, an alkyl has 1-3 carbon atoms. In one embodiment, an alkyl has 1-4 carbon atoms. In one embodiment, an alkyl has 1-5 carbon atoms. In one embodiment, an alkyl has 1-6 carbon atoms. In one embodiment, an alkyl has 1-8 carbon atoms. In one embodiment, an alkyl has 1-10 carbon atoms. In one embodiment, an alkyl has 1-12 carbon atoms. In another embodiment, a branched alkyl is an alkyl substituted with an alkyl side chain having 1-5 carbon atoms. In one embodiment, an alkyl group can be unsubstituted. In another embodiment, an alkyl group is substituted with halogen, haloalkyl, hydroxyl, alkoxy, carbonyl, amido, alkylamido, dialkylamido, cyano, nitro, CO2H, amino, alkylamino, dialkylamino, carboxyl, thio, and / or thioalkyl.

[0212] As used herein, the term "aryl" used alone or as part of another group refers to an aromatic ring system having 5 to 14 ring carbon atoms. The aryl ring can be monocyclic, bicyclic, tricyclic, etc. Non-limiting examples of aryl groups include phenyl and naphthyl (e.g., 1-naphthyl, 2-naphthyl), etc. The aryl group can be unsubstituted or substituted through available carbon atoms with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxamido, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, and alkylsulfonyl groups. The optional substituents may be unsubstituted or further substituted with any of the above substituents.

[0213] 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, etc.

[0214] The term "SMe moiety" refers to alkali salts of SMe, such as Me-S-Na, Me-SK, Me-S-Li, etc.

[0215] The term "SO2Me moiety" refers to SO2-alkali salts such as S(O)(ONa)Me, S(O)(OLi)Me, S(O)(OK)Me, etc. In some embodiments, Ph-Br is converted to Ph-SO2Me by a Cu-catalyzed Ullmann reaction.

[0216] The term "pharmaceutically acceptable salt" refers to a salt selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, perphosphate, sulfate, bisulfate, formate, gluconate, glucuronate, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, gentisate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, acid tartrate, toluene-p-sulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid) salts). Each represents a separate embodiment of the present invention. In another embodiment, pridopidine is in the form of HCl (hydrochloric acid).

[0217] In one embodiment, the present invention provides a compound I represented by formula (I):

[0218] [ka]

[0219] During the ceremony, A is a halide, a nitro group, a protected amine, SOMe, or SMe; X - is an anion.

[0220] In one embodiment, the present invention provides a compound I represented by formula I:

[0221] [ka]

[0222] During the ceremony, A is SO2Me or SMe.

[0223] In one embodiment, the present invention provides compound 1 having the formula:

[0224] [ka]

[0225] During the ceremony, X - is an anion.

[0226] In one embodiment, the present invention provides compound 2 having the formula:

[0227] [ka]

[0228] During the ceremony, X - is an anion.

[0229] In one embodiment, the present invention provides compound 3 having the formula:

[0230] [ka]

[0231] During the ceremony, X - is an anion.

[0232] In one embodiment, the present invention provides a compound IV represented by formula IV:

[0233] [ka]

[0234] During the ceremony, R1 is H, propyl, or an amine protecting group; R2 and R3 are each independently an alkyl group or together form a 5- to 8-membered ring, which is optionally substituted.

[0235] In one embodiment, the present invention provides compound 10 having the formula:

[0236] [ka]

[0237] In one embodiment, the present invention provides a compound XIII represented by formula (XIII):

[0238] [ka]

[0239] During the ceremony, R1 is H, propyl, or an amine protecting group.

[0240] In one embodiment, the present invention provides compound 9 having the formula:

[0241] [ka]

[0242] In some embodiments, the present invention provides a method for producing pridopidine using at least one of compounds 1, 2, 9, 10, I, IV, or XIII.

[0243] The following non-limiting examples are presented to more fully illustrate certain embodiments of the present invention. However, they should not be interpreted as limiting the broad scope of the present disclosure in any way. Those skilled in the art can easily devise various variations and modifications of the principles disclosed herein without departing from the scope of the present invention.

[0244] Working Example

[0245] Example 1: Method for producing pridopidine

[0246] [ka]

[0247] 4-(3-Bromophenyl)pyridine

[0248] 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 equiv, 61.0 mmol), PdCl2(dppf) (1.49 g, 0.05 equiv, 2.03 mmol) and Na2CO3 (12.9 g, 61.0 mL, 2 mol, 3 equiv, 122 mmol) were dissolved in 1,2-dimethoxyethane (125 mL) and degassed with N2 for 15 min before heating at 85 °C for 3 h. EtOAc (400 mL) and water (200 mL) were added. The reaction mixture was filtered over a bed of celite and the phases were separated. The organic phase was washed with water (2 x 200 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica; heptane / EtOAc). Fraction 1 (tubes 67-95) was concentrated under reduced pressure to give 4-(3-bromophenyl)pyridine (5.31 g, 22.7 mmol, 55.8%).

[0249] [ka]

[0250] 4-(3-bromophenyl)-1-propylpyridin-1-ium iodide

[0251] 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 at 85° C. overnight. Volatiles were removed under reduced pressure to give 4-(3-bromophenyl)-1-propylpyridin-1-ium iodide (260 mg, 643 μmol, yield=quantitative).

[0252] [ka]

[0253] 4-(3-bromophenyl)-1-propylpiperidine

[0254] PtO2 (33.2 mg, 0.17 equiv., 146 μmol) was added to a brown clear solution of 4-(3-bromophenyl)-1-propylpyridin-1-ium iodide (348 mg, 861 μmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under 5 bar hydrogen pressure for 2 nights. The material was diluted with MeOH and filtered over a pad of Celite. The filter cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure to give 276 mg (HI salt). The material was dissolved in EtOAc (20 mL) and saturated NaHCO3 solution (20 mL). The layers were separated and the organic layer was washed with saturated NaHCO3 solution (20 mL). The combined aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 190 mg (free base). This material was purified by column chromatography (silica; 0-5% 7N NH3 in MeOH in DCM). Fraction 1 (tubes 8-25) was concentrated to give 4-(3-bromophenyl)-1-propylpiperidine (164 mg, 581 μmol, yield=67.5%).

