WO2014111949A1 - Intermediates and process for the preparation of high purity fingolimod hydrochloride - Google Patents

Intermediates and process for the preparation of high purity fingolimod hydrochloride Download PDF

Info

Publication number
WO2014111949A1
WO2014111949A1 PCT/IN2013/000044 IN2013000044W WO2014111949A1 WO 2014111949 A1 WO2014111949 A1 WO 2014111949A1 IN 2013000044 W IN2013000044 W IN 2013000044W WO 2014111949 A1 WO2014111949 A1 WO 2014111949A1
Authority
WO
WIPO (PCT)
Prior art keywords
mass
range
temperature
compound
yield
Prior art date
Application number
PCT/IN2013/000044
Other languages
French (fr)
Inventor
Durga Prasad Konakanchi
Subba Rao PULA
Ramakrishna Pilli
Kali Satya Bhujanga Rao ADIBHATLA
Venkaiah Chowdary Nannapaneni
Original Assignee
Natco Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Natco Pharma Limited filed Critical Natco Pharma Limited
Priority to PCT/IN2013/000044 priority Critical patent/WO2014111949A1/en
Publication of WO2014111949A1 publication Critical patent/WO2014111949A1/en

Links

Classifications

    • 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
    • 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
    • C07C213/08—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the present invention relates to a simple and commercially feasible preparation of high purity Fingolimod hydrochloride.
  • the present invention also provides novel intermediates for the preparation of Fingolimod Hydrochloride and a process for the preparation of the intermediate.
  • Fingolimod Hydrochloride is a sphingosine 1 -phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
  • Fingolimod hydrochloride is marketed under the trade name GILENYA and is chemically known as 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l , 3-diol hydrochloride of Formula 1
  • AICI3 gave 2-(4-octanoylphenyl) ethyl acetate (la). After reaction work-up the crude residue was purified by column chromatography to obtain (la) as oil in 38% yield. The compound (la) was reduced with triethylsilane in presence of trifluoroacetic acid to give 2-(4-octylphenyl) ethyl acetate (lb). After the work-up crude residue was purified by column chromatography to obtain (lb) as oil in 87 % yield.
  • the process employs pyridine as solvent, which is undesirable due to toxic effects.
  • the process requires anhydrous THF (tetrahydrofuran), a large excess of LiOH which is not desirable from an economic point of view.
  • 2-(4-2Hydroxyphenyl) ethanol was treated with ethyl acetate in the presence of immobilized NaHS0 4 /Si0 2 as a solid promoter and after work-up the crude compound was purified by flash column chromatography to give a colorless solid of monoacetate compound(5a) with 98% yield.
  • the phenolic-OH group was later protected by triflate group by using triflic anhydride with an yield of 94% yield for 5b.
  • the triflate protected (5b) was treated with octylmagnesium bromide in the presence of iron catalyst and after reaction work-up of the crude compound and subsequent flash column chromatography gave colorless syrup- (lb) with 64% yield.
  • the ester derivative (lb) was treated with sodium methoxide in presence of methanol converted to crude alcohol which was purified by flash column chromatography to give colorless syrup " (lc) with 93 % yield.
  • the alcohol derivative (lc) was treated with methanesulfonyl chloride in presence of triethyl amine gave methanesulfonate derivative (Id).
  • the sulfonate derivative (Id) compound was treated with lithium iodide to give oily compound of 2- (4-octylphenyl)-l- iodoethane (le) with 89% yield.
  • the " present invention adopts the same method reported in US 3888818 for preparing intermediate of 4-octylaeetophenone (7c), the method reported in JrHet. Chem., 21, 1741 (1984) for the preparation of 2-bromo-l-(4-octyl-pheny)-ethanone (2a), the method reported in Synthesis (2000), (4), 505-506 for the preparation of 2-(acetyl amino)-2-[2- (4-octylphenyl)-2-oxo-ethyl] propanedioic acid diethyl ester (2b) and the method reported in WO 2000/53569 for preparing compound 7f. All these intermediates of 7c, 2a, 2b, were also reported and were prepared by methods given in the basic patent US5719176.
  • step-1 of the present scheme octanoyl chloride is reacted with benzene in presence of aluminum chloride to give n-octanophenone (7a) with 93 % of yield and the product is having over 99.0 % purity by G.C.
  • the temperature range for the reaction of Friedel crafts reaction is -10 °C to 35 °C.
  • Step-2 n-octanophenone is catalytically hydrogenated using 10% palladium on carbon to give n-octyl benzene (7b), -
  • step-2 of the ch on catalytical hydrogenation using 10% palladium on carbon gave n-octyl benzene (7b) with over 90% yield .
  • the hydrogenation is carried ⁇ out at ambient temperature and the n-octyl benzene (7b) is purified by high vacuum distillation to get the product with over 99.0 % purity by GC.
  • Step-3 n-octyl benzene is reacted with acetyl chloride in presence of aluminium chloride to obtain 4-n-octyl acetophenone (7c),
  • n-octyl benzene (7b) is acylated using acetyl chloride in presence of aluminium chloride to obtain 4-octyl acetophenone (7c) with an yield of above 95% by theory.
  • the reaction can be carried out at temperature condition of -10 to 35 °C.
  • the crude product of phenaceyl bromide derivative (7d) obtained can be directly taken for the subsequent step.
  • the mole ratios of n-octyl benzene (7b) to acetyl chloride and aluminium chloride are typically in the range of 1.0: 1. Oil .0 tol .0:3.0:3.0, preferably in the ratio range of 1.0:1.0:1.0 tol .0:2.0:2.0, and more preferable of ratio range of 1.0: 1.5:1.5.
  • the solvents used are methylene dichloride, ethylene dichloride or chloroform.
  • the most preferable solvent is methylene dichloride and its quantity is typically in the range of n- octyl benzene (7b) to methylene chloride 1 : 5 w/v to 1 :30 w/v ratios; preferably in the range of 1 : 5 w/v to 1 : 15 w/v ratios, the most preferable range is 1 : 10 w/v ratio.
  • the addition temperature of acetyl chloride is typically in the range of 0 to 40 °C, preferably in the range of about 0-20 °C, more preferably in the range of 10-15°C.
  • n-octyl benzene (7b) is typically in the range of -10 to 40 °C, preferably in the range of about -10 to 10 °C, more preferably in the range of -5 to 0°C.
  • the reaction temperature is typically in the range of about 0 to 60 °C, preferably in the range of about 10-40 °C, more preferably in the range of 25-30°C.
  • the reaction time is typically in the range of about lhour to 24 hours, preferably in the range of about 2 to 8 hours, more preferably in the range of 3 to 4 hours.
  • Step-4 4-octyl acetophenone (7c) is reacted with liquid bromine in methylene chloride to obtain the phe
  • step-4 of the present scheme 4-octyl acetophenone (7c) prepared as above is brominated on the side chain by using bromine liquid in methylene chloride with or without 1.4-dioxane.
  • the reaction has been carried out at temperature range of -10 to 35 °C,
  • the other solvents optionally used are ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, and acetohitrile.
  • 4-octyl acetophenone (7c) to bromine are typically in the mole ratios range of 1.0:0.50 to 1.0:2.0, preferably in the ratio range of 1.0:0.90 to 1.0: 1.30, more preferably in the ratio- of 1.0: 1.10.
  • the ratio of 4-octyl acetophenone (7c) to 1,4 - dioxane is typically in the range of 1 :0.50 w/v to 1 :30 w/v ratios; preferably in the range of 1 : 1 w/v to 1 :2 w/v, and more preferably in the raiige of 1 : 1 w/v.
  • the addition temperature of bromine is typically in the range of -10 to 40 °C, preferably in the range of about 10 to 35 °C, and more preferably in the range of 25-30°C.
