PROCESS FOR THE PRODUCTION OF OZANIMOD

Abstract

The present invention relates a new process for the preparation of ozanimod of the formula and acid addition salts, via new intermediates and a new polimop form of ozanimod base.

Claims

1. Process for the production of formula ##STR00039## ozanimod or its acid addition salts, characterised by that the protective group or groups that may be removed in an acidic medium are removed in an organic solvent from a.) the compound of general formula ##STR00040## in which R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, or b.) from the compound of formula ##STR00041## or c.) from a mixture of any ratio of the compound of general formula (IV) and the compound of formula (V), and the formula (I) ozanimod obtained in this way is optionally transformed into an acid addition salt.

2. Process according to claim 1, characterised by that substituted methyl ether type compounds, preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group are used as the protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group in the compound of general formula (IV).

3. Process according to claim 1, characterised by that a mixture of compound of general formula (IV) and compound of formula (V) is used in the reaction.

4. Process according to claim 1, characterised by that an ether type solvent, preferably dioxane, a 1 to 4 carbon atom alcohol, preferably 2-propanol, ethanol or methanol, most preferably 2-propanol, or an aromatic solvent, preferably toluene or xylene, more preferably toluene is used as the organic solvent.

5. Process according to claim 1, characterised by that to cleave the protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group acid is used, preferably aqueous hydrochloric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, hydrogen fluoride (HF), sulphuric acid, nitric acid, or their salts, tetrabutylammonium fluoride (TBAF), a mixture of TBAF and acetic acid, an aqueous mixture of HF and THF, or 1 M aqueous HIO.sub.4 dissolved in THF.

6. Process according to claim 1, characterised by that the cleaving of the protective group that may be removed in an acidic medium is carried out in an aqueous solution, in a mixture of organic solvent and water or dissolved in a solvent, preferably using dioxane, 2-propanol, ethanol or methanol, preferably 2-propanol, ethanol or methanol, most preferably 2-propanol as the solvent.

7. Process according to claim 1, characterised by that the production of the compound of general formula ##STR00042## in which R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, or of the compound of formula (V), or of a mixture of the compound of general formula (IV) and the compound of formula (V) is carried out so that a.) the formula ##STR00043## 3-cyano-4-(i-propyloxy)benzoic acid is activated in an organic solvent, then reacted with the compound of general formula ##STR00044## in which compound R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, then optionally b.) the obtained compound of general formula (IV) and the compound of formula (V) are isolated from each other.

8. Process according to claim 7, characterised by that the formula (VIII) 3-cyano-4-(i-propyloxy)benzoic acid is activated in an organic solvent, then reacted with the compound of general formula (III).

9. Process according to claim 7, characterised by that preferably amide, aromatic, ether, ester, nitrile or sulfoxide type solvents are used as the organic solvent, most preferably dimethylformamide is used as the amide type solvent, preferably xylene or toluene is used as the aromatic solvent, most preferably toluene, most preferably tetrahydrofuran or dioxane is used as the ether type solvent, acetonitrile is used as the nitrile type solvent, dimethyl sulfoxide is used as the sulfoxide type solvent, and preferably toluene or ester type solvents are used, most preferably ethyl acetate is used as the organic solvent.

10. Process according to claim 7, characterised by that the benzoic acid of formula (VIII) is preferably activated with disubstituted carbodiimide, preferably with dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in the presence of an organic base, more preferably in the presence of DIPEA, TEA, or with carbonyl-diimidazole in the presence of hydroxybenzotriazole or ethyl cyano glyoxylate-2-oxime, or with propanephosphonic acid anhydride (T3P), most preferably activated with propanephosphonic acid anhydride (T3P).

11. Process according to claim 7, characterised by that the compounds of general formula (IV) or (V), or a mixture of these are transformed into ozanimod without isolation or any further purification.

