Method and intermediate for producing pridopidine

Abstract

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

Description

[Technical Field]

[0001] This invention relates to a method and intermediates for producing pridopidine. [Background technology]

[0002] Pridopidine, or 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, is a potent sigma-1 receptor (S1R) agonist currently in clinical development as a treatment for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Recent data, including in vivo PET imaging and in vitro binding assays in rats, have shown that pridopidine acts primarily via the sigma-1 receptor (S1R). Pridopidine has been shown to have 100 to 500 times higher binding affinity to 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 primarily located in the mitochondrial association membrane (MAM), and it regulates various cellular processes such as calcium signaling, ion channel regulation, and 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 (nerve cell) 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 its pharmaceutically acceptable salts are disclosed in Patent Documents 1 to 3.

[0005] This invention relates to a method and intermediates for producing pridopidine. [Prior art documents] [Patent Documents]

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

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

[0008] [ka]

[0009] In some embodiments, the present invention provides a method for producing from compound I described above a pridopidine represented by the following formula, namely 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, or a pharmaceutically acceptable salt thereof.

[0010] [ka]

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

[0012] [ka]

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

[0014] [ka] [Brief explanation of the drawing]

[0015] The subject matter considered to be the invention is specifically pointed out and explicitly asserted in the concluding section of this specification. However, the present invention, with respect to both its structure and method of operation, as well as its purpose, features, and advantages, will be best understood by reading the following detailed description with reference to the accompanying drawings.

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

[0017] For the sake of simplification and clarity, please understand that the elements shown are not necessarily drawn to a consistent scale. For example, the dimensions of some elements may be exaggerated compared to others for clarity. Furthermore, where appropriate, reference numbers are repeatedly used across drawings to indicate corresponding or similar elements. [Modes for carrying out the invention]

[0018] The following detailed description includes numerous specific details to provide a complete understanding of the invention. However, it will be understood by those skilled in the art that the invention may be carried out without using these specific details. In other examples, well-known methods, procedures, and components are not described in detail so as not to obscure the invention.

[0019] In some embodiments, the present invention relates to a method for producing a pridopidine represented by the following formula, namely 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, or a pharmaceutically acceptable salt thereof,

[0020] [ka]

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

[0022] [ka]

[0023] During the ceremony, A is a halide, nitro group, protective amine, -SMe, or -SO2Me. X - It is an anion.

[0024] In some embodiments, the present invention relates to a method for producing a pridopidine represented by the following formula, namely 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, or a pharmaceutically acceptable salt thereof,

[0025] [ka]

[0026] The present invention provides a method comprising the step of using 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 either alkyl groups independently or cooperate to form a 5-8 membered ring. This 5-8 membered ring can be optionally substituted.

[0029] In some embodiments, the present invention relates to a method for producing a pridopidine represented by the following formula, namely 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine, or a pharmaceutically acceptable salt thereof,

[0030] [ka]

[0031] The present invention provides a method comprising the step of using 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 is a method for producing pridopidine (1), The pyridinium ring of compound I, represented by the following formula (I), is reduced.

[0035] [ka]

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

[0037] The steps include obtaining compound 7 represented by the following formula (7) or pridopidine,

[0038] [ka]

[0039] The present invention provides a method comprising the step of oxidizing -SMe of compound 7 to -SO2Me to obtain pridopidine.

[0040] In one embodiment, the present invention is a method for producing pridopidine (1A), When compound I, represented by the following formula (I), is oxidized,

[0041] [ka]

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

[0043] The present invention provides a method comprising 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 is a method for producing pridopidine (2), The pyridinium ring of compound I, represented by the following formula (I), is reduced.

[0046] [ka]

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

[0048] The steps include obtaining compound 4 represented by the following formula (4) or compound 5 represented by the following formula (5),

[0049] [ka]

[0050] [ka]

[0051] The present invention provides a method comprising the steps of: reducing the double bond of compound 5 to obtain pridopidine; oxidizing -SMe of compound 4 to -SO2Me, then reducing the double bond to obtain pridopidine; or reducing the double bond of compound 4, then oxidizing -SMe to -SO2Me to obtain pridopidine.

[0052] In another embodiment, pridopidine is prepared as described in Example 3 and Figure 6.

[0053] In another embodiment, pridopidine is prepared as described in Example 4 and Figure 7.

[0054] In one embodiment, the present invention provides a method for producing compound I represented by formula (I) (3),

[0055] [ka]

[0056] During the ceremony, A is a halide, nitro group, protective amine, -SMe, or -SO2Me. X - It is an anion.

[0057] (a) Compound II represented by the following formula (II) in the presence of a palladium catalyst and a weak base,

[0058] [ka]

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

[0060] [ka]

[0061] The steps include reacting with to obtain compound III represented by the following formula (III) (wherein A is a halide, a nitro group, a protective amine, -SMe, or -SO2Me),

[0062] [ka]

[0063] (b) A method is provided that includes reacting compound III with a propyl moiety to obtain compound I.

[0064] In another embodiment, compound I represented by formula (I) is produced as described in FIG. 3.

[0065] In another embodiment, compound I represented by formula (I) is produced as described in FIG. 4 when A is a bromide.

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

[0067] [Chemical formula]

[0068] ​​​​​​​​​​​​​​​A method for producing a pridopidine using an anion (wherein A is an anion) as an intermediate is provided, comprising the steps of reacting compound I with an SMe moiety (which is further oxidized to SO2Me) or an SO2Me moiety, and then reducing the pyridinium ring to obtain a pridopidine. In one embodiment, compound I represented by formula I (wherein A is a halide and X is an anion) is provided, comprising the steps of reacting compound I with an SMe moiety (which is further oxidized to SO2Me) or an SO2Me moiety, and then reducing the pyridinium ring to obtain a pridopidine. - A method for producing a pridopidine using an anion as an intermediate is provided, comprising the steps of reducing a pyridinium ring and then reacting the halogenated group with an SMe moiety (which is further oxidized to SO2Me) or an SO2Me moiety to obtain a 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 producing a pridopidine as shown in Figure 4 and Example 1.

[0070] In one embodiment, compound I represented by formula I (wherein A is a nitro group, X - A method is provided for producing pridopidine using an anion as an intermediate. In one embodiment, compound I represented by formula I (wherein A is a nitro group and X) is provided. - A method for producing pridopidine using an anion as an intermediate is provided, comprising the steps of reducing the pyridinium ring and nitro group to an amine, and then converting the amine to an SMe group (which is further oxidized to SO2Me) or an SO2Me group to obtain pridopidine. In another embodiment, the oxidation of SMe to SO2Me is performed before or after the reduction of the pyridinium ring. In another embodiment, according to the present disclosure, a method for producing pridopidine is provided as shown in Figure 10 and Example 7.

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

[0072] In one embodiment, the present invention is a method for producing pridopidine (4a), (a) In the presence of a second palladium catalyst and a weak base, compound IV represented by the following formula (IV) is prepared.

[0073] [ka]

[0074] During the ceremony, R1 is H, propyl, or a protecting group. R2 and R3 are either alkyl groups independently or cooperate to form a 5-8 membered ring. This 5-8 membered ring can be optionally substituted.

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

[0076] [ka]

[0077] If R1 of compound V is hydrogen (R1=H), compound V is optionally reacted with the propyl moiety to obtain a derivative of compound V (compound 4). If R1 of compound V is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound V is optionally reacted with the propyl moiety to obtain a derivative of compound V (compound 4). (d) A step of oxidizing compound V to obtain compound VI represented by the following formula (VI) (wherein R1 is hydrogen or a protecting group),

[0078] [ka]

[0079] If R1 of compound VI is hydrogen (R1=H), compound VI is optionally reacted with the propyl moiety to obtain a derivative of compound VI (compound 5). If R1 of compound VI is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound VI is optionally reacted with the propyl moiety to obtain a derivative of compound VI (compound 5). (e) A step of reducing compound VI to obtain pridopidine or compound VII represented by the following formula (VII) (wherein R6 is H or a protecting group),

[0080] [ka]

[0081] The present invention provides a method comprising the step of reacting compound VII with a propyl moiety to obtain pridopidine if R6 of compound VII is hydrogen (R6=H), and optionally deprotecting the protecting group if R6 of compound VII is a protecting group (R6=protecting group), and then optionally reacting compound VII with a propyl moiety to obtain pridopidine.

[0082] In one embodiment, the present invention is a method for producing pridopidine (4b), (a) In the presence of a second palladium catalyst and a weak base, compound VI represented by the following formula (VI)

[0083] [ka]

[0084] During the ceremony, R1 is H, propyl, or a protecting group. R2 and R3 are either alkyl groups independently or cooperate to form a 5-8 membered ring. This 5-8 membered ring can be optionally substituted.

