CN103189349A - Process for making fingolimod - Google Patents
Process for making fingolimod Download PDFInfo
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- CN103189349A CN103189349A CN2011800514156A CN201180051415A CN103189349A CN 103189349 A CN103189349 A CN 103189349A CN 2011800514156 A CN2011800514156 A CN 2011800514156A CN 201180051415 A CN201180051415 A CN 201180051415A CN 103189349 A CN103189349 A CN 103189349A
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- JUYJIPQLCGHGGX-UHFFFAOYSA-N C=Cc1ccc(CCC(CO)(CO)N)cc1 Chemical compound C=Cc1ccc(CCC(CO)(CO)N)cc1 JUYJIPQLCGHGGX-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 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
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- 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
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- 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
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- 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
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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
Background of invention
Fen Gemode (being encoded to FTY720 usually) chemically is being 2-amino-2-[2-(4-octyl phenyl) ethyl of following formula (1)]-the third-1, the 3-glycol,
Be a kind of pharmaceutical active compounds, test as immunosuppressive drug and as the promoting agent in the treatment multiple sclerosis at present.It can form stable acid salt, and wherein hydrochloric acid Fen Gemode is the most frequently used salt.
Fen Gemode is originally presented among the EP627406 of Yoshitomi, has wherein also described two kinds of its approach of basic preparation.
In first kind of approach (embodiment 28 of EP ' 406), last synthesis step comprises by basic hydrolysis makes protected glycol-amine (2) deacetylated:
In second kind of approach (embodiment 234 of EP ' 406), last synthesis step comprises reduction diester-amine (4):
Subsequently, developed the alternative approach of several preparation Fen Gemode.Wherein, use the method for the nitro-intermediate reduction that is fit to have remarkable meaning.People such as Kalita are at Synlett2001, No.9, and disclosed first kind of such method is included in and reduces nitro-glycol (6) in the last step among the 1411-1414, and it is prepared by nitro-alkane (7) reaction with paraformaldehyde:
Chinese patent CN1310869C discloses second method, wherein by reduction/hydrogenolysis hydroxylation nitro glycol (8) preparation Fen Gemode.(8) are changed into Fen Gemode can directly carry out, or can carry out via above-mentioned nitro glycol (6):
The third method is disclosed among the Chinese patent CN1212308C and comprises reduction nitro-diester (10):
When comparing these known approach, seem that optimal raw material is hydroxylation nitroparaffins (9), because it can be by available starting material, by the shortest and economic way preparation.Yet, OH-and the NO of intermediate (8)
2-group successively or parallel reduction/hydrogenolysis very slow, therefore more uneconomical.
Therefore, although known many methods for preparing Fen Gemode, the improvement for preparing the method for Fen Gemode remains desirable.
The invention summary
In first aspect, the invention provides the new compound of formula (11) and/or (14)
In second aspect, the invention provides the method for a kind of preparation formula (11) compound, it comprises the compound that makes formula (8)
With strong acid, most preferably react in organic anhydrous solvent with tosic acid.
In the third aspect, the invention provides the Fen Gemode of a kind of preparation formula (1) or the method for its acid salt,
This method comprises the steps: to make the compound of formula (11) and hydrogen at hydrogenation catalyst, reacts under the existence of preferred palladium catalyst, randomly subsequently the Fen Gemode of formula (1) is changed into acid salt.
One concrete aspect, the present invention also provides the Fen Gemode of a kind of preparation formula (1) or the method for its acid salt, its compound that comprises the steps: to make formula (8) in anhydrous solvent at hydrogenation catalyst, under the existence of preferred palladium catalyst and at strong acid, under the existence of preferred tosic acid or hydrogenchloride and H-H reaction.
On the other hand, the invention provides a kind of method for preparing compound (8), it comprises makes compound (9)
With the solution reaction of formaldehyde solution in water and methanol mixture.
Compound (11) preparation Fen Gemo German-Chinese application constituted of the present invention another concrete aspect.
The accompanying drawing summary
Fig. 1. the XRPD pattern of the Fen Gemode of the method preparation by embodiment 10.
Detailed Description Of The Invention
The present invention relates to the compound Fen Gemode of compound formula (1) or improving one's methods of its acid salt by formula (9), this method has shown multiple advantage with respect to other modes that compound (9) is changed into compound (1) as known in the art.In the relevant place that further describes this advantage has been discussed.