[0255] [ka]

[0256] Pridopidine via 4-(3-bromophenyl)-1-propylpiperidine (8)

[0257] A mixture of 4-(3-bromophenyl)-1-propylpiperidine (164 mg, 581 μmol), sodium methanesulfinate (89.0 mg, 1.5 equiv, 872 μmol), copper(II) trifluoromethanesulfonate (21.0 mg, 0.1 equiv, 58.1 μmol), and 1,2-diaminocyclohexane (mixture of cis and trans) (26.5 mg, 28.3 μL, 0.4 equiv, 232 μmol) in DMSO (3 mL) was deoxygenated, purged with nitrogen, and then stirred at 190 °C for 6 h. 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 under reduced pressure. The crude product was purified by column chromatography (silica; 0-10% MeOH in DCM). Fraction 1 (tubes 15-20) was concentrated under reduced pressure to give 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (25 mg, 89 μmol, yield=15%).

[0258] Example 2: Method for producing pridopidine (Figure 5)

[0259] [ka]

[0260] To a solution of 3-bromophenylmethylsulfone (3.0 g, 12.76 mmol, 1.0 equiv.) in 1,4-dioxane (60 mL) and water (6 mL), pyridine-4-boronic acid (11.88 g, 15.31 mmol, 1.2 equiv.) and Cs2CO3 (12.47 g, 38.28 mmol, 3.0 equiv.) were added and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (740 mg, 0.64 mmol, 0.05 equiv.) was added and the mixture was stirred at 80° C. overnight. The mixture was then cooled to room temperature, filtered through a pad of Celite®, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM and washed with water (3 times), after which the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:acetone 100:0->80:20). This gave 3.03 g (yield=quantitative) of 4-(3-methanesulfonylphenyl)pyridine as a brown oil (LCMS purity 99%). LCMS (ESI): 12 H 11 Exact mass of NO2S: 233.29; [M+H] + =233.60 was detected.

[0261] 1 H 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).

[0262] [ka]

[0263] 4-(3-Methanesulfonylphenyl)pyridine (560 mg, 2.43 mmol, 1.0 equiv) was dissolved in ACN (10 mL) and placed in an ice-cooled bath. 1-Iodopropane (474 ​​μL, 4.86 mmol, 2.0 equiv) was added and the reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was refluxed with EtOAc (10 mL) for 1 h, cooled to room temperature, washed with EtOAc and dried under reduced pressure. This afforded 800 mg (yield=81%) of 4-(3-methanesulfonylphenyl)-1-propylpyridine iodide as a brown solid (LCMS purity 100%). LCMS (ESI): C 15 H 18 Exact mass of NO2S: 276.37; [M+H] + =276.60 was detected.

[0264] 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).

[0265] [ka]

[0266] To a solution of 4-(3-methanesulfonylphenyl)-1-propylpyridine iodide (800 mg, 1.98 mmol, 1.0 equiv) in methanol (20.0 mL) was added PtO2 (90 mg, 0.4 mmol, 0.2 equiv) under a gentle argon flow and the reaction mixture was degassed by vacuum and filled with hydrogen three times. It was then stirred overnight under hydrogen atmosphere (balloon). After completion of the reaction, the mixture was filtered through a pad of Celite® 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 min. The phases were separated and the aqueous phase was washed with DCM (2 times). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. This gave 635 mg (yield=quantitative) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (LCMS purity 100%). The resulting material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281. [M+H] + =281.65 was detected.

[0267] [ka]

[0268] A solution of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (558 mg, 1.98 mmol, 1.0 equiv) was dissolved in iPrOH (6.0 mL) followed by dropwise addition of 6N HCl in iPrOH (400 μL, 2.38 mmol, 1.2 equiv). The reaction mixture was stirred at 80° C. for 2 h and at room temperature overnight. The precipitate was filtered, washed with iPrOH and then dried under reduced pressure. This gave 492 mg (yield=88%) of 4-(3-methylsulfonylphenyl)pyridine hydrochloride as a pale yellow solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] + = 281.65 was detected. HPLC purity: 99.89% (268 nm).

[0269] 1 H NMR (300MHz, methanol-d4) δ7.88-7.79(m,2H),7.69-7.55(m,2H),3.74-3.63(m,2H) ,33.20-2.98(m,8H),2.24-1.94(m,4H),1.90-1.71(m,2H),1.02(t,J=7.4Hz,3H).

[0270] Example 3: Method for producing pridopidine (Figure 6)

[0271] Compound 2 was prepared according to Example 2.

[0272] [ka]

[0273] A solution of 4-(3-methanesulfonylphenyl)-1-propylpyridine iodide (1.0 g, 3.62 mmol, 1.0 equiv) in methanol (10.0 mL) and water (20.0 mL) was placed in an ice-cooled bath. NaBH4 (821 mg, 21.71 mmol, 6 equiv) was added and the reaction mixture was left at room temperature for 2 h. The mixture was then quenched with 1N HCl solution and extracted with DCM (3 times). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. This gave 726 mg (yield=66%) of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (LCMS purity 93%). The material obtained was used directly in the next step. LCMS (ESI): C 15 H 21 Exact mass of NO2S: 279.40; [M+H] + =279.60 was detected.

[0274] 1H NMR(300MHz,DMSO-d6)δ7.92-7.89(m,1H),7.80(d,J=1.7Hz,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).

[0275] [ka]

[0276] To a solution of 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (616 mg, 2.20 mmol, 1.0 equiv) in methanol (30.0 mL) was added Pd(OH)2 / C (20% wt. loading, 50% wet, 62 mg, 0.4 mmol, 0.2 equiv) under a gentle argon flow and the reaction mixture was degassed by vacuum and filled with hydrogen three times. It was then stirred overnight under hydrogen atmosphere (balloon). The mixture was then filtered through a pad of Celite® 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 min. The phases were separated and the aqueous phase was extracted with DCM (2 times). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. This gave 548 mg (yield=88%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (LCMS purity 100%). The resulting material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =281.65 was detected.

[0277] 1H 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).

