WO2012041405A1 - Process for making fingolimod - Google Patents

Process for making fingolimod Download PDF

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Publication number
WO2012041405A1
WO2012041405A1 PCT/EP2010/070535 EP2010070535W WO2012041405A1 WO 2012041405 A1 WO2012041405 A1 WO 2012041405A1 EP 2010070535 W EP2010070535 W EP 2010070535W WO 2012041405 A1 WO2012041405 A1 WO 2012041405A1
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Prior art keywords
compound
formula
process according
fingolimod
reaction
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PCT/EP2010/070535
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French (fr)
Inventor
Jozef Krajzovic
Reinerus Gerardus Gieling
Bohumil Dymacek
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Synthon B.V.
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Priority to ES11758448.2T priority Critical patent/ES2682649T3/en
Priority to EP11758448.2A priority patent/EP2621886B1/en
Priority to PCT/EP2011/065975 priority patent/WO2012041707A1/en
Priority to CN2011800514156A priority patent/CN103189349A/en
Publication of WO2012041405A1 publication Critical patent/WO2012041405A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/13Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
    • C07C205/14Compounds 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
    • C07C205/16Compounds 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06Preparation of nitro compounds
    • C07C201/12Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02Preparation 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08Preparation 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02Compounds 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
    • C07C215/22Compounds 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
    • C07C215/28Compounds 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 deacetylation of protected diol-amine (2) by a basic hydrolysis
  • the last synthetic step comprises reduction of a diester-amine (4)
  • the first such process disclosed by Kalita et al. in Synlett 2001, No.9, 1411-1414, comprises, in the last step, a reduction of a nitro-diol (6), which has been prepared by a reaction of a nitro-alkane (7) with paraformaldehyde :
  • 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
  • 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., tetrahydroiuran.
  • 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 finglolimod 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 hydroxylated nitro-diol (8) is converted to fingolimod (1) by substitution of the alpha-positioned to the benzene ring (in further "benzylic") OH- group by hydrogen and reduction of the nitro-group to amino group.
  • 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 reaction times are extremely long, which makes the process economically very inconvenient.
  • 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. 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 .
  • 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%.
  • 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.
  • 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. After 90 minutes of stirring, the pressure of hydrogen was increased to 35 bar and internal temperature increased from 21°C to 50°C (600 rpm). After 70 reaction minutes was reaction mixture filtered over celite and MeOH evaporated (40°C, 210-15 mbar) to dryness.
  • 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).

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

Abstract

The invention relates to a process of making fingolimod of formula (1), or an acid addition salt thereof comprising a step of reacting the compound of formula (11) and/or a compound of formula (14) or an acid addition salt thereof, in a solvent with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, and optionally converting fingolimod of formula (1) into an acid addition salt, to compounds of formula (11) and (14), processes of making them and to their use in making fingolimod.

