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WO2012041707A1 - Procédé de fabrication de fingolimod - Google Patents

Procédé de fabrication de fingolimod Download PDF

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Publication number
WO2012041707A1
WO2012041707A1 PCT/EP2011/065975 EP2011065975W WO2012041707A1 WO 2012041707 A1 WO2012041707 A1 WO 2012041707A1 EP 2011065975 W EP2011065975 W EP 2011065975W WO 2012041707 A1 WO2012041707 A1 WO 2012041707A1
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WIPO (PCT)
Prior art keywords
compound
formula
process according
fingolimod
reaction
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/EP2011/065975
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English (en)
Inventor
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
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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 CN2011800514156A priority Critical patent/CN103189349A/zh
Priority to EP11758448.2A priority patent/EP2621886B1/fr
Priority to ES11758448.2T priority patent/ES2682649T3/es
Publication of WO2012041707A1 publication Critical patent/WO2012041707A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 627406 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 compound of formula (11) and/or (14)
  • the invention provides for a process for making the compound of formula (1 1) comprising reacting the compound of formula (8) with a strong acid, most preferably p-toluene sulfonic acid, in an organic anhydrous solvent.
  • a strong acid most preferably p-toluene sulfonic acid
  • the invention provides for a process of making fingolimod of formula
  • a hydrogenation catalyst preferably palladium catalyst
  • the present invention also provides for a process of making fingolimod of formula (1), or an acid addition salt thereof, comprising the step of reacting the compound of formula (8) in a non-aqueous solvent with hydrogen under catalysis of a hydrogenation catalyst, preferably palladium catalyst, and in presence of a strong acid, preferably p-toluene sulfonic acid or hydrogen chloride.
  • a hydrogenation catalyst preferably palladium catalyst
  • the invention provides a process for making the compound (8) comprising the reaction of compound (9)
  • the present invention deals with an improved 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.
  • acid addition salts 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 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 extraction from an aqueous solution with a suitable water immiscible solvent.
  • nitro-alcohol (9) is converted to the next fingolimod intermediate, a hydroxylated nitro-diol (8), by a hydroxymethylation reaction with two molecules of formaldehyde.
  • the prior art uses paraformaldehyde as the source of formaldehyde.
  • the process employing 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 conversion may be either direct, by a 48 hour hydrogenation by hydrogen catalyzed by Pd/C, performed in concentrated aqueous HC1 and methanol, or it may run indirectly via the compound (6).
  • the conversion to the compound (6) by Pd-catalyzed hydrogenation takes also 48 hours, and the subsequent reduction of the compound (6) to the desired product takes the next 20 hours.
  • the overall conversion time of the compound (8) to fingolimod (1) may be dramatically decreased if the compound (8) is subjected to a reaction with a strong acid in an inert organic solvent, which is typically non-aqueous.
  • a strong acid in an inert organic solvent, which is typically non-aqueous.
  • the preferred strong acid is a sulfonic acid, preferably methane sulfonic acid, benzene sulfonic acid and most preferably p-toluene sulfonic acid, anhydrous hydrogen chloride or hydrogen bromide, sulphuric acid, phosphoric acid, perchloric acid, trifluoroacetic acid.
  • Strongly acidic ion-exchange resins may also serve as a strong acid for purpose of this process.
  • the preferred inert nonaqueous solvent is an aliphatic or aromatic hydrocarbon of 5 to 12 carbons, most preferably toluene, an aliphatic alcohol of 1 to 6 carbons, most preferably methanol and/or an aliphatic ester, most preferably ethyl acetate.
  • the reactive contact of the compound (8) with a strong acid in an inert nonaqueous solvent results in removing the benzylic OH- group and in forming a substrate, which, as will appear in the next steps, is very reactive in the hydrogenation reaction. Due to this reactive contact of the compound (8) with the acid in the nonaqueous solvent, the hydrogenation to the compound (1) may be finalized in less than 4 hours.
  • the strong acid first protonates the benzylic -OH group.
  • a molecule of water is then split upon forming a reactive substrate of the formula (15). Its further fate depends on the reaction conditions.
  • the unstable compound (15) is stabilized by cyclization upon forming the compound of formula (11).
  • Such compound is adequately reactive for the hydrogenation reaction; it can alternately be isolated from the reaction mixture, if desirable, and subjected to the hydrogenation reaction in a subsequent step.
  • 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 or other suitable strong acid in a suitable inert nonaqueous solvent, which is typically an aliphatic or aromatic hydrocarbon, preferably of 5 to 12 carbon atoms, most preferably toluene, or an aliphatic alcohol, preferably of 1 to 6 carbon atoms, most preferably methanol.
  • a suitable inert nonaqueous solvent which is typically an aliphatic or aromatic hydrocarbon, preferably of 5 to 12 carbon atoms, most preferably toluene, or an aliphatic alcohol, preferably of 1 to 6 carbon atoms, most preferably methanol.
  • Useful molar ratio between the compound of formula (8) and the strong acid is from 10 : 1 to 1 : 3.
  • 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.
  • a suitable hydrogenation catalyst such as a palladium- or platinum comprising catalyst.