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

[0086] [ka]

[0087] If R1 of compound VI is hydrogen (R1=H), compound VI is optionally reacted with the propyl moiety to obtain a propyl derivative of compound VI (compound 5). If R1 of compound VI is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound VI is optionally reacted with the propyl moiety to obtain a propyl derivative of compound VI (compound 5). (b) A step of 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] The present invention provides a method comprising the step of reacting compound VII with the propyl moiety to obtain pridopidine if R6 of compound VII is hydrogen (R6=H), and deprotecting the protecting group if R6 of compound VII is a protecting group (R6=protecting group), and then reacting compound VII with the propyl moiety to obtain pridopidine.

[0090] In one embodiment, the present invention provides a method for producing pridopidine (4c), (a) In the presence of a second palladium catalyst and a weak base, compound (10) represented by the following formula (10) is used.

[0091] [ka]

[0092] The step of reacting with 3-halothioanisole to obtain compound 4 represented by the following formula (4),

[0093] [ka]

[0094] (d) The step of oxidizing -SMe of compound 4 to -SO2Me to obtain compound 5 represented by the following formula (5),

[0095] [ka]

[0096] (e) A method is provided comprising the step of reducing compound 5 to obtain pridopidine.

[0097] In one embodiment, the present invention provides a method for producing pridopidine (4d), (a) In the presence of a second palladium catalyst and a weak base, compound (10) represented by the following formula (10) is used.

[0098] [ka]

[0099] The step of reacting with 1-halo-3-(methylsulfonyl)benzene to obtain compound 5 represented by the following formula (5),

[0100] [ka]

[0101] (b) A method is provided comprising the step of reducing compound 5 to obtain pridopidine.

[0102] In one embodiment, the present invention provides a method for producing pridopidine (4e), (a) In the presence of a second palladium catalyst and a weak base, compound IV represented by the following formula (IV) is prepared.

[0103] [ka]

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

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

[0106] [ka]

[0107] If R1 of compound V is hydrogen (R1=H), compound V is optionally reacted with the propyl moiety to obtain a propyl derivative of compound V (compound 4). If R1 of compound V is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound V is optionally reacted with the propyl moiety to obtain a derivative of compound V (compound 4). (c) A step of reducing compound V to obtain compound XIV represented by the following formula (XIV) (wherein R1 is H or a protecting group),

[0108] [ka]

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

[0110] [ka]

[0111] The present invention provides a method comprising the step of reacting compound VII with the propyl moiety to obtain pridopidine if R6 of compound VII is hydrogen (R6=H), and deprotecting the protecting group if R6 of compound VII is a protecting group (R6=protecting group), and then reacting compound VII with the propyl moiety to obtain pridopidine.

[0112] In one embodiment, the present invention provides a method for producing pridopidine (5a), (a) Compound IV, represented by the following formula (IV), is obtained by the Suzuki-Miyaura reaction.

[0113] [ka]

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

[0115] By reacting with compound VIII represented by the following formula (VIII) (wherein X1 and X2 are independently halos),

[0116] [ka]

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

[0118] [ka]

[0119] If R1 of compound IX is hydrogen (R1=H), compound IX is optionally reacted with the propyl moiety to obtain a propyl derivative of compound IX; if R1 of compound IX is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound IX is optionally reacted with the propyl moiety to obtain a propyl derivative of compound IX; and (b) A step of reacting compound IX, in which X1 is a halo, with sodium methyl sulfinate and copper(II) trifluoromethanesulfonic acid by an Ullmann reaction using 1,2-diaminocyclohexane (a mixture of cis and trans) as a catalyst to obtain a sulfone represented by the following formula (VI) (wherein R1 is H or a protecting group),

[0120] [ka]

[0121] If R1 of compound VI is hydrogen (R1=H), compound VI is optionally reacted with the propyl moiety to obtain a propyl derivative of compound VI (compound 5). If R1 of compound VI is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound VI is optionally reacted with the propyl moiety to obtain a propyl derivative of compound VI (compound 5). (c) A step of reducing compound VI to obtain pridopidine or compound VII represented by the following formula (VII) (wherein R6 is H or a protecting group),

[0122] [ka]

[0123] The present invention provides a method comprising the steps of: if R6 of compound VII is hydrogen (R6=H), compound VII is optionally reacted with a propyl moiety to obtain pridopidine; if R1 of compound VII is a protecting group (R6=protecting group), the protecting group is optionally deprotected, and compound VII is optionally reacted with a propyl moiety to obtain pridopidine.

[0124] In one embodiment, the present invention provides a method for producing pridopidine (5b), (a) Compound 10 represented by the following formula (10) is obtained by the Suzuki-Miyaura reaction,

[0125] [ka]

[0126] By reacting with compound VIII represented by the following formula (VIII) (wherein X1 and X2 are independently halos),

[0127] [ka]

[0128] The steps include obtaining compound XVII represented by the following formula (XVII) (wherein X1 is a halo),

[0129] [ka]

[0130] (b) Using 1,2-diaminocyclohexane (a mixture of cis and trans) as a catalyst, a step is taken in which compound XVII, in which X1 is a halo, is reacted with sodium methyl sulfinate and copper(II) trifluoromethanesulfonic acid by an Ullmann reaction to obtain a sulfone which is compound V represented by the following formula (V):

[0131] [ka]

[0132] (c) A method is provided which includes the step of reducing compound V to obtain pridopidine.

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

[0134] [ka]

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

[0136] (a) Compound X represented by the following formula (X)

[0137] [ka]

[0138] The step involves reacting the compound with a strong base, and then further reacting the trifluoro moiety to obtain compound XI represented by the following formula (XI) (wherein R1 is hydrogen or a protecting group),

[0139] [ka]

[0140] If R1 of compound XI is hydrogen (R1=H), compound XI is optionally reacted with the propyl moiety to obtain a propyl derivative of compound XI; if R1 of compound XI is a protecting group (R1=protecting group), the protecting group is optionally deprotected, and compound XI is optionally reacted with the propyl moiety to obtain a propyl derivative of compound XI; and (b) A step of reacting compound XI with diborane, a moderate base, and a second palladium catalyst to obtain compound IV represented by the following formula (IV) (wherein R6 is H or a protecting group),

[0141] [ka]

[0142] When R1 of Compound IV is hydrogen (R1 = H), Compound IV is optionally reacted with a propyl moiety to obtain a propyl derivative of Compound IV. When R1 of Compound IV is a protecting group (R1 = protecting group), the protecting group is optionally deprotected, and Compound IV is optionally reacted with a propyl moiety to obtain a propyl derivative of Compound IV. Provided is a method comprising the step.

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

[0144]

Chemical formula

[0145] (a) Reacting Compound X represented by the following formula (X)

[0146]

Chemical formula

[0147] with a strong base and then further reacting with a trifluoro moiety to obtain Compound XI represented by the following formula (XI) (wherein R1 is hydrogen or a protecting group),

[0148]

Chemical formula

[0149] When R1 of Compound XI is hydrogen (R1 = H), Compound XI is optionally reacted with a propyl moiety to obtain a propyl derivative of Compound XI. When R1 of Compound XI is a protecting group (R1 = protecting group), the protecting group is optionally deprotected, and Compound XI is optionally reacted with a propyl moiety to obtain a propyl derivative of Compound XI. The step, (b) A step of reacting compound XI with diborane, a moderate 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] The present invention provides a method comprising the steps of: if R6 of compound XII is hydrogen (R6=H), compound XII is optionally reacted with the propyl moiety to obtain compound 10; and if R6 of compound XII is a protecting group (R6=protecting group), the protecting group is optionally deprotected, and compound XII is optionally reacted with the propyl moiety to obtain compound 10.

[0152] In one embodiment, the present invention is a method for producing pridopidine (7a), (a) Compound XIII represented by the following formula (XIII) (wherein R1 is H, propyl, or a protecting group),

[0153] [ka]

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

[0155] [ka]

[0156] 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. This step, (c) A step of oxidizing compound XIV to obtain pridopidine or compound XV represented by the following formula (XV) (wherein R6 is hydrogen or a protecting group),

[0157]

Chemical formula

[0158] When R6 of compound XV is hydrogen (R6 = H), compound XV is optionally reacted with a propyl moiety to obtain pridopidine. When R6 of compound XV is a protecting group (R6 = protecting group), the protecting group is deprotected, and compound XV is reacted with a propyl moiety to obtain pridopidine. This step, and, a method is provided that includes.

[0159] In another embodiment, the present invention is a method for producing pridopidine (7a), (a) Reacting compound 9 represented by the following formula (9) with,

[0160]

Chemical formula

[0161] a strong base to obtain compound 7 represented by the following formula (7), and,

[0162]

Chemical formula

[0163] (c) A step of oxidizing compound 7 to obtain pridopidine, and, a method is provided that includes.

[0164] In one embodiment, the present invention relates to a method for producing compound XIII represented by the following formula (XIII) (wherein R1 is H, propyl, or a protecting group) (8a),

[0165] [ka]

[0166] A step of reacting 2-(3-(methylthio)phenyl)acetonitrile with 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 compound XIII,

[0167] [ka]

[0168] The present invention provides a method comprising the steps of: reacting compound XIII with a propyl moiety of any choice if R1 of compound XIII is hydrogen (R1=H) to obtain a propyl derivative of compound XIII; and deprotecting the protecting group if R1 of compound XIII is a protecting group (R1=protecting group) and reacting it with the propyl moiety to obtain a propyl derivative of compound XIII.