" acid salt " that uses in whole the present invention typically is the salt that authority allows to be used for medicinal application, for example hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, formate, acetate, propionic salt, oxalate, malonate, maleate, fumarate, Citrate trianion, malate etc.Can obtain these acid salt by any conventional method.
In essence, novel method involved in the present invention can be described as following scheme:
The raw material of this method, namely nitro-the alkylol cpd of formula (9) is known compound.Its preparation method is disclosed among the CN1310869 and based on the nitro-ketone with sodium borohydride reduction formula (12).Although this method is useful in general, its existing problem, namely it follows going-nitro impurity of the formula of formation (13) sometimes.
The present inventor finds, substitutes sodium borohydride with lithium borohydride and has reduced the amount of impurity (13) in the reaction product, need not long reaction times or not convenient temperature of reaction.Therefore, advantageously be, can be by nitroketone and the lithium borohydride prepared in reaction compound (9) in solvent that makes formula (12).Useful reaction solvent is tetrahydrofuran (THF) for example.Temperature of reaction is-20～0 ℃ easily.The mol ratio of raw ketone and hydride is about 2:1 advantageously.Can advantageously for example pass through HPLC or TLC monitoring reaction course by the analytical technology that is fit to.After reaction is finished, can be for example solvent by can not be miscible with suitable and water from the aqueous solution, extract reaction product isolated from reaction mixture.
By with the hydroxymethylation of two molecule formaldehyde, nitro-alcohol (9) is changed into the German-Chinese mesosome of next Fen Gemo, i.e. hydroxylation nitro-glycol (8).
Prior art (CN ' 869) is with the source of paraformaldehyde as formaldehyde.Yet, use the method for paraformaldehyde to have some shortcomings, because in reaction mixture, form yuban.This yuban very firmly adheres on the wall of reaction vessel and utility appliance for example on agitator and the thermometer, its need be after reaction extensively cleaning vessel and utility appliance.This polymkeric substance also makes reaction mixture and reaction product impure.The present inventor finds can advantageously use by the stable formalin of methyl alcohol (formalin) and substitutes paraformaldehyde.Can react in aqueous environment then, this is favourable economically, and the methyl alcohol that is present in thus in the formalin reagent makes formaldehyde stable, avoids forming the polymkeric substance of not expecting.
Therefore, under the reaction conditions that is fit to is arranged, nitro-alcohol (9) and the aqueous solution of formaldehyde are reacted in the presence of methyl alcohol, this exists the formalin advantageously commercially available 20% of methyl alcohol or 37% formalin, and it comprises about 10% methyl alcohol.
Advantageously 30～60 ℃ of temperature of reaction are preferably 45～50 ℃.Useful compound (9) is 1:3～1:8 with the mol ratio of formaldehyde.Advantageously the analytical technology by being fit to is for example passed through HPLC or TLC monitoring reaction course.After reaction is finished, can be for example by using the solvent with water immiscibility from the aqueous solution, to extract reaction product isolated from reaction mixture.
In alternative mode, can also be by reacting carrying out the methylolation of (9) with methylal (formaldehyde dimethyl-acetal).
In step subsequently, by becoming amino with the OH-group that (claims " benzylic " in addition) on the hydrogen substituted benzene ring alpha-position and with nitroreduction, hydroxylation nitro-glycol (8) is changed into Fen Gemode (1).According to CN ' 869, this conversion can be direct, namely by with Pd/C catalysis carry out hydrogenation in 48 hours with hydrogen, in the dense HCl aqueous solution and methyl alcohol, carry out, or it can carry out indirectly via compound (6).Hydrogenation by Pd-catalysis changes into compound (6) also needs 48 hours, and the product that subsequently compound (6) is reduced into expectation needs 20 hours again.Therefore, the obvious reaction times is extremely long, and this makes this method extremely not convenient economically.
