2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of sodium borohydride (0.60 g) and lithium bromide (1.66 g) in ethanol (17 ml) was stirred at room temperature for 25 minutes. Ethyl 2-amino-2-ethoxycarbonyl-4-(4-octylphenyl)butyrate (1.24 g) was dropwise added thereto over 3 minutes and the mixture was stirred at room temperature for 5 hours. Water (40 ml) was added to the reaction mixture and the mixture was stirred for 40 minutes. The crystals precipitated was collected by filtration and dried to give 0.68 g of the subject compound, melting point=125°-126° C. Treatment of the subject compound with hydrochloric acid-ethanol gives the corresponding hydrochloride. over 3 minutes the mixture was stirred at room temperature for 5 hours the mixture was stirred for 40 minutes The crystals precipitated was collected by filtration dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (7 g) was dissolved in ethanol (50 ml) and a 1N hydrochloric acid/ether solution (50 ml) was added thereto. The solvent was distilled away and the resultant crystals were recrystallized from ethanol to give 4.2 g of the subject compound. The solvent was distilled away the resultant crystals were recrystallized from ethanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of sodium borohydride (0.60 g) and lithium bromide (1.66 g) in ethanol (17 ml) was stirred at room temperature for 25 minutes. Ethyl 2-amino-2-ethoxycarbonyl-4-(4-octylphenyl)butyrate (1.24 g) was dropwise added thereto over 3 minutes and the mixture was stirred at room temperature for 5 hours. Water (40 ml) was added to the reaction mixture and the mixture was stirred for 40 minutes. The crystals precipitated was collected by filtration and dried to give 0.68 g of the subject compound, melting point=125-126° C. Treatment of the subject compound with hydrochloric acid-ethanol gives the corresponding hydrochloride. over 3 minutes the mixture was stirred at room temperature for 5 hours the mixture was stirred for 40 minutes The crystals precipitated was collected by filtration dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (7 g) was dissolved in ethanol (50 ml) and a 1 N hydrochloric acid/ether solution (50 ml) was added thereto. The solvent was distilled away and the resultant crystals were recrystallized from ethanol to give 4.2 g of the subject compound. The solvent was distilled away the resultant crystals were recrystallized from ethanol

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol (FrY 720) using procedures analogous to those described in EXAMPLE 2, except that lithium dilsopropylamide was substituted for n-butyllithium in Step C and diethyl difluoromethylphosphonate was substituted for dimethyl methylphosphonate in Step C: Mass spectrum (NH3—CI) 422 (M+H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3.07 g (10.0 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol and 3.00 g (30.0 mmol) of KHCO3 in 200 mL of EtOAc and 150 mL of H2O was treated with 1.50 mL (10.0 mmol) of benzyl chloroformate, then stirred at rt for 2 h. The organic layer of the reaction mixture was separated, dried over MgSO4 and concentrated to afford 5.29 g of the title compound: 1H NMR (500 Mhz) δ0.88 (t, J=6.5, 3H), 1.22-1.34 (12H), 1.55-1.60 (m, 2H), 1.87-1.91 (m, 2H), 2.53-2.59 (4H), 3.23 (br s, 2H), 3.67 (dd, J=6.5, 11.5, 1H), 3.90 (dd, J=6.5, 11.5, 1H), 5.08 (s, 2H), 5.30 (s, 1H), 7.05-7.09 (4H), 7.32-7.36 (5H); HPLC A 5.34 min. The organic layer of the reaction mixture was separated dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3.07 g (10.0 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol and 3.00 g (30.0 mmol) of KHCO3 in 200 mL of EtOAc and 150 mL of H2O was treated with 1.50 mL (10.0 mmol) of benzyl chloroformate, then stirred at rt for 2 h. The organic layer of the reaction mixture was separated, dried over MgSO4 and concentrated to afford 5.29 g of the title compound: 1H NMR (500 Mhz) δ0.88 (t, J=6.5, 3H), 1.22-1.34 (12H), 1.55-1.60 (m, 2H), 1.87-1.91 (m, 2H), 2.53-2.59 (4H), 3.23 (br s, 2H), 3.67 (dd, J=6.5, 11.5, 1H), 3.90 (dd, J=6.5, 11.5, 1H), 5.08 (s, 2H), 5.30 (s, 1H), 7.05-7.09 (4H), 7.32-7.36 (5H); HPLC