Description

PROCESS FOR MAKING FINGOLIMOD
[0001] Fingolimod (often coded as FTY 720), chemically 2-amino-2-[2-(4- octylphenyl)ethyl]-propane-l,3-diol of the formula (1)
Figure imgf000002_0001
is a pharmaceutically active compound currently tested as an immunosuppressive drug and as an active agent in treatment of multiple sclerosis. It may form stable acid addition salts, of which fingolimod hydrochloride is the most common one.
[0002] Fingolimod has been first disclosed in EP 627 406 of Yoshitomi, where also two basic routes for making it have been described.
In the first route (Example 28 of EP'406), the last synthetic step comprises deacetylation of protected diol-amine (2) by a basic hydrolysis
Figure imgf000002_0002
(3) (2) (1)
[0003] In the second route (Example 234of EP'406), the last synthetic step comprises reduction of a diester-amine (4)
Figure imgf000002_0003
(5) (4) (1)
[0004] Subsequently, several alternate routes for making fingolimod were developed.
Among them, processes employing reduction of a suitable nitro -intermediate are of considerable interest. The first such process, disclosed by Kalita et al. in Synlett 2001, No.9, 1411-1414, comprises, in the last step, a reduction of a nitro-diol (6), which has been prepared by a reaction of a nitro-alkane (7) with paraformaldehyde :
Figure imgf000003_0001
(7) (6) (1)
[0005] Chinese patent CN 1310869C has disclosed a second process, in which fingolimod is made by a reduction/hydrogenolysis of a hydroxylated nitrodiol (8). The conversion of (8) to fingolimod may be either direct, or may run via the above nitrodiol (6):
Figure imgf000003_0002
(6) CD
[0006] A third process was disclosed in Chinese patent CN 1212308C and comprises reduction of a nitro-diester (10):
Figure imgf000003_0003
(5) (10) (1)
[0007] When comparing these known routes, it appears that the most suitable starting material is the hydroxylated nitroalkane (9) as it may be made from available raw materials by the shortest and most economic way. However, the sequential or parallel reduction/hydrogenolysis of both the OH- and the N02-groups of the intermediate (8) is very slow and thus less economical. Thus, while many processes are known for making fingolimod, an improvement in the matter is still desirable.
Brief description of the present invention
[0008] In a first aspect, the present invention provides for a new compound of formula (11) and/or (14)
Figure imgf000004_0001
(11) (14)
In a second aspect, the invention provides for a process for making the compound of formula (1 1) comprising reacting the compound of formula (8)
Figure imgf000004_0002
with a strong acid, most preferably p-toluene sulfonic acid, in an organic anhydrous solvent.
In a third aspect, the invention provides for a process of making fingolimod of formula
(1),
Figure imgf000004_0003
or an acid addition salt thereof, comprising a step of reacting the compound of formula (11) with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, optionally followed by converting fingolimod of formula (1) into an acid addition salt.
[0010] In a specific aspect, 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.
[0011] In a further aspect, the invention provides a process for making the compound (8) comprising the reaction of compound (9)
Figure imgf000005_0001
(9)
with a solution of formaldehyde in a mixture of water and methanol.
The use of compound (11) in making fingolimod forms other specific aspect of the present invention.
Detailed description of the present invention
[0012] 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.
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.
In essence, the new process, which the present invention deals with, may be depicted by the following scheme:
Figure imgf000006_0001
(11)
[0013] The starting material of the process, the nitro-alcohol compound of formula (9), 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).
Figure imgf000006_0002
[0014] It was found by the present inventors that replacing the sodium borohydride by lithium borohydride decreases the amount of the impurity (13) in the reaction product without requiring longer reaction times or inconvenient reaction temperatures. Thus, advantageously, 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., tetrahydroiuran. 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. After the reaction is complete, the reaction product may be isolated from the reaction mixture, e.g. by extraction from an aqueous solution with a suitable water immiscible solvent.
[0015] The nitro-alcohol (9) is converted to the next finglolimod intermediate, a hydroxylated nitro-diol (8), by a hydroxymethylation reaction with two molecules of formaldehyde.
Figure imgf000007_0001
[0016] The prior art (CN '869) 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. It was found by the present inventors that 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.
[0017] Thus, in a suitable arrangement of reaction conditions, 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. [0018] 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. After the reaction is complete, the reaction product may be isolated from the reaction mixture, e.g. by an extraction from an aqueous solution by a water- immiscible solvent.