  • Reaction temperature is typically in the range of about 0 to 60 °C, preferably in the range of about 10-40 °C, and more preferably in the range of 25-30°C.
  • Reaction time is typically in the range of lhour to 24 hours, preferably in the range of 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
  • Step-5 The phenaceyl bromide derivative (2a) is reacted jwith diethyl acetamidomalonate " in presence of sodium ethoxide to obtain diethyl ester acetamide derivative (2b).
  • step-5 of the present scheme phenaceyl bromide derivative (2a) is reacted with diethyl acetamidomalonate in presence of sodium ethoxide to obtain diethyl ester acetamide derivative (2b) product.
  • the reaction temperature can be in the range of 25 °C to 80 °C.
  • the solvents used are lower alcohols such as methanol, ethanol, isopropanol, n- butanol etc., dimethyl formamide, and tetrahydrofuran.
  • the crude diethyl ester acetamide derivative (2b) is obtained with about 80% of yield and is directly taken for the "subsequent step.
  • the ratio of phenacyl bromide derivative (2a) to sodium ethoxide and diethyl acetamidomalonate are typically in the ⁇ range of 1.0:0.90:0.90-tol.0:3.0:3.0, preferably in the range of 1.0:1.0:1.0 tol .50: 1.50, and more preferably in the range of 1.0: 1.10:1.10.
  • the ratio of phenacyl bromide derivative (2a) to ethanol is typically in the range of 1 : 5 w/v to 1 : 15 w/v ; preferably in the range of 1 : 5 w/v to 1 :10 w/v, and more preferably in the range 1 :5 w/v.
  • the addition temperature diethyl acetamidomalonate is typically in the range of 0 to 60 °C, preferably in the range of about 10-40 °C, and more preferably in the range of 25- 30°C.
  • the phenacyl bromide derivative (2a) addition temperature is typically in the range of -0 to 60 °C, preferably in the range of about 10 to 40 °C, and more preferably in the range of 25 to 30°C.
  • the reaction temperature is typically in the range of about 10 to 1 10 °C, preferably in the range of about 40-80 °C, and more preferably in the range of 65-70°C.
  • the reaction time is typically in the range of about lhour to 24 hours 5 preferably typically in the range of about 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
  • Step-6 The diethyl ester acetamide derivative (7e) is reacted with sodium borohydride in presence of tetrahydrofuran and ethanol to obtain trihydroxy acetamide derivative (7f).
  • the ratio of ethanol quantity to diethyl ester acetamide derivative (2b) is typically in the range of 1 :5.0 w/v to 1 :30 w/v, preferably in the range of 1 : 10 w/v to 1 :30 w/v, and more preferably 1 :20 w/v.
  • the addition temperature of sodium borohydride is typically in the range of 0 to 40 °C, preferably in the range of about 10 to 35 °C, more preferably in the range of 25-30°C.
  • the addition temperature of ethanol is typically in the range of -5 to 40 °C, preferably in the range of about 0 to 20 °C, and more preferably in the range of 5-15°C.
  • - Reaction temperature is typically in the range of about 0 to 60 °C, preferably in the range of about 0-20 °C, and more preferably in the range of 5-15°C.
  • Reaction time is typically in the range of about lhour to 12 hours, preferably in the range of about 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
  • Step-7 In the step-7 of the present scheme, trihydroxy acetamide derivative (7f) is reacted with IPA.HC1 in IPA at reflux temperature under dry conditions to obtain E/Z-2-
  • the IPA HC1 addition temperature is typically in the range of 30 to 1 10 °C, preferably in the range of about 50 to 80 °C, and more preferably in the range of 60-65°C.
  • the reaction temperature is typically in the range of about 30 to 1 10 °C, preferably in the " range of about 50-80 °C, and more preferably in range of 70-75°C.
  • the reaction time is typically in the range of about 2hour to 12 hours, preferably in the range of about 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
  • T e ratio of Z-2-am no-2-[2-(4-octy phenyl) vinyl] propane- 1, 3-diol hydrochloride (7g) to 5% Pd/c is in the range of 1.0:0.4 to 1.0:1.50, preferably in the ratio range of 1.0:8.0 tol .0:1.20, and more preferably in the range of 1.0:1.0.
  • the reaction temperature is typically in the range of about 10 to 40 °C, preferably in the range of about 15-35 °C, and more preferably in the range of 25-3Q°C.
  • the reaction time is typically in the range of about 2 to 12 hours, preferably in the range of about 2 to 8 hours, and more preferably in the range of 4 to 6 hours.
  • Step-9 The technical grade product is recrystallised from ethanol and ethyl acetate ⁇ mixture. The melting range of the final product is 104.6 to 107.5 °C. - -
  • Octanophenone (50 g, 0.245 mol) was dissolved in -500 ml of methanol. Reaction mass was transferred into 1.0 L hydrogenator kettle. 5.0 g of 5% palladium on carbon was charged and hydrogenation was carried out at 50-60 psi pressure and continued till the consumption was stopped. Filtered the catalyst on hyflow bed and washed the bed with 200 ml of methanol. Methanol was completely distilled off under vacuum at temperature below 60 °C. The pure fraction as n-octylbenzene was collected under high vacuum distillation (lmm/Hg) at vapour temperature 135°C and- obtained 42.60 g (91.5 % yield) " of the product with 99.4 % of purity by G.C.
  • reaction mass was monitored by TLC. Quenched the reaction mass into 400 g of crushed ice and 10 ml of cone, hydrochloric acid maintaining the mass . temperature at 0 to 5 °C. 200.0 ml of DM Water was added to reaction mass. Raised the mass temperature to 25-30 °C and the organic layer was separated. Aqueous layer was extracted further with 200 ml of methylene chloride. The organic layers were combined and washed with 200 ml of 10% sodium carbonate solution. The organic layer was dried over anhydrous sodium sulphate and filtered. Methylene chloride was completely distilled off under vacuum at below 50 °C. Finally applied high-vacuum to completely remove the traces of solvent at below 50 °C to obtain 1 15.0 g (94.2 % yield) of oily compound (99 4% of purity by GC).
  • reaction mass maintaining the temperature at 25-30 °C. Stirred the mass for 30 min. Cooled the mass temperature to 5-15°C. 1000 ml of ethanol was added to reaction mass maintaining the temperature at 5-15 °C over a period of 45-60 min. Maintained the mass temperature at 5-15 °C for 3 hours. The progress and completion of reaction was monitored by TLC. Reaction mass was quenched in 1000 ml of DM water. Raised the mass temperature to 25-30 °C. Maintained the mass temperature to 25-30 °C for 20 min. 5 Extracted the compound with 2x 500 ml of ethyl acetate. The organic layer was washed with 3x500 ml of saturated sodium chloride solution and dried over anhydrous sodium sulphate.
  • Ethyl acetate was completely distilled off under vacuum below 80 °C. Finally applied high vacuum to remove traces of solvent below 80 °C. Cooled the mass temperature to 45-50°C. Added 160 ml of acetone. Raised the mass temperature to reflux0 and maintained for 30 min. Cooled the mass temperature to 0-5 °C and maintained for 30 min. Filtered the solid and washed the solid with 40 ml of chilled acetone. Wet compound was charged into a flask, added 160 ml of ethyl acetate. Raised the mass temperature to reflux and maintained for 30 min, cooled the mass temperature to 0-5°C and maintained for 30 min.
  • Isopropyl alcohol 500 ml was charged into a 2 L 4 necked round bottom flask, connected to a mechanical stirrer, equipped with therrno meter socket, addition funnel, and condenser. 3-Amino-3-(hydroxymethyl)-l-(4-octylphenyl) butane- 1, 4-diol (50 g, 0.136 mol) was added and the mass temperature was raises to 60-65°C. 271.0g of isopropyl alcohol-HC fchemical assay: 15.0 % w/w] was added at temperature 60-65°C. - Maintained the mass temperature at 60-65°C for 4 hours. The progress and completion of reaction was monitored by TLC.
