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(12) Patent Application Publication (10) Pub. No.: US 2017/0022158A1 Barel Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0022158A1 Barel Et Al US 20170022158A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0022158A1 Barel et al. (43) Pub. Date: Jan. 26, 2017 (54) PROCESS FOR PREPARING PRIDOPIDNE (22) Filed: Jul. 22, 2016 (71) Applicants: Offir Barel, Netanya (IL); Ramy Related U.S. Application Data Lidor-Hadas, Kvar-Sava (IL); Ronen Gottesfeld, Netanya (IL); Orel Yosef (60) Provisional application No. 62/195,756, filed on Jul. Mizrahi, Elad (IL); Anders Olof 22, 2015. Ingemar Bergh, Karlskoga (SE); Ba-Vu Nguyen, Karlskoga (SE) Publication Classification (51) Int. Cl. (72) Inventors: Offir Barel, Netanya (IL); Ramy C07D 2II/24 (2006.01) Lidor-Hadas, Kvar-Sava (IL); Ronen (52) U.S. Cl. Gottesfeld, Netanya (IL); Orel Yosef CPC ......... C07D 211/24 (2013.01); C07B 2.200/13 Mizrahi, Elad (IL); Anders Olof (2013.01) Ingemar Bergh, Karlskoga (SE); Ba-Vu Nguyen, Karlskoga (SE) (57) ABSTRACT (73) Assignee: Teva Pharmaceuticals International This invention provides a pridopidine base in a solid form, GmbH, Jona (CH) a method of preparing the solid pridopidine base, and a composition comprising the pridopidine base including a (21) Appl. No.: 15/217,683 pharmaceutical composition. US 2017/0022.158 A1 Jan. 26, 2017 PROCESS FOR PREPARNG PRIDOPIDNE 0016 c) filtering the solution, and 0001. This application claims priority of U.S. Provisional 0017 d) adding to the solution a mixture of hydro Application No. 62/195,756, filed Jul. 22, 2015, the entire chloric acid and an alcohol which is the same as the contents of which are hereby incorporated by reference alcohol in which the pridopidine base is dissolved in herein. step (b) to precipitate pridopidine hydrochloride. 0002 Throughout this application, certain publications 0018. This invention also provides isolated pridopidine are referenced in parentheses. Full citations for these pub base prepared by the process of the invention. lications are presented in a References section immediately 0019. The invention also provides a composition com before the claims. Disclosures of the publications cited in the prising Compound 9, wherein the composition is free of References section are hereby incorporated by reference in 3-bromothioanisole. their entireties into this application in order to more fully 0020. The invention also provides a composition com describe the state of the art as of the date of the invention prising Compound 9, wherein the composition is free of described herein. THF, chloride, hexylbromide, 1-chlorobutanol, or thioani Sol. BACKGROUND OF INVENTION 0021. The invention also provides a composition com 0003 Pridopidine (Huntexilr) is a unique compound prising Compound 9, wherein the composition is free of developed for the treatment of patients with motor symp chloride. toms associated with Huntington's disease. The chemical 0022. The invention also provides a composition com name of pridopidine is 4-(3-(Methylsulfonyl)phenyl)-1-pro prising Compound 8, wherein the amount of Compound 11 pylpiperidine, and its Chemical Registry Number is CAS present in the composition is less than 0.30% by weight or 34.6688-38-8 (CSID:797 1505, 2016). The Chemical Regis less than 0.15% by weight. try number of pridopidine hydrochloride is 882737-42-0 0023 The invention also provides, a composition com (CSID:25948790 2016). Processes of synthesis of pridopi prising pridopidine HCl, wherein the amount of Compound dine and a pharmaceutically acceptable salt thereof are 4 present in the composition is less than 0.15% by weight or disclosed in U.S. Pat. No. 7,923,459. U.S. Pat. No. 6,903, less than 0.10% by weight. 120 claims pridopidine for the treatment of Parkinson's 0024. The invention also provides, a composition com disease, dyskinesias, dystonias, Tourette's disease, iatro prising Compound 9, wherein the amount of Compound 12 genic and non-iatrogenic psychoses and hallucinoses, mood present in the composition is less than 0.30% by weight. and anxiety disorders, sleep disorder, autism spectrum dis 0025. The invention also provides, a composition com order, ADHD, Huntington's disease, age-related cognitive prising pridopidine HCl, wherein the amount of Compound impairment, and disorders related to alcohol abuse and 13 present in the composition is less than 0.15% by weight. narcotic Substance abuse. 0004 US Patent Application Publication Nos. DETAILED DESCRIPTION OF THE 20140378508 and 20150202302, describe methods of treat INVENTION ment with high doses of pridopidine and modified release formulations of pridopidine, respectively. 0026. The present invention is based in part on the identification of a method to synthesize solid pridopidine BRIEF SUMMARY OF THE INVENTION base that can be used perse or converted to a salt for use as a drug Substance. 