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WO2012041359A1 - Procédé de fabrication du fingolimod - Google Patents

Procédé de fabrication du fingolimod Download PDF

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Publication number
WO2012041359A1
WO2012041359A1 PCT/EP2010/006039 EP2010006039W WO2012041359A1 WO 2012041359 A1 WO2012041359 A1 WO 2012041359A1 EP 2010006039 W EP2010006039 W EP 2010006039W WO 2012041359 A1 WO2012041359 A1 WO 2012041359A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
reaction
making
fingolimod
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/006039
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English (en)
Inventor
Jozef Krajcovic
Reinerus Gerardus Gieling
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Priority to PCT/EP2010/006039 priority Critical patent/WO2012041359A1/fr
Priority to PCT/EP2010/070535 priority patent/WO2012041405A1/fr
Priority to EP11758448.2A priority patent/EP2621886B1/fr
Priority to CN2011800514156A priority patent/CN103189349A/zh
Priority to PCT/EP2011/065975 priority patent/WO2012041707A1/fr
Priority to ES11758448.2T priority patent/ES2682649T3/es
Publication of WO2012041359A1 publication Critical patent/WO2012041359A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
    • C07C205/16—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • Fingolimod (often coded as FTY 720), chemically 2-amino-2-[2-(4- octylphenyl)ethyl]-propane-l ,3-diol of the formula (1)
  • fingolimod hydrochloride is the most common one.
  • Fingolimod has been first disclosed in EP 627 406 of Yoshitomi, where also two basic routes for making it have been described.
  • the last synthetic step comprises
  • the last synthetic step comprises reduction of a diester-amine (4)
  • a third process was disclosed in Chinese patent CN 1212308C and comprises reduction of a nitro-diester (10):
  • the present invention provides for a new process of making fmgolimod of formula (1),
  • a hydrogenation catalyst preferably palladium catalyst, optionally followed by converting fmgolimod of formula (1) into an acid addition salt.
  • the invention also provides a process for making the compound of formula (1 1) comprising a step of reacting the compound of formula (8)
  • the present invention provides a process of making fingolimod of formula (1), or an acid addition salt thereof, comprising a step of reacting the compound of formula (8) in a solvent with hydrogen in presence of a hydrogenation catalyst, preferably palladium catalyst, and in presence of a strong acid, preferably p-toluene sulfonic acid, and optionally converting fingolimod of formula (1) into an acid addition salt.
  • a hydrogenation catalyst preferably palladium catalyst
  • a strong acid preferably p-toluene sulfonic acid
  • the invention provides a process for making the compound (8) comprising the reaction of compound (9)
  • nitro-alkene intermediate of formula (1 1), the amino-alkene intermediate of formula (14) and/or their use in making fingolimod form other specific aspects of the present invention.
  • the present invention deals with a new and advantageous process for making the compound fingolimod of formula (1), or an acid addition salt thereof, from the compound of formula (9), which exhibits various advantages over other ways of conversion of compound (9) to the compound (1) known in the art.
  • the advantages are discussed on the relevant places of further description.
  • the "acid addition salts” as used throughout the invention are typically those allowed for pharmaceutical use by regulatory authorities, e.g., hydrochloride, hydrobromide, sulphate, nitrate , phosphate, formate, acetate, propionate, oxalate, malonate, maleate, fumarate, citrate, malate and the like. These acid addition salts may be obtained by any conventional methods.
  • the starting material of the process is a known compound.
  • the process of making it has been disclosed in CN 1310869 and is based on a reduction of a nitro-ketone of formula (12) with sodium borohydride. While this process is generally useful, it suffers from a problem, that it is sometimes accompanied with a formation of a des-nitro impurity of formula (13).
  • the compound (9) may be made by reacting the nitroketone of formula (12) by lithium borohydride in a solvent.
  • the useful reaction solvent is ,e.g., tetrahydrofuran.
  • the convenient reaction temperature is from -20 to 0°C.
  • the molar ratio of the starting ketone and the hydride is advantageously about 2 : 1 .
  • the course of the reaction may be
  • reaction product may be isolated from the reaction mixture, e.g. by extraction from an aqueous solution with a suitable water immiscible solvent.
  • nitro-alcohol (9) is converted to the next finglolimod intermediate, a hydroxylated nitro-diol (8), by a hydroxymethylation reaction with two molecules of formaldehyde.