  • Isopropyl alcohol was excreted off under vacuum at below 70 °C. Finally applied high vacuum to completely remove traces of solvent at below 70 °C. Cooled the mass temperature to 45-50°C. 200 ml of acetone was added to the residual mass. Raised the mass temperature to reflux and maintained for 30 min then cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the solid and washed the solid with 50 ml of chilled acetone. Compound was dried at 50- 55°C to obtain 42.5 g of 7g (90.85 % yield) with a purity of 99.1 % by HPLC. Melting range: 179.2C to 184.3°C.
  • Hydrochloride (1) [Fingolimod hydrochloride] by Hydrogen gas bubbling.
  • the solvent was completely distilled off under vacuum at below 60°C. Cooled the mass temperature to 45-50°C. Acetone (500 ml) was added to remaining mass. Raised the mass temperature " to reflux and maintained for 30 min. Cooled the mass temperature to 0- 5°C and maintained for 30 min. Filtered the solid formed and washed the solid with 50 ml of chilled acetone.
  • the crude compound was dissolved in 2200 ml of DM water and pH was adjusted between 9.5 and 10.5 with aqueous ammonia solution. Stirred the mass for 1 hour at 25-30°C. Filtered the solid and washed with 200 ml of DM water. Dried the compound at 55-60°C under vacuum.
  • the base compound was charged into a flask and added 200 ml of acetone. Added 78.0 g of 15.0% w/w IPA HCI solution and stirred the mass for 1 hour at 25-30°C. Cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the- solid and washed the solid with 40 ml of chilled acetone. The thus ⁇ obtained compound was dissolved in 90.0 ml of methanol at 55 60°C, 900 ml of ethyl acetate was added at 55-60 °C then cooled to 25-30°C and maintained the mass temperature at 25-30°C for 1 hour. Cooled the mass temperature to_ 0-5°C and maintained for 30 min.
  • the crude compound was dissolved in 90.0 ml of methanol at 55- 60 °C and 900 ml of ethyl acetate was added at 55- 60 °C. Cooled to 25- 30 °C and maintained the mass temperature at 25-30 °C for 1 hour. Cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the solid and washed the solid with 90 ml of chilled ethyl acetate. ⁇ Compound was dried at 50- 55 °C under vacuum to obtain 38.60 g (76.7% yield) with 99.50 % of purity by HPLC. Melting range 104.8-107.9 o C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a simple and commercially feasible preparation of Fingolimod hydrochloride with high purity of greater than 99.9%. The.present invention also provides novel intermediates for the preparation of Fingolimod Hydrochloride of Formula 1.

Description

INTERMEDIATES AND PROCESS FOR THE PREPARATION OF HIGH PURITY FINGOLIMOD HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to a simple and commercially feasible preparation of high purity Fingolimod hydrochloride. The present invention also provides novel intermediates for the preparation of Fingolimod Hydrochloride and a process for the preparation of the intermediate. BACKGROUND OF THE INVENTION:
Fingolimod Hydrochloride is a sphingosine 1 -phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Fingolimod hydrochloride is marketed under the trade name GILENYA and is chemically known as 2-amino-2-[2-(4-octylphenyl)ethyl]propan-l , 3-diol hydrochloride of Formula 1
Figure imgf000002_0001
US 5604229 discloses 2-amino-l,3-propanediol compounds and particularly discloses process for the preparation of Fingolimod Hydrochloride as shown in scheme I
Figure imgf000003_0001
AICI3 gave 2-(4-octanoylphenyl) ethyl acetate (la). After reaction work-up the crude residue was purified by column chromatography to obtain (la) as oil in 38% yield. The compound (la) was reduced with triethylsilane in presence of trifluoroacetic acid to give 2-(4-octylphenyl) ethyl acetate (lb). After the work-up crude residue was purified by column chromatography to obtain (lb) as oil in 87 % yield. The deprotection of 2-(4- octylphenyl) ethyl acetate (lb) with sodium ethoxide in ethanol gave 2-(4-Octylphenyl) ethanol and after work-up the crude residue was purified by column chromatography to obtain (lc) as oil in 97 % yield. The 2-(4-octylphenyl) ethyl alcohol (lc) was then treated methanesulfonyl chloride in presence of triethyl amine gave 2-(4-Octylphenyl) ethyl methanesulfonate (Id). After the work-up crude residue was purified by column chromatography to obtain as oil in 95% yield. The 2-(4-octylphenyl) ethyl methanesulfonate (Id) was treated with sodium iodide by refluxing in presence of methylethyl ketone gave 2-(4-Octylphenyl) ethyl iodide (le). After reaction work-up crude residue was purified by column chromatography to get as oil in 80 % yield. Then condensation of compound (le) with diethyl acetamidomalonate in presence of sodium ethoxide in ethanol /THF gave diethyl 2-acetamido-2- (4-octylphenyl) ethyl malonate and after further work-up followed by column chromatography gave a low melting solid (49-51°C) with 61 % yield. Later the diethyl 2-acetamido-2- (4-octylphenyl) ethyl malonate (If) was reduced with lithium aluminum hydride in THF and subsequent treatment with acetic anhydride in pyridine gave 2-acetamido-2-(acetoxymethyl)-4-(4- octylphenyl) butyl acetate (lg). After work-up the crude compound was purified by column chromatography to obtained solid (lg) with 69 % yield. Then hydrolysis of 2- acetamido-2-(acetoxymethyl)-4-(4-octylphenyl) butyl acetate (lg) with lithium hydroxide ■_' in refluxing methanol/ water gave 2-amino-2- [2-(4-octylphenyl) ethyl]- 1, 3-propanediol followed by work-up the obtained crude compound was recrystalized from ethyl acetate gave compound (lh) with 70 % yield. Finally the 2-amino-2- [2-(4-octylphenyl) ethyl]- 1,3 -propanediol lh) was treated with IN HC1 in ethanol and diethyl ether mixture gave 2- amino-2- (2-(4-octylphenyl) ethyl] -1,3 -propanediol hydrochloride(l) [Fingolimod Hydrochloride] with 53.5 % yield.
The disadvantages of the process of scheme-I are given below:
1. Very laborious and time consuming methods are involved as column chromatography was used in several stages from stage- la to stage- lg.
2. The process employs pyridine as solvent, which is undesirable due to toxic effects. In addition^ the process requires anhydrous THF (tetrahydrofuran), a large excess of LiOH which is not desirable from an economic point of view.
3. The overall yield, starting from phenethyl acetate was only 8.0 %." Scheme-II [Reported synthetic scheme in Durandef.al Synthesis 2000, (4), 505-506.
Friedel Grafts acylation of octylberizene with bromo acetyl chloride in presence of aluminum chloride and using dichloromethane as solvent gave phenacyl bromide derivative (2a). The phenacyl bromide was condensed with 2-acetamido malonic acid diethyl ester (2a) in presence of sodium ethoxide in ethanol and THF gave compound (2b) which was purified by column chromatography. Reduction of purified compound (2b) with triethylsilylhydride in presence . of titanium tetrachloride in dichloromethane to give the key intermediate, diethyl 2-acetamido-2- (4-octylpheriyl) ethyl malonate (If).