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

[0170] [ka]

[0171] The present invention provides a method comprising the step of reacting 2-(3-(methylthio)phenyl)acetonitrile with compound 11 represented by the following formula (11) (wherein Pr is propyl) 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, the anion X - Compounds containing are provided. In one embodiment, the anion is a halide such as a mesylate or 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 a sulfonate (R-SO2 - )

[0174] In some embodiments, the present disclosure provides a method for producing pridopidine via an intermediate compound of compound I. The pridopidine production method of the present disclosure uses a commercially available, relatively inexpensive (low-cost) starting material and a readily isolated solid pyridinium salt, and comprises three main steps.

[0175] In some embodiments, the manufacturing method 1 of the present disclosure includes the step of reducing the pyridinium ring of compound I, where A is SMe or SO2Me, to obtain compound 7 or pridopidine. In other embodiments, the step of reducing the pyridinium ring includes the step of reacting compound I with PtO2 and H2 (gas).

[0176] In some embodiments, the manufacturing methods of the present disclosure include an oxidation step of oxidizing the -SMe group to the -SO2Me group (see, for example, 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 a 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 a reaction with a peroxide. In another embodiment, the oxidation step includes a reaction with a peroxide and Na2WO4. In another embodiment, the oxidation step includes a reaction with a tungsten-catalyzed oxidizing agent in the presence of a peroxide oxidizing agent at a pH of less than 2. In another embodiment, the oxidation step includes a 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 manufacturing method of the present disclosure includes the step of obtaining an alkene piperidine ring by partial reduction of a pyridinium ring, as shown below (see, for example, manufacturing method 2, and Figures 2, 4, 6, and 9).

[0178] [ka]

[0179] In another embodiment, the pyridinium ring reduction step includes 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 manufacturing method of the present disclosure includes a reduction step of reducing an alkene piperidine ring to a saturated piperidine ring, wherein the double bond is reduced to obtain a piperidine ring (see, for example, manufacturing methods 2, 4a, 4b, 4c, 4d, and 4e, and Figures 2, 4, 6, 9, and 13).

[0181] [ka]

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

[0183] In another embodiment, the rhodium catalyst is 5% rhodium-supported carbon. In yet another embodiment, the platinum catalyst is platinum dioxide.

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

[0185] In some embodiments, the production method 3 of the present disclosure includes the step of reacting compound II with pyridine-4-ylboronic acid in the presence of a first palladium catalyst to obtain compound III. In other embodiments, the palladium catalyst includes tetrakis(triphenylphosphine)palladium(O)(Pd(Ph3P)4), palladium(II) acetate (Pd(OAc)2), bis(triphenylphosphine palladium chloride)(Pd(Ph3P)2Cl2), or [1,1'bis(diphenylphosphine)ferrocene]palladium(II) dichloride (Pd(Cl2)dppf).

[0186] In some embodiments, manufacturing methods 3, 4a, 4b, 4c, 4d, and 4e of the present disclosure include steps for producing compound III, compound V, compound VI, compound 4, and compound 5, using a weak base. In other embodiments, the weak base includes potassium phosphate, sodium bicarbonate, potassium carbonate, pyridine, or any combination thereof. Each of these is a separate embodiment of the present invention.

[0187] In another embodiment, the weak base used in method 3 for producing compound III includes sodium ethoxide, cesium carbonate, or any combination thereof. In another embodiment, the weak base used in method 3 for producing compound III includes 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, for example, manufacturing methods 3, 4a, 4b, 4e, 7a, and 8a, and Figures 7-11). In other embodiments, “propyl moiety” refers to a propyl group substituted with propionaldehyde or a leaving group. In yet another embodiment, “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, and propyl methane. sulfonate , propyl p-toluene sulfonate , or propylbenzene sulfonate Examples include: In some embodiments, the "propyl moiety" is propionaldehyde. In other embodiments, when the propyl moiety is propionaldehyde, the reaction is carried out by "reductive amination" with the addition of a reducing agent.

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

[0190] In some embodiments, the manufacturing methods of the present disclosure 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 other embodiments, the second palladium catalyst includes 1,1'-bis(diphenylphosphino)felsen-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 methods of the present disclosure utilize 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 the Boc group is carried out using trifluoroacetic acid, methanesulfonic acid, trimethylsilyl chloride, or hydrochloric acid. In another embodiment, the deprotection of the Fmoc group is carried out using a base such as ammonia, piperidine, or morpholine. In another embodiment, the deprotection of the benzyl group is carried out by catalytic hydrogenation. In another embodiment, the deprotection step includes a known procedure for removing a protecting group, which is described in detail, for example, in "Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999" (this document is incorporated herein by reference in its entirety).

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

[0193] In some embodiments, methods 6a and 6b for producing compounds IV and XII involve the use of a moderate base. In other embodiments, the moderate 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 moderate base is potassium acetate. In yet another embodiment, the moderate base is pyridine.

[0194] In another embodiment, the moderate base used in methods 6a and 6b for producing compound IV and compound XII includes the weak bases described herein.

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

[0196] In some embodiments, the manufacturing method 4b of the present disclosure uses 1-halo-3-(methylsulfonyl)benzene to obtain compound VI from compound IV. In other embodiments, 1-halo-3-(methylsulfonyl)benzene includes 1-bromo-3-(methylsulfonyl)benzene, 1-chloro-3-(methylsulfonyl)benzene, or 1-iodo-3-(methylsulfonyl)benzene.

[0197] In some embodiments, the manufacturing methods 6a and 6b of the present disclosure use diborane to produce compounds IV and XII. In other embodiments, diborane is bis(catecorato)diborane, bis(neopentylglycolato)diborane, 2,2'-bi-1,3,2-dioxaborinane, bis(hexenyleneglycolato)dibis(diethyl-D-tartrate glycolate)diborane, bis(N,N,N',N'-tetramethyl-L-tartrateamide glycolate)diborane, or bis(pinacolato)diborane. In yet another embodiment, diborane is bis(pinacolato)diborane. Each of these is a distinct embodiment of the present invention.

[0198] In some embodiments, the manufacturing methods 6a and 6d of the present disclosure use a trifluoro moiety for the production of compound XI. In other embodiments, the trifluoro moiety is 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide, trifluoromethylsulfonic anhydride, or trimethylsilyltrifluoromethanesulfonic acid.

[0199] 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 propyl. Each of these 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 includes t-Boc (tert-butoxycarbonyl), Fmoc (fluorenyl methoxycarbonyl), Cbz (benzyloxycarbonyl), Bn (benzyl), Bz (benzoyl), Ts (tosyl), or a carbamate group, each representing 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 representing 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 representing 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, for example, in "Protecting Groups in Organic Synthesis, TW Green and PGM Wuts, 3rd edition, John Wiley & Sons, 1999" (this document 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 cooperate to form a 5- to 8-membered ring, which is optionally substituted. In another embodiment, R2 and R3 of compound IV cooperate to form a 5- to 8-membered ring, which contains the OBO shown below, which is optionally substituted.

[0204] [ka]

[0205] In another embodiment, R2 and R3 of compound IV cooperate to form a substituted or unsubstituted 5- to 8-membered ring, or a substituted or unsubstituted condensed 5- to 8-membered ring. In another embodiment, R2 and R3 of compound IV cooperate to form a substituted or unsubstituted 5- to 8-membered ring, which contains N (nitrogen), O (oxygen), or both, in addition to the OBO atom. In another embodiment, the N in this ring is optionally R A It is substituted with. In another embodiment, R2 and R3 of compound IV cooperate to form a substituted or unsubstituted condensed 5- to 8-membered ring, which contains N (nitrogen), O (oxygen), or both, in addition to the OBO atom. In another embodiment, the N in this condensed ring is optionally R A It is replaced by R. In another embodiment, AThe substituent is an alkyl, heteroalkyl, aryl, heteroaryl, alkoxy, or acyl group, each being a distinct embodiment of the present invention. In another embodiment, the substituent is one or more groups selected from the group consisting of alkyl, ester, amide, 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, carboxamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, and alkylsulfonyl groups, each being a distinct embodiment of the present invention. Any substituent may be unsubstituted or further substituted with any of the above substituents.

[0206] In another embodiment, R2 and R3 of compound IV cooperate to form a five-membered ring substituted with 1 to 4 methyl groups. In yet another embodiment, R2 and R3 of compound IV cooperate to form a pinacolboronic acid ester. Non-limiting examples of R2 and R3 forming an OBO-containing ring 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 yet another embodiment, X1 of compound II is I. In yet another embodiment, X1 of compound II is Cl. In yet another embodiment, X1 of compound II is F.