  • paraformaldehyde however suffers from a certain disadvantage, as a formaldehyde polymer is formed in the reaction mixture.
  • This formaldehyde polymer very firmly adheres on walls of reaction vessels and auxiliary equipment such as stirrers and thermometers, which requires extensive cleaning of the vessel and auxiliaries after the reaction.
  • the polymer also impurifies the reaction mixture and the reaction product.
  • paraformaldehyde may be advantageously replaced by an aqueous solution of formaldehyde stabilized by methanol (formalin).
  • the reaction then may be performed in an aqueous environment, which is economically advantageous, whereby the methanol present in the formalin agent stabilizes formaldehyde against forming undesirable polymers.
  • the nitro-alcohol (9) reacts with an aqueous solution of formaldehyde under presence of methanol, which advantageously is the commercially available 20 % or 37% solution of formaldehyde in water comprising about 10% of methanol.
  • the reaction temperature is advantageously from 30 to 60°C, preferably from 45 to 50°C.
  • Useful molar ratio between compound (9) and formaldehyde is from 1 : 3 to 1 : 8.
  • the course of the reaction may be advantageously monitored by a suitable analytical technique, e.g. by HPLC or TLC.
  • the reaction product may be isolated from the reaction mixture, e.g. by an extraction from an aqueous solution by a water- immiscible solvent.
  • the hydroxymethylation of (9) may be also performed by a reaction with methylal (formaldehyde dimethylacetal).
  • the hydroxylated nitro-diol (8) is converted to fingolimod (1) by substitution of the alpha-positioned OH-group by hydrogen and reduction of the nitro- group to amino group.
  • the conversion may be either direct, by a 48 hour reduction by hydrogen catalysed by Pd/C, performed in concentrated HCl and methanol, or it may run indirectly via the compound (6).
  • the conversion to the compound (6) by Pd- catalysed hydrogenation takes also 48 hours, and the subsequent reduction of the compound (6) to the desired product takes the next 20 hours.
  • the reaction times are extremely long, which makes the process economically very inconvenient.
  • Such conversion is achieved by a reaction of the compound (8) with a strong acid, preferably a sulfonic acid, most preferably p-toluene sulfonic acid.
  • a strong acid preferably a sulfonic acid, most preferably p-toluene sulfonic acid.
  • Other possible acids may be, e.g., sulphuric acid, phosphoric acid, perchloric acid, hydroiodic acid , methane sulfonic acid, benzene sulfonic acid or trifluoroacetic acid.
  • the compound (8) is heated, preferably at a temperature of at least 40°C and most preferably under reflux conditions , with p-toluene sulfonic acid in a suitable inert solvent, which is typically an aliphatic or aromatic hydrocarbon, most preferably toluene, or an aliphatic alcohol, most preferably methanol.
  • a suitable inert solvent typically an aliphatic or aromatic hydrocarbon, most preferably toluene, or an aliphatic alcohol, most preferably methanol.
  • Useful molar ratio between the compound of formula (8) and p- toluenesulfonic acid is from 10 : 1 to 1 : 3.
  • the course of the reaction may be advantageously monitored by a suitable analytical technique, e.g by HPLC or TLC.
  • the reaction product may be isolated from the reaction mixture by an extraction of an alkalinized aqueous solution with a water-immiscible organic solvent, e.g. by toluene or ethyl acetate.
  • a water-immiscible organic solvent e.g. by toluene or ethyl acetate.
  • the compound of formula (1 1) is converted to the desired fingolimod of the formula(l) by a reaction with hydrogen under catalysis by a suitable hydrogenation catalyst, such as a palladium- or platinum comprising catalyst.
  • a suitable hydrogenation catalyst such as a palladium- or platinum comprising catalyst.
  • the hydrogenation reaction runs in a suitable inert solvent, e.g. in an aliphatic or aromatic hydrocarbon such as toluene or in an aliphatic alcohol such as methanol; otherwise the reaction mixture serves as the reaction medium.
  • CN '869 i.e. using Pd/C as the hydrogenation catalyst
  • the reaction time may take 60 - 180 minutes, i.e. is dramatically shorter.
  • the compound of formula (1 1) is thus a very useful intermediate for making fingolimod, as it provides the desired product by a far shorter process than that of the prior art.
  • the compound of formula (1 1) is subjected to the hydrogenation reaction under catalysis by palladium on carbon.
  • the hydrogenation is performed under a hydrogen pressure of about 30 - 50 bar and/or at a temperature from 25 to 100 °C.
  • the course of the reaction may be advantageously monitored by a suitable analytical technique, e.g. by HPLC or TLC.