EtONa
Figure imgf000005_0001
octyl benzene
Figure imgf000005_0002
Disadvantages of Scheme-II:
1. Pyrophoric and expensive reagent triethylsilylhydride is used,
2. Very time consuming method, column chromatography has been used in the stage-2 purification step.
Scheme -III [Reported synthetic scheme by Biswajit kalita et.al in Synlett 2001, 9141 1] Condensation of 4-chlorobenzaldehyde with octylzinc iodide in presence of Ni (O) gave 4-octylbenzaldehyde (3a). The 4-octylbenzaldehyde (3a) was then treated with vinyl magnesium bromide to give allyl alcohol derivative (3b) followed by epoxidation with MCPBA gave the epoxide compound (3c). The epoxide ring was opened with sodium nitrite and magnesium sulphate in refluxing methanol gave 3-nitro-l-(4-octylphenyl) propane- 1, 2-diol (3d). Then reaction of the diol derivative with trimethylsilyl chloride and sodium iodide in acetonitrile gave the nitro propene derivative (3e). The nitro propene derivative was hydrogenated with H2 and Pd/c in ethanol to give the nitro propane derivative (3f). Next, the bis-formylation of nitro propane derivative with aqueous formaldehyde in the presence of Amberlyst A-21 in dichloromethane gave 2- nitro-2-[2-(4-octylphenyl) ethyl] propane- 1 , 3 -diol (3g). Finally, the nitro derivative was reduced catal tic hydrogenation using H2 over Ra-Ni gave Fingolimod (lh).
Figure imgf000006_0001
1. Expensive reagents such as vinyl magnesium bromide, Amberlyst A-21 are used in the process makes the process uneconomical.
2. The nitro group containing intermediates are of explosive nature. Scheme .Bull 56 (4) 595-
Figure imgf000007_0001
Friedel-Crafts condensation of phenethyl bromide with octanoyl chloride in presence of A1C13 gave 4'-(2-b~romoethyl) octanophenone. After reaction work-up obtained an oily compound with 83% yield by theory. The compound 4a condensation with acetamidomalonate gave diethyl 2-acetylamino-2-(2-(4-octanoylphenyl) ethyl) propane - 1 , 3-dicarboxylate. After reaction work-up the crude compound was purified by column chromatography and obtained a solid compound with 67 % yield by theory. Diethyl 2- acetylamino-2-(2-(4-octanoylphenyl) ethyl) propane -1, 3- dicarboxylate was hydrogenated with 5% Pd/c at atmospheric pressure. After reaction work-up the crudecompound was recrystallised from hexane gave -diethyl 2-acetylamino-2- (2-(4- octylphenyl) ethyl) propane -1, 3- dicarboxylate with 75 % yield. Disadvantages of Scheme-IV: _
1. Very expensive and time consuming method as column chromatography has been used in the stage-4b purification step. Scheme -V [Reported synthetic scheme by Gunter Seidel et.al, in J.O.C. 2004, 69, 3950- 3 -
Tf20
pyridine
Figure imgf000008_0001
Figure imgf000008_0002
2-(4-2Hydroxyphenyl) ethanol was treated with ethyl acetate in the presence of immobilized NaHS04/Si02 as a solid promoter and after work-up the crude compound was purified by flash column chromatography to give a colorless solid of monoacetate compound(5a) with 98% yield. The phenolic-OH group was later protected by triflate group by using triflic anhydride with an yield of 94% yield for 5b. the triflate protected (5b) was treated with octylmagnesium bromide in the presence of iron catalyst and after reaction work-up of the crude compound and subsequent flash column chromatography gave colorless syrup- (lb) with 64% yield. The ester derivative (lb) was treated with sodium methoxide in presence of methanol converted to crude alcohol which was purified by flash column chromatography to give colorless syrup" (lc) with 93 % yield. The alcohol derivative (lc) was treated with methanesulfonyl chloride in presence of triethyl amine gave methanesulfonate derivative (Id). Then the sulfonate derivative (Id) compound was treated with lithium iodide to give oily compound of 2- (4-octylphenyl)-l- iodoethane (le) with 89% yield. The iodo compound (le) was alkylated with diethyl acetamidomalonate in presence of sodium hydride Using DMF as solvent. After work up, the crude compound purified was purified by flash chromatography to give a colorless solid of diethyl 2-acetamido-2-[2-(4-octylphenyl) ethyl] malonate (If) with 82% yield. Disadvantages of Scheme-V:
1. Very expensive and time consuming method.
2. Flash chromatography has been used- in the stages-5a, lb, lc, If. - . ~ ■ '
Scheme -VI [Reported synthetic scheme in Chinese patent, WO 00/53569]
Figure imgf000009_0001
Essentially the compound 2a mentioned in scheme II was prepared by acylation of n- octylbenzene followed by side chain bfomination with bromine liquid to get" 2b. The diester was reduced to di-alcohol by using sodium borohydride to get 6d. The
deprotection oh N-atom was carried out by using lithium hydroxide to obtain compound 6e. The compound 6e was finally "converted to Fingolimod.
_ ■ - - _ -
The disadvantages of the scheme- VI are:
1. Formation of several impurities at 6d stage because of usage of methanol as solvent for the reduction. ' ~ ;
2. Conversion of 6d to 6f is tedious and the product obtained is found to have impurities not pure enough for pharmaceutical use. OBJECT OF THE INVENTION:
Accordingly, it is an object of the present invention to provide an expedient commercially viable and useful process for the synthesis of Fingolimod hydrochloride.
It is another object of the present invention to provide an expedient commercially viable and useful process for the. preparation of Fingolimod hydrochloride using four novel intermediates. - ~
It is another object of the present invention to provide an expedient process for the preparation of Fingolimod hydrochloride without using column chromatography and pyrophoric reagents.
It is a further object of the present invention to provide an operationally simple route of synthesis for the production of Fingolimod" hydrochloride in high yield and purity of more than 99.9%.
It is further object of the reactions to provide an expedient process under normal conditions and no extreme reaction conditions are needed for the present process.
SUMMARY OF INVENTION: :
In accordance with an aspect of the present invention, there is provided a method for preparing Fingolimod HC1 (I) different from that of the prior art methods through utilization of novel intermediates, which forms the basis of the present invention.
In accordance with another aspect of the present invention, there is provided a process for the preparation of Fingolimod HC1 (I) by the use of novel intermediates individually represented by the following formulae.
Figure imgf000010_0001
3-Chloro-l, 1-bis (hydroxymethyl)-3-(4-octylphenyl) propyl acetamide (8a)
Figure imgf000011_0001
[(E/Z)-l , 1-bis (hydroxymethyl)-3-(4-oct l hen l all l acetamide (9a)
Figure imgf000011_0002
2-amino-2-[(E/Z)-2-(4-octylphenyl) vinyl] propane- 1, 3-diol (1 1a)
Figure imgf000011_0003
2-amino-2-[(E/Z)-2-(4-octylphenyl) vinyl] propane- 1, 3-diol hydrochloride (7g) In accordance with another aspect of the present invention a process is provides for the preparation of Fingolimod HCl having high purity of more than 99.9% and impurity of less than 0.1%.
In accordance with another aspect of the present invention, there is provided an environmentally friendly process without using pyrophoric reagents such as Lithium
of high
Figure imgf000011_0004
The process may be schematized as follows: Scheme -VII
The" present invention adopts the same method reported in US 3888818 for preparing intermediate of 4-octylaeetophenone (7c), the method reported in JrHet. Chem., 21, 1741 (1984) for the preparation of 2-bromo-l-(4-octyl-pheny)-ethanone (2a), the method reported in Synthesis (2000), (4), 505-506 for the preparation of 2-(acetyl amino)-2-[2- (4-octylphenyl)-2-oxo-ethyl] propanedioic acid diethyl ester (2b) and the method reported in WO 2000/53569 for preparing compound 7f. All these intermediates of 7c, 2a, 2b, were also reported and were prepared by methods given in the basic patent US5719176.
Figure imgf000013_0001
In the step-1 of the present scheme, octanoyl chloride is reacted with benzene in presence of aluminum chloride to give n-octanophenone (7a) with 93 % of yield and the product is having over 99.0 % purity by G.C. The temperature range for the reaction of Friedel crafts reaction is -10 °C to 35 °C.