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

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

[0211] As used herein, the term “alkyl,” used alone or as part of another group, refers to a linear or branched alkyl group having up to about 24 carbon atoms, unless otherwise specified. In one embodiment, the alkyl group has 1 to 3 carbon atoms. In one embodiment, the alkyl group has 1 to 4 carbon atoms. In one embodiment, the alkyl group has 1 to 5 carbon atoms. In one embodiment, the alkyl group has 1 to 6 carbon atoms. In one embodiment, the alkyl group has 1 to 8 carbon atoms. In one embodiment, the alkyl group has 1 to 10 carbon atoms. In one embodiment, the alkyl group has 1 to 12 carbon atoms. In another embodiment, a branched alkyl group is an alkyl group substituted with an alkyl side chain having 1 to 5 carbon atoms. In one embodiment, the alkyl group may be unsubstituted. In another embodiment, the alkyl group is substituted with halogens, haloalkyl groups, hydroxyl groups, alkoxy groups, carbonyl groups, amide groups, alkylamide groups, dialkylamide groups, cyano groups, nitro groups, CO2H groups, amino groups, alkylamino groups, dialkylamino groups, carboxyl groups, thio groups, and / or thioalkyl groups.

[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. Aryl rings can be monocyclic, bicyclic, tricyclic, etc. Non-limiting examples of aryl groups include phenyl and naphthyl (e.g., 1-naphthyl, 2-naphthyl). Aryl groups may be unsubstituted or substituted via 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, carboxamide, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, and alkylsulfonyl groups. Any substituent may be unsubstituted or may be further substituted with any of the substituents described above.

[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, or Cbz.

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

[0215] The term "SO2Me moiety" refers to SO2-alkali salts such as S(O)(ONa)Me, S(O)(OLi)Me, and S(O)(OK)Me. 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 hydrochlorides, hydrobroms, hydroiodides, nitrates, perchlorates, phosphates, superphosphates, sulfates, bisulfates, formates, glucons, glucurons, saccharates, isonicotinates, acetates, aconates, ascorbicates, benzenesulfons, benzoates, cinnamates, citrates, embonates, enantates, fumarates, glutamates, glycolates, lactates, maleates, gentisinates, malons, mandelates, methanesulfons, ethanesulfons, naphthalene-2-sulfons, phthalates, salicylates, sorbates, stearates, succinates, tartrates, pantothenates, acid tartrates, toluene-p-sulfons, and pamoates (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 compound I, represented by the following formula (I).

[0218] [ka]

[0219] During the ceremony, A is a halide, nitro group, protective amine, SO2Me, or SMe. X - It is an anion.

[0220] In one embodiment, the present invention provides compound I represented by the following formula (I).

[0221] [ka]

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

[0223] In one embodiment, the present invention provides a compound 1 represented by the following formula.

[0224] [ka]

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

[0226] In one embodiment, the present invention provides compound 2 represented by the following formula.

[0227] [ka]

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

[0229] In one embodiment, the present invention provides a compound 3 represented by the following formula.

[0230] [ka]

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

[0232] In one embodiment, the present invention provides compound IV represented by the following formula (IV).

[0233] [ka]

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

[0235] In one embodiment, the present invention provides a compound 10 represented by the following formula.

[0236] [ka]

[0237] In one embodiment, the present invention provides compound XIII, which is represented by the following 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 a compound 9 represented by the following 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 embodiments are provided to more fully illustrate specific embodiments of the invention. However, they should not be construed as limiting the broad scope of this disclosure. Those skilled in the art can readily devise various variations and modifications of the principles disclosed herein without departing from the scope of the invention.

[0244] Examples

[0245] Example 1: Method for producing pridopidine

[0246] [ka]

[0247] 4-(3-bromophenyl)pyridine

[0248] A clear solution of pyridine-4-ylboronic acid (5.00 g, 40.7 mmol), 1,3-dibromobenzene (14.4 g, 7.37 mL, 1.5 equivalents, 61.0 mmol), PdCl2 (dppf) (1.49 g, 0.05 equivalents, 2.03 mmol), and Na2CO3 (12.9 g, 61.0 mL, 2 moles, 3 equivalents, 122 mmol) were dissolved in 1,2-dimethoxyethane (125 mL), degassed with N2 for 15 minutes, and then heated at 85°C for 3 hours. SiO2 (400 mL) and water (200 mL) were added. The reaction mixture was filtered over a Celite layer to separate the phases. The organic phase was washed with water (2 × 200 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica; heptane / ethylethanol). Fraction 1 (tubes 67-95) was concentrated under reduced pressure to obtain 4-(3-bromophenyl)pyridine (5.31 g, 22.7 mmol, 55.8%).

[0249] [ka]

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

[0251] 1-iodopropane (290 mg, 167 μL, 2.50 equivalents, 1.71 mmol) was added to a solution of 4-(3-bromophenyl)pyridine (160 mg, 683 μmol) dissolved in acetonitrile (3 mL). The reaction mixture was heated overnight at 85 °C. Volatile substances were removed under reduced pressure to obtain 4-(3-bromophenyl)-1-propylpyridine-1-ium iodide (260 mg, 643 μmol, yield = quantitative).

[0252] [ka]

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

[0254] PtO2 (33.2 mg, 0.17 equivalents, 146 μmol) was added to a clear brown solution of 4-(3-bromophenyl)-1-propylpyridine-1-ium iodide (348 mg, 861 μmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature for two nights under a hydrogen pressure of 5 bar. This substance was diluted with MeOH and filtered over a Celite layer. The filtration cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure to obtain 276 mg (HI salt). This substance was dissolved in HCl (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 HCl (20 mL). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain 190 mg (free base). This substance was purified by column chromatography (silica; 0-5% 7N NH3 in MeOH in DCM). Fraction 1 (tubes 8-25) was concentrated to obtain 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 equivalents, 872 μmol), copper(II) trifluoromethanesulfonate (21.0 mg, 0.1 equivalents, 58.1 μmol), and 1,2-diaminocyclohexane (a mixture of cis and trans forms) (26.5 mg, 28.3 μL, 0.4 equivalents, 232 μmol) dissolved in DMSO (3 mL) was deoxygenated, purged with nitrogen, and stirred at 190 °C for 6 hours. SiO (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 obtain 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 prepared by dissolving 3-bromophenylmethylsulfone (3.0 g, 12.76 mmol, 1.0 equivalent) in 1,4-dioxane (60 mL) and water (6 mL), pyridine-4-boronic acid (11.88 g, 15.31 mmol, 1.2 equivalents) and Cs2CO3 (12.47 g, 38.28 mmol, 3.0 equivalents) were added, and the reaction mixture was purged with argon for 15 minutes. Pd(PPh3)4 (740 mg, 0.64 mmol, 0.05 equivalents) was added, and the mixture was stirred overnight at 80°C. The mixture was then cooled to room temperature, filtered through a Celite® pad, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM, 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 silica gel column chromatography (DCM: acetone 100:0 -> 80:20). This yielded 3.03 g of 4-(3-methanesulfonylphenyl)pyridine (yield = quantitative) as a brown oil (LCMS purity 99%). LCMS(ESI):C 12 H 11 Precise 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 equivalent) was dissolved in ACN (10 mL) and placed in an ice bath. 1-iodopropane (474 ​​μL, 4.86 mmol, 2.0 equivalent) was added, and the reaction mixture was heated overnight at 70°C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layers were dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The resulting solid was refluxed with ethyl acetate (10 mL) for 1 hour, cooled to room temperature, washed with ethyl acetate, and dried under reduced pressure. This yielded 800 mg (yield = 81%) of 4-(3-methanesulfonylphenyl)-1-propylpyridine iodide as a brown solid (LCMS purity 100%). LCMS(ESI):C 15 H 18 Precise 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] 800 mg, 1.98 mmol, 1.0 equivalent of 4-(3-methanesulfonylphenyl)-1-propylpyridine iodide was dissolved in methanol (20.0 mL). PtO2 (90 mg, 0.4 mmol, 0.2 equivalents) was added to the solution while slowly flowing argon. The reaction mixture was degassed under vacuum and hydrogen was added three times. The mixture was then stirred overnight under a hydrogen atmosphere (balloon). After the reaction was complete, the mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure. 10 mL of DCM and 10 mL of 2 M NaOH solution were added, and the mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was washed with DCM (twice). The organic phases were combined, dried over sodium sulfate, filtered, and evaporated. This yielded 635 mg of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (yield = quantitative) (LCMS purity 100%). The obtained substance was purified in the next step to produce the hydrochloride salt. LCMS(ESI):C 15 H 23 Precise 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 equivalent) was dissolved in iPrOH (6.0 mL), and then 6N HCl was added dropwise to the iPrOH (400 μL, 2.38 mmol, 1.2 equivalents). The reaction mixture was stirred at 80°C for 2 hours and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and then dried under reduced pressure. This yielded 492 mg of 4-(3-methylsulfonylphenyl)pyridine hydrochloride (yield = 88%) as a pale yellow solid (LCMS purity 100%). LCMS(ESI):C 15 H 23 Precise mass of NO2S: 281.14 [M+H] + A value of 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 equivalent) dissolved in methanol (10.0 mL) and water (20.0 mL) was placed in an ice bath. NaBH4 (821 mg, 21.71 mmol, 6 equivalents) was added, and the reaction mixture was allowed to stand at room temperature for 2 hours. The mixture was then quenched with 1N HCl solution and extracted by DCM (3 times). The organic phases were combined, dried on sodium sulfate, filtered, and evaporated. This yielded 726 mg of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (yield = 66%) (LCMS purity 93%). The obtained substance was used directly in the next step. LCMS(ESI):C 15 H 21 Precise 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] 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (616 mg, 2.20 mmol, 1.0 equivalent) was dissolved in methanol (30.0 mL). Pd(OH)2 / C (20% wt. loading, 50% wet, 62 mg, 0.4 mmol, 0.2 equivalents) was added to the solution while slowly flowing argon. The reaction mixture was degassed under vacuum and filled with hydrogen three times. The mixture was then stirred overnight under a hydrogen atmosphere (balloon). The mixture was then filtered through a Celite® pad and the solvent was removed under reduced pressure. DCM (10 mL) and 2 M NaOH solution (10 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was extracted with DCM (twice). The organic phases were combined, dried over sodium sulfate, filtered, and evaporated. This yielded 548 mg of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (yield = 88%) (LCMS purity 100%). The obtained substance was purified in the next step to produce the hydrochloride salt. LCMS(ESI):C 15 H 23 Precise 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 equivalent) was dissolved in iPrOH (6.0 mL), and then 6N HCl was added dropwise to the iPrOH (653 μL, 3.89 mmol, 2 equivalents). The reaction mixture was stirred at 80°C for 2 hours and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and dried under reduced pressure. This yielded 170 mg of 4-(3-methylsulfonylphenyl)pyridine hydrochloride as a pale yellow solid (100% purity by LCMS). LCMS(ESI):C 15 H 23 Precise 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 prepared by dissolving 1-bromo-3-(methylsulfanyl)benzene (5.0 g, 24.61 mmol, 1.0 equivalent) in 1,4-dioxane (200 mL) and water (20 mL), pyridine-4-borone (3.93 g, 32.00 mmol, 1.3 equivalents) and Cs2CO3 (24.06 g, 73.85 mmol, 3.0 equivalents) were added, and the reaction mixture was purged with argon for 15 minutes. Pd(PPh3)4 (2.84 g, 2.46 mmol, 0.1 equivalent) was added, and the mixture was stirred overnight at 80°C. The mixture was then cooled to room temperature, filtered through a Celite® pad, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM, 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 silica gel column chromatography (DCM: acetone 100:0 -> 80:20). This yielded 3.0 g of 4-[3-(methylsulfanyl)phenyl]pyridine (yield = 48%) as a brown oil (LCMS purity 96%). LCMS(ESI):C 12 H 11 NS precision mass: 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 equivalent) dissolved in ACN (60 mL) was placed in an ice bath. 1-iodopropane (2.91 mL, 29.80 mmol, 2.0 equivalent) was added dropwise, and the reaction mixture was heated overnight at 70°C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The resulting solid was refluxed with ethyl acetate (10 mL) for 1 hour, cooled to room temperature, washed with ethyl acetate, and dried under reduced pressure. This yielded 5.0 g (yield = 86%) of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridine-1-ium iodide as a brown solid (LCMS purity 95%). LCMS(ESI):C 15 H 18 NS precision mass: 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] A solution of 4-[3-(methylsulfanyl)phenyl]-1-propylpyridine-1-ium iodide (1.0 g, 4.09 mmol, 1.0 equivalent) was dissolved in methanol (50 mL). PtO2 (186 mg, 0.81 mmol, 0.2 equivalents) was added to this solution while slowly flowing argon. The reaction mixture was degassed under vacuum, and hydrogen was added three times. The mixture was then stirred at 40°C for 7 days under a hydrogen atmosphere (using a balloon).