  • Other suitable catalyst may be, e.g., Raney- nickel.
  • 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 (11) 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 (11) 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 (11) has two chiral carbons and may exist in four (two pairs of) diastereomers differing by spatial orientation of substituents at the five-membered ring. Any of the diastereomers is equally suitable for making fingolimod according to the present invention. Therefore, the compound of formula (11) may be used in the process for making fingolimod as a mixture of diastereomers, as well as in a form of any of the single diastereomer or a pair thereof.
  • the compound of formula (11) has two centers that must be hydrogenated for to obtain fingolimod - the five-membered ring 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. For instance, the ring- opening reaction leading to (6) is preferred at higher temperatures, while hydrogenation reaction at lower temperatures runs preferably via the intermediate (14).
  • 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) exhibits two chiral carbons and may exist as any of four possible diastereomers.
  • 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 or anhydrous hydrogen chloride.
  • a strong acid e.g. p-toluenesulfonic acid or anhydrous hydrogen chloride.
  • the reactive intermediate (15) formed by the action of the strong acid is preferentially transformed by the reaction with hydrogen directly to the compound (6), essentially without forming the compound (11).
  • the conversion of (8) to (6) is then essentially a one-step technological process; however, contrary to a similar process disclosed in CN '869, the presence of strong anhydrous acid substantially increases the speed of the reaction and, accordingly, dramatically shortens the necessary reaction time.
  • hydrogenation over palladium catalyst and in presence of anhydrous hydrogen chloride may proceed at a temperature, which is ambient or close to ambient, and at low pressure of hydrogen (about 1 bar and/or , in some embodiments, even less than 1 bar), whereby full conversion (96-98%) may be obtained in few hours.
  • reaction partners solvent, catalyst, strong acid
  • reaction partners solvent, catalyst, strong acid
  • the process generally runs at milder conditions than that in the variant a] (i.e. lower amount of the acid, lower pressure and lower temperature of the hydrogenation , typically from 10 to 60C, are necessary for the full conversion).
  • the compound (6) may be isolated from the reaction mixture, if desirable, by conventional procedures and may be subjected by a separate reduction reaction of the nitro- group.
  • any suitable reductant may be used; except of a hydrogenation reaction with hydrogen under a presence of a hydrogenation catalyst, also a chemical reduction may be used, e.g. by a hydride, a dithionite, a borane, sodium sulfite etc.
  • the compound (6) is not isolated from the reaction mixture and the hydrogenation of the compound (8) is directed in such a way that full conversion of the compound (8) to fingolimod of formula (1) is obtained.
  • a full hydrogenation over palladium catalyst may be obtained at temperatures between 30 - 50°C and at a hydrogen pressure of between 1-50 bar.
  • the fingolimod compound obtained 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.
  • fingolimod free base may be purified by a recrystallization from ethyl acetate, in which the crystalline polymorphic form A is obtained.
  • Fingolimod may be used as a pharmaceutically active compound for making pharmaceutical compositions for treatment various diseases, as shown in the art.
  • the crude product was recrystallized from a mixture of heptane and ethyl acetate, yielding a white solid in a yield of 2.06 g (52%) with a purity of>99%.
  • Crude product can be crystallized from pentane with yield 80% and purity 99.9% (HPLC IN).
  • 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. After this time, hydrogen pressure was interrupted and internal temperature decreased to 30°C.
  • 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.
  • Autoclave vessel was loaded with 3-(hydroxymethyl)-3-nitro-l-(4-octylphenyl)butane- 1,4-diol (10 g, 28.2 mmol) dissolved in MeOH (100 ml) followed by the addition of palladium /C (10%) (3.00 g, 2.82 mmol) and hydrogen chloride solution in 2-propanol (0.539 ml, 2.82 mmol). System was stirred under hydrogen pressure (less than 1 bar) at room temperature.
  • Autoclave vessel was loaded with (3-nitro-5-(4-octylphenyl)tetrahydrofuran-3-yl)- methanol (compound (11), 5 g, 14.91 mmol) dissolved in methanol (100 ml) followed addition of palladium/C (10%) (anhydrous) (1.586 g, 1.491 mmol) and hydrogen chloride solution in 2-propanol (11.23 ml, 59.6 mmol).
  • the autoclave was flushed twice with nitrogen and pressurized with hydrogen up to 35 bars and heated to 100°C.
  • the reaction mixture was stirred (600 rpm) at this temperature for 2 hours. After this time was internal temperature of reaction mixture decreased to 30°C and filtered over celite. MeOH was evaporated (40°C, 210-15 mbar) to dryness.
  • Autoclave vessel was loaded with (3-nitro-5-(4-octylphenyl)tetrahydrofuran-3- yl)methanol (2 g, 5.96 mmol) dissolved in toluene (60 ml) followed by the addition of palladium/C (5%) (0.063 g, 0.596 mmol). Autoclave was flushed twice with nitrogen and pressurized with hydrogen up to 35 bar at 30°C (600 rpm).
  • fingolimod 0.5 g was dissolved in 6 ml of ethyl acetate at reflux. The solution was allowed to cool to room temperature. As a result, a solid was formed rapidly. The solid was isolated by filtration over a P3-glass filter (reduced pressure) and air-dried overweekend at room temperature. White to off-white aggregates of thin flakes were obtained. The yield was 0.45 g.
  • Apparatus XRPD Bruker-AXS D8 vario, ⁇ /2 ⁇ geometry, reflection mode, Vantec PSD detector
  • Scan step time between 0.2-2.0 seconds