Step-2: n-octanophenone is catalytically hydrogenated using 10% palladium on carbon to give n-octyl benzene (7b), -
In the step-2 of the
Figure imgf000014_0001
ch on catalytical hydrogenation using 10% palladium on carbon gave n-octyl benzene (7b) with over 90% yield .The hydrogenation is carried~out at ambient temperature and the n-octyl benzene (7b) is purified by high vacuum distillation to get the product with over 99.0 % purity by GC.
Step-3: n-octyl benzene is reacted with acetyl chloride in presence of aluminium chloride to obtain 4-n-octyl acetophenone (7c),
Figure imgf000014_0002
In the step-3 of the present scheme, n-octyl benzene (7b) is acylated using acetyl chloride in presence of aluminium chloride to obtain 4-octyl acetophenone (7c) with an yield of above 95% by theory. The reaction can be carried out at temperature condition of -10 to 35 °C. The crude product of phenaceyl bromide derivative (7d) obtained can be directly taken for the subsequent step.
The mole ratios of n-octyl benzene (7b) to acetyl chloride and aluminium chloride are typically in the range of 1.0: 1. Oil .0 tol .0:3.0:3.0, preferably in the ratio range of 1.0:1.0:1.0 tol .0:2.0:2.0, and more preferable of ratio range of 1.0: 1.5:1.5.
The solvents used are methylene dichloride, ethylene dichloride or chloroform. The most preferable solvent is methylene dichloride and its quantity is typically in the range of n- octyl benzene (7b) to methylene chloride 1 : 5 w/v to 1 :30 w/v ratios; preferably in the range of 1 : 5 w/v to 1 : 15 w/v ratios, the most preferable range is 1 : 10 w/v ratio.
The addition temperature of acetyl chloride is typically in the range of 0 to 40 °C, preferably in the range of about 0-20 °C, more preferably in the range of 10-15°C.
The addition temperature of n-octyl benzene (7b) is typically in the range of -10 to 40 °C, preferably in the range of about -10 to 10 °C, more preferably in the range of -5 to 0°C.
The reaction temperature is typically in the range of about 0 to 60 °C, preferably in the range of about 10-40 °C, more preferably in the range of 25-30°C.
The reaction time is typically in the range of about lhour to 24 hours, preferably in the range of about 2 to 8 hours, more preferably in the range of 3 to 4 hours.
Step-4: 4-octyl acetophenone (7c) is reacted with liquid bromine in methylene chloride to obtain the phe
Figure imgf000015_0001
In the step-4 of the present scheme, 4-octyl acetophenone (7c) prepared as above is brominated on the side chain by using bromine liquid in methylene chloride with or without 1.4-dioxane. The reaction has been carried out at temperature range of -10 to 35 °C, The other solvents optionally used are ethylene dichloride, chloroform, carbon tetrachloride, chlorobenzene, and acetohitrile.
4-octyl acetophenone (7c) to bromine are typically in the mole ratios range of 1.0:0.50 to 1.0:2.0, preferably in the ratio range of 1.0:0.90 to 1.0: 1.30, more preferably in the ratio- of 1.0: 1.10. The ratio of 4-octyl acetophenone (7c) to 1,4 - dioxane is typically in the range of 1 :0.50 w/v to 1 :30 w/v ratios; preferably in the range of 1 : 1 w/v to 1 :2 w/v, and more preferably in the raiige of 1 : 1 w/v.
The addition temperature of bromine is typically in the range of -10 to 40 °C, preferably in the range of about 10 to 35 °C, and more preferably in the range of 25-30°C.
Reaction temperature is typically in the range of about 0 to 60 °C, preferably in the range of about 10-40 °C, and more preferably in the range of 25-30°C.
Reaction time is typically in the range of lhour to 24 hours, preferably in the range of 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
Step-5: The phenaceyl bromide derivative (2a) is reacted jwith diethyl acetamidomalonate " in presence of sodium ethoxide to obtain diethyl ester acetamide derivative (2b).
Figure imgf000016_0001
In the step-5 of the present scheme, phenaceyl bromide derivative (2a) is reacted with diethyl acetamidomalonate in presence of sodium ethoxide to obtain diethyl ester acetamide derivative (2b) product. The reaction temperature can be in the range of 25 °C to 80 °C. The solvents used are lower alcohols such as methanol, ethanol, isopropanol, n- butanol etc., dimethyl formamide, and tetrahydrofuran. The crude diethyl ester acetamide derivative (2b) is obtained with about 80% of yield and is directly taken for the "subsequent step.
The ratio of phenacyl bromide derivative (2a) to sodium ethoxide and diethyl acetamidomalonate are typically in the^range of 1.0:0.90:0.90-tol.0:3.0:3.0, preferably in the range of 1.0:1.0:1.0 tol .50: 1.50, and more preferably in the range of 1.0: 1.10:1.10. The ratio of phenacyl bromide derivative (2a) to ethanol is typically in the range of 1 : 5 w/v to 1 : 15 w/v ; preferably in the range of 1 : 5 w/v to 1 :10 w/v, and more preferably in the range 1 :5 w/v.
- The addition temperature diethyl acetamidomalonate is typically in the range of 0 to 60 °C, preferably in the range of about 10-40 °C, and more preferably in the range of 25- 30°C. The phenacyl bromide derivative (2a) addition temperature is typically in the range of -0 to 60 °C, preferably in the range of about 10 to 40 °C, and more preferably in the range of 25 to 30°C.
The reaction temperature is typically in the range of about 10 to 1 10 °C, preferably in the range of about 40-80 °C, and more preferably in the range of 65-70°C.
The reaction time is typically in the range of about lhour to 24 hours5 preferably typically in the range of about 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
Step-6: The diethyl ester acetamide derivative (7e) is reacted with sodium borohydride in presence of tetrahydrofuran and ethanol to obtain trihydroxy acetamide derivative (7f).
Figure imgf000017_0001
The ratio of ethanol quantity to diethyl ester acetamide derivative (2b) is typically in the range of 1 :5.0 w/v to 1 :30 w/v, preferably in the range of 1 : 10 w/v to 1 :30 w/v, and more preferably 1 :20 w/v.
The addition temperature of sodium borohydride is typically in the range of 0 to 40 °C, preferably in the range of about 10 to 35 °C, more preferably in the range of 25-30°C. The addition temperature of ethanol is typically in the range of -5 to 40 °C, preferably in the range of about 0 to 20 °C, and more preferably in the range of 5-15°C.
- Reaction temperature is typically in the range of about 0 to 60 °C, preferably in the range of about 0-20 °C, and more preferably in the range of 5-15°C.
Reaction time is typically in the range of about lhour to 12 hours, preferably in the range of about 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
Step-7: In the step-7 of the present scheme, trihydroxy acetamide derivative (7f) is reacted with IPA.HC1 in IPA at reflux temperature under dry conditions to obtain E/Z-2-
Figure imgf000018_0001
The ratio of tr ydroxy acetam e er vat ve (7 ) to sopropy alcohol is typically in the range of 1 :5.0 w/v to 1 :30 w/v; preferably in the range of 1 =5 w/v to 1:15 w/v, and more preferably in the range >f 1 :10 w/v. The IPA HC1 addition temperature is typically in the range of 30 to 1 10 °C, preferably in the range of about 50 to 80 °C, and more preferably in the range of 60-65°C.
The reaction temperature is typically in the range of about 30 to 1 10 °C, preferably in the" range of about 50-80 °C, and more preferably in range of 70-75°C.
The reaction time is typically in the range of about 2hour to 12 hours, preferably in the range of about 2 to 8 hours, and more preferably in the range of 3 to 4 hours.