  • the reaction product may be isolated from the reaction mixture , e.g. by an extraction of an alkalinized aqueous solution with a water-immiscible solvent, e.g. by toluene or ethyl acetate.
  • the compound of formula (1 1) may exist in two possible forms differing by spatial orientation of substituents along the double bond, the E-isomer and/or Z-isomer. Both isomers are equally suitable for making fingolimod according to the present invention. Therefore, the compound of formula (1 1) may be used in the process for making fingolimod as a mixture of E/Z-isomers, as well as in a form of any of the single E- isomer or Z- isomer.
  • the compound of formula (1 1) has two centers that must be hydrogenated for to obtain fingolimod - the double bond and the nitro-group.
  • the hydrogenation reaction may run via two possible intermediates (6) and (14), resp.:
  • Both reactions may proceed in parallel or one of the reaction pathways may be significantly preferred. This depends primarily on the nature of the chosen catalyst, pH of the reaction mixture, nature of the solvent and the reaction temperature. However, in general, it is not essential for purpose of the present invention whether the reaction will run via the compound (6) or compound (14). If it is necessary or desirable, any of the intermediates (6) and (14) may be isolated for the reaction mixture, as a free compound or as an acid addition salt thereof, and subjected to the conversion to fingolimod of formula (1) in a separate step.
  • the compound (14) may exist as an E-isomer and/or Z- isomer.
  • the present invention also refers to a convenient variant of the above processes, which comprises direct making the fingolimod of formula (1) by a catalytic hydrogenation of the compound (8) in the presence of a strong acid, e.g. p-toluenesulfonic acid. It is presumed that the reaction runs via the intermediate (1 1), which is immediately transformed further by the reaction with hydrogen.
  • the conversion of (8) to (1) is then essentially a one-step technological process; however, contrary to a similar process disclosed in CN '869, the presence of p-toluene sulfonic acid or other strong acid substantially increases the speed of the reaction and , accordingly, dramatically shortens the necessary reaction time.
  • the reaction conditions (solvent, catalyst, strong acid) of this variant of the process are, mutatis mutandis, the same as those disclosed above for the respective steps.
  • the fingolimod compound produced by the process of the present invention may be isolated as a free base or preferably in a form of an acid addition salt, advantageously in a form of hydrochloride, and purified by processes known in the art. It may be used as a pharmaceutically active compound for making pharmaceutical compositions for treatment various diseases, as shown in the art.
  • the present invention is illustrated by following non-limiting examples .
  • Autoclave vessel was loaded with p-toluenesulfonic acid monohydrate (8.04 g, 42.3 mmol), and with 3-(hydroxymethyl)-3-nitro-l-(4-octylphenyl)butane-l ,4-diol (5 g, 14.13 mmol) dissolved in MeOH (100 ml) followed by the addition of palladium /C (1.5 g, 1.410 mmol) . Autoclave was flushed twice with nitrogen and pressurized with hydrogen to 50 bar. The reaction mixture was hydrogenated at 50°C and 600rpm.Total reaction time was 230 min.
  • the mixture was stored to freezer at -12°C for 18 h.
  • the solid material was filtered off, washed with 2x5 ml of ethyl acetate and dried at 30°C, and 10 mbar for 120 min.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé de fabrication du fingolimod, représenté par la formule (1), ou de l'un de ses sels d'addition acides. Ce procédé consiste à faire réagir, dans un solvant, le composé représenté par la formule (11), et/ou un composé représenté par la formule (14), ou l'un de leurs sels d'addition acides, avec l'hydrogène, en présence d'un catalyseur d'hydrogénation, de préférence en présence d'un catalyseur au palladium. Le procédé pourra éventuellement consister ensuite à convertir en un sel d'addition acide le fingolimod représenté par la formule (1). L'invention concerne également des composés représentés par les formules (11) et (14), et leur utilisation dans l'élaboration du fingolimod.
PCT/EP2010/006039 2010-10-01 2010-10-01 Procédé de fabrication du fingolimod Ceased WO2012041359A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PCT/EP2010/006039 WO2012041359A1 (fr) 2010-10-01 2010-10-01 Procédé de fabrication du fingolimod
PCT/EP2010/070535 WO2012041405A1 (fr) 2010-10-01 2010-12-22 Procédé de fabrication du fingolimode
EP11758448.2A EP2621886B1 (fr) 2010-10-01 2011-09-15 Procédé de fabrication de fingolimod
CN2011800514156A CN103189349A (zh) 2010-10-01 2011-09-15 制备芬戈莫德的方法
PCT/EP2011/065975 WO2012041707A1 (fr) 2010-10-01 2011-09-15 Procédé de fabrication de fingolimod
ES11758448.2T ES2682649T3 (es) 2010-10-01 2011-09-15 Proceso de preparación de fingolimod