12. Process according to claim 11, characterised by that the compound of general formula (III), preferably the compound with general formula (III/A) is reacted with the compound of formula (VIII) in an aromatic solvent, preferably toluene or xylene, most preferably toluene, so that the compound of formula (VIII) is preferably activated with disubstituted carbodiimide, preferably with dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in the presence of an organic base, more preferably in the presence of DIPEA, TEA, or with carbonyl-diimidazole in the presence of hydroxybenzotriazole or ethyl cyano glyoxylate-2-oxime, or with propanephosphonic acid anhydride (T3P), most preferably with propanephosphonic acid anhydride (T3P), then after the reaction has completed the reaction mixture is washed if necessary with an aqueous base and/or saturated salt solution, then concentrated hydrochloric acid is added to the aromatic solvent, preferably toluene solution and the ozanimod hydrochloride precipitating is isolated, and optionally purified.

13. Process according to claim 12, characterised by that the compound of general formula (III), preferably the compound of formula (III/A) and the compound of formula (VIII), the base and the activating reagents are combined at a temperature between 20-30 C., preferably between 20-25 C., then the temperature of the reaction mixture is raised preferably to between 60 C. and the boiling point of the solvent, preferably to between 65-100 C., most preferably to between 80-85 C. and maintained at that temperature until the reaction is complete, then the reaction mixture is cooled and then, if necessary, washed with an aqueous alkali, preferably with sodium or potassium hydrocarbonate solution, and, if necessary, with saturated sodium chloride solution, then the organic phase is reacted with concentrated aqueous hydrochloric acid solution (37%) preferably at a temperature of between 60 C. and the boiling point of the solvent, preferably between 65-85 C., most preferably between 70-75 C., then following this the reaction mixture is cooled, the precipitated crystals are filtered out, dried and optionally transformed into a base.

14. Process according to claim 1, characterised by that the ozanimod is precipitated in the form of hydrochloride salt, and the crystalline ozanimod is transformed into a base.

15. Process according to claim 7, characterised by that the compound of general formula (III) used in the process, in which formula R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, is produced so that the compound of general formula ##STR00045## in which R is as defined above, most preferably a t-butyldimethylsilyl group, is reacted with hydroxylamine hydrochloride in an organic solvent in the presence of a base.

16. Process according to claim 15, characterised by that the derivative of general formula (III) is produced from the compound of formula (VI) in such a way that the intermediate product of general formula (II) is not isolated; or a process as recited above, characterised by that when producing the compound of general formula (II), after the reaction has completed, the reaction mixture containing the DMF and the surplus alkylating agent is extracted with a mixture of water and an ester type solvent, preferably a mixture of iced water and ethyl acetate and the oil obtained by evaporating the ethyl acetate phase is, without further purification, dissolved in an alcohol type solvent, preferably a 1 to 4 carbon atom alcohol, most preferably ethanol and then reacted with hydroxylamine in the presence of a base, preferably trimethylamine; or a process as recited above, characterised by that (2-bromoethoxy)-t-butyldimethylsilane is used as the alkylating agent, sodium hydride is used as the base, and the obtained compound of formula (II/A) is dissolved in an alcohol type solvent, preferably in a 1 to 4 carbon atom alcohol, most preferably ethanol and reacted with a base, preferably hydroxylamine hydrochloride in the presence of trimethylamine; or a process as recited above, characterised by that a 1 to 4 carbon atom alcohol, preferably ethanol is used as the organic solvent; or characterised by that a tertiary amine, preferably triethylamine or diisopropyl-ethylamine is used as the base; or characterised by that the compound of general formula (II) is produced so that the compound of formula ##STR00046## is reacted with a base in an organic solvent, then reacted with the compound of formula ##STR00047## in which formula R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, and X represents Cl, Br or I; or a process as recited above, characterised by that an amide type solvent, preferably dimethylformamide, an ether type solvent, preferably tetrahydrofuran, acetonitrile or a mixture of the listed solvents is used as the organic solvent, preferably dimethylformamide; or characterised by that sodium hydride, potassium tert-butoxide, caesium carbonate or hexamethyldisilazane, preferably sodium hydride is used; or characterised by that (2-bromoethoxy)-t-butyldimethylsilane is used as compound (VII).