Figure imgf000019_0001
T e ratio of Z-2-am no-2-[2-(4-octy phenyl) vinyl] propane- 1, 3-diol hydrochloride (7g) to 5% Pd/c is in the range of 1.0:0.4 to 1.0:1.50, preferably in the ratio range of 1.0:8.0 tol .0:1.20, and more preferably in the range of 1.0:1.0.
The reaction temperature is typically in the range of about 10 to 40 °C, preferably in the range of about 15-35 °C, and more preferably in the range of 25-3Q°C.
The reaction time is typically in the range of about 2 to 12 hours, preferably in the range of about 2 to 8 hours, and more preferably in the range of 4 to 6 hours. Step-9: The technical grade product is recrystallised from ethanol and ethyl acetate^ mixture. The melting range of the final product is 104.6 to 107.5 °C. - -
Example - 1:
Preparation of 2-amino-2-[2-(4-octylphenylJ ethyl] propane-1, 3-diol Hydrochloride (1) [Fingolimod hydrochloride]
(a)Preparation of octanophenone (7a)
Figure imgf000020_0001
Methylene chloride (250 ml) was charged into a 1000 ml 4 necked round bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket, addition funnel and a condenser. Then 47.08 g (0.3526 mol) of aluminium chloride was charged. Stirred the" mass for 10-15 min. Cooled the mass temperature to 10-15 °C. 57.3 g (0.3526 mol) of octanoyl chloride was added maintaining the mass temperature at 10-15 °C. Maintained the mass temperature at 10-15 _°C for 30 min then cooled the mass temperature to -5 to 0 °C. 25.0 g (0.3205 mol) of benzene was diluted with 25.0 ml of methylene chloride and added to reaction mass maintaining the mass temperature at -5 to 0 °C. Raised the mass temperature to 25-30 °C. Maintained the mass temperature at 25- 30 °C for 2 hours. Quenched the reaction mass into a mixture of 40.0 g of crushed ice and 2.5 ml of cone, hydrochloric acid at maintaining the mass temperature at 0 to 5 °C. 200.0 ml of DM Water was added to reaction mass. Raised the mass temperature to 25-30 °C. The organic layer was separated. Aqueous layer was extracted with 100 ml of methylene chloride. The organic layers were combined and washed with 50 ml of 10% sodium carbonate solution. The organic layer was dried with sodium sulphate and filtered the sodium sulphate. Methylene chloride was completely distilled under vacuum at below 50 °C. Finally applied high vacuum to remove the traces of solvent at below 50 °C to obtain 60.30g (92.23% yield) of octanophenone as oil with purity by G.C: 99.0 %.
Spectral data: FT- IR (Neat) (Cm-13: 2928.3 2856.6, 1687.2, and 1598.1. 1 HNMR (400 MHz, CDCI3) 6- Value (ppm): 0.86-0.90 (t, 3H, CH3), 1.20-1.40(m, 10 H, 5-CH2), 1.69- 1.77 (t, 2H, CH2), 7.43-7.47(d, 2H), 7;54-7.56(t, 1H), 7.94-7.95 (d, 2H). 13 CNMR-(400 MHz, CDCI3) δ- Value (ppm):13.94(lC), 22.50(1C),■ 24.23.(1 C), 29.03(1C), 29.24(1C), 3 L59(1C), 38.44 (lC), 127.89(2C), 128.37 (2C), 132.69 (l C), 136.93 (1C), 200.35(1C). Mass: 206.24[M+2], 205.21 [M+1]. (b) Preparation of n- octyl benzene (7b)
Figure imgf000021_0001
Octanophenone (50 g, 0.245 mol) was dissolved in -500 ml of methanol. Reaction mass was transferred into 1.0 L hydrogenator kettle. 5.0 g of 5% palladium on carbon was charged and hydrogenation was carried out at 50-60 psi pressure and continued till the consumption was stopped. Filtered the catalyst on hyflow bed and washed the bed with 200 ml of methanol. Methanol was completely distilled off under vacuum at temperature below 60 °C. The pure fraction as n-octylbenzene was collected under high vacuum distillation (lmm/Hg) at vapour temperature 135°C and- obtained 42.60 g (91.5 % yield) " of the product with 99.4 % of purity by G.C.
Spectral data:
FT-IR (Neat) (Cm'1': 2927.3, 2856.0, and 1604.1. 1 HNMR (400 MHz, CDC13) δ- Value (ppm): 0.85-0.89 (t, 3H, CH3), 1.26-1.30(m, 10 H, 5-CH2), 2.57-2.61 (t, 2H, CH2), 7.16- 7.18(d, 2H), 7.54-7.56(d, 2H), 7.94-7.95 (t, 1H). 13 CNMR (400 MHz, CDC13) δ- Value (ppm): 14.08(lC), 22.67(1C), 29.27(1C), 29.36(1C), 29.49(1C), 31.53(1C), 31.90(1C), 36.0 (1C), 125.51(1C), 128.18(2C), 128.36 (2C), 142.91 (1C)
(c) Preparation of 4-bctyl acetophenone (7c)
found bottom flask, cket, addition funnel,
Figure imgf000021_0002
and condenser. Then 105.4 g (0.789 mol) of aluminium chloride was charged. Stirred the mass for 10-15 min. Cooled the mass temperature to 10- H> °C and 62.0 g (0.789 mol) of acetyl- chloride was added maintaining the mass temperature at 10-15 °C. Maintained the mass temperature at 10-15 °C for 30 min. Cooled the mass temperature to -5 to 0 °C, 100.0 g (0.526 mol) of octyl benzene was diluted with 100.0 ml of methylene chloride and added to reaction mass maintaining the mass temperature at -5 to 0 °C. Raised the mass temperature to 25-30 °C. Maintained the mass temperature at 25-30 °C for 2 hours. The completion of reaction was monitored by TLC. Quenched the reaction mass into 400 g of crushed ice and 10 ml of cone, hydrochloric acid maintaining the mass . temperature at 0 to 5 °C. 200.0 ml of DM Water was added to reaction mass. Raised the mass temperature to 25-30 °C and the organic layer was separated. Aqueous layer was extracted further with 200 ml of methylene chloride. The organic layers were combined and washed with 200 ml of 10% sodium carbonate solution. The organic layer was dried over anhydrous sodium sulphate and filtered. Methylene chloride was completely distilled off under vacuum at below 50 °C. Finally applied high-vacuum to completely remove the traces of solvent at below 50 °C to obtain 1 15.0 g (94.2 % yield) of oily compound (99 4% of purity by GC).
Spectral data: FT-IR (Neat) (Cm-1^. 2929.7, 2856.0, 1685.1, 1607.0 1357.7, 1267. 7, 597.2 1 HNMR (400 MHz, CDC13) δ- Value (ppm): 0.859-0.893 (t, 3H), 1.262-1.312 (m, 10 H), 1.587-1.642 (m, 211), 2.587-2.676 (s, 3H), 2.638-2.676 (t, 2H), 7.254-7.275 (d, 2H), 7.870-7.890 (d, 2H). 13 CNMR (400 MHz, CDC13) 5- Value (ppm): 13.96(1 C), 22.53(1C), 26.35(1C), 29.1 1(1C), 29.13(1C), 29.30(1C), 31.0(1C), 31.73(1C), 35.85(1C), 128.33(2C), 128.44 (2C), 134.71 (1C), 148.68 (1C), 197.71 (1C). Mass: 233.34[M+1]
(
Figure imgf000022_0001
750 ml of methylene chloride was charged into a 2L 4 necked jound bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket, addition funnel, and condenser. Then 100.0 g (0.431 mol) of 4-octyl acetophenone was charged. Stirred mass for 10 min then 100 g of 1, 4-dioxan was charged. Cooled the mass temperature to 0-5 °C and slowly added a solution of 76.0 g (0.475mol) of bromine in 250 ml methylene chloride at 0-5 °C. Maintained the mass temperature at 0-5 °C for 4 hours. 500 ml of DM water was charged. Raised the mass temperature to 25-30 °C. Stirred the mass for 30 min. The organic layer was separated and washed with 500 ml of DM water. The organic layer was dried over anhydrous sodium sulphate and filtered. Methylene chloride was completely distilled off at temperature below 50 °C. Finally applied high vacuum to remove traces of solvent at below 50°C to obtain 130.6 g the compound 2a as oil (97.4%~ yield).