[0019] In an alternate mode, the hydroxymethylation of (9) may be also performed by a reaction with methylal (formaldehyde dimethylacetal).
[0020] In subsequent steps, the hydroxylated nitro-diol (8) is converted to fingolimod (1) by substitution of the alpha-positioned to the benzene ring (in further "benzylic") OH- group by hydrogen and reduction of the nitro-group to amino group. According to CN'869, 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. Thus, it is evident that the reaction times are extremely long, which makes the process economically very inconvenient.
[0021] Now it was found out that 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. Such reaction of the compound (8) with the strong acid may occur prior to or simultaneously with the hydrogenation reaction. 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.
Dependent on the amount of the strong acid and mutual timing of both reactions, the overall mechanism of the conversion of compound (8) to fingolimod (1) is apparently as follows:
Figure imgf000009_0001
[0022] In the first step, the strong acid first protonates the benzylic -OH group. In an nonaqueous solvent, a molecule of water is then split upon forming a reactive substrate of the formula (15). Its further fate depends on the reaction conditions. Variant a]
If treated with sufficient amount of the strong acid for a sufficient time, 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.
[0023] Thus, in a non-limiting example of the process, 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. Useful molar ratio between the compound of formula (8) and the strong 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. After the reaction is complete, 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. However, it is possible, and in some aspects even advantageous, not to isolate the compound of formula (11) from the reaction mixture and to subject this reaction mixture to the subsequent hydrogenation reaction directly, in a so-called one-pot arrangement.
[0024] The compound of formula (11), either in its isolated form or in a reaction mixture obtained by the preceded step, is converted to the desired fingolimod of the formula (1) by a reaction with hydrogen under catalysis by a suitable hydrogenation catalyst, such as a palladium- or platinum comprising catalyst. Other suitable catalyst may be, e.g., Raney- nickel. If the compound of formula (11) has been isolated, then 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. Under comparative reaction conditions to those disclosed in the prior art (CN '869), i.e. using Pd/C as the hydrogenation catalyst, the reaction time may take 60 - 180 minutes, i.e. is dramatically shorter.
[0025] 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.
[0026] In an advantageous arrangement, the compound of formula (11) is subjected to the hydrogenation reaction under catalysis by palladium on carbon. Yet advantageously, 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. After the reaction is complete, 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.
[0027] It should be noted that 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.
[0028] It should be further noted that the compound of formula (11) has two centers that must be hydrogenated for to obtain fingolimod - the five-membered ring and the nitro- group. Thus, in essence, the hydrogenation reaction may run via two possible intermediates (6) and (14), resp. :
Figure imgf000012_0001
[0029] 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).
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.
Similarly as the (11), the compound (14) exhibits two chiral carbons and may exist as any of four possible diastereomers.
[0030] Variant b]
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. It is presumed that 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. For instance, 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.
The reaction partners (solvent, catalyst, strong acid) of this variant of the process are, mutatis mutandis, essentially the same as those disclosed above for the respective steps of variant a]. In an important aspect, 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. In such case, 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.
However, in an advantageous mode, 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. Typically, 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. [0031] 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. 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 .
Example 1
[0032] 3 -nitro-l-(4-octylphenyl)propan-l-ol
A solution of 11.0 g of 3 -nitro-l-(4-octylphenyl)propan-l-one(37.8 mmol) in 48 g
THF, 3.6 g water and 1.2 g methanol was cooled to 0 °C. Into the solution, 0.6 g of NaBH4 (15.9 mmol) was added and the solution was stirred at the same temperature. After 2 hours, the reaction mixture was quenched by 65 g water. Then 80 g EtOAc was added and the aqueous phase was extracted with 2 x 20 g EtOAc. The combined organic phases were washed with 2 x 15 g water. Carbofiltration of the yellow organic phase with 0.4 g activated carbon followed by removal of the solvent by rotary evaporation provided 9.72 g of the title compound (33.1 mmol, 88%) as a colourless oily residue. Content of the impurity (13) : 1.34% (HPLC)