[0291] The mixture was then filtered through a Celite® pad and the solvent was removed under reduced pressure. 20 mL of DCM and 20 mL of 2 M NaOH solution were added, and the mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was washed with DCM (twice). 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 yielded 292 mg of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (yield = 25%) (LCMS purity 90%). LCMS(ESI):C 15 H 23 NS precision mass: 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 prepared by dissolving 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (292 mg, 1.17 mmol, 1.0 equivalent) in water (14.6 mL), 96% sulfuric acid (770 μL, 14.48 mmol, 12.37 equivalents) was added, followed by sodium tungstate dihydrate (27 mg, 0.08 mmol, 0.07 equivalents) and 30% H2O2 (90 μL, 2.92 mmol, 2.50 equivalents). The reaction mixture was stirred at 55°C for 2 hours, then cooled to 10°C, and toluene (50 mL) was added, followed by the addition of NaOH solution. The aqueous layer was extracted with toluene (three times). The organic layers were combined, dried on sodium sulfate, and evaporated under reduced pressure. This yielded 124 mg of 4-(3-methanesulfonylphenyl)-1-propylpiperidine (yield = 30%) as a brown solid (LCMS purity 62%). The obtained substance was purified in the next step to produce the hydrochloride salt. LCMS(ESI):C 15 H 23 Precise 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 equivalent) was dissolved in iPrOH (3.0 mL), and then 6N HCl was added dropwise to the iPrOH (147 μL, 0.88 mmol, 1.2 equivalents). The reaction mixture was stirred at 80°C for 2 hours and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and dried under reduced pressure. This yielded 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 Precise 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 in Figure 7).

[0301] [ka]

[0302] To a solution prepared by dissolving 4-[3-(methylsulfanyl)phenyl]-1-propylpyridine-1-ium iodide (1.0 g, 4.09 mmol, 1.0 equivalent) in water (50 mL), 96% sulfuric acid (2.69 mL, 50.61 mmol, 12.37 equivalents) was added, followed by sodium tungstate dihydrate (94 mg, 0.286 mmol, 0.07 equivalents) and 30% H2O2 (313 μL, 10.23 mmol, 2.50 equivalents). The reaction mixture was stirred at 55°C for 2 hours, then cooled to 10°C, 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 yielded 630 mg of 4-(3-methylsulfonylphenyl)-1-propylpyridine-1-ium hydroxide (yield = 50%) as a yellow oil (LCMS purity 96%). LCMS(ESI):C 15 H 18 Precise 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] A solution of 4-(3-methanesulfonylphenyl)-1-propylpyridine-1-ium hydroxide (630 mg, 2.15 mmol, 1.0 equivalent) was dissolved in methanol (31 mL). PtO2 (117 mg, 0.516 mmol, 0.2 equivalents) was added to this solution while slowly flowing argon. The reaction mixture was degassed under vacuum and then filled with hydrogen three times. The mixture was then stirred overnight under a hydrogen atmosphere. The mixture was then filtered through a Celite® pad and the solvent was removed under reduced pressure. DCM (20 mL) and 2M NaOH solution (20 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was washed with DCM (twice). The organic phases were combined, dried over sodium sulfate, filtered, and evaporated. This yielded 512 mg of 4-(3-methanesulfonylphenyl)-1-propylpiperidine (yield 85%) (LCMS purity 100%). The obtained substance was purified in the next step to produce the hydrochloride salt. LCMS(ESI):C 15 H 23 Precise 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 equivalent) was dissolved in iPrOH (5.0 mL), and 6N HCl was added dropwise to the iPrOH (606 μL, 3.63 mmol, 2.0 equivalents). The reaction mixture was stirred at 80°C for 2 hours and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and dried under reduced pressure. This yielded 50 mg (9% yield) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a pale yellow solid (100% purity by LCMS). LCMS(ESI):C 15 H 23 Precise 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 in Figure 7).

[0312] [ka]

[0313] 4-[3-(methylsulfanyl)phenyl]-1-propylpyridine-1-ium iodide (800 mg, 3.27 mmol, 1.0 equivalent) was dissolved in methanol (8.0 mL) and water (16.0 mL), and the solution was placed in an ice bath. NaBH4 (743 mg, 19.64 mmol, 6 equivalents) was added, and the reaction mixture was left at room temperature for 2 hours. The mixture was then quenched with 1N HCl solution and extracted by DCM (3 times). The organic phases were combined, dried over sodium sulfate, passed through, and evaporated. The crude product was purified by flash column chromatography (DCM:MeOH, 9:1). This yielded 240 mg of 4-[3-(methylsulfanyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (yield = 28%) (LCMS purity 95%). LCMS(ESI):C 15 H 21 NS precision mass: 247.14; [M+H] + A value of 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] A solution of 4-[3-(methylsulfanyl)phenyl]-1-propyl-1,2,3,6-tetrahydropyridine (240 mg, 0.97 mmol, 1.0 eq) in water (12.0 mL) was added with 96% sulfuric acid (1.17 mL, 12.0 mmol, 12.37 eq), then sodium tungstate dihydrate (22 mg, 0.068 mmol, 0.07 eq) and 30% H2O2 (74 μL, 10.23 mmol, 2.42 eq) were added. The reaction mixture was stirred at 55 °C for 2 h, then cooled to 10 °C, toluene (50 mL) was added, and then an aqueous NaOH solution was added. The aqueous layer was extracted with toluene (3 times). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. Thereby, 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine was obtained as 162 mg (yield = 58%) of a yellow oily substance (LCMS purity 97%). LCMS (ESI): C 15 H 21 The exact mass of NO2S: 279.13; [M+H] + = 280.05 was detected.

