WO2012041359A1

WO2012041359A1 - Process for making fingolimod

Info

Publication number: WO2012041359A1
Application number: PCT/EP2010/006039
Authority: WO
Inventors: Jozef Krajcovic; Reinerus Gerardus Gieling
Original assignee: Synthon B.V.
Priority date: 2010-10-01
Filing date: 2010-10-01
Publication date: 2012-04-05
Also published as: ES2682649T3; WO2012041707A1; CN103189349A; WO2012041405A1

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 acidaddition salt, to compounds of formula (11) and (14) and 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)

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

(3) (2) ( I )

[0003] In the second route (Example 234of EP'406), the last synthetic step comprises reduction of a diester-amine (4)

(5) (4) ( I )

[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, 141 1 -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 :

(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):

(6) (1 )

[0006] A third process was disclosed in Chinese patent CN 1212308C and comprises reduction of a nitro-diester (10):

(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 fmgolimod, 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 process of making fmgolimod of formula (1),

(1)

or an acid addition salt thereof,

comprising a step of reacting the compound of formula (1 1)

(1 1)

and/or the compound of formula (14)

(14)

or an acid addition salt thereof,

with hydrogen in a presence of a hydrogenation catalyst, preferably palladium catalyst, optionally followed by converting fmgolimod of formula (1) into an acid addition salt.

[0009] In a second aspect, the invention also provides a process for making the compound of formula (1 1) comprising a step of reacting the compound of formula (8)

(8) with a strong acid, most preferably p-toluene sulfonic acid.

[0010] In a specific aspect, the above processes for making compound (1 1) and compound (1) run sequentionally, advantageously in a one-pot arrangement, i.e. without isolation of the compound (1 1) from the reaction mixture.

Thus, within another specific aspect,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.

[0011] In a further aspect, the invention provides a process for making the compound (8) comprising the reaction of compound (9)

(9)

with a solution of formaldehyde in a mixture of water and methanol.

The 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.

Detailed description of the present invention

[0012] 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.

In essence, the new process, which the present invention deals with, may be depicted by the following scheme:

(Π ) (1 )

[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).

[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., 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. 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.

[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 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 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. 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 first converted to the unsaturated nitro-compound of formula (1 1).

(1 1) [0022] 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. Other possible acids may be, e.g., sulphuric acid, phosphoric acid, perchloric acid, hydroiodic acid , methane sulfonic acid, benzene sulfonic acid or trifluoroacetic acid. By heating the compound (8) with the acid in a solvent, the conversion of the compound (8) to the compound (1 1) may be obtained in 0.5 to 2 hours.

[0023] Thus, in a suitable and 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 in a suitable inert solvent, which is 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. 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 (1 1) 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 (1 1), either in its isolated form or in a reaction mixture obtained by the preceded step, 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. If the compound of formula (1 1) 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 (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.

[0026] In an advantageous arrangement, the compound of formula (1 1) 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 (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.

[0028] It should be further noted that the compound of formula (1 1) has two centers that must be hydrogenated for to obtain fingolimod - the double bond and the nitro-group. Thus, in essence, the hydrogenation reaction may run via two possible intermediates (6) and (14), resp.:

[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. 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 (1 1), the compound (14) may exist as an E-isomer and/or Z- isomer.

[0030] 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.

[0031] 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 .

Example 1

[0032] 3 -nitro-l-(4-octylphenyl)propan-l-ol

A solution of 1 1.0 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 NaB¾ (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 ^χ 20 g EtOAc. The combined organic phases were washed with 2 ^χ 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- 1 -(4-octylphenyl)butane- 1 ,4-diol

The 3 -nitro- l-(4-octylphenyl)propan-l-ol (3.27 g, 1 1.15 mmol) was dissolved in methanol (1 1.15 ml) to give a turbid orange solution. To the resulting solution, triethyl amine (1.553 ml, 1 1.15 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. 1 M 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 (1 1) 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 Na₂C0₃. 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).

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-propanoI (5 ml). Into heterogenic mixture, 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).

[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 fmgolimod of formula (1),

(1)

or an acid addition salt thereof

comprising a step of reacting the compound of formula (1 1)

( Π )

and/or a compound of formula (14)

(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 fmgolimod of formula (1) into an acid addition salt.

2. The process according to claim 1 , wherein the solvent is an aliphatic or aromatic hydrocarbon such as toluene or in an aliphatic alcohol such as methanol.

3. The process according to claims 1-2, wherein the reaction temperature is from 25 to 100°C.

The process according to claims 1-3, wherein fingolimod of formula (1) is isolated from the reaction mixture, preferably as a hydrochloride.

A process of the claims 1 -4, further comprising a step for making the compound of formula (1 1) comprising reacting the compound of formula (8)

(8)

in a solvent with a strong acid, most preferably p-toluene sulfonic acid.

6. A process of claims 1-5, 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 of claims 1-6 wherein both steps run sequentionally without isolation of the compound (1 1) 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)

(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)

(12)

with lithium borohydride.

10. The compound of formula (1 1),

( 1 1)

a (E)-isomer thereof , and/or a (Z)-isomer thereof .

1 1. A process for making the compound of formula (1 1) comprising reacting the

compound of formula (8)

(8)

with a strong acid, most preferably p-toluene sulfonic acid.

12. A process of claim 1 1, 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.

13. The process of claims 1 1-12 comprising also isolating the compound (1 1) from the reaction mixture.

14. The process of claims 1 1 -12 comprising also a step of converting the compound (11) to fingolimod of formula (1).

15. The compound of formula (14)

( 14)

a (E)-isomer thereof , and/or a (Z)-isomer thereof,

and/or an acid addition salt thereof.

16. A process of making fingolimod of formula (1),

(1 )

or an acid addition salt thereof,

comprising a step of reacting the compound of formula (8)

(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 fmgolimod of formula (1) into an acid addition salt.

17. Use of compounds (1 1) and/or (14) for making fmgolimod of formula (1), acid addition salts thereof and/or pharmaceutical compositions comprising the same.