Find now that if compound (8) is carried out and the reaction of strong acid in inert organic solvents (typically being non-water), compound (8) to total transformation time of Fen Gemode (1) obviously reduces.The reaction of this compound (8) and strong acid can be carried out between hydrogenation or with it simultaneously.Preferred strong acid is sulfonic acid, and preferably methylsulfonic acid, Phenylsulfonic acid most preferably are tosic acid, anhydrous hydrogen chloride or hydrogen bromide, sulfuric acid, phosphoric acid, perchloric acid, trifluoroacetic acid.Strong-acid ion exchange resin also can be with the strong acid that acts on this method purpose.Fatty alcohol (most preferably being methyl alcohol) and/or the aliphatic ester (most preferably being ethyl acetate) of the aliphatic series that preferred inertia non-aqueous solvent is 5-12 carbon or aromatic hydrocarbons (most preferably being toluene), a 1-6 carbon.
Compound (8) contacts with the reaction of strong acid in the inertia non-aqueous solvent and causes removing benzylic OH-group, and forms substrate, its (will appear in the following step) quite reactive in hydrogenation.Because compound (8) contacts with this reactivity of described acid in non-aqueous solvent, the hydrogenation of compound (1) can be finished being less than in 4 hours.
According to the amount of the strong acid of two kinds of reactions and time limit mutually, so compound (8) is obviously as follows to whole mechanism of the conversion of Fen Gemode (1):
In the first step, strong acid at first makes Bian Xing – OH group protonated.In non-aqueous solvent, water molecules is cleaved when forming the reaction substrate of formula (15) then.Its further destiny depends on reaction conditions.
Version a]
If with the enough time of strong acid treatment of capacity, then when forming the compound of formula (11), stablize unstable compounds (15) by cyclisation.This compound has enough reactivities to hydrogenation; As cater to the need, then can alternately it be separated from reaction mixture, and in step subsequently, carry out hydrogenation.
Therefore, in the limiting examples of this method, preferably under at least 40 ℃ temperature, most preferably under refluxad, compound (8) is heated in the inertia non-aqueous solvent that is fit to tosic acid or other strong acid that is fit to, described suitable inertia non-aqueous solvent is aliphatic series or aromatic hydrocarbons typically, the aliphatic series of preferred 5～12 carbon atoms or aromatic hydrocarbons, most preferably toluene; Or fatty alcohol, the fatty alcohol of preferred 1～6 carbon atom, most preferably methyl alcohol.Useful mol ratio is 10:1～1:3 between the compound of formula (8) and the strong acid.Can for example pass through advantageously monitoring reaction course of HPLC or TLC by the analytical technology that is fit to.After reaction is finished, can be by using the organic solvent with water immiscibility, for example with the aqueous solution of toluene or ethyl acetate extraction alkalization from reaction mixture reaction product isolated.Yet possible is, and in some aspects even advantageously be the compound of separate type (11) from reaction mixture not, and directly make this reaction mixture stand the hydrogenation that carries out in so-called single jar of mode subsequently.
By under the catalyst that for example comprises palladium or platinum with the hydrogenation catalyst that is fit to H-H reaction, the unpack format that will obtain by above-mentioned steps or the compound of the formula in the reaction mixture (11) change into the Fen Gemode of the formula (1) of expectation.Other catalyzer that are fit to can be Raney nickels for example.If separated the compound of formula (11), then hydrogenation carries out in the inert solvent that is fit to (for example at aliphatic series or aromatic hydrocarbons, toluene for example, or at fatty alcohol, for example in the methyl alcohol); Otherwise reaction mixture is as reaction medium.With prior art (CN ' 869) under the suitable reaction conditions of those disclosed, namely use Pd/C as hydrogenation catalyst, the reaction times may need 60 – 180 minutes, and is namely obviously shorter.
The compound of formula (11) is the intermediate of extremely useful preparation Fen Gemode thus, because by the product of expectation is provided more than the shorter process of prior art.
In favourable mode, make the compound of formula (11) under the catalysis of palladium on carbon, carry out hydrogenation.Still advantageously be that hydrogenation is at about 30 –, 50 bar hydrogen pressures and/or carry out under 25-100 ℃ of temperature.Can for example pass through advantageously monitoring reaction course of HPLC or TLC by the analytical technology that is fit to.After reaction is finished, can be by using the organic solvent with water immiscibility, for example with the aqueous solution of toluene or ethyl acetate extraction alkalization from reaction mixture reaction product isolated.