[0317] 1 H NMR (300 MHz, DMSO-d6) δ 7.95 - 7.87 (m, 1H), 7.83 - 7.73 (m, 2H), 7.66 - 7.55 (m, 1H), 6.36 - 6.28 (m, 1H), 3.23 (s, 3H), 3.14 - 3.06 (m, 2H), 2.68 - 2.59 (m, 2H), 2.41 - 2.30 (m, 2H), 1.58 - 1.43 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). * 2H overlaps with DMSO.

[0318]

Chemical Structure

[0319] A solution of 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (162 mg, 0.580 mmol, 1.0 equivalent) in methanol (8 mL) was purged with argon, and d(OH)2 / C (20% wt. loading, 50% wet, 16 mg, 0.012 mmol, 0.02 equivalent) was added while gently flowing argon. The reaction mixture was evacuated and degassed, and hydrogen was charged three times. Then, it was stirred overnight 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. DCM (20 mL) and 2M NaOH solution (20 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was washed with DCM (twice). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Thereby, 4-(3-methanesulfonylphenyl)-1-propylpiperidine was obtained as 88 mg (yield 54%) (LCMS purity 100%). The obtained substance was purified when generating the hydrochloride salt in the next step. LCMS (ESI): C 15 H 23 The exact mass of NO2S: 281.14; [M+H] + =282.10 was detected.

[0320]

Chemical formula

[0321] [[ID=,18]]A solution of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (88 mg, 0.313 mmol, 1.0 equivalent) in iPrOH (4 mL) was dissolved, and 6N HCl was added dropwise thereto (114 μL, 0.62 mmol, 2.0 equivalents). The reaction mixture was stirred at 80 °C for 2 hours and at room temperature overnight. The precipitate was filtered, washed with iPrOH, and dried under reduced pressure. Thereby, 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride was obtained as 43 mg (yield = 48%) as a pale yellow solid (LCMS purity 100%). LCMS (ESI): C 15 H 23 The 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] A solution was prepared by dissolving 1-bromo-3-nitrobenzene (2.0 g, 9.90 mmol, 1.0 equivalent) in 1,4-dioxane (40 mL) and water (4 mL). Pyridine-4-boronic acid (1.58 g, 12.87 mmol, 1.3 equivalents) and Cs2CO3 (9.68 g, 29.70 mmol, 3.0 equivalents) were added to this solution, and the reaction mixture was purged with argon for 15 minutes. Then, Pd(PPh3)4 (1.14 g, 0.99 mmol, 0.1 equivalent) was added, and the mixture was stirred overnight at 80°C. After cooling to room temperature, the mixture was filtered through a Celite® pad, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM, 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:MeOH100:0->90:10). This yielded 1.4 g of 4-(3-nitrophenyl)pyridine (yield = 72%) as a brown solid (LCMS purity 100%). LCMS(ESI):C 11 Precise mass of H8N2O2: 200.2; [M+H] + =201.0 was detected.