[0278] [ka]

[0279] A solution of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (548 mg, 1.94 mmol, 1.0 equiv) was dissolved in iPrOH (6.0 mL) followed by dropwise addition of 6N HCl in iPrOH (653 μL, 3.89 mmol, 2 equiv). The reaction mixture was stirred at 80° C. for 2 h and at room temperature overnight. The precipitate was filtered, washed with iPrOH and dried under reduced pressure. This gave 170 mg (yield=30%) of 4-(3-methylsulfonylphenyl)pyridine hydrochloride as a pale yellow solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =281.65 was detected.

[0280] HPLC purity: 99.89% (@268nm).

[0281] 1 H NMR (300MHz, methanol-d4) δ7.95-7.81(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=7.4Hz, 3H).

[0282] Example 4: Method for producing pridopidine (Figure 7)

[0283] [ka]

[0284] To a solution of 1-bromo-3-(methylsulfanyl)benzene (5.0 g, 24.61 mmol, 1.0 equiv.) in 1,4-dioxane (200 mL) and water (20 mL), pyridine-4-boron (3.93 g, 32.00 mmol, 1.3 equiv.) and Cs2CO3 (24.06 g, 73.85 mmol, 3.0 equiv.) were added and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (2.84 g, 2.46 mmol, 0.1 equiv.) was added and the mixture was stirred at 80° C. overnight. The mixture was then cooled to room temperature, filtered through a pad of Celite®, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM and washed with water (3 times), after which the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:acetone 100:0->80:20). This gave 3.0 g (yield=48%) of 4-[3-(methylsulfanyl)phenyl]pyridine as a brown oil (LCMS purity 96%). LCMS (ESI): 12 H 11 Exact mass of NS: 201.29; [M+H] + =202.05 was detected.

[0285] 1 H 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).

[0286] [ka]

[0287] A solution of 4-[3-(methylsulfanyl)phenyl]pyridine (3.0 g, 14.9 mmol, 1.0 equiv) in ACN (60 mL) was 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 at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (3 times). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was refluxed with EtOAc (10 mL) for 1 h, cooled to room temperature, washed with EtOAc and dried under reduced pressure. This afforded 5.0 g (yield=86%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide as a brown solid (LCMS purity 95%). LCMS (ESI): C 15 H 18 Exact mass of NS: 244.12; [M] + =243.80 was detected.

[0288] 1 H NMR(300MHz,DMSO-d6)δ9.16-9.06(m,2H),8.61-8.51(m,2H),7.91-7.77(m,2H),7.62-7.4 8(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).

[0289] [ka]

[0290] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide (1.0 g, 4.09 mmol, 1.0 equiv) in methanol (50 mL) was added PtO2 (186 mg, 0.81 mmol, 0.2 equiv) under a gentle argon stream, and the reaction mixture was degassed by evacuating and backfilling with hydrogen three times, then stirred under a hydrogen atmosphere (balloon) at 40 °C for 7 days.

[0291] The mixture was then filtered through a pad of Celite® and the solvent 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 min. 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 product was purified by flash column chromatography (ACN:water 40:60). This gave 292 mg (yield=25%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (LCMS purity 90%). LCMS (ESI): C 15 H 23 Exact mass of NS: 249.16; [M+H] + =250.10 was detected.

[0292] 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).

[0293] [ka]

[0294] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (292 mg, 1.17 mmol, 1.0 equiv) in water (14.6 mL) was added 96% sulfuric acid (770 μL, 14.48 mmol, 12.37 equiv), followed by sodium tungstate dihydrate (27 mg, 0.08 mmol, 0.07 equiv) and 30% H2O2 (90 μL, 2.92 mmol, 2.50 equiv). The reaction mixture was stirred at 55° C. for 2 h, then cooled to 10° C., and toluene (50 mL) was added, followed by NaOH solution. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure. This gave 124 mg (yield=30%) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine as a brown solid (LCMS purity 62%). The material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =282.10 was detected.

[0295] [ka]

[0296] A solution of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (124 mg, 0.44 mmol, 1.0 equiv) was dissolved in iPrOH (3.0 mL) followed by dropwise addition of 6N HCl in iPrOH (147 μL, 0.88 mmol, 1.2 equiv). The reaction mixture was stirred at 80° C. for 2 h and at room temperature overnight. The precipitate was filtered, washed with iPrOH and dried under reduced pressure. This gave 13 mg (yield=9%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a pale yellow solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =281.65 was detected.

[0297] HPLC purity: 97.06% (@268nm).

[0298] 1 H NMR (300MHz, methanol-d4) δ7.92-7.83(m,2H),7.72-7.58(m,2H),3.75-3.61(m,2H) ,33.20-3.01(m,8H),2.25-1.93(m,4H),1.88-1.77(m,2H),1.06(t,J=7.4Hz,3H).

[0299] Example 5: Method for producing pridopidine (Figure 8)

[0300] Compound 1 was prepared according to Example 4 (Steps 1 and 2 of FIG. 7).

[0301] [ka]

[0302] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide (1.0 g, 4.09 mmol, 1.0 equiv) in water (50 mL) was added 96% sulfuric acid (2.69 mL, 50.61 mmol, 12.37 equiv), followed by sodium tungstate dihydrate (94 mg, 0.286 mmol, 0.07 equiv) and 30% H2O2 (313 μL, 10.23 mmol, 2.50 equiv). The reaction mixture was stirred at 55° C. for 2 h, then cooled to 10° C. and toluene (50 mL) was added followed by NaOH solution. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried over sodium sulfate, filtered and evaporated. This gave 630 mg (yield=50%) of 4-(3-methylsulfonylphenyl)-1-propylpyridin-1-ium hydroxide as a yellow oil (LCMS purity 96%). LCMS (ESI): 15 H 18 Exact mass of NO2S: 276.11; [M+H] + =277.35

[0303] 1H 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).