17-24. (canceled)

25. Process according to claim 1, characterised by that a.) the compound or compounds of general formula ##STR00048## in which R represents a t-butyldimethylsilyl group, or b.) the compound of formula ##STR00049## or c.) a mixture at any proportion of the compound of general formula (IV) (R represents a t-butyldimethylsilyl group) and the compound of formula (V) are reacted in a 1 to 4 carbon atom alcohol, preferably 2-propanol, with an inorganic acid, preferably hydrochloric acid and the ozanimod obtained is optionally transformed into a salt, preferably hydrochloride salt; or a process as recited above, characterised by that the compound of general formula (IV), in which R represents a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, or the compound of formula (V) or a mixture of these is produced so that a.) the compound of formula ##STR00050## is reacted in organic dimethylformamide using sodium hydride as a base with the compound of formula ##STR00051## in which R represents a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, X represents Cl, Br or I, then b.) the obtained compound of formula ##STR00052## in which R represents a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group, is reacted with hydroxylamine hydrochloride in a 1 to 4 carbon atom alcohol, preferably ethanol in the presence of triethylamine as organic base, then c.) the obtained compound of general formula ##STR00053## is reacted with the formula (VIII) 3-cyano-4-(i-propyloxi)benzoic acid activated with propanephosphonic acid anhydride (T3P) in ethyl acetate.

26-37. (canceled)

38. The compound of general formula ##STR00054## in which R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, preferably R is a substituted methyl ether type group, such as a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, such as an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, such as a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group; or a compound of general formula ##STR00055## in which R represents a protective group that may be removed in an acidic medium serving for the temporary protection of the hydroxyl group, preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group; or a compound of formula ##STR00056## or a compound of formula ##STR00057## in which R represents preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group; or a compound of formula ##STR00058## or a compound of formula ##STR00059## in which R represents preferably a substituted methyl ether type group, more preferably a methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, or [(3,4-dimethoxybenzyl)oxy]methyl group, a tetrahydropyranyl group, or a substituted ethyl ether type group, preferably an ethoxyethyl, or 1-[2-(trimethylsilyl)ethoxy]ethyl group, a silyl ether type group, preferably a trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl or triphenylsilyl group, most preferably a t-butyldimethylsilyl group; or a compound of formula ##STR00060## or a compound of formula ##STR00061## or a compound of general formula (IV) and formula (V), or a mixture in any proportion of the compounds of formula (IVA) and (V); or a formula (I) ##STR00062## ozanimod base Form I crystalline polymorph form, characterised by that the positions of the characteristic x-ray powder diffraction peaks are [ 20.2]: 5.77; 11.56; 15.36; 19.54; 27.00, preferably [ 20.2]: 5.77; 11.56; 12.98; 13.38; 13.90; 15.36; 16.23; 19.54; 25.37; 27.00, even more preferably [ 20.2]: 2.86; 5.77; 8.66; 10.77; 10.87; 11.14; 11.56; 12.20; 12.98; 13.38; 13.90; 14.59; 15.36; 16.23; 17.19; 17.43; 17.73; 18.44; 18.94; 19.54; 20.28; 20.41; 21.10; 21.65; 21.87; 22.10; 22.43; 22.79; 23.36; 23.75; 23.95; 24.62; 25.37; 26.16; 27.00; 27.90; 28.86; 29.20; 29.85; 31.00; 31.62; 32.85; 33.13; 34.33; or the formula (I) ozanimod base Form I polymorph as recited above, characterised by that its characteristic x-ray powder diffraction peaks are summarised in the following table: TABLE-US-00003 Relative intensity Peak 2 () d () (%) 1 2.86 30.90 28 2 5.77 15.32 100 3 8.66 10.22 21 4 10.77 8.22 13 5 10.87 8.14 8 6 11.14 7.94 14 7 11.56 7.65 28 8 12.20 7.25 9 9 12.98 6.82 42 10 13.38 6.62 97 11 13.90 6.37 34 12 14.59 6.07 24 13 15.36 5.77 14 14 16.23 5.46 45 15 17.19 5.16 12 16 17.43 5.09 4 17 17.73 5.00 9 18 18.44 4.81 6 19 18.94 4.69 13 20 19.54 4.54 37 21 20.28 4.38 8 22 20.41 4.35 2 23 21.10 4.21 4 24 21.65 4.11 24 25 21.87 4.07 6 26 22.10 4.02 11 27 22.43 3.97 19 28 22.79 3.90 6 29 23.36 3.81 31 30 23.75 3.75 11 31 23.95 3.72 16 32 24.62 3.62 61 33 25.37 3.51 55 34 26.16 3.41 28 35 27.00 3.30 41 36 27.90 3.20 26 37 28.86 3.09 12 38 29.20 3.06 2 39 29.85 2.99 1 40 31.00 2.89 2