It should be noted that the compound of formula (11) has two chiral carbon, can have 4 kinds of (2 pairs) diastereomers, its difference is the dimensional orientation of 5-unit substitution in ring base.Any described diastereomer equates to be suitable for Fen Gemode produced according to the present invention.Therefore, the compound of formula (11) can be for the preparation of in the method as the Fen Gemode of the mixture of diastereomer and any single diastereomer or its matching form.
The compound that should also be noted that formula (11) has two centers, and it must be hydrogenated to obtain Fen Gemode-5-unit ring and nitro.Therefore, in essence, hydrogenation can carry out via two kinds of possible intermediates (6) and (14) respectively:
Two kinds of reactions can be carried out or obvious one of preferred reaction approach abreast.This depends primarily on the character of selected catalyzer, pH, solvent property and the temperature of reaction of reaction mixture.For example, the ring-opening reaction that produces (6) is preferably carried out under higher temperature, and the hydrogenation under lower temperature preferably carries out via intermediate (14).
Yet reaction still is to carry out via compound (14) via compound (6), is not essential with regard to purpose of the present invention.
If must or expectation, intermediate (6) that then can separate reacted mixture and in (14) any one are as free cpds or its acid salt, and the conversion to the Fen Gemode of formula (1) that makes that it stands to carry out in independent step.
Similar with (11), compound (14) shows two chiral carbon, can be used as any one existence in 4 kinds of possible diastereomers.
Version b]
The invention still further relates to the version easily of aforesaid method, it comprises by at strong acid, for example under the existence of tosic acid or anhydrous hydrogen chloride to the Fen Gemode of the direct preparation formula of compound (8) catalytic hydrogenation (1).Suppose that reaction intermediate (15) that the effect by strong acid forms preferentially by directly being converted to compound (6) with H-H reaction, does not form compound (11) basically.(8) to change into (6) be a step process process basically then; Yet, opposite with disclosed similar approach among the CN ' 869, exist anhydrous strong acid mainly to increase the speed of described reaction, obviously shortened the essential reaction times thus.For example, hydrogenation can be in envrionment temperature or near the temperature of envrionment temperature and low hydrogen pressure (about 1 bar and/or in some embodiments with palladium catalyst with in the presence of anhydrous hydrogen chloride, even be lower than 1 bar) under carry out, may in several hours, be transformed (96～98%) fully thus.
The reaction mating partner of this version of described method (solvent, catalyzer, strong acid) do under necessary the correction in essence with above at version a] corresponding steps disclosed those are identical.Aspect important, this method is generally than version a] the condition of condition milder under carry out (be the acid of less amount, lower hydrogenation pressure and lower hydrogenation temperature, typically 10～60 ℃ say so to being converted fully essential).
If expectation can be by ordinary method separating compound (6) from reaction mixture, and can make it stand the independent reduction reaction of nitro.In this case, can use the reductive agent that is fit to arbitrarily; Except in the presence of hydrogenation catalyst with the hydrogenation of hydrogen, also can use chemical reduction, for example use hydride, hyposulfite, borine, S-WAT etc.
Yet, in favourable mode, separating compound (6) from reaction mixture not, and the hydrogenation of compound (8) carried out in such a manner, this mode obtains compound (8) to the conversion fully of the Fen Gemode of formula (1).Typically, can under the hydrogen pressure between the temperature between 30～50 ℃ and 1～50 bar, obtain using the complete hydrogenation of palladium catalyst.
The Fen Gemo Dehua compound that obtains by the inventive method can be separated, as free alkali or preferably with the form of acid salt, advantageously be form with hydrochloride, and by method purifying as known in the art.For example, can wherein obtain the polymorphic A of crystallization by recrystallization purifying Fen Gemode free alkali from ethyl acetate.
Fen Gemode can be as the pharmaceutical active compounds of pharmaceutical compositions, and described pharmaceutical composition is used for the treatment of the multiple disease shown in this area.
Illustrate the present invention by following non-limiting examples.