Example 2
[0033] 3 -nitro-l-(4-octylphenyl)propan-l-ol
The 3-nitro-l-(4-octylphenyl)propan-l-one (5 g, 17.16 mmol) was dissolved in dry THF(75 mL) under a nitrogen atmosphere. The solution was cooled to 0°C and 4M lithium borohydride solution in THF (2.145 mL, 8.58 mmol) was added over a period of 12 min. Stirring was continued at 0 °C and followed by monitoring by HPLC. After 25 min HPLC showed that no starting material was present anymore. The reaction mixture was poured in ice-water and 4M aqueous hydrochloric acid was added (evolution of gas!) until pH<6. The mixture was extracted with diethyl ether (3 x 100 ml), washed with brine (100 ml), dried (sodium sulfate), filtered and evaporated to dryness to afford 3-nitro-l-(4-octylphenyl)propan- l-ol as a yellow oil in a yield of 4.72 g (94%).
Example 3
[0034] 3-(hydroxymethyl)-3-nitro-l-(4-octylphenyl)butane-l,4-diol
The 3 -nitro-l-(4-octylphenyl)propan-l-ol (3.27 g, 11.15 mmol) was dissolved in methanol (11.15 ml) to give a turbid orange solution. To the resulting solution, triethyl amine (1.553 ml, 11.15 mmol) was added followed by formalin (37% solution in water, stabilized with 12% methanol) (5.02 ml, 66.9 mmol). The mixture was heated to 40 °C and the reaction was monitored by HPLC. The HPLC after 120 minutes showed complete conversion of the starting material. Water (100 mL) was added giving a white emulsion. 1M aqueous hydrochloric acid was added until pH <6. The mixture was extracted with ethyl acetate (2x100 ml), washed with brine (25 ml), dried (sodium sulfate), filtered and evaporated to dryness to afford product 2 as a brown solid/oil in a yield of 3.54 g (97%).
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%.
Example 4
Preparation of compound (11)
3-(hydroxymethyl)-3-nitro-l-(4-octylphenyl)butane-l,4-diol (5 g, 14.10 mmol) was dissolved in 50 ml of toluene at 50°C. To this solution, 4-methylbenzenesulfonic acid hydrate (0.537 g, 2.82 mmol) was added and internal temperature was increased to reflux. Water was removed from reaction mixture by Dean-Stark distillation head. After 30 minutes, total conversion of the starting material was observed. Temperature of the reaction mixture was decreased to 21°C and organic layer was extracted four times with 20 ml of 0.5 mol aqueous solution of Na2CC"3. Finally the organic layer was washed with 3x20 ml of water. Organic layer was dried with solid Na2S04 and filtered with charcoal over celite. The solvent was removed by evaporator.
Yield: 4.2 g (89.3%) of the compound (11) [ mixture of diastereomers].
Crude product can be crystallised from pentane with yield 80% and purity 99.9% (HPLC IN)
Example 5
[0035] Fingolimod
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. Reaction mixture was filtered over celite and methanol was evaporated (50°C, 200 mbar). Ethyl acetate (80 ml) was added to the white solid residue and the mixture was heated to 65°C. Then 40 ml of aqueous solution of Na2C03 (0.5 mol) was added and ,at 50-55°C, the biphasic mixture was allowed to settle after vigorous stirring .The organic phase was separated and the aqueous phase was extracted with 80 ml ethyl acetate under the same conditions twice more.. The combined organic layers were washed with 4x30 ml of water. Organic layer was dried with solid sodium sulphate at 55-60°C and partially evaporated to a mass of 30 g (Formation of off white crystals observed during evaporation).
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.
Yield: 3.3 g (76%) of off white solid material with purity 99.8% (HPLC IN).
Example 6
[0036] Fingolimod hydrochloride
2-amino-2-(2-(4-octylphenyl)ethyl)propane-l,3-diol (1 g, 3.24 mmol) was stirred with 2-propanol (5 ml). Into heterogenic mixture, anhydrous HC1 in 2-propanol (3.3 ml, 21 %) was dropwise added . The mixture was warmed to 65°C. Solid material was completely dissolved. The solution was dropwise added into n-heptane (20 ml) for 5 min and intensively stirred. Formation of an off white precipitate was observed. Mixture was stirred for 60 min at 0°C. The solid material was filtered off, washed with 2x5 ml of n-heptane and dried at 35°C (10 mbar) for 120 min.
Yield: 0.98 g (88%) of off white solid material with purity 99.97% (HPLC IN).
Example 7
Fingolimod via Compound (6)
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. After 90 minutes of stirring, the pressure of hydrogen was increased to 35 bar and internal temperature increased from 21°C to 50°C (600 rpm). After 70 reaction minutes was reaction mixture filtered over celite and MeOH evaporated (40°C, 210-15 mbar) to dryness.
Yield: 8.3 g (93%) of pale grey solid material.
Example 8
Fingolimod
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 .
Yield: 4.2 g (86%>) of grey solid material.
Example 9
Compound (14)
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).
After 120 reaction minutes was reaction mixture filtered over celite and solvent evaporated (50°C, 90-15 mbar). Yield: 1.8 g (90%) of dark grey solid material which contains mixture of desired product (14) and fingolimod in mutual ratio 70 / 30 (measured by HPLC IN).
[0037] The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the scope of the invention as defined by the following claims.