Description

FIGURES

[0062] FIGS. 1 and 2: the formulas of the intermediates and reagents of the present process

[0063] FIG. 3: The x-ray powder diffractogram of the ozanimod base Form I form

[0064] FIG. 4: The water sorption isotherm of the ozanimod base Form I form at 25 C.

[0065] FIG. 5: The x-ray powder diffractogram of the ozanimod base Form I form after two DVS cycles (see example 6).

[0066] The invention is henceforward illustrated with the following examples without limiting the scope of protection to the examples.

EXAMPLES

[0067] The Chromatographic Purification Method Used:

[0068] The extraction of the individual components from the mixtures was performed using a column chromatography method, with a Teledyne ISCO CombiFlash Rf chromatograph, in RediSep Rf columns with a hexane-ethyl acetate eluent mixture, gradient used: 0-140 min. hexane: ethyl-acetate 100:0-34:66; 140-160 min. 34:66-0:100.

[0069] The .sup.1H NMR spectra were recorded using a Varian Gemini 200, Bruker Avance III, and an Inova 500 spectrometer in CDCl.sub.3 or DMSO-d.sub.6 solvents, using the tetramethylsilane (TMS) internal standard. The chemical displacements (6) were given in parts per million (ppm) units, and the coupling constants (J) were given in hertz (Hz).

[0070] At least 95% pure standards were made of the diastereomer contaminants using similar processes to those used when producing the ozanimod intermediates. The monitoring of the reactions and the testing of the intermediates were performed using a flash chromatography method, on a Shimadzu LC-MS device. The samples were dissolved in a water-acetonitrile 80:20 mixture, and tested using a neutral (in an ammonium-acetate buffer solution), and an acidic (in a formic acid solution) method.

[0071] The x-ray powder diffraction measurements were performed as follows:

X-Ray Powder Diffraction Measurement Conditions

[0072] Device: PANalytical Empyrean x-ray powder diffractometer
Measurement alignment: Transmission

X-Ray Tube

[0073] Type: Empyrean long fine focussing, high resolution tube

Anode: Cu

Wavelength: K(1.541874 )

[0074] Focus: line focus

Source-Side Optical Elements

[0075] Divergence slit: Fixed slit 1/2
Mirror: Focussing elliptical mirror
Soller slit: 0.04 rad
Diffusion inhibitor slit: Fixed slit 1/2

Diffracted Side Optical Elements

[0076] Diffusion inhibitor slit: Programmable slit in fixed mode: 1/2
Soller slit: 0.04 rad

Sample Table

[0077] Type: Reflection-transmission, with rotatable sample holders
Sample rotation speed: 1 rotation/second
Direct beam catcher
(beam knife): Transmission

Detector

[0078] Type: PIXcel 3D 11 area detector
Operation mode: Scanning line detector (ID) operation mode
Active detector window
size: 3.3473
Sample preparation: samples placed between two Mylar sheets, without pulverising

Measurement Conditions

[0079] Temperature: room temperature
Accelerating voltage: 45 kV
Anode heating current: 40 mA
Scanning method: continuous (/) scanning
Measurement range: 2.0000-34.9964 2