Embodiment
Embodiment 1
3-nitro-1-(4-octyl phenyl) third-1-alcohol
The solution of 11.0g3-nitro-1-(4-octyl phenyl) third-1-ketone (37.8mmol) in 48g THF, 3.6g water and 1.2g methyl alcohol is cooled to 0 ℃.In this solution, add 0.6g NaBH
4(15.9mmol), stir this solution and under uniform temp.After 2 hours, make this reaction mixture quencher with 65g water.Add 80g EtOAc then, with 2 * 20g EtOAc aqueous phase extracted.Organic phase with 2 * 15g water washing merging.With the 0.4g gac yellow organic phase is carried out carbon and filter, by the rotary evaporation desolventizing, obtain 9.72g title compound (33.1mmol, 88%) then, be colorless oil residue.Impurity (13) content: 1.34% (HPLC).
3-nitro-1-(4-octyl phenyl) third-1-alcohol
(5g 17.16mmol) is dissolved among the anhydrous THF (75mL) with 3-nitro-1-(4-octyl phenyl) third-1-ketone in nitrogen atmosphere.This solution is cooled to 0 ℃, in 12 minute time limit, added THF (2.145mL, 8.58mmol) solution of 4M lithium borohydride.Continue to stir at 0 ℃, monitor by HPLC then.After 25 minutes, HPLC shows that no longer including raw material exists.With this reaction mixture impouring ice-water, and adding 4M aqueous hydrochloric acid (is emitted gas! ) to pH＜6.(3x100ml) extracts this mixture with ether, and with salt solution (100ml) washing, dry (sodium sulfate) filters, and is evaporated to driedly, obtains 3-nitro-1-(4-octyl phenyl) third-1-alcohol, is yellow oil, and yield is 4.72g (94%).
Embodiment 3
3-(methylol)-3-nitro-1-(4-octyl phenyl) fourth-1, the 4-glycol
(3.27g 11.15mmol) is dissolved in methyl alcohol (11.15ml), obtains muddy orange solution with 3-nitro-1-(4-octyl phenyl) third-1-alcohol.In the solution that obtains, add triethylamine (1.553ml, 11.15mmol), add then formalin (37% the aqueous solution is stablized with 12% methyl alcohol) (5.02ml, 66.9mmol).With this mixture heating up to 40 ℃, and by the HPLC monitoring reaction.After 120 minutes, HPLC shows that raw material transforms fully.Add water (100mL), obtain white emulsion.Add the 1M aqueous hydrochloric acid to pH＜6.(2x100ml) extracts this mixture with ethyl acetate, and with salt solution (25ml) washing, dry (sodium sulfate) filters, and is evaporated to driedly, obtains product 2, is brown solid/oily matter, and yield is 3.54g (97%).
Make crude product recrystallization from the mixture of heptane and ethyl acetate, obtain white solid, yield is 2.06g (52%), purity〉99%.
Embodiment 4
The preparation of compound (11)
50 ℃ with 3-(methylol)-3-nitro-1-(4-octyl phenyl) fourth-1, (5g 14.10mmol) is dissolved in 50ml toluene to the 4-glycol.In this solution, (0.537g 2.82mmol), makes internal temperature increase to backflow to add hydration 4-toluene sulfonic acide.By Dean-Rodney Stark (Dean-Stark) still head from reaction mixture except anhydrating.After 30 minutes, observe raw material and transform fully.Make the temperature of this reaction mixture be down to 21 ℃, use 20ml0.5mol Na
2CO
3The aqueous solution is with organic layer extraction 4 times.Final with 3x20ml water washing organic layer.Use solid Na
2SO
4Dry organic layer filters with gac/C salt (celite).Use the vaporizer desolventizing.
The compound (11) [mixture of diastereomer] of yield: 4.2g (89.3%).
Can make crude product crystallization from pentane, yield is 80%, and purity is 99.9% (HPLCIN).
Embodiment 5
Fen Gemode
In autoclave, add a hydration tosic acid (8.04g, 42.3mmol) and be dissolved in 3-(methylol)-3-nitro-1-(4-octyl phenyl) fourth-1 among the MeOH (100ml), the 4-glycol (5g, 14.13mmol), add then palladium/C (1.5g, 1.410mmol).Lead to nitrogen 2 times to autoclave, cling to pressurized with hydrogen to 50.At 50 ℃ and this reaction mixture of 600rpm hydrogenation.Total reaction time is 230 minutes.