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2010/006039 WO2012041359A1 (fr) 2010-10-01 2010-10-01 Procédé de fabrication du fingolimod

Publications (1)

Publication Number Publication Date
WO2012041359A1 true WO2012041359A1 (fr) 2012-04-05

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Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/EP2010/006039 Ceased WO2012041359A1 (fr) 2010-10-01 2010-10-01 Procédé de fabrication du fingolimod
PCT/EP2010/070535 Ceased WO2012041405A1 (fr) 2010-10-01 2010-12-22 Procédé de fabrication du fingolimode
PCT/EP2011/065975 Ceased WO2012041707A1 (fr) 2010-10-01 2011-09-15 Procédé de fabrication de fingolimod

Family Applications After (2)

Application Number Title Priority Date Filing Date
PCT/EP2010/070535 Ceased WO2012041405A1 (fr) 2010-10-01 2010-12-22 Procédé de fabrication du fingolimode
PCT/EP2011/065975 Ceased WO2012041707A1 (fr) 2010-10-01 2011-09-15 Procédé de fabrication de fingolimod

Country Status (3)

Country Link
CN (1) CN103189349A (fr)
ES (1) ES2682649T3 (fr)
WO (3) WO2012041359A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539683A (zh) * 2012-07-17 2014-01-29 广东东阳光药业有限公司 治疗硬化病的药物的新晶型及其制备方法
WO2014111949A1 (fr) * 2013-01-21 2014-07-24 Natco Pharma Limited Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur
WO2015107548A1 (fr) 2014-01-07 2015-07-23 Emcure Pharmaceuticals Limited Procédé de préparation de fingolimod amélioré
EP2945927A4 (fr) * 2013-01-17 2017-01-18 Shilpa Medicare Limited Procédé pour la préparation de fingolimod et de ses sels
US11518733B2 (en) 2019-02-15 2022-12-06 Shivalik Rasayan Limited Process for preparation of highly pure Fingolimod hydrochloride