Step gap: 0.01312

[0080] Step duration: 109.650 seconds
No of measurement cycles: 1
Measurement duration: 20 minutes

Dynamic Vapour Sorption (DVS)

[0081] Device: TA Q5000SA dynamic vapour sorption analyser (DVS)
Atmosphere: Flowing nitrogen
Carrier gas flow rate: 200 mL/min N.sub.2

Solvent: Water

[0082] Balance house flow rate: 10 mL/min N.sub.2
Temperature maintained [0083] 35 C.
in balance house:
Crucible type: Platinum 100 l, open
Measuring method: Custom

Predrying: None

[0084] Measuring temperature: 25 C., isotherm
Measurement range: Between 0% and 95% RH
Initial relative humidity: 20% RH
Measurement phases: Desorption-adsorption-desorption
Step size: 5% RH
Mass constant criterion: 0.01% for 5 minutes
Maximum step length: 360 minutes
Sampling frequency: 5 sec/point
Number of cycles: 2

Example 1

(S)N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropan-2-sulfinamide (IIA)

[0085] ##STR00033##

[0086] Sodium hydride (4.85 g; 60% dispersion in oil; 121.2 mmol) is measured into a 500 ml multi-neck flask in an argon atmosphere, dimethylformamide is added at room temperature (30 ml), then cooled to 0 C., and a dimethylformamide (30 ml) solution of (S)N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (VI (see WO 2011060392) 7.96 g; 30.3 mmol) is added to it drop by drop; is added to it drop by drop. (2-Bromoethoxy)(tert-butyl)dimethylsilane ((VIIA), 30.0 g 97%; 33.0 ml; 121.6 mmol) is added to it drop by drop. Then the mixture is left to warm up to room temperature and stirred. Then saturated sodium hydrogen carbonate solution is added to the reaction mixture. While being stirred it is diluted with water and ethyl acetate, the phases are separated, the organic phase is washed with water (2150 ml), and dried on magnesium sulphate, and evaporated in a vacuum. The oil obtained in this way is used in the following synthesis step without purification.

[0087] .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.58 (1H, d, J=7.6 Hz), 7.54 (1H, d, J=7.6 Hz), 7.32 (1H, t, J=7.6 Hz), 5.15 (1H, t, J=7.6 Hz), 3.58-3.72 (2H, m), 3.18-3.26 (1H, ddd, J=12.3, 9.3, 3.9 Hz), 3.08-3.16 (1H, m), 3.05 (1H, t, J=8.4 Hz), 2.92-3.02 (1H, m), 2.47-2.57 (1H, m), 2.25-2.36 (1H, m), 1.23 (9H, s), 0.85 (9H, s), 0.05 (6H, s).

Example 2

(1 S)-1-({2-[(tert-butyldimethylsilyl)oxy]ethyl}[(S)-2-methylpropane-2-sulfinyl]amino)-N-hydroxy-2,3-dihydro-1H-indene-4-carboximidamide (IIIA)

[0088] ##STR00034##

[0089] In a 500 ml single-neck flask under an argon atmosphere at 25 C. ethanol (128 ml), triethylamine (12.5 ml; 9.1 g; 91.0 mmol), and hydroxylamine hydrochloride (6.32 g; 91.0 mmol) are added to the (S)N-{2-[(tert-Butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropan-2-sulfinamide (IIA) obtained in the previous step, the mixture is heated to 50 C., then stirred at this temperature for approximately 6 hours. The reaction mixture is evaporated, then water and dichloromethane are added to the evaporation residue, the phases are then separated, the organic phase is washed with water (200 ml), and then with saturated sodium chloride solution, and then dried and evaporated. The evaporation residue is washed with diisopropylether (60 ml), the crystalline material is filtered off, washed with cold diisopropylether (10 ml), thereby producing 14.7 g (82% yield calculated for (VI) (S)N-[(1S)-4-cyano-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide) of white crystals.