[0304] [ka]

[0305] To a solution of 4-(3-methanesulfonylphenyl)-1-propylpyridin-1-ium hydroxide (630 mg, 2.15 mmol, 1.0 equiv) in methanol (31 mL) was added PtO2 (117 mg, 0.516 mmol, 0.2 equiv) under a gentle argon flow and the reaction mixture was degassed by vacuum and filled with hydrogen three times. It was then stirred under hydrogen atmosphere overnight. The mixture was then filtered through a pad of Celite® 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 min. The phases were separated and the aqueous phase was washed with DCM (2 times). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. This gave 512 mg (85% yield) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine (100% LCMS purity). The resulting material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =282.10 was detected.

[0306] [ka]

[0307] A solution of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (512 mg, 1.81 mmol, 1.0 equiv) was dissolved in iPrOH (5.0 mL) and 6N HCl in iPrOH was added dropwise (606 μL, 3.63 mmol, 2.0 equiv). The reaction mixture was stirred at 80° C. for 2 h and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and dried under reduced pressure. This gave 50 mg (9% yield) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a pale yellow solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =281.65 was detected.

[0308] HPLC purity: 92.58% (@268nm).

[0309] 1 H NMR (300MHz, methanol-d4) δ7.92-7.81(m,2H),7.74-7.57(m,2H),3.78-3.61(m,2H) ,33.22-3.01(m,8H),2.25-1.97(m,4H),1.92-1.76(m,2H),1.06(t,J=7.4Hz,3H).

[0310] Example 6: Method for producing pridopidine (Figure 9)

[0311] Compound 1 was prepared according to Example 4 (Steps 1 and 2 of FIG. 7).

[0312] [ka]

[0313] 4-[3-(Methylsulfanyl)phenyl]-1-propylpyridin-1-ium iodide (800 mg, 3.27 mmol, 1.0 equiv) 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 equiv) was added and the reaction mixture was left at room temperature for 2 h. The mixture was then quenched with 1N HCl solution and extracted with DCM (3 times). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography (DCM:MeOH, 9:1). This gave 240 mg (yield=28%) of 4-[3-(Methylsulfanyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (LCMS purity 95%). LCMS (ESI): 15 H 21 Exact mass of NS: 247.14; [M+H] + =248.05 was detected.

[0314] 1 H NMR(300MHz,DMSO-d6)δ7.39-7.18(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=7.4Hz,3H). * 2H overlaps with DMSO.

[0315] [ka]

[0316] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (240 mg, 0.97 mmol, 1.0 equiv) in water (12.0 mL) was added 96% sulfuric acid (1.17 mL, 12.0 mmol, 12.37 equiv), followed by sodium tungstate dihydrate (22 mg, 0.068 mmol, 0.07 equiv) and 30% H2O2 (74 μL, 10.23 mmol, 2.42 equiv). The reaction mixture was stirred at 55° C. for 2 h, then cooled to 10° C., and toluene (50 mL) was added, followed by aqueous NaOH. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. This gave 162 mg (yield=58%) of 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine as a yellow oil (LCMS purity 97%). LCMS (ESI): 15 H 21 Exact mass of NO2S: 279.13; [M+H] + =280.05 was found.

[0317] 1 H NMR(300MHz,DMSO-d6)δ7.95-7.87(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=7.4Hz,3H). * 2H overlaps with DMSO.

[0318] [ka]

[0319] To a solution of 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (162 mg, 0.580 mmol, 1.0 equiv) in methanol (8 mL) was added d(OH)2 / C (20% wt. loading, 50% wet, 16 mg, 0.012 mmol, 0.02 equiv) under a gentle argon flow and the reaction mixture was degassed by vacuum and backfilled with hydrogen three times. It was then stirred overnight under hydrogen atmosphere (balloon). After completion of the reaction, the mixture was filtered through a pad of Celite® 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 min. The phases were separated and the aqueous phase was washed with DCM (2 times). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 88 mg (54% yield) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine (LCMS purity 100%). The resulting material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): 15 H 23 Exact mass of NO2S: 281.14. [M+H] + =282.10 was detected.

[0320] [ka]

[0321] A solution of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (88 mg, 0.313 mmol, 1.0 equiv) was dissolved in iPrOH (4 mL) and 6N HCl was added dropwise (114 μL, 0.62 mmol, 2.0 equiv). The reaction mixture was stirred at 80° C. for 2 h and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and dried under reduced pressure. This gave 43 mg (yield=48%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a pale yellow solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] +=281.65 was detected.

[0322] HPLC purity: 95.37% (@268nm).

[0323] 1 H NMR (300MHz, methanol-d4) δ7.92-7.83(m,2H),7.70-7.58(m,2H),3.78-3.66(m,2H) ,33.22-3.02(m,8H),2.25-1.94(m,4H),1.91-1.74(m,2H),1.06(t,J=7.3Hz,3H).

[0324] Example 7: Method for producing pridopidine (Figure 10)

[0325] [ka]

[0326] To a solution of 1-bromo-3-nitrobenzene (2.0 g, 9.90 mmol, 1.0 equiv) in 1,4-dioxane (40 mL) and water (4 mL) were added pyridine-4-boronic acid (1.58 g, 12.87 mmol, 1.3 equiv) and Cs2CO3 (9.68 g, 29.70 mmol, 3.0 equiv) and the reaction mixture was purged with argon for 15 min. Then Pd(PPh3)4 (1.14 g, 0.99 mmol, 0.1 equiv) was added and the mixture was stirred at 80° C. overnight. After cooling to room temperature, it was filtered through a pad of Celite®, washed with DCM and concentrated under reduced pressure. The residue was dissolved in DCM and washed with water (3 times) and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM:MeOH 100:0->90:10). This gave 1.4 g (yield=72%) of 4-(3-nitrophenyl)pyridine as a brown solid (LCMS purity 100%). LCMS (ESI): 11 Exact mass of H8N2O2: 200.2; [M+H] + =201.0 was detected.

[0327] 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).

[0328] [ka]

[0329] 4-(3-Nitrophenyl)pyridine (1.3 g, 6.49 mmol, 1.0 equiv) was dissolved in ACN (26 mL) and the solution was placed in an ice-cooled bath. 1-Iodopropane (1.27 mL, 12.99 mmol, 2.0 equiv) was added dropwise and the reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was refluxed with EtOAc (30 mL) for 1 h, cooled to room temperature, washed with EtOAc and dried under reduced pressure. This afforded 4-(3-nitrophenyl)-1-propylpyridin-1-ium iodide, 2.16 g (yield=89%) as a yellow solid (LCMS purity 100%). LCMS (ESI): C 14 H 15 Exact mass of N2O2: 243.29; [M] + =242.85 was detected.