A 5.34 min. The organic layer of the reaction mixture was separated dried over MgSO4 concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 450 mg (1.5 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol, 0.32 mL (1.75 mmol) of triethylorthoacetate and 0.56 mL (3.2 mmol) of DIEA in 6 mL of DMF was stirred at 75° C. for 2 h. The mixture was cooled, partitioned between 40 mL of 3:1 v/v ether/EtOAc and water and the layers were separated. The organic layer was washed with water and dried. Flash chromatography on silica gel using 4:1 v/v CH2Cl2/EtOAc as the eluant afforded 440 mg (91%) of the title compound: Mass spectrum (NH3—CI) 332 (M+H). The mixture was cooled partitioned between 40 mL of 3:1 v/v ether/EtOAc and water the layers were separated The organic layer was washed with water dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 450 mg (1.5 mmol) of 2-amino-2-hydroxymethyl-4-(4-(octyl)phenyl)butanol, 0.32 mL (1.75 mmol) of triethylorthoacetate and 0.56 mL (3.2 mmol) of DIEA in 6 mL of DMF was stirred at 75° C. for 2 h. The mixture was cooled, partitioned between 40 mL of 3:1 v/v ether/EtOAc and water and the layers were separated. The organic layer was washed with water and dried. Flash chromatography on silica gel using 4:1 v/v CH2Cl2/EtOAc as the eluant afforded 440 mg (91%) of the title compound: Mass spectrum (NH3—CI) 332 (M+H). The mixture was cooled partitioned between 40 mL of 3:1 v/v ether/EtOAc and water the layers were separated The organic layer was washed with water dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 100.0 gm of fingolimod was dissolved in ethanol 250 ml and conc HCl 49 ml solutions. The reaction mass was stirred for about 30 min at room temperature; then concentrated under vacuum at about 40-45° C. 250 ml of ethanol was added. The reaction mass was heated to about 65-70° C. and 800 ml ethyl acetate was added in to reaction mass. The reaction mass was cooled to about 20-25° C. and stirred for about 30 min. The solid obtained was filtered and washed with ethyl, acetate to get 85 g of compound of Fingolimod hydrochloride. Purity 99.75% and Impurity compound of Formula XII: 0.06% by HPLC. then concentrated under vacuum at about 40-45° C 250 ml of ethanol was added The reaction mass was heated to about 65-70° C. 800 ml ethyl acetate was added in to reaction mass The reaction mass was cooled to about 20-25° C. stirred for about 30 min The solid obtained was filtered washed with ethyl, acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 17.0 gm of fingolimod was dissolved in (1:1) ethanol 120 ml:IPE.HCl 120 ml solutions. The reaction mass was stirred for about 30 min at room temperature; then concentrated under vacuum at about 40-45° C. 51 ml ethanol was added. The reaction mass was heated to about 50-55° C. and 200 ml ethyl acetate was added into the reaction mass. The reaction mass was cooled to about 5-10° C. and stirred for about 30 min. The solid obtained was filtered and washed with ethyl acetate to get 14.6 g of compound of Fingolimod hydrochloride. Purity 99.75% and regioisomer impurity compound of Formula IA: 0.006% by HPLC. then concentrated under vacuum at about 40-45° C 51 ml ethanol was added The reaction mass was heated to about 50-55° C. 200 ml ethyl acetate was added into the reaction mass The reaction mass was cooled to about 5-10° C. stirred for about 30 min The solid obtained was filtered washed with ethyl acetate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Nitro-2-(4-octylphenethyl)propane-1,3-diol (25 g), absolute ethanol (250 mL) and 10% Pd on carbon (5 g, 50% wet) are charged into a 500 mL steel hydrogenation flask under a N2 atmosphere and the flask is equipped with a para shaker hydrogen operator. The mixture is hydrogenated with a H2 pressure of 60 psi (415 kPa) at room temperature for 2 hours and filtered through a Celite bed and washed with ethylacetate (200 mL). The filtrate is concentrated under reduced pressure at 50° C. to give the title compound as a white solid. Yield: 16 g. filtered through a Celite bed washed with ethylacetate (200 mL) The filtrate is concentrated under reduced pressure at 50° C.