[0090] .sup.1H NMR (CDCl.sub.3, 400 MHz) 7.43 (1H, d, J=7.6 Hz), 7.41 (1H, d, J=7.6 Hz), 7.27 (1H, m), 5.11 (1H, t, J=7.6 Hz), 4.82 (2H, bs), 3.58-3.72 (2H, m), 3.20-3.30 (1H, ddd, J=12.3, 9.3, 3.9 Hz), 3.10-3.20 (1H, m), 2.95-3.05 (2H, m), 2.38-2.48 (1H, m), 2.14-2.26 (1H, m), 1.25 (9H, s), 0.86 (9H, s), 0.01 (6H, s).

Example 3

[0091] The production of the mixture of (S)N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (IVA) and ((S)N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-N-(2-hydroxyethyl)-2-methylpropane-2-sulfinamide (V)

##STR00035##

[0092] The (S)N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide ((IIIA); 12.25 g; 27.0 mmol) is added to a multi-neck 500 ml device in an argon atmosphere at 25 C., while being stirred it is dissolved with toluene (220 ml), and 3-cyano-4-(propan-2-yloxy)benzoic acid ((VIII); 8.31 g; 40.5 mmol) and triethylamine (13.65 g; 18.7 ml; 135 mmol) are added, and then the T3P is added drop by drop (17.16 g 50% solution; 16.0 ml; 27.0 mmol). The reaction mixture obtained in this way is stirred at 85-90 C., then cooled to room temperature, then water is added and the phases are separated. The organic phase is washed with saturated sodium hydrogen carbonate solution, dried and then evaporated in a vacuum. The mixture obtained in this way, which contains the (S)N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (IVA) and the (S)N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-N-(2-hydroxyethyl)-2-methylpropan-2-sulfinamide (V) formed from it, is used in the next synthesis step without purification.

[0093] Using the acidic method disclosed in the descriptive part, in a Shimadzu LC-MS device the IVA compound comes at a retention time of RT: 6.31 min, and the V compound at a retention time RT: 4.24 min.

[0094] Column chromatography separation was used to identify the components of the mixture, according to the method given in the descriptive part, the retention time of the (IVA) compound: 56 min.

(IVA) (sample purified with chromatographic process):

[0095] .sup.1H NMR (CDCl.sub.3, 400 MHz) 8.44 (1H, d, J=2.1 Hz), 8.35 (1H, dd, J=8.9, 2.2 Hz), 8.11 (1H d, J=7.6 Hz), 7.53 (1H, d, J=7.6 Hz), 7.39 (1H, t, J=7.6 Hz), 7.17 (1H, d, J=8.9 Hz), 5.18 (1H, t, J=7.6 Hz), 4.80 (1H, quint, J=6.0 Hz), 3.58-3.72 (2H, m), 3.20-3.30 (1H, ddd, J=12.3, 9.3, 3.9 Hz), 3.10-3.20 (1H, m), 2.95-3.05 (2H, m), 2.50-2.60 (1H, m), 2.25-2.38 (1H, m), 1.48 (6H, d, J=6.0 Hz), 1.25 (9H, s), 0.86 (9H, s), 0.01 (6H, s).

(V) (sample purified with chromatographic process): according to the method given in the descriptive part, the retention time of the V compound: 145 min.

[0096] .sup.1H NMR (CDCl.sub.3, 400 MHz) 8.43 (1H, d, J=1.8 Hz), 8.33 (1H, dd, J=8.8, 1.9 Hz), 8.13 (1H d, J=7.5 Hz), 7.58 (1H, d, J=7.1 Hz), 7.42 (1H, t, J=7.5 Hz), 7.13 (1H, d, J=8.8 Hz), 5.11 (1H, t, J=7.6 Hz), 4.80 (1H, quint, J=6.0 Hz), 3.46-3.50 (5H, m), 3.25-3.29 (2H, m), 2.55-2.59 (1H, m), 2.35-2.38 (1H, m), 1.53 (1H, s); 1.48 (5H, d, J=6.0 Hz), 1.26 (9H, s).