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  • 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

L'invention concerne un procédé de fabrication de fingolimod de formule (1), ou d'un sel d'addition d'acide de celui-ci, comprenant une étape de mise en réaction d'un composé de formule (11) et/ou d'un composé de formule (14) ou d'un sel d'addition acide de celui-ci, dans un solvant avec de l'hydrogène en présence d'un catalyseur d'hydrogénation, de préférence, d'un catalyseur de palladium, et une étape de conversion éventuelle du fingolimod de formule (1) en un sel d'addition d'acide. L'invention concerne également des composés de formules (11) et (14), leurs procédés de fabrication et leur utilisation dans la fabrication de fingolimod.
PCT/EP2011/065975 2010-10-01 2011-09-15 Procédé de fabrication de fingolimod Ceased WO2012041707A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN2011800514156A CN103189349A (zh) 2010-10-01 2011-09-15 制备芬戈莫德的方法
EP11758448.2A EP2621886B1 (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 (4)

Application Number Priority Date Filing Date Title
EPPCT/EP2010/006039 2010-10-01
PCT/EP2010/006039 WO2012041359A1 (fr) 2010-10-01 2010-10-01 Procédé de fabrication du fingolimod
EPPCT/EP2010/070535 2010-12-22
PCT/EP2010/070535 WO2012041405A1 (fr) 2010-10-01 2010-12-22 Procédé de fabrication du fingolimode

Publications (1)

Publication Number Publication Date
WO2012041707A1 true WO2012041707A1 (fr) 2012-04-05

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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

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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

Country Status (3)

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

Cited By (3)

* 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
WO2015107548A1 (fr) 2014-01-07 2015-07-23 Emcure Pharmaceuticals Limited Procédé de préparation de fingolimod amélioré
EP2658840B1 (fr) * 2010-12-28 2019-07-03 Synthon BV Procédé de fabrication de cristaux de chlorhydrate de fingolimod

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US9216943B2 (en) * 2011-04-29 2015-12-22 Dr. Reddy's Laboratories Ltd. Preparation of fingolimod and its salts
AU2014206588A1 (en) * 2013-01-17 2015-07-23 Shilpa Medicare Limited Process for preparation of Fingolimod and its salts
WO2014111949A1 (fr) * 2013-01-21 2014-07-24 Natco Pharma Limited Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur
KR102255357B1 (ko) * 2013-03-05 2021-05-24 바이오콘 리미티드 2-아미노-1,3-프로판디올 화합물 및 이의 염의 제조방법
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
WO2020165672A1 (fr) 2019-02-15 2020-08-20 Shivalik Rasayan Limited Procédé de préparation de chlorhydrate de fingolimod pur

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2658840B1 (fr) * 2010-12-28 2019-07-03 Synthon BV Procédé de fabrication de cristaux de chlorhydrate de fingolimod
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
WO2015107548A1 (fr) 2014-01-07 2015-07-23 Emcure Pharmaceuticals Limited Procédé de préparation de fingolimod amélioré

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