Claims

1. A process of making fingolimod of formula (1),
Figure imgf000020_0001
or an acid addition salt thereof
comprising a step of reacting the compound of formula (11)
Figure imgf000020_0002
(11)
and/or a compound of formula (14)
Figure imgf000020_0003
(14)
or an acid addition salt thereof,
in a solvent with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, and optionally converting fingolimod of formula (1) into an acid addition salt.
2. The process according to claim 1, wherein the solvent is an aliphatic or aromatic hydrocarbon ,preferably toluene or an aliphatic alcohol, preferably methanol.
3. The process according to claims 1-2, wherein the reaction temperature is from 25 to 100°C.
4. The process according to claims 1-3, wherein the starting material is the compound of formula (11) and wherein the intermediate compound of formula (6)
Figure imgf000021_0001
(6)
isolated from the reaction mixture.
A process according to claims 1-4, further comprising a step for making the compound of formula (11) comprising reacting the compound of formula (8)
Figure imgf000021_0002
(8)
in a nonaqueous solvent with a strong acid, most preferably p-toluene sulfonic acid.
6. A process according to claim 5, wherein the compound (8) reacts with the strong acid in an aliphatic or aromatic hydrocarbon and/or in an aliphatic alcohol solvent, preferably at reflux.
7. A process according to claims 1-6 wherein both steps run sequentionally without isolation of the compound (11) from the reaction mixture.
8. A process according to claims 1-7 further comprising a step of making the
compound (8) comprising the reaction of compound (9)
Figure imgf000021_0003
(9)
with a solution of formaldehyde in a mixture of water and methanol.
9. A process according to claims 1-8 further comprising a step of making the
compound (9) by reacting the compound of formula (12)
Figure imgf000022_0001
(12)
with lithium borohydride.
10 The compound of formula (11),
Figure imgf000022_0002
(11)
and/or a diastereomer thereof .
11. A process for making the compound of formula (11) comprising reacting the
compound of formula (8)
Figure imgf000022_0003
(8)
with a strong acid, most preferably p-toluene sulfonic acid.
12. A process according to claim 11, wherein the compound (8) reacts with the strong acid in a nonaqueous solvent , typically in an aliphatic or aromatic hydrocarbon and/or in an aliphatic alcohol solvent, preferably at reflux.
13. The process according to claims 11-12 comprising also isolating the compound (11) from the reaction mixture.
14. The process according to claims 11-13 comprising also a step of converting the compound (11) to fingolimod of formula (1).
15. The compound of formula (14)
Figure imgf000023_0001
and/or an acid addition salt thereof.
. A process of making fingolimod of formula (1),
Figure imgf000023_0002
(1)
or an acid addition salt thereof,
comprising a step of reacting the compound of formula (8)
Figure imgf000023_0003
(8)
in a non-aqueous solvent with hydrogen in presence of a hydrogenation catalyst, preferably palladium catalyst, and in a presence of a strong acid, preferably p- toluene sulfonic acid or hydrogen chloride ,
and optionally converting fingolimod of formula (1) into an acid addition salt.
17. The process according to claim 16 , wherein the solvent is an aliphatic or aromatic hydrocarbon , preferably toluene, or an aliphatic alcohol, preferably methanol.
18. The process according to claims 16-17, wherein the intermediate compound of formula (6)
Figure imgf000023_0004
(6)
is isolated from the reaction mixture .
19. The process according to claim 18 further comprising a step of a conversion of the compound of formula (6) to fingolimod by reduction.
20. The process according to claims 16-17 wherein the intermediate compound of formula (6) is not isolated from the reaction mixture.
21. Use of compounds of formulas (11) and/or (14) for making fingolimod of formula
(1), acid addition salts thereof and/or pharmaceutical compositions comprising the same.
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