Example 4

5-{3-[(1S)-1-[(2-Hydroxyethyl)amino]-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl}-2-(propan-2-yloxy)benzonitrile Hydrochloride (Ozanimod Hydrochloride, Hydrochloride Salt of Compound (I))

[0097] ##STR00036##

[0098] a) Process

[0099] The mixture (11.2 g) obtained according to example 3 is stirred with 2-propanol (80 ml) until a homogenous solution is obtained, then 2-propanol hydrogen chloride solution (20.25 ml; 6.35 mmol/ml; 128.6 mmol) at room temperature is added to it drop by drop, the mixture is then stirred at 50 C., then cooled, then stirred again for 2 hours at 0-5 C. The precipitated crystals are filtered out, washed with 2-propanol, thereby 6.2 g (yield calculated for IIIA (S)N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-il]-2-methylpropane-2-sulfinamide is 52%) ozanimod hydrochloride is obtained. The gross yield of the synthesis performed without extracting the intermediate products (B), (IIA), (IVA) and (V) calculated for the initial material 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (A) is 26.6%.

[0100] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) 9.19 (2H, bs), 8.53 (1H, d, J=2.3 Hz), 8.41 (1H, dd, J=9.9, 2.3 Hz), 8.16 (1H, d, J=7.2 Hz), 7.95 (1H, d, J=7.5 Hz), 7.58 (2H, m), 5.28 (1H, t, J=5.0 Hz), 4.99 (1H, quint, J=6.0 Hz), 4.90 (1H, m), 3.71 (2H, q, J=5.0 Hz), 3.47 (1H, m), 3.35 (2H, m), 3.05 (1H, m), 3.00 (1H, m), 2.32 (1H, m), 1.39 (6H, d, J=6.0 Hz).

[0101] b) Process

[0102] The (S)N-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (IVA; 220 mg; 0.353 mmol) is stirred with 2-propanol (1.5 ml) until a homogenous solution is obtained, then concentrated hydrochloride acid solution (37%; 0.1 ml) is added to it drop by drop at room temperature, the reaction mixture is then stirred at 50 C. and cooled, and once again stirred for 2 hours at 0-5 C. The precipitated crystals are filtered out, washed with 2-propanol, thereby producing 120 mg (77%) ozanimod hydrochloride.

[0103] c) Process

[0104] The (S)N-[(1S)-4-{5-[3-cyano-4-(propan-2-yloxy)phenyl]-1,2,4-oxadiazol-3-yl}-2,3-dihydro-1H-inden-1-yl]-N-(2-hydroxyethyl)-2-methylpropane-2-sulfinamide (V; 114 mg; 0.224 mmol) is stirred with 2-propanol (1.0 ml) until a homogenous solution is obtained, then concentrated hydrochloric acid (37%; 0.05 ml) is added to it at room temperature, and then the reaction mixture is stirred at room temperature, then cooled and stirred once again for 2 hours at 0-5 C. The precipitated crystals are filtered out, washed with 2-propanol, thereby producing 89 mg (90%) ozanimod hydrochloride.

Example 5

[0105] The production of ozanimod hydrochloride (one pot process):

##STR00037## ##STR00038##

Reaction:

[0106] Coupling and the production of raw hydrochloride:

[0107] 13.75 g (30.3 mmol) compound of formula (III/A) is measured into a 500-ml multi-neck flask fitted with a gas inlet, cooler, bubbler, dropper funnel and thermometer at 25 C. in an argon atmosphere in 80.0 ml of absolute toluene, 6.22 g (30.3 mmol) compound of formula (VIII) and 21.0 ml (15.33 g; 151.5 mmol) Et.sub.3N are added to the suspension obtained while stirring and 9.0 ml (15.15 mmol) T3P 50% in ethyl acetate solution is added to it drop by drop. The solution obtained is heated to 90 C., and then stirred at this temperature until the compound of formula (III/A), the precursor of compound of formula (IV/A) and the precursor of compound of formula (V) can be detected in the reaction mixture on the basis of LC-MS.