After this, interrupt hydrogen pressure, make internal temperature be down to 30 ℃.With C salt filter reaction mixture, and evaporation methyl alcohol (50 ℃, 200mbar).In the white solid resistates, add ethyl acetate (80ml), and with this mixture heating up to 65 ℃.Add 40mlNa at 50-55 ℃ then
2CO
3The aqueous solution (0.5mol) makes the biphase mixture sedimentation after the vigorous stirring.Separate organic phase, again water is extracted 2 times with the 80ml ethyl acetate under the same conditions.Organic layer with 4x30ml water washing merging.
55-60 ℃ with the dry organic layer of solid sodium sulfate, part is evaporated to 30g quality (observing the formation of canescence crystallization in evaporative process).
This mixture is stored to-12 ℃ of refrigerator 18h.Filter out solid matter, with the washing of 2x5ml ethyl acetate, dry 120 minutes of 30 ℃ and 10mbar.
Yield: 3.3g (76%) pale solid material, purity are 99.8% (HPLC IN).
Embodiment 6
Hydrochloric acid Fen Gemode
With 2-amino-2-(2-(4-octyl phenyl) ethyl) the third-1, (1g 3.24mmol) stirs with 2-propyl alcohol (5ml) the 3-glycol.Drip the 2-propanol solution (3.3ml, 21%) of anhydrous HCl in the heterogeneous mixture.With this mixture temperature to 65 ℃.Solid matter dissolves fully.This drips of solution was added in the normal heptane (20ml) 5 minutes powerful the stirring.Observe the formation of pale precipitation.Mixture was stirred 60 minutes at 0 ℃.Filter out solid matter, with the washing of 2x5ml normal heptane, 35 ℃ (10mbar) dry 120 minutes.
Yield: 0.98g (88%) pale solid material, purity are 99.97% (HPLC IN).
Embodiment 7
Via compound (6) preparation Fen Gemode
In autoclave vessel, add 3-(methylol)-3-nitro-1-(4-octyl phenyl) fourth-1 that is dissolved among the MeOH (100ml), (10g 28.2mmol), adds palladium/C (10%) (3.00g to the 4-glycol then, 2.82mmol) and the 2-propanol solution of hydrogenchloride (0.539ml, 2.82mmol).At room temperature stirring system under hydrogen pressure (being lower than 1 bar).
Stir after 90 minutes, make hydrogen pressure increase to 35 bar, internal temperature is increased to 50 ℃ (600rpm) from 21 ℃.After the reaction in 70 minutes, with C salt filter reaction mixture, evaporation MeOH (40 ℃, 210-15mbar) to doing.
Yield: 8.3g (93%) light gray solid material.
Embodiment 8
Fen Gemode
In autoclave vessel, add (3-nitro-5-(4-octyl phenyl) tetrahydrofuran (THF)-3-yl)-methyl alcohol (compound (11) that is dissolved in the methyl alcohol (100ml), 5g, 14.91mmol), add palladium/C (10%) (anhydrous) (1.586g then, 1.491mmol) and the 2-propanol solution of hydrogenchloride (11.23ml, 59.6mmol).Lead to nitrogen 2 times to autoclave, with pressurized with hydrogen to 35 bar, and be heated to 100 ℃.This reaction mixture was stirred (600rpm) 2 hours under this temperature.After this, make the internal temperature of reaction mixture be down to 30 ℃, filter with C salt.Evaporation MeOH (40 ℃, 210-15mbar) to doing.
Yield: 4.2g (86%) gray solid material.
Embodiment 9
Compound (14)
Add in the autoclave vessel (3-nitro-5-(4-octyl phenyl) tetrahydrofuran (THF)-3-yl) methyl alcohol of being dissolved in the toluene (60ml) (2g, 5.96mmol), add then palladium/C (5%) (0.063g, 0.596mmol).Lead to nitrogen 2 times to autoclave, cling to pressurized with hydrogen to 35 at 30 ℃ (600rpm).
After 120 minute reaction times, with C salt filter reaction mixture, evaporating solvent (50 ℃, 90-15mbar).
Yield: 1.8g (90%) Dark grey solid matter, it comprises the product (14) of expectation and the mutual ratio of Fen Gemode is 70/30 mixture (measuring by HPLC IN).
The purifying of Fen Gemode alkali (method of the embodiment 28 of EP0627406B1)
0.5g Fen Gemode is dissolved in the 6ml ethyl acetate under refluxing.Allow this solution be cooled to room temperature.As a result, form solid fast.By with P3-glass filter (decompression) filtering separation solid, and at the air-dry mistake of room temperature weekend.Obtain white to the laminar aggregation of canescence.Yield is 0.45g.