[0330] 1 H NMR (300MHz, methanol-d4) δ9.15-9.08(m,2H),8.90-8.84(m,1H),8.58-8.50(m,3H),8.46-8.38(m ,1H),7.93(t,J=8.1Hz,1H),4.67(t,J=7.4Hz,2H),2.13(h,J=7.4Hz,2H),1.08(t,J=7.4Hz,3H).

[0331] [ka]

[0332] To a solution of 4-(3-nitrophenyl)-1-propylpyridin-1-ium iodide (1.0 g, 2.70 mmol, 1.0 equiv.) in methanol (40.0 mL) was added PtO2 (307 mg, 1.35 mmol, 0.5 equiv.) under a gentle argon flow and the reaction mixture was degassed by vacuum and filled with hydrogen three times. It was then stirred overnight under hydrogen atmosphere (balloon). After completion of the reaction, the mixture was filtered through a pad of Celite® 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 min. The phases were separated and the aqueous phase was washed with DCM (2 times). The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol, 4N HCl in dioxane was added and the solution was evaporated under reduced pressure. This gave 1.05 g (yield=quantitative) of 3-(1-propylpiperidin-4-yl)aniline dihydrochloride (LCMS purity 100%). LCMS (ESI): 14 H 22 Exact mass of N2: 218.34; [M+H] + =219.10 was detected.

[0333] 1 H NMR (300MHz, methanol-d4) δ7.04(t,J=7.7Hz,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=7.4Hz,3H).

[0334] [ka]

[0335] 3-(1-Propylpiperidin-4-yl)aniline dihydrochloride (445 mg, 1.53 mmol, 1.0 equiv) was dissolved in glacial acetic acid (13 mL) and the solution was cooled to 0° C. in an ice bath. A solution (7 mL) of O-benzenesulfonimide (536 mg, 2.45 mmol, 1.2 equiv) in glacial AcOH (7 mL) was added to glacial acetic acid over 10 min, keeping the temperature below 5° C. The reaction mixture was stirred at 0° C. for 10 min, after which isoamyl nitrite (302 μL, 2.24 mmol, 1.1 equiv) was added dropwise over 10 min. The solution was stirred at 0° C. for 20 min and the compound was precipitated as an orange solid by addition of diethyl ether, filtered, washed with diethyl ether, and dried under vacuum at room temperature. 3-(1-Propylpiperidin-4-yl)benzene-1-diazonium O-benzenesulfonimide (914 mg, 2.04 mmol, 1.0 equiv) was added in one portion to a solution of sodium methyl mercaptan (160 mg, 2.28 mmol, 1.12 equiv) in methanol (20 mL) at 0° C. The reaction mixture was stirred below 5° C. for 1 h, then quenched with water (50 mL) and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH 100:0 to >85:15) followed by pTLC (CHCl3:iPrOH, 9:1). This gave 161 mg (yield=30%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine as a yellow solid (LCMS purity 71%). LCMS (ESI): C 15 H 23 Exact mass of NS: 249.42; [M] + =250.10 detected.

[0336] 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).

[0337] [ka]

[0338] 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% sulfuric acid (370 μL, 6.94 mmol, 12.37 equiv), followed by sodium tungstate dihydrate (13 mg, 0.04 mmol, 0.07 equiv) and 30% aqueous hydrogen peroxide (144 μL, 1.40 mmol, 2.50 equiv). The reaction mixture was stirred at 55° C. for 2 h, then cooled to 10° C., and toluene (50 mL) was added, followed by NaOH solution. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by pTLC (DCM:MeOH=9:1). This gave 27 mg (yield=17%) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine as a yellow solid (LCMS purity 56%). The material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =282.00 was detected.

[0339] [ka]

[0340] 4-(3-Methanesulfonylphenyl)-1-propylpiperidine (26 mg, 0.09 mmol, 1.0 equiv) was dissolved in iPrOH (300 μL) and heated to 70° C., followed by the addition of 6N HCl in iPrOH (19 μL, 0.11 mmol, 1.2 equiv). The mixture was heated to 80° C. and stirred for 10 min. It was then cooled to 65° C. and pure 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride was added and cooled to room temperature to precipitate the product. The white solid was filtered, washed with iPrOH and dried under reduced pressure. This gave 11 mg (yield=37%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a white solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =282.05 was detected.

[0341] HPLC purity: 99.32% (@268nm)

[0342] 1 H NMR (300MHz, methanol-d4) δ7.92-7.84(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=7.4Hz, 3H).

[0343] Example 8: Method for producing pridopidine (Figure 11)

[0344] [ka]

[0345] To a solution of tert-butyl N-(3-bromophenyl)carbamate (3.5 g, 12.86 mmol, 1.0 equiv.) in 1,4-dioxane (140 mL) and water (14 mL), pyridine-4-boronic acid (2.05 g, 16.71 mmol, 1.2 equiv.) and Cs2CO3 (12.57 g, 38.58 mmol, 3.0 equiv.) were added and the reaction mixture was purged with argon for 15 min. Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.1 equiv.) was added and the mixture was stirred at 80° C. overnight. The mixture was then cooled to room temperature, filtered through a pad of Celite®, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM and washed with water (3 times), after which the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH 100:0->85:15). This gave 3.1 g (yield=quantitative) of tert-butyl N-[3-(pyridin-4-yl)phenyl]carbamate as a brown solid (LCMS purity 100%). LCMS (ESI): 16 H 18 Exact mass of N2O2: 270.14; [M+H] + =270.60 was detected.

[0346] 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).

[0347] [ka]

[0348] tert-Butyl N-[3-(pyridin-4-yl)phenyl]carbamate (3.0 g, 11.08 mmol, 1.0 equiv) was dissolved in ACN (60 mL) and the solution was placed in an ice-cooled bath. 1-Iodopropane (4.32 mL, 44.39 mmol, 4.0 equiv) was added dropwise and the reaction mixture was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was refluxed with EtOAc (10 mL) for 1 h, cooled to room temperature, washed with EtOAc and dried under reduced pressure. This afforded 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridin-1-ium iodide, 3.5 g (yield=72%) as a yellow solid (LCMS purity 100%). LCMS(ESI):C 19 H 25 Exact mass of N2O2: 313.19; [M+H] + =313.9 was detected.