Spectral data: FT-IR '(Jfeat) (Cm-1}: 2921.3, 2851.5, 1696.3, 1606.4, 1466J, 1415.5, 1 195.6, 994.3, 814.7r 690.8, 611.9, and 558.1. 1 HNMR (400 MHz, CDG13) δ- Value (ppm): 0.86 -0.89 (t, 3H), 1.25-1.30(m, 10H), 1.59-1.66(m, 2H), 2.65-2.68(t, 2H), 4.43(s, 2H), 7.28-7.30 (d, 2H), 7.89-7.91(d, 2H). 13 CNMR (400 MHz, CDC13) δ- Value (ppm): 14.03(1C), 22.58(1C), 29.14(1C), 29.19(1C), 29.33(1C), 30.95(2C), 31.78(1C), 36.01(1C), 128.82(2C), 129.00(2C), 131.57(1C), 149.86(1C), 190.83 (1C). Mass: 313.2[M+2], 31 1.12[M]. d
Figure imgf000023_0001
Ethanol 300 ml was charged into a 2L 4 necked round bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket, addition funnel, condenser under nitrogen atmosphere. Charged 24.0 g (0.352 mol) of sodium=ethoxide and stirred the mass for 15 min at 25-30 °C. 76.8 g (0.353mol) of diethyl acetamidomalonate was added in lots to the reaction mass at 25-30 °C. Stirred the mass for 30 min at 25-30 °C. 2-Bromo- l-(4-octylphenyl)-l-ethanone (100.0 g , 0.32 mol) was diluted separately in 200.0 ml of ethanol and added to reaction mass at 25-30 °C. Stirred the mass for 30 min at 25-30 °C. Raised the mass temperature to 65-70°C and maintained for 3 hours. The progress and completion of reaction was monitored by TLC. The reaction mass was cooled to 25-30 °C and added to 2500 ml of DM water. Extracted the compound with 2x500 ml of ethyl acetate and the organic layer was dried over sodium sulphate. The organic layer was treated with activated carbon and then filtered. Ethyl acetate was completely distilled off under vacuum at below 80 °C. Finally applied high vacuum to remove the solvent completely at below 80 °C to obtain 119.6 g (83.2 % yield) of oily compound (2b).
FT-IR (Neat) (Cm- : 2923.3, 2856.3, 1747.1, 1686.0, 1605.5, 1499.3, 1295.4, 1227.2, 1195.4, 1 HNMR (400 MHz, CDC13) δ- Value (ppm): 0.85-0.89(t, 3H), 1.22-1.29(m, 16H), 1.59-1.63(m, 2H),1.96(s,3H), 2.63-2.67(t, 2H), 4.24-4.29(m, 6H), 7.11(s, 1H),- 7.25-7.27(d, 2H), 7.86-7.88(d, 2H). 13 CNMR (400 MHz, CDC13) δ- Value (ppm): 13784 (2C), 14.02(1C), 22.58(1C), 22.86(1C), 29.16(2C), 29.33(1C), 31.01(1C), 3.1.78(1C), 35.97(1C), 42.15(1C), 62.80(2C), 63.98(1C), 128.31(2C),128.69(2C), 133.79(1C), 149.61(1C), 167.31(2C),169.44(1C),196.51(1C). Mass: 449.28[M+2], 448.29[M+1]
(f) Preparation of 3-amino-3-(hydroxymethyl)-l-(4-octylphenyl) butane-1, 4-diol (7f)
Figure imgf000024_0001
~ reaction mass maintaining the temperature at 25-30 °C. Stirred the mass for 30 min. Cooled the mass temperature to 5-15°C. 1000 ml of ethanol was added to reaction mass maintaining the temperature at 5-15 °C over a period of 45-60 min. Maintained the mass temperature at 5-15 °C for 3 hours. The progress and completion of reaction was monitored by TLC. Reaction mass was quenched in 1000 ml of DM water. Raised the mass temperature to 25-30 °C. Maintained the mass temperature to 25-30 °C for 20 min. 5 Extracted the compound with 2x 500 ml of ethyl acetate. The organic layer was washed with 3x500 ml of saturated sodium chloride solution and dried over anhydrous sodium sulphate. Ethyl acetate was completely distilled off under vacuum below 80 °C. Finally applied high vacuum to remove traces of solvent below 80 °C. Cooled the mass temperature to 45-50°C. Added 160 ml of acetone. Raised the mass temperature to reflux0 and maintained for 30 min. Cooled the mass temperature to 0-5 °C and maintained for 30 min. Filtered the solid and washed the solid with 40 ml of chilled acetone. Wet compound was charged into a flask, added 160 ml of ethyl acetate. Raised the mass temperature to reflux and maintained for 30 min, cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the solid and washed the solid with 40 ml of chilled5 ethyl acetate. Wet compound was charged into a flask, added 400 ml of DM Water. " Raised the mass temperature to 60-65 °C and maintained for 30 min, cooled the mass temperature to 25-30°C and maintained for 60 min. Filtered the solid and washed the solid with 50 mi of DM Water. Compound was dried at 55-60° to obtain 54.10 g (66.2 % yield) compound (7f) (98.9% of purity by HPLC).
0 FT-IR (KBr) (Cm-0: 3220.3, 2954.2, 2927.6, 2854.7, 1640.9, 1565.0, 1071.0, 1037.5, 700.3, 656.8. 1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.866(t, 3H), 1.24- 1.26(m, 10H), 1.53(d, 2H), 1.83(s, 3H), 2.04-2.08 (d, 2H),2.506-2.543(t,2H), 3.47- 3.51(m.2H),3.61-3.65( m,2H), 4.86-4.69(d,lH), 4.82-4.84(t,lH), 4.97-5.0(t,lH), 5.52 (d, lH), 7.09-7.1 l(d,2H), 7.18(d,2H), 7.33(s, 1H). 13 CNMR (400 MHz, DMSO-d6) 6- Value5 (ppm):14.19(lC), 22.36(1C), ~~ 23.75(1C),~ .28,95(1 C), . 29.12(2C), 31.38(1C),~
- " 31.56(1C),35.11(1C), 41,54(1C), 61.02(1C), 63.01(1C), 63.47(1C), 68.98(1C), 125.74(2C), 128.1 1(2C), 140,89(1C),144.28(LC), 170.74(1C). Mass: 367.53[M¾ 366.52[M ]. (g) Preparation of 2-amino-2-[(E/Z)-2-(4-octylphenyl) vinyl] propane-1, 3-diol hydrochloride 7g)
Figure imgf000026_0001
Isopropyl alcohol (500 ml) was charged into a 2 L 4 necked round bottom flask, connected to a mechanical stirrer, equipped with therrno meter socket, addition funnel, and condenser. 3-Amino-3-(hydroxymethyl)-l-(4-octylphenyl) butane- 1, 4-diol (50 g, 0.136 mol) was added and the mass temperature was raises to 60-65°C. 271.0g of isopropyl alcohol-HC fchemical assay: 15.0 % w/w] was added at temperature 60-65°C. - Maintained the mass temperature at 60-65°C for 4 hours. The progress and completion of reaction was monitored by TLC. Isopropyl alcohol was„completely distilled off under vacuum at below 70 °C. Finally applied high vacuum to completely remove traces of solvent at below 70 °C. Cooled the mass temperature to 45-50°C. 200 ml of acetone was added to the residual mass. Raised the mass temperature to reflux and maintained for 30 min then cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the solid and washed the solid with 50 ml of chilled acetone. Compound was dried at 50- 55°C to obtain 42.5 g of 7g (90.85 % yield) with a purity of 99.1 % by HPLC. Melting range: 179.2C to 184.3°C.