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2746016T3 (es) * 2010-12-28 2020-03-04 Synthon Bv Procedimiento para la preparación de cristales de clorhidrato de fingolimod
WO2012146980A2 (fr) * 2011-04-29 2012-11-01 Dr. Reddy's Laboratories Ltd. Préparation du fingolimod et ses sels
CA2903708C (fr) * 2013-03-05 2021-07-13 Biocon Limited Procede pour la preparation de composes de 2-amino-1,3-propanediol et de sels de ceux-ci
US9078241B2 (en) * 2013-03-22 2015-07-07 Sharp Kabushiki Kaisha Systems and methods for establishing multiple radio connections
CN103724215A (zh) * 2013-11-28 2014-04-16 镇江圣安医药有限公司 2-氨基-2-[2-(4-辛基苯基)乙基]-1,3-丙二醇的新型衍生物及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0627406A1 (fr) 1992-10-21 1994-12-07 Yoshitomi Pharmaceutical Industries, Ltd. Compose 2-amino-1,3-propanediol et immunosuppresseur
CN1310869A (zh) 1998-05-22 2001-08-29 莱珀技术有限公司 提供电接触的装置
CN1212308C (zh) 2003-07-24 2005-07-27 漆又毛 2－氨基－2－（2－（4－辛基苯基）乙基）－1，3－丙二醇盐酸盐的制备方法
CN1765872A (zh) * 2005-11-22 2006-05-03 江苏吴中苏药医药开发有限责任公司 2－氨基－2－[2－(4－烷基苯基)乙基]－1,3－丙二醇的制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101610674A (zh) * 2006-12-21 2009-12-23 艾博特公司 鞘氨醇-1-磷酸酯受体激动剂和拮抗剂化合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0627406A1 (fr) 1992-10-21 1994-12-07 Yoshitomi Pharmaceutical Industries, Ltd. Compose 2-amino-1,3-propanediol et immunosuppresseur
CN1310869A (zh) 1998-05-22 2001-08-29 莱珀技术有限公司 提供电接触的装置
CN1212308C (zh) 2003-07-24 2005-07-27 漆又毛 2－氨基－2－（2－（4－辛基苯基）乙基）－1，3－丙二醇盐酸盐的制备方法
CN1765872A (zh) * 2005-11-22 2006-05-03 江苏吴中苏药医药开发有限责任公司 2－氨基－2－[2－(4－烷基苯基)乙基]－1,3－丙二醇的制备方法
CN1310869C (zh) 2005-11-22 2007-04-18 江苏吴中苏药医药开发有限责任公司 2－氨基－2－[2－(4－烷基苯基)乙基]－1,3－丙二醇的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BISWAJIT KALITA, NABIN C. BARUA, MAITREYEE BEZBARUA, GHANASHYAM BEZ: "Synthesis of 2-Nitroalcohols by Regioselective Ring Opening of Epoxides with MgSO4/MeOH/NaNO2 System: A Short Synthesis of Immunosuppressive Agent FTY-720", SYNLETT, 2001, pages 1411 - 1414, XP002607731, DOI: 10.1055/s-2001-16776 *
KALITA ET AL., SYNLETT, no. 9, 2001, pages 1411 - 1414

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539683A (zh) * 2012-07-17 2014-01-29 广东东阳光药业有限公司 治疗硬化病的药物的新晶型及其制备方法
EP2945927A4 (fr) * 2013-01-17 2017-01-18 Shilpa Medicare Limited Procédé pour la préparation de fingolimod et de ses sels
WO2014111949A1 (fr) * 2013-01-21 2014-07-24 Natco Pharma Limited Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur
WO2015107548A1 (fr) 2014-01-07 2015-07-23 Emcure Pharmaceuticals Limited Procédé de préparation de fingolimod amélioré
US11518733B2 (en) 2019-02-15 2022-12-06 Shivalik Rasayan Limited Process for preparation of highly pure Fingolimod hydrochloride

Also Published As

Publication number Publication date
CN103189349A (zh) 2013-07-03
WO2012041707A1 (fr) 2012-04-05
WO2012041405A1 (fr) 2012-04-05
ES2682649T3 (es) 2018-09-21

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