[0327] 1 ¹H NMR (300MHz, methanol-d4): δ 8.68 (d, J=1.7Hz, 1H), 8.67 (d, J=1.8Hz, 1H), 8.61 (t, J=2.1Hz, 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 equivalent) was dissolved in ACN (26 mL), and the solution was placed in an ice bath. 1-iodopropane (1.27 mL, 12.99 mmol, 2.0 equivalent) was added dropwise, and the reaction mixture was heated overnight at 70°C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The resulting solid was refluxed with ethyl acetate (30 mL) for 1 hour, cooled to room temperature, washed with ethyl acetate, and dried under reduced pressure. This yielded 2.16 g (yield = 89%) of 4-(3-nitrophenyl)-1-propylpyridine-1-ium iodide as a yellow solid (LCMS purity 100%). LCMS(ESI):C 14 H 15 Precise 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] In a solution prepared by dissolving 4-(3-nitrophenyl)-1-propylpyridine-1-ium iodide (1.0 g, 2.70 mmol, 1.0 equivalent) in methanol (40.0 mL), PtO2 (307 mg, 1.35 mmol, 0.5 equivalent) was added while slowly flowing argon. The reaction mixture was degassed under vacuum and hydrogen was added three times. The mixture was then stirred overnight under a hydrogen atmosphere (balloon). After the reaction was complete, the mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure. DCM (30 mL) and 2 M NaOH solution (30 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was washed with DCM (twice). 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 yielded 1.05 g of 3-(1-propylpiperidine-4-yl)aniline dihydrochloride (yield = quantitative) (LCMS purity 100%). LCMS (ESI):C 14 H 22 Precise mass of N2: 218.34; [M+H] + A value of 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-propylpiperidine-4-yl)aniline dihydrochloride (445 mg, 1.53 mmol, 1.0 equivalent) 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 equivalents) dissolved in ice AcOH (7 mL) was added to the glacial acetic acid over 10 minutes while maintaining the temperature below 5°C. The reaction mixture was stirred at 0°C for 10 minutes, and then isoamyl nitrite (302 μL, 2.24 mmol, 1.1 equivalents) was added dropwise over 10 minutes. The solution was stirred at 0°C for 20 minutes, diethyl ether was added to precipitate the compound as an orange solid, filtered, washed with diethyl ether, and dried under reduced pressure at room temperature. 3-(1-propylpiperidine-4-yl)benzene-1-diazonium O-benzenesulfonimide (914 mg, 2.04 mmol, 1.0 equivalent) was added all at once at 0°C to a methanol (20 mL) solution containing methyl mercaptan sodium (160 mg, 2.28 mmol, 1.12 equivalents). The reaction mixture was stirred at below 5°C for 1 hour, 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 to >85:15) followed by pTLC (CHCl3:iPrOH, 9:1). This yielded 161 mg of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (yield = 30%) as a yellow solid (LCMS purity 71%). LCMS(ESI):C 15 H 23 NS precision mass: 249.42; [M] + =250.10 was 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 prepared by dissolving 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (140 mg, 0.56 mmol, 1.0 equivalent) in water (7 mL), 96% sulfuric acid (370 μL, 6.94 mmol, 12.37 equivalents) was added, followed by sodium tungstate dihydrate (13 mg, 0.04 mmol, 0.07 equivalents) and 30% hydrogen peroxide aqueous solution (144 μL, 1.40 mmol, 2.50 equivalents). The reaction mixture was stirred at 55°C for 2 hours, 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 on sodium sulfate, and evaporated under reduced pressure. The crude product was purified by pTLC (DCM:MeOH=9:1). This yielded 27 mg of 4-(3-methanesulfonylphenyl)-1-propylpiperidine (yield = 17%) as a yellow solid (LCMS purity 56%). The obtained substance was purified in the next step to produce the hydrochloride salt. LCMS(ESI):C 15 H 23 Precise 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 equivalent) was dissolved in iPrOH (300 μL), heated to 70°C, and then 6N HCl was added to the iPrOH (19 μL, 0.11 mmol, 1.2 equivalents). The mixture was heated to 80°C and stirred for 10 minutes. It was then cooled to 65°C, pure 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride was added, and the mixture was cooled to room temperature to precipitate the product. The white solid was filtered, washed with iPrOH, and dried under reduced pressure. This yielded 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 Precise mass of NO2S: 281.14 [M+H] + A value of 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 prepared by dissolving tert-butyl N-(3-bromophenyl)carbamate (3.5 g, 12.86 mmol, 1.0 equivalent) in 1,4-dioxane (140 mL) and water (14 mL), pyridine-4-boronic acid (2.05 g, 16.71 mmol, 1.2 equivalents) and Cs2CO3 (12.57 g, 38.58 mmol, 3.0 equivalents) were added, and the reaction mixture was purged with argon for 15 minutes. Pd(PPh3)4 (1.48 g, 1.28 mmol, 0.1 equivalent) was added, and the mixture was stirred overnight at 80°C. The mixture was then cooled to room temperature, filtered through a Celite® pad, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM, 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 silica gel column chromatography (DCM:MeOH100:0->85:15). This yielded 3.1 g of tert-butyl N-[3-(pyridine-4-yl)phenyl]carbamate (yield = quantitative) as a brown solid (LCMS purity 100%). LCMS(ESI):C 16 H 18 Precise 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] 3.0 g, 11.08 mmol, 1.0 equivalent of tert-butyl N-[3-(pyridine-4-yl)phenyl]carbamate was dissolved in 60 mL of ACN, and the solution was placed in an ice bath. 4.32 mL, 44.39 mmol, 4.0 equivalents of 1-iodopropane were added dropwise, and the reaction mixture was heated overnight at 70°C. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (three times). The combined organic layer was dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The resulting solid was refluxed with ethyl acetate (10 mL) for 1 hour, cooled to room temperature, washed with ethyl acetate, and dried under reduced pressure. This yielded 3.5 g (yield = 72%) of 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridine-1-ium iodide as a yellow solid (LCMS purity 100%). LCMS(ESI):C 19 H 25 Precise 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] In a solution prepared by dissolving 4-(3-{[(tert-butoxy)carbonyl]amino}phenyl)-1-propylpyridine-1-ium iodide (1.0 g, 2.27 mmol, 1.0 equivalent) in methanol (50 mL), PtO2 (362 mg, 1.59 mmol, 0.7 equivalents) was added while slowly flowing argon. The reaction mixture was degassed under vacuum and then filled with hydrogen three times. The mixture was then stirred overnight at 40°C under a hydrogen atmosphere (balloon). After the reaction was complete, the mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure. This yielded 1.1 g of tert-butyl N-[3-(1-propylpiperidine-4-yl)phenyl]carbamate (yield = quantitative) (LCMS purity 100%). LCMS(ESI):C 19 H 30 Precise 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-propylpyridine-1-ium iodide (1.0 g, 2.27 mmol, 1.0 equivalent) dissolved in methanol (10 mL) and water (20 mL) was placed in an ice bath. NaBH4 (724 mg, 19.14 mmol, 8.4 equivalents) was added, and the reaction mixture was allowed to stand for 2 hours. The mixture was then quenched with 1N HCl solution and extracted by DCM (3 times). The organic phases were combined, dried over sodium sulfate, filtered, and evaporated. This yielded 815 mg (yield = quantitative) of tert-butyl N-[3-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl]carbamate (LCMS purity 91%). The obtained substance was used directly in the next step. LCMS(ESI):C 19 H 28 Precise 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] In a solution prepared by dissolving tert-butyl N-[3-(1-propyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl]carbamate (800 mg, 3.23 mmol, 1.0 equivalent) in methanol (80 mL), 10% Pd / C (60-65% wet, 229 mg, 1.13 mmol, 0.35 equivalents) was added while slowly flowing argon. The reaction mixture was degassed under vacuum and then filled with hydrogen (3 times). The mixture was then stirred overnight at 40°C under a hydrogen atmosphere (balloon). After the reaction was complete, the mixture was filtered through a Celite® pad and the solvent was removed under reduced pressure. This yielded 470 mg of tert-butyl N-[3-(1-propylpiperidine-4-yl)phenyl]carbamate (yield = 45%) (LCMS purity 100%). LCMS(ESI):C 19 H 30 Precise 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 equivalent) was dissolved in dioxane (36 mL). 4N HCl (10.4 mL, 43.71 mmol, 29.7 equivalents) was added dropwise to the dioxane, and the reaction mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure. This yielded 416 mg (yield = 97%) of 3-(1-propylpiperidine-4-yl)aniline dihydrochloride as a brown solid (LCMS purity 100%). LCMS(ESI):C 14 H22 Precise mass of N2: 218.18; [M+H] + A value of 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-propylpiperidine-4-yl)aniline dihydrochloride (445 mg, 1.53 mmol, 1.0 equivalent) was dissolved in glacial acetic acid (13 mL), and the solution was cooled to 0°C in an ice bath. A solution of O-benzenesulfonimide (536 mg, 2.45 mmol, 1.2 equivalents) (7 mL) was added to the glacial acetic acid over 10 minutes while maintaining the temperature below 5°C. The reaction mixture was stirred at 0°C for 10 minutes, and then isoamyl nitrite (302 μL, 2.24 mmol, 1.1 equivalents) was added dropwise over 10 minutes. The solution was stirred at 0°C for 20 minutes, diethyl ether was added to precipitate the compound as an orange solid, filtered, washed with diethyl ether, and dried under reduced pressure at room temperature. 3-(1-propylpiperidine-4-yl)benzene-1-diazonium O-benzenesulfonimide (914 mg, 2.04 mmol, 1.0 equivalent) was added all at once at 0°C to a solution of sodium methyl mercaptan (160 mg, 2.28 mmol, 1.12 equivalents) dissolved in MeOH (20 mL). The reaction mixture was stirred at below 5°C for 1 hour, 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:MeOH100:0->85:15) followed by pTLC (CHCl3:iPrOH, 9:1). This yielded 161 mg of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine as a yellow solid (30% yield) (LCMS purity 71%). LCMS(ESI):C 15 H 23 NS precision mass: 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 an aqueous solution prepared by adding 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (140 mg, 0.56 mmol, 1.0 equivalent) to water (7 mL), 96% sulfuric acid (370 μL, 6.94 mmol, 12.37 equivalents) was added, followed by sodium tungstate dihydrate (13 mg, 0.04 mmol, 0.07 equivalents) and 30% H2O2 aqueous solution (144 μL, 1.40 mmol, 2.50 equivalents). The reaction mixture was stirred at 55°C for 2 hours, then cooled to 10°C, and toluene (50 mL) was added, followed by aqueous NaOH solution. The aqueous layer was extracted with toluene (3 times). The organic layers were combined, dried on sodium sulfate, and evaporated under reduced pressure. The crude product was purified by pTLC (DCM:MeOH9:1). This yielded 27 mg (Y=17%) of 4-(3-methanesulfonylphenyl)-1-propylpiperidine as a yellow solid (LCMS purity 56%). The obtained substance was purified during hydrochloride formation in the next step. LCMS(ESI):C 15 H 23 Precise 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 prepared by dissolving (3-methylsulfanylphenyl)acetonitrile (2.0 g, 12.3 mmol, 1.0 equivalent) in DMSO (16 mL), sodium hydride (60% dispersion, mineral oil, 1.47 g, 36.8 mmol, 3.0 equivalents) was added in portions. The resulting suspension was stirred at room temperature for 30 minutes. Then, N,N-bis(2-chloroethyl)propan-1-amine hydrochloride (2.97 g, 13.5 mmol, 1.1 equivalents) was slowly added over 5 minutes, and the suspension was heated at 65°C for 1 hour. The reaction mixture was then diluted with water and extracted with ethyl acetate (3 times). The combined extracts were washed with water (5 times), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This yielded 3.44 g of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine-4-carbonitride as a brown oil (yield = 94%) (LCMS purity 92%). LCMS(ESI):C 16 H 22 Precise mass of N2S: 274.15; [M+H] + A value of 275.05 was detected.

[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 prepared by dissolving 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine-4-carbonitride (2.9 g, 10.6 mmol, 1.0 equivalent) in DMSO (58 mL), potassium hydroxide (5.93 g, 105.7 mmol, 10.0 equivalent) was added in fractions. The reaction mixture was heated to 160°C and stirred for 72 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted by DCM (3 times). The combined extract was washed with water (5 times), dried on 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 yielded 223 mg of 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine as a brown solid (yield = 8%) (LCMS purity 98%). LCMS(ESI):C 15 H 23 NS precision mass: 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 the optimization of the manufacturing process, the reaction was successfully carried out on a 50 mg scale, yielding 41 mg of product (yield = 91%) with LC-MS purity of 80%.

[0375] [ka]

[0376] To a solution prepared by dissolving 4-[3-(methylsulfanyl)phenyl]-1-propylpiperidine (200 mg, 0.80 mmol, 1.0 equivalent) in water (10 mL), 96% sulfuric acid (528 μL, 9.9 mmol, 12.37 equivalents) was added, followed by sodium tungstate dihydrate (20 mg, 0.10 mmol, 0.07 equivalents) and 30% H2O2 (200 μL, 2.0 mmol, 2.50 equivalents). The reaction mixture was stirred at 55°C for 2 hours. The mixture was then cooled to 10°C, and toluene, followed by NaOH solution, was added until the pH was approximately 12. The aqueous layer was extracted with toluene (three times). The organic layers were combined, dried over sodium sulfate, and evaporated under reduced pressure. This yielded 192 mg of 4-(3-methanesulfonylphenyl)-1-propylpiperidine (yield = 85%) as a brown oily substance (LCMS purity 92%). The obtained substance was purified in the next step to produce the hydrochloride salt. LCMS(ESI):C 15 H 23 Precise mass of NO2S: 281.14 [M+H] + A value of 282.05 was detected.