[0349] 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).

[0350] [ka]

[0351] To a solution of 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridin-1-ium iodide (1.0 g, 2.27 mmol, 1.0 equiv) in methanol (50 mL) was added PtO2 (362 mg, 1.59 mmol, 0.7 equiv) under a gentle argon flow and the reaction mixture was degassed under vacuum and backfilled with hydrogen three times. It was then stirred overnight at 40 °C under a hydrogen atmosphere (balloon). After completion of the reaction, the mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure. This afforded 1.1 g (yield = quantitative) of tert-butyl N-[3-(1-propylpiperidin-4-yl)phenyl]carbamate (LCMS purity 100%). LCMS (ESI): C 19 H 30 Exact mass of N2O2: 318.23; [M+H] + =319.15 was detected.

[0352] 1 H NMR (300MHz, methanol-d4) δ7.43(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=7.3Hz,3H).

[0353] [ka]

[0354] A solution of 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridin-1-ium iodide (1.0 g, 2.27 mmol, 1.0 equiv) in methanol (10 mL) and water (20 mL) was placed in an ice-cooled bath. NaBH4 (724 mg, 19.14 mmol, 8.4 equiv) was added and the reaction mixture was left for 2 h. The mixture was then quenched with 1N HCl solution and extracted with DCM (3 times). The organic phases were combined, dried over sodium sulfate, filtered and evaporated. This gave 815 mg (yield = quantitative) of tert-butyl N-[3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]carbamate (LCMS purity 91%). The material obtained was used directly in the next step. LCMS (ESI): C 19 H 28 Exact mass of N2O2: 316.22; [M+H] + =316.65 was detected.

[0355] 1 H NMR (300MHz, methanol-d4) δ7.60(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=7.4Hz,3H).

[0356] [ka]

[0357] 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 equiv) in methanol (80 mL) was added 10% Pd / C (60-65% wet, 229 mg, 1.13 mmol, 0.35 equiv) under a gentle argon flow and the reaction mixture was degassed under vacuum and backfilled with hydrogen (3 times). It was then stirred overnight at 40° C. under a hydrogen atmosphere (balloon). After completion of the reaction, the mixture was filtered through a pad of Celite® and the solvent was removed under reduced pressure. This gave 470 mg (yield=45%) of tert-butyl N-[3-(1-propylpiperidin-4-yl)phenyl]carbamate (LCMS purity 100%). LCMS (ESI):C 19 H 30 Exact mass of N2O2: 318.23; [M+H] + =319.15 was detected.

[0358] 1 H NMR (300MHz, methanol-d4) δ7.44(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=7.4Hz,3H).

[0359] [ka]

[0360] (470 mg, 1.47 mmol, 1.0 equiv) was dissolved in dioxane (36 mL). 4N HCl in dioxane (10.4 mL, 43.71 mmol, 29.7 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The solution was concentrated under reduced pressure. This gave 416 mg (yield=97%) of 3-(1-propylpiperidin-4-yl)aniline dihydrochloride as a brown solid (LCMS purity 100%). LCMS (ESI): C 14 H22 Exact mass of N2: 218.18; [M+H] + =218.75 was detected.

[0361] 1 H NMR (300MHz, methanol-d4) δ7.53(t,J=7.8Hz,1H),7.49-7.41(m,1H),7.39-7.34(m,1H),7.33-7.27(m,1 H),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=7.4Hz,3H).

[0362] [ka]

[0363] 3-(1-Propylpiperidin-4-yl)aniline dihydrochloride (445 mg, 1.53 mmol, 1.0 equiv) was dissolved in glacial acetic acid (13 mL) and the solution was cooled to 0° C. in an ice bath. A solution (7 mL) of O-benzenesulfonimide (536 mg, 2.45 mmol, 1.2 equiv) was added to glacial acetic acid over 10 min, keeping the temperature below 5° C. The reaction mixture was stirred at 0° C. for 10 min, after which isoamyl nitrite (302 μL, 2.24 mmol, 1.1 equiv) was added dropwise over 10 min. The solution was stirred at 0° C. for 20 min and the compound was precipitated as an orange solid by addition of diethyl ether, filtered, washed with diethyl ether, and dried under vacuum at room temperature. 3-(1-Propylpiperidin-4-yl)benzene-1-diazonium O-benzenesulfonimide (914 mg, 2.04 mmol, 1.0 equiv) was added in one portion to a solution of sodium methyl mercaptan (160 mg, 2.28 mmol, 1.12 equiv) in MeOH (20 mL) at 0° C. The reaction mixture was stirred below 5° C. for 1 h, then quenched with water (50 mL) and extracted with DCM (3 times). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH 100:0->85:15) followed by pTLC (CHCl3:iPrOH, 9:1). This gave 161 mg (30% yield) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine as a yellow solid (LCMS purity 71%). LCMS (ESI): C 15 H 23 Exact mass of NS: 249.42; [M] + =250.10 was detected.

[0364] 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 .302.16(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).

[0365] [ka]

[0366] 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% sulfuric acid (370 μL, 6.94 mmol, 12.37 equiv), followed by sodium tungstate dihydrate (13 mg, 0.04 mmol, 0.07 equiv) and 30% aqueous H2O2 (144 μL, 1.40 mmol, 2.50 equiv). The reaction mixture was stirred at 55° C. for 2 h, then cooled to 10° C., and toluene (50 mL) was added, followed by aqueous NaOH. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by pTLC (DCM:MeOH 9:1). This gave 27 mg (Y=17%) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine as a yellow solid (LCMS purity 56%). The material obtained was purified in the next step during hydrochloride salt formation. LCMS (ESI): 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =282.00 was detected.