0005. This invention provides a pridopidine base in a 0027. The known process for the synthesis of pridopidine solid form. HCl is flawed in that it requires, inter alia, harsh conditions 0006. This invention also provides a composition com including extreme temperatures (e.g. lithiation at less than prising pridopidine base. -35° C. and elimination at 110° C.), distillation and extrac 0007. This invention also provides a composition com tions. The present disclosure provides, inter alia, an opti prising pridopidine base, wherein the composition is free of mized process for the synthesis of solid form of pridopidine isopropyl alcohol. base, which can be used per se or converted to a salt, 0008. In some embodiments, the composition is free of including pridopidine HC1. chloride or free of pridopidine hydrochloride. 0028. This invention provides a pridopidine base in a 0009. This invention also provides a pharmaceutical solid form. composition comprising pridopidine base. 0029. This invention also provides a composition com 0010. This invention also provides a process for prepar prising pridopidine base. ing solid pridopidine base comprising 0030 This invention also provides a composition com 0011 a) obtaining a solution comprising pridopidine prising pridopidine base, wherein the composition is free of base, and isopropyl alcohol. 0012 b) precipitating pridopidine base from the solu 0031. In an embodiment, the composition is free of tion to form solid pridopidine base. chloride or free of pridopidine hydrochloride. 0013 This invention also provides a process for prepar 0032. This invention also provides a pharmaceutical ing pridopidine hydrochloride from pridopidine free base composition comprising pridopidine base. In some embodi compr1S1ng ments the pharmaceutical composition is free of isopropyl 0014) a) obtaining solid pridopidine free base, alcohol. In some embodiments, the pharmaceutical compo 0015 b) dissolving solid pridopidine free base in an sition is free of chloride or free of pridopidine hydrochlo alcohol to form a solution, ride. US 2017/0022.158 A1 Jan. 26, 2017 0033. This invention also provides a process for prepar 0053. In an embodiment, the catalyst is a JM type 402 ing solid pridopidine base comprising catalyst. 0034 a) obtaining a solution comprising pridopidine 0054. In an embodiment, the amount of the reduction base, and catalyst is present in an amount of 5%-20% w/w, 5%-15% 0035 b) precipitating pridopidine base from the solu w/w, 5%–12% w/w, 8%-10% w/w, about 10% w/w or about tion to form solid pridopidine base. 8% w/w. In an embodiment, the catalytic reduction is 0036. In an embodiment, the process further comprises complete in 0.1-20 hours, 0.1-10 hours, 0.1-5 hours, 0.5-5 precipitating pridopidine base with a Volume of one or more hours, 0.5-1 hour or about 50 minutes. alkanes. 0055. In an embodiment, the predetermined reduction 0037. In an embodiment, the alkane is n-heptane. temperature is 5-60° C., 30-50° C., 40-50° C., 36-50° C. or 0038. In an embodiment, the solution comprises one or about 40° C. more organic solvents or water, or a mixture thereof. 0056. In an embodiment, the predetermined reduction 0039. In an embodiment, the solution is a mixture of temperature is 0-39° C., 0-35° C., 0-30° C., 10-30° C., or toluene and water. 20-30° C. 0040. In an embodiment, the process further comprises 0057. In an embodiment, the pridopidine base formed is adding a strong base to the solution. free of pridopidinium. 0041. In an embodiment, the strong base is NaOH. 0058. In an embodiment, the catalyst is a JM type 402 0042. In an embodiment, the strong base is added until catalyst and the amount of the JM type 402 catalyst present the pH of the solution is pH 8-14, pH 11-14 or about pH 13. in the reaction is 8%-10% w/w. 0043. In an embodiment, the solution comprises an aque ous layer and an organic layer, and the process further 0059. In an embodiment, the reaction is complete after comprises separating the organic layer from the aqueous 0.1-2 hours, 0.1-1 hours, about 1 hour or about 50 minutes. layer and washing the organic layer with water. 0060. In an embodiment, the process further comprises 0044. In an embodiment, the step of washing the organic dissolving Compound 8 in water. layer with water removes Compound 1 from the organic 0061. In an embodiment, the process further comprises layer. comprising mixing Compound 8 with a weak acid. 0045. In an embodiment, the process further comprises 0062. In an embodiment, the weak acid is formic acid. forming the pridopidine base with a chemical purity in 0063. In an embodiment, the process further comprises which the weight percent of Compound 1 is less than 0.2% cold addition to prevent the formation of pridopidinium. or less than 0.15% of the total amounts of pridopidine base 0064. In an embodiment, the process further comprises and Compound 4. oxidizing the sulfide of Compound 10: 0046. In an embodiment, the process further comprises removing an amount of the organic solvent under vacuum distillation to obtain a mixture comprising a volume of the Compound 10 organic solvent.
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