[0377] [ka]

[0378] 4-(3-methanesulfonylphenyl)-1-propylpiperidine (192 mg, 0.68 mmol, 1.0 equivalent) was dissolved in iPrOH (2.1 mL) and heated to 70°C. Then, 6N HCl (136 μL, 0.82 mmol, 1.2 equivalents) was added to the iPrOH. The mixture was heated to 80°C and stirred for 10 minutes. Afterward, it was cooled to 65°C, and pure crystals of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride were added. The mixture was then cooled to room temperature. A white precipitate formed upon cooling of the solution, which was washed with iPrOH and dried. This yielded 73 mg (yield = 34%) of 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine hydrochloride as a white solid (LCMS purity 100%). LCMS(ESI):C 15 H 23Precise 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-tetrahydropyridine-4-yltrifluoromethanesulfonic acid

[0384] A clear brown solution of 1-propylpiperidine-4-one (506 mg, 3.58 mmol) dissolved in THF (2.5 mL) was cooled to -75°C. LiHMDS (779 mg, 4.66 mL, 1 M, 1.3 equivalents, 4.66 mmol) was added dropwise while maintaining the temperature below -70°C. The reaction mixture was stirred at -75°C for 30 minutes. NFSI (1.41 g, 1.1 equivalents, 3.94 mmol) was added in installments. After addition, the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with HCl (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 on sodium sulfate and concentrated under reduced pressure to obtain 1.84 g. This substance 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 obtain 1-propyl-1,2,3,6-tetrahydropyridine-4-yltrifluoromethanesulfonic acid (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-tetrahydropyridine-4-yltrifluoromethanesulfonic acid (1.95 g, 7.14 mmol), KOAc (2.10 g, 3 equivalents, 21.4 mmol), and B2Pin2 (2.17 g, 1.2 equivalents, 8.56 mmol) were dissolved in 1,4-dioxane (22 mL) and stirred at room temperature. PdCl2 (dppf) (261 mg, 0.05 equivalents, 357 μmol) was added, and the reaction mixture was degassed under nitrogen for 15 minutes. The reaction mixture was then heated at 80°C for 2.5 hours. The reaction mixture was filtered over a celite layer. The filtered cake was washed with 1,4-dioxane. The combined filtrate was concentrated under reduced pressure to obtain 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). The obtained substance was used 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 equivalents, 4.41 mmol) was added, followed by Na2CO3 (280 mg, 1.32 mL, 2 mol, 3 equivalents, 2.64 mmol) and PdCl2 (dppf) (32.2 mg, 0.05 equivalents, 44.1 μmol). The reaction mixture was degassed under nitrogen for 15 minutes and stirred at 80°C for 3 hours. HCl (100 mL) and water (50 mL) were added. The mixture was filtered over a Celite layer. The phases were separated, and the organic phase was washed with water (2 × 50 mL). The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure to obtain 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 obtain 4-(3-bromophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (95 mg, 0.34 mmol, yield = 38%).

[0391] Similar to what was described in Example 1, this chemical reaction converts the alkene bromo intermediate to predopidine. The double bond of compound 6 is first reduced to obtain compound 8, which is then further converted to predopidine.

[0392] Example 11: Method for producing pridopidine

[0393] [ka]

[0394] A boronic acid ester (compound 10) was synthesized as described in Example 10, and further reacted with 1-bromo-3-(methylsulfonyl)benzene to obtain compound 5. The double bond of compound 5 was reduced as described in step 5 of Example 6 to obtain pridopidine.

[0395] Step 1: Suzuki Coupling

[0396] To a solution prepared by dissolving 1-bromo-3-(methylsulfonyl)benzene (0.415 g, 1.76 mmol, 1.0 equivalent) 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 equivalents) and potassium acetate (0.52 g, 5.28 mmol, 3.0 equivalents) were added, and the reaction mixture was purged with argon for 15 minutes. Pd(dppf)Cl2 (66 mg, 0.09 mmol, 0.05 equivalents) was added, and the mixture was stirred overnight at 80°C. The mixture was then cooled to room temperature, filtered through a Celite® pad, washed with DCM, and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water (3 times), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Subsequently, the solution was purified by chromatography to obtain 0.18 g (yield = 37%) of 4-(3-methylsulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine as an oily substance. LCMS(ESI):C 15 H 21 Precise mass of NO2S: 279.13; [M+H] + =280.05 was detected.

[0397] Step 2: Reduction with formic acid

[0398] To a cold solution prepared by dissolving 4-(3-methanesulfonylphenyl)-1-propyl-1,2,3,6-tetrahydropyridine (1 g, 3.58 mmol, 1 equivalent) in water (2.5 times the volume), formic acid (0.264 g, 5.73 mmol, 1.6 equivalents) and 0.1% (w / w) 10% Pd / C were added. The reaction mixture was heated at 30°C for 4-5 hours. The mixture was filtered to remove the catalyst, and the filtrate was added to toluene. The mixture was then basicized with a dilute NaOH solution. The lower aqueous phase was separated, and the toluene phase was washed several times with 5 times the volume of water to remove residual NaOH. Toluene was removed by distillation under reduced pressure, and 4 times the volume of n-heptane was added to the residue to form a slurry, which was cooled to 0°C. The formed solid was recovered by filtration and vacuum-dried at 40°C. This yielded 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine (yield = 85%).

[0399] While specific features of the present invention have been illustrated and described herein, various modifications, substitutions, alterations, and equivalents may be conceivable to those skilled in the art. Therefore, it should be understood that the appended claims are intended to encompass all such modifications and alterations that fall within the scope of the present invention.

Claims

1. A compound, which is compound 1 represented by the following formula (1). In the formula, X － It is an anion.

2. A method for producing pridopidine via the compound 1 described in claim 1, The steps include reducing the pyridinium ring of compound 1 to obtain compound 7 represented by the following formula (7), The -SMe of compound 7 is -SO ２ A method comprising the step of oxidizing to Me to obtain pridopidine.

3. The method according to claim 2, The reduction of the pyridinium ring is PtO ２ and H ２ A method involving a reaction with (a gas).

4. A method for producing pridopidine via the compound 1 described in claim 1, The steps include reducing the pyridinium ring of compound 1 to obtain compound 4 represented by the following formula (4), The -SMe of compound 4 is -SO ２ After oxidation to Me, the double bond is reduced to obtain pridopidine, or after reduction of the double bond of compound 4, -SMe is converted to -SO ２ A method comprising the step of oxidizing to Me to obtain pridopidine.

5. The method according to claim 4, To obtain compound 4, the reducing agent for reducing the pyridinium ring of compound 1 is sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or H in the presence of a Pd / C catalyst. ２ A method involving (gas).

6. The method according to claim 4, The step of reducing the double bond of compound 4 to obtain a piperidine ring includes a reaction between a hydrogen source and a catalyst, The method wherein the catalyst comprises a second palladium catalyst, a platinum catalyst, or a ruthenium catalyst.

7. The method according to claim 6, The hydrogen source comprises hydrogen gas, formic acid, or a formate salt, in a method.

8. The method according to claim 7, The method wherein the formate salt is ammonium formate.

9. The method according to claim 2, The -SMe-SO of compound 7. ２ Methods for the oxidation of Me include reactions with tungsten-catalyzed oxidizing agents, peroxides, or combinations thereof.

10. The method according to claim 4, Oxidation of the -SMe group of the compound 4 to -SO ２ Me group includes a method involving reaction with a tungsten catalyst oxidizing agent, a peroxide, or a combination thereof.

11. The method according to claim 9 or 10, The method wherein the tungsten catalyst oxidizing agent is sodium tungstate.

12. The method according to claim 9 or 10, The method wherein the peroxide is sodium peroxide.

13. A method for producing compound 1 represented by the following formula (1), In the formula, X － It is an anion. (a) Compound II represented by the following formula (II) is prepared in the presence of a palladium catalyst and a weak base. In the formula, A is -SMe, and X １ is a halogen selected from Br, Cl, F, and I. Pyridine-4-boronic acid, represented by the following formula The step of reacting with to obtain compound III represented by the following formula (III), In the formula, A is -SMe. (b) A method comprising the step of reacting compound III with a propyl moiety to obtain compound 1, wherein the propyl moiety is a compound selected from propyl bromide, propyl chloride, propyl iodide, propyl methanesulfonate, propyl p-toluenesulfonate, and propylbenzenesulfonate.

14. The method according to claim 13, The method wherein the weak base comprises potassium carbonate, potassium phosphate, sodium bicarbonate, sodium ethoxide, cesium carbonate, or any combination thereof.

15. The method according to claim 13, The palladium catalyst is tetrakis(triphenylphosphine)palladium(0)(Pd(Ph ３ P) ４ ), palladium(II) acetate (Pd(OAc) ２ ), bis(triphenylphosphine) palladium chloride (Pd(Ph ３ P) ２ Cl ２ ), or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (Pd(Cl) ２ The method is )dppf).

16. The method according to claim 13, The propyl portion is propyl iodide, in this method.

17. A method for producing pridopidine using compound 1 represented by the following formula (1), In the formula, X － It is an anion. The aforementioned method, - Replace -SMe of compound 1 with -SO ２ Oxidize to Me, then reduce the pyridinium ring to obtain pridopidine; - The pyridinium ring of compound 1 is reduced to obtain compound 4 represented by the following formula (4). Next, (i) the -SMe of compound 4 is converted to -SO ２ (ii) After oxidation to Me, the double bond is reduced to obtain pridopidine, or (ii) after reduction of the double bond of compound 4, -SMe is reduced to -SO ２ Oxidize to Me to obtain pridopidine; or - The pyridinium ring of compound 1 is reduced to obtain compound 7 represented by the following formula (7). The -SMe of compound 7 is -SO ２ The step includes oxidizing to Me to obtain pridopidine, A method for producing the compound 1 according to any one of claims 13 to 16.

18. A method according to any one of claims 2 to 10, The compound 1 is produced according to the method described in claim 13.

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