[0367] Example 9: Method for producing pridopidine (Figure 12)

[0368] [ka]

[0369] To a solution of (3-methylsulfanylphenyl)acetonitrile (2.0 g, 12.3 mmol, 1.0 equiv) in DMSO (16 mL) was added sodium hydride (60% dispersion, mineral oil, 1.47 g, 36.8 mmol, 3.0 equiv) in portions. The resulting suspension was stirred at room temperature for 30 min. N,N-bis(2-chloroethyl)propan-1-amine hydrochloride (2.97 g, 13.5 mmol, 1.1 equiv) was then added slowly over 5 min and the suspension was heated at 65° C. for 1 h. The reaction was then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with water (5×), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This gave 3.44 g (yield=94%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine-4-carbonitrile as a brown oil (LCMS purity 92%). LCMS (ESI): 16 H 22 Exact mass of N2S: 274.15; [M+H] + =275.05 was found.

[0370] 1 H NMR (300MHz, methanol-d4) δ7.47-7.41(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).

[0371] [ka]

[0372] To a solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine-4-carbonitrile (2.9 g, 10.6 mmol, 1.0 equiv) in DMSO (58 mL) was added potassium hydroxide (5.93 g, 105.7 mmol, 10.0 equiv) 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 (3×). The combined extracts were washed with water (5×), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (DCM:DCM / MeOH=9:1 +1% NH3). This afforded 223 mg (yield=8%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine as a brown solid (LCMS purity 98%). LCMS (ESI): C 15 H 23 Exact mass of NS: 249.16; [M+H] + =250.10 was detected.

[0373] 1 H NMR (300MHz, methanol-d4) δ7.23-7.15(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=7.4Hz,3H).

[0374] Note: During process optimization, the reaction was successfully carried out on a 50 mg scale, giving 41 mg (yield=91%) of product with LCMS purity of 80%.

[0375] [ka]

[0376] 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% sulfuric acid (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. The mixture was then cooled to 10° C. and toluene was added followed by NaOH solution until the pH was about 12. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried over sodium sulfate and evaporated under reduced pressure. This gave 192 mg (yield=85%) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine as a brown oil (LCMS purity 92%). The material was purified in the next step to produce the hydrochloride salt. LCMS (ESI): 15 H 23 Exact mass of NO2S: 281.14; [M+H] + =282.05 was detected.

[0377] [ka]

[0378] 4-(3-Methanesulfonylphenyl)-1-propylpiperidine (192 mg, 0.68 mmol, 1.0 equiv) was dissolved in iPrOH (2.1 mL) and heated to 70° C., after which 6N HCl (136 μL, 0.82 mmol, 1.2 equiv) was added in iPrOH. The mixture was heated to 80° C. and stirred for 10 min. It was then cooled to 65° C. and pure crystals of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride were added and cooled to room temperature. Upon cooling the solution a white precipitate was formed, which was washed with iPrOH and dried. This gave 73 mg (yield=34%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a white solid (LCMS purity 100%). LCMS (ESI): C 15 H 23Exact mass of NO2S: 281.14; [M+H] + =282.10 was detected.

[0379] HPLC purity: 94.40% (@268nm)

[0380] 1 H NMR (300MHz, methanol-d4) δ8.00-7.90(m,2H),7.62-7.53(m,2H),3.78-3.66(m,2H) ,33.23-3.00(m, 8H), 2.23-1.95(m, 4H), 1.94-1.75(m, 2H), 1.06(t, J=7.4Hz, 3H).

[0381] Example 10: Method for producing pridopidine (Figure 13)

[0382] [ka]

[0383] 1-Propyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonic acid

[0384] A brown clear solution of 1-propylpiperidin-4-one (506 mg, 3.58 mmol) in THF (2.5 mL) was cooled to -75 °C. LiHMDS (779 mg, 4.66 mL, 1 M, 1.3 equiv, 4.66 mmol) was added dropwise while maintaining the temperature below -70 °C. The reaction mixture was stirred at -75 °C for 30 min. NFSI (1.41 g, 1.1 equiv, 3.94 mmol) was added in portions. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (5 mL). The reaction mixture was cooled in an ice bath. Saturated NH4Cl solution (5 mL) was added dropwise. The phases were separated and the organic phase was washed with NH4Cl solution (5 mL) and water (5 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 1.84 g. This material was purified by column chromatography (silica; 0-3% 7N NH3 in MeOH in DCM). Fraction 3 (tubes 37-43) was concentrated under reduced pressure to give 1-propyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (626 mg, 2.29 mmol, yield=63.9%) as a pale yellow oil.

[0385] [ka]

[0386] 1-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (Compound 10)

[0387] 1-Propyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (1.95 g, 7.14 mmol), KOAc (2.10 g, 3 equiv, 21.4 mmol), and B2Pin2 (2.17 g, 1.2 equiv, 8.56 mmol) were dissolved in 1,4-dioxane (22 mL) and stirred at room temperature. PdCl2(dppf) (261 mg, 0.05 equiv, 357 μmol) was added and the reaction mixture was degassed with nitrogen for 15 min. The reaction mixture was then heated at 80° C. for 2.5 h. The reaction mixture was filtered over a layer of Celite. The filter cake was washed with 1,4-dioxane. The combined filtrates were concentrated under reduced pressure to give the crude product 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%, purity 36% based on HQ NMR), which was used as is without further purification.

[0388] [ka]

[0389] 4-(3-Bromophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (Compound 6)

[0390] 1-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (615 mg, 36% Wt, 881 μmol) was dissolved in 1,2-dimethoxyethane (10 mL). 1,3-Dibromobenzene (1.04 g, 533 μL, 5 eq, 4.41 mmol) was added followed by Na2CO3 (280 mg, 1.32 mL, 2 mol, 3 eq, 2.64 mmol) and PdCl2(dppf) (32.2 mg, 0.05 eq, 44.1 μmol). The reaction mixture was degassed with nitrogen for 15 min and stirred at 80° C. for 3 h. EtOAc (100 mL) and water (50 mL) were added. The mixture was filtered over a bed of Celite. The phases were separated and the organic phase was washed with water (2 x 50 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give 1 g of crude product. This crude product was purified by column chromatography (silica; 0-3% 7N NH3 in MeOH in DCM). Fraction 3 (tubes 21-34) was concentrated under reduced pressure to give 4-(3-bromophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (95 mg, 0.34 mmol, yield = 38%).