[0108] The reaction mixture is allowed to cool to room temperature. The phases are then separated, and the organic phase is washed with 270 ml saturated NaCl solution. The toluene phase is heated to 85 C., and during intensive stirring 10.0 ml (4 equiv., 121.2 mmol) 37% aqueous hydrochloric acid solution is added drop by drop. The temperature increases to 90 C., and within a short time the crystals start to precipitate. Stirring is continued at this temperature until the compound of formula (IV/A) (M+H: 623), the compound of formula (V) (M+H: 509), and the O-silylated ozanimod derivative (M+H: 519) can be detected on the basis of LC-MS. Following this the reaction mixture is left to cool to room temperature while being stirred, then cooled to 0-5 C. with the stirring being continued for 1 hour.

[0109] The crystalline product is filtered, and washed with 310 ml cold toluene. Thereby producing 8.5 g (63.6%) ozanimod hydrochloride.

Example 6

[0110] The production of the Form I polymorph of ozanimod base: 3.60 g raw ozanimod hydrochloride is suspended in a mixture of 58 ml dichloromethane and 35 ml water, while stirring 9 ml 2 M NaHCO.sub.3 solution is added drop by drop. The phases are separated, and the organic phase is evaporated until dry. The 1.85 g raw ozanimod base obtained in this way is suspended in 36 ml acetonitrile. The mixture is kept at boiling point until a homogenous solution is obtained. The solution is boiled for 5 minutes with 0.2 g active carbon, then filtered. The crystal mass precipitating from the filtrate is heated back up to the boiling point of the solvent, then the solution obtained in this way is left to cool to room temperature. Then maintaining it at a temperature between 0-5 C. the mixture is stirred for a further 1 hour. Following this the mixture is filtered, and the crystals washed with 23 ml cold acetonitrile. In this way 1.51 g Form I polymorph crystalline product is obtained, the x-ray powder diffraction lines of which are summarised in the following table:

TABLE-US-00002 Relative intensity Peak 2 () d () (%) 1 2.86 30.90 28 2 5.77 15.32 100 3 8.66 10.22 21 4 10.77 8.22 13 5 10.87 8.14 8 6 11.14 7.94 14 7 11.56 7.65 28 8 12.20 7.25 9 9 12.98 6.82 42 10 13.38 6.62 97 11 13.90 6.37 34 12 14.59 6.07 24 13 15.36 5.77 14 14 16.23 5.46 45 15 17.19 5.16 12 16 17.43 5.09 4 17 17.73 5.00 9 18 18.44 4.81 6 19 18.94 4.69 13 20 19.54 4.54 37 21 20.28 4.38 8 22 20.41 4.35 2 23 21.10 4.21 4 24 21.65 4.11 24 25 21.87 4.07 6 26 22.10 4.02 11 27 22.43 3.97 19 28 22.79 3.90 6 29 23.36 3.81 31 30 23.75 3.75 11 31 23.95 3.72 16 32 24.62 3.62 61 33 25.37 3.51 55 34 26.16 3.41 28 35 27.00 3.30 41 36 27.90 3.20 26 37 28.86 3.09 12 38 29.20 3.06 2 39 29.85 2.99 1 40 31.00 2.89 2

[0111] The characteristic x-ray powder diffractogram of this corresponds to FIG. 3.

Example 7

[0112] The dynamic vapour sorption (DVS) measurement of the ozanimod base Form I polymorph according to example 6

[0113] The ozanimod base Form I polymorph is slightly hygroscopic. The mass of the sample increased by 0.6% under 95% relative humidity. The sorption isotherm of the first cycle is shown in FIG. 4. On repeating the cycle the sorption isotherm did not change. What is more is that after the two cycles the unchanged nature of the crystal structure is proved by the x-ray power diffractogram shown in FIG. 5, which is the same as the diffractogram of the initial crystals shown in FIG. 3. From this it can be seen that the ozanimod base Form I polymorph form is stable at 25 C., and not sensitive to humidity.