DSC: about 124～125 ℃ of fusing point
XRPD: referring to Fig. 1.
Measuring condition:
Instrument XRPD:Bruker-AXS D8vario, Θ/2 Θ geometric type, reflective-mode, Vantec PSD detector
Initial angle (2 θ): 2.0 °
End angle (2 θ): 35.0 °
Scanning step: 0.02 °
Scanning is during the step: 0.2～2.0 second
Emission types: Cu
Radiation wavelength:
Used main monochromator
Though described the present invention, but those skilled in the art are apparent, be easy under not breaking away from as situation about awaiting the reply according to the defined scope of the invention of claim, reality is implemented theory and embodiment as herein described carry out or obtain other change and modification by implementing the present invention.
Claims (21)
1. the Fen Gemode of preparation formula (1) or the method for its acid salt,
This method comprises the steps: to make the compound of formula (11)
And/or the compound of formula (14)
Or its acid salt,
In solvent, at hydrogenation catalyst, under the existence of preferred palladium catalyst and H-H reaction, and randomly the Fen Gemode of formula (1) is changed into acid salt.
2. according to the process of claim 1 wherein that described solvent is aliphatic series or aromatic hydrocarbons, be preferably toluene or fatty alcohol, be preferably methyl alcohol.
3. according to the method for claim 1～2, wherein temperature of reaction is 25～100 ℃.
4. according to the method for claim 1～3, wherein said raw material is the compound of formula (11), and the midbody compound of separate type (6) from reaction mixture wherein
5. according to the method for claim 1～4, the step that it also comprises preparation formula (11) compound comprises the compound that makes formula (8)
In non-aqueous solvent, with strong acid, most preferably react with tosic acid.
6. according to the method for claim 5, wherein make compound (8) and strong acid in aliphatic series or aromatic hydrocarbons and/or in the fatty alcohol solvent, preferably reaction under refluxing.
7. according to the method for claim 1～6, wherein two steps in sequence are carried out, not separating compound (11) from reaction mixture.
8. according to the method for claim 1～7, it also comprises the step for preparing compound (8), comprises to make compound (9)
With the solution reaction of formaldehyde in water and methanol mixture.
9. according to the method for claim 1～8, it also comprises the step for preparing compound (9) as follows: the compound that makes formula (12)
React with lithium borohydride.
10. the compound of formula (11),
And/or its diastereomer.
11. the method for preparation formula (11) compound, it comprises the compound that makes formula (8)
With strong acid, most preferably react with tosic acid.
12. according to the method for claim 11, wherein make compound (8) and strong acid at non-aqueous solvent, typically in aliphatic series or aromatic hydrocarbons and/or in the fatty alcohol solvent, preferably under refluxing, react.
13. according to the method for claim 11～12, it also comprises separating compound from reaction mixture (11).
14. according to the method for claim 11～13, it also comprises the step that compound (11) is transformed the Fen Gemode of an accepted way of doing sth (1).
15. the compound of formula (14)
And/or its acid salt.
16. the Fen Gemode of preparation formula (1) or the method for its acid salt,
This method comprises the steps: to make the compound of formula (8)
In non-aqueous solvent at hydrogenation catalyst, under the existence of preferred palladium catalyst and at strong acid, under the existence of preferred tosic acid or hydrogenchloride and H-H reaction,
And randomly the Fen Gemode of formula (1) is changed into acid salt.
17. according to the method for claim 16, wherein said solvent is aliphatic series or aromatic hydrocarbons, preferred toluene, or fatty alcohol, particular methanol.
18. according to the method for claim 16～17, the midbody compound of separate type (6) from reaction mixture wherein
19. according to the method for claim 18, it also comprises the step that the compound of formula (6) is changed into Fen Gemode by reduction.
20. according to the method for claim 16～17, the midbody compound of separate type (6) from reaction mixture not wherein.