[0391] Chemical reactions to convert the alkene bromo intermediate to pridopidine similar to those described above in Example 1. The double bond of compound 6 is first reduced to give compound 8, which is further converted to pridopidine.

[0392] Example 11: Method for producing pridopidine

[0393] [ka]

[0394] The boronic 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 as described in step 5 of Example 6 to give pridopidine.

[0395] Step 1: Suzuki coupling

[0396] To a solution of 1-bromo-3-(methylsulfonyl)benzene (0.415 g, 1.76 mmol, 1.0 equiv.) in 1,4-dioxane (5 mL) and water (1 mL), N-propyl-2H-pyridine-4-boronic acid pinacol ester (0.53 g, 2.11 mmol, 1.2 equiv.) and potassium acetate (0.52 g, 5.28 mmol, 3.0 equiv.) were added and the reaction mixture was purged with argon for 15 min. Pd(dppf)Cl2 (66 mg, 0.09 mmol, 0.05 equiv.) was added and the mixture was stirred at 80° C. overnight. The mixture was then cooled to room temperature, filtered through a pad of Celite®, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM and washed with water (3 times), after which the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was followed by purification by chromatography to give 0.18 g (yield=37%) of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine as an oil. LCMS (ESI): 15 H 21 Exact mass of NO2S: 279.13; [M+H] + =280.05 was found.

[0397] Step 2: Reduction with formic acid

[0398] To a cold solution of 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (1 g, 3.58 mmol, 1 equiv.) in water (2.5 vol.) was added formic acid (0.264 g, 5.73 mmol, 1.6 equiv.) and 0.1% (w / w) 10% Pd / C. The reaction was heated at 30° C. for 4-5 h. The mixture was filtered to remove the catalyst, the filtrate was added to toluene, and the mixture was basified with 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. The toluene was distilled off under reduced pressure and the residue was added to 4 volumes of n-heptane to form a slurry and cooled to 0° C. The solid material formed was collected by filtration and dried in vacuum at 40° C. This gave 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (yield=85%).

[0399] While certain features of the invention have been illustrated and described herein, various modifications, substitutions, changes, and equivalents will occur to those skilled in the art, and it is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit and scope of the invention.

Claims

1. Compound I represented by the following formula (I): During the ceremony, A is -SMe or -SO ２ Me, X － is an anion.

2. 2. The compound of claim 1 , Compound 1 represented by the following formula (1).

3. 2. The compound of claim 1 , A compound represented by the following formula (2):

4. A method for producing pridopidine, comprising the steps of: A method for producing pridopidine via the intermediate compound according to any one of claims 1 to 3.

5. 5. The method of claim 4, The pyridinium ring of compound 1 is reduced, and then -SMe is replaced with -SO ２ to Me to obtain pridopidine.

6. 5. The method of claim 4, In the compound 1, -SMe is replaced with -SO ２ Me and then reducing the pyridinium ring to give pridopidine.

7. 5. The method of claim 4, reducing the pyridinium ring of compound 2 to give pridopidine.

8. A method for producing pridopidine, comprising the steps of: By reducing the pyridinium group of compound I represented by the following formula (I), In the formula, A is -SMe or -SO ２ Me and X － is an anion. Obtaining compound 7 or pridopidine represented by the following formula (7): In the compound 7, -SMe is replaced with -SO ２ and C. oxidizing to Me to obtain pridopidine.

9. The method according to any one of claims 5 to 8, The reduction of the pyridinium ring is carried out by using PtO ２ and H ２ (gas).

10. A method for producing pridopidine, comprising the steps of: By reducing the pyridinium group of compound I represented by the following formula (I), In the formula, A is -SMe or -SO ２ Me and X － is an anion. Obtaining a compound 4 represented by the following formula (4) or a compound 5 represented by the following formula (5); reducing the double bond of compound 5 to give pridopidine, or replacing -SMe of compound 4 with -SO ２ After the double bond of compound 4 is reduced, -SMe is oxidized to -SO ２ and C. oxidizing to Me to obtain pridopidine.

11. 11. The method of claim 10, The reducing agent for reducing the pyridinium ring of compound I to obtain compound 4 or compound 5 is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or H ２ (gas).

12. 11. The method of claim 10, The step of reducing the double bond of compound 4 or compound 5 to obtain a piperidine ring comprises reacting a hydrogen source with a catalyst; The method, wherein the catalyst comprises a second palladium catalyst, a platinum catalyst, or a ruthenium catalyst.

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

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

15. 11. The method of claim 8 or 10, -SMe-SO ２ The process wherein the oxidation to Me comprises reaction with a tungsten-catalyzed oxidant, a peroxide, or a combination thereof.

16. 16. The method of claim 15, The method of claim 1, wherein the tungsten catalytic oxidant is sodium tungstate.

17. 16. The method of claim 15, The method according to claim 1, wherein the peroxide is sodium peroxide.

18. A method for producing compound I represented by the following formula (I): In the formula, A is -SMe or -SO ２ Me and X － is an anion. (a) reacting a compound II represented by the following formula (II) with a palladium catalyst and a weak base in the presence of the compound II: In the formula, A is -SMe or -SO ２ Me and X １ is a halide. Pyridine-4-boronic acid represented by the following formula: to obtain a compound III represented by formula (III): (b) reacting said compound III with a propyl moiety to obtain compound I.

19. 20. The method of claim 18, The method of claim 1, wherein the weak base comprises potassium carbonate, potassium phosphate, sodium bicarbonate, sodium ethoxide, cesium carbonate, or any combination thereof.

20. 20. The method of claim 18, 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 C ２ ), or [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(Cl ２ ) dppf).

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

22. A method for producing pridopidine using an intermediate compound I represented by the following formula (I): In the formula, A is -SMe or -SO ２ Me and X － is an anion. The compound I is prepared according to the method of any one of claims 18 to 21.

22. A method for producing pridopidine according to any one of claims 4 to 17, comprising the steps of: The compound I is prepared according to the method of any one of claims 18 to 21.

Images