21. the compound of formula (11) and/or (14) is at Fen Gemode, its acid salt of preparation formula (1) and/or comprise application in their pharmaceutical composition.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EPPCT/EP2010/006039 | 2010-10-01 | ||
| PCT/EP2010/006039 WO2012041359A1 (en) | 2010-10-01 | 2010-10-01 | Process for making fingolimod |
| EPPCT/EP2010/070535 | 2010-12-22 | ||
| PCT/EP2010/070535 WO2012041405A1 (en) | 2010-10-01 | 2010-12-22 | Process for making fingolimod |
| PCT/EP2011/065975 WO2012041707A1 (en) | 2010-10-01 | 2011-09-15 | Process for making fingolimod |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103189349A true CN103189349A (en) | 2013-07-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800514156A Pending CN103189349A (en) | 2010-10-01 | 2011-09-15 | Process for making fingolimod |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN103189349A (en) |
| ES (1) | ES2682649T3 (en) |
| WO (3) | WO2012041359A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012089238A1 (en) * | 2010-12-28 | 2012-07-05 | Synthon Bv | Process for making fingolimod hydrochloride crystals |
| WO2012146980A2 (en) * | 2011-04-29 | 2012-11-01 | Dr. Reddy's Laboratories Ltd. | Preparation of fingolimod and its salts |
| CN103539683A (en) * | 2012-07-17 | 2014-01-29 | 广东东阳光药业有限公司 | Novel crystal form of medicament for treating scleredema and preparation method thereof |
| AU2014206588A1 (en) * | 2013-01-17 | 2015-07-23 | Shilpa Medicare Limited | Process for preparation of Fingolimod and its salts |
| WO2014111949A1 (en) * | 2013-01-21 | 2014-07-24 | Natco Pharma Limited | Intermediates and process for the preparation of high purity fingolimod hydrochloride |
| US9078241B2 (en) * | 2013-03-22 | 2015-07-07 | Sharp Kabushiki Kaisha | Systems and methods for establishing multiple radio connections |
| CN103724215A (en) * | 2013-11-28 | 2014-04-16 | 镇江圣安医药有限公司 | Novel derivative of 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol and application of novel derivative |
| CA2928966A1 (en) | 2014-01-07 | 2015-07-23 | Emcure Pharmaceuticals Limited | Improved fingolimod process |
| WO2020165672A1 (en) | 2019-02-15 | 2020-08-20 | Shivalik Rasayan Limited | Process for preparation of highly pure fingolimod hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1765872A (en) * | 2005-11-22 | 2006-05-03 | 江苏吴中苏药医药开发有限责任公司 | 2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method |
| CN101610674A (en) * | 2006-12-21 | 2009-12-23 | 艾博特公司 | Sphingosine-1-phosphate ester receptor stimulating agent and agonist compounds |
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| DE122011100012I1 (en) | 1992-10-21 | 2011-10-20 | Mitsubishi Tanabe Pharma Corp | 2-amino-1,3-propanediol compound and immunosuppressant. |
| AU3407699A (en) | 1998-05-22 | 1999-12-13 | Reipur Technology A/S | Means for providing electrical contact |
| CN1212308C (en) | 2003-07-24 | 2005-07-27 | 漆又毛 | Process for preparing amino-2-(2-(4-otylphenyl) ethyl)-1, 3-propylene glycol hydrochloride |
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2010
- 2010-10-01 WO PCT/EP2010/006039 patent/WO2012041359A1/en active Application Filing
- 2010-12-22 WO PCT/EP2010/070535 patent/WO2012041405A1/en active Application Filing
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2011
- 2011-09-15 ES ES11758448.2T patent/ES2682649T3/en active Active
- 2011-09-15 WO PCT/EP2011/065975 patent/WO2012041707A1/en active Application Filing
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1765872A (en) * | 2005-11-22 | 2006-05-03 | 江苏吴中苏药医药开发有限责任公司 | 2-amido-2-[2-(4-alkylphenyl)ethyl]-1,3-methyl glycol preparation method |
| CN101610674A (en) * | 2006-12-21 | 2009-12-23 | 艾博特公司 | Sphingosine-1-phosphate ester receptor stimulating agent and agonist compounds |
Also Published As
| Publication number | Publication date |
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| WO2012041359A1 (en) | 2012-04-05 |
| ES2682649T3 (en) | 2018-09-21 |
| WO2012041405A1 (en) | 2012-04-05 |
| WO2012041707A1 (en) | 2012-04-05 |
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