FT-IR (KBr) (Cm-1}: 3343.0, 2924.6, 2852.2, 1654J, 1604.1, 1505.3, 1467.0, 1070.0, 823.9, 672.1, 574.8. 1 IINMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.866 (t,3H), 1.23-1.26(m, 10'H), 1.54(s, 2H), 1.84-1.85 (m, 1H), 2.36 (d,lH), 2.53(d,2H), - 3.57(s,lH), 3.64(t,lH), 3.76(d,lH), 3.97-4.06(m,lH), 4.78-4.82(m,lH), 5.07 (d,lH), 5.70-5.74 (m,lH),7.16- 7.18(d,2H) 7.22 ( d,l H), 7.32-7.34(d,2H), 8.35 (broad s, 3H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 14.10(-1CY 22.26(1 C), 28.85(1C), 31.46(1C), 35.04(1C), 41.80(1C), 62.80(1C), 63.53(1C), 64.08(1C), 64.19(1C), 72.44(1C), - 79.52(1C), 80.3(1C), 126.03(1C), 126.51(1C), 128,30(1C), 128.42(1C), 138.39(1C), 142.12(1C). Mass: 340.31 [M"1] (h) Preparation of 2-amino-2-[2-(4-octylphenyl) ethyl] propane-1 ,
Hydrochloride (1) [Fingolimod hydrochloride] by Hydrogen gas bubbling.
Figure imgf000027_0001
2-Amino-2-[(E/Z)-2-(4-octylphenyl) vinyl] propane-1 , 3-diol hydrochloride (50 g) was dissolved in 1250 mhof methanol and the solution was treated with activated carbon and filtered. The filtered solution was transferred into a 2L 4 necked round bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket, gas inlet and condenser. 50 g of 5% palladium on carbon was charged. Hydrogen gas was bubbled in to the~reaction mass and he progress and completion of reaction was monitored by HPLC. The catalyst was filtered on hyflow bed and washed the bed with 500 ml of methanol. The solvent was completely distilled off under vacuum at below 60°C. Cooled the mass temperature to 45-50°C. Acetone (500 ml) was added to remaining mass. Raised the mass temperature" to reflux and maintained for 30 min. Cooled the mass temperature to 0- 5°C and maintained for 30 min. Filtered the solid formed and washed the solid with 50 ml of chilled acetone. The crude compound was dissolved in 2200 ml of DM water and pH was adjusted between 9.5 and 10.5 with aqueous ammonia solution. Stirred the mass for 1 hour at 25-30°C. Filtered the solid and washed with 200 ml of DM water. Dried the compound at 55-60°C under vacuum. The base compound was charged into a flask and added 200 ml of acetone. Added 78.0 g of 15.0% w/w IPA HCI solution and stirred the mass for 1 hour at 25-30°C. Cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the- solid and washed the solid with 40 ml of chilled acetone. The thus ~ obtained compound was dissolved in 90.0 ml of methanol at 55 60°C, 900 ml of ethyl acetate was added at 55-60 °C then cooled to 25-30°C and maintained the mass temperature at 25-30°C for 1 hour. Cooled the mass temperature to_ 0-5°C and maintained for 30 min. Filtered the solid and washed the solid with 90 ml of chilled ethyl acetate .Compound was dried at 50- 55°C under vacuum to obtain 36.0 g (71.5 % yield) with 99.70 % of purity by HPLC. Melting range 104.6-107.5 °C. FT-IR (KBr) (Cm-0: 3371.9, 3266.6, 2922.3, 2851.4, 1601.8, 1069.6
1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.867 (t,3H), 1.24-1.26(m, 10H),
1.528(m, 2H), 1.748-1.792(m,2H), 2.535-2.578(m, 4H), 3.512-3.525(d, 4H), 5.373- 5.398(t, 2H), 7.10(s, 4H), 7.84(s , 3H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.95(1C), 22.08(1C), 27.93(1C), 28.66 (1C), 28.82(1C), 31.04(1C), 31.27(1C), 33.16(1C), 34.75(1C), 60.10(2C), 60.83(2C), 128.05(2C), 128.25(2C), 138.81(1C), 139.81(lC).Mass: 344.2 [M+1], 342.2 [M'1]. (i) Preparation of 2-amino-2-[2-(4-oetylphenyl) ethyl] propane-1, 3-diol Hydrochloride (1) [Fingolimod hydrochloride] by hydrogenation under mild pressure.
Figure imgf000028_0001
2-Amino-2-[(E/Z)-2-(4-octylphenyl) vinyl] propane-1, 3-diol hydrochloride (50 g) was dissolved in 1250 ml of methanol and solution was treated with carbon. Reaction mass was transferred into a 2L hydrogenator kettle. 50 g of 5% palladium carbon was charged. Carried out hydrogenation at 50-60 psi till the hydrogen gas intake stopped. The catalyst was filtered on hyflow bed and washed the bed with 100 ml of methanol. Methanol was completely distilled off under vacuum at below 60 °C. The crude compound was dissolved in 90.0 ml of methanol at 55- 60 °C and 900 ml of ethyl acetate was added at 55- 60 °C. Cooled to 25- 30 °C and maintained the mass temperature at 25-30 °C for 1 hour. Cooled the mass temperature to 0-5°C and maintained for 30 min. Filtered the solid and washed the solid with 90 ml of chilled ethyl acetate.^Compound was dried at 50- 55 °C under vacuum to obtain 38.60 g (76.7% yield) with 99.50 % of purity by HPLC. Melting range 104.8-107.9oC. FT-IR (KBr) (Cm-,}: 3371.9, 3266.6, 2922.3 2851.4, 1601.8, 1069.6 1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.867 (t,3H), 1.24-1.26(m, 10H), 1.528(m„ 2H), 1.748-1.792(m,2H), 2.535-2.578(m, 4H), 3.512-3.525(d, 4H), 5.373- 5.398(t, 2H), 7.10(s, 4H), 7.84(s , 3H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.95(1C), 22.08(1C), 27.93(1C), 28.66 (1C), 28.82(1C), 31.04(1C), 31.27(1 CX 33.16(1C), 34.75(1C), 60.10(2C), 60.83(2C), 128.05(2C), 128.25(2C), 138.81(1C), 139.81(1C). Mass: 344.2 [M+l].
(j) Recrystallization of 2-amino-2-[2-(4-octylphenyl) ethyl] propane- 1, 3-diol
Hydrochloride [Fingolimod hydrochloride] from ethanol and ethyl acetate.
Figure imgf000029_0001
2-Amino-2-[2-(4-octylphenyl) ethyl] propane- 1, 3-diol Hydrochloride [40 g, Fingolimod hydrochloride] was dissolved in 160 ml of ethanol at 65-70°C and added 825 ml of ethyl acetate. Cooled to 25- 30 °C and maintained the mass temperature at 25- 30°C for 1 hour. Cooled the mass temperature to 0-5°C and maintained for 90 min. Filtered the solid and washed with 80 ml of chilled ethyl acetate. The compound was dried at 50- 55°C under vacuum to obtain 35.0 g (87.5% yield). Purity by HPLC: 99.8 %
FT-IR (KBr) (Cm-1': 3371.9, 3266.6, 2922.3, 2851.4, 1601.8, 1069.6. 1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.867 (t,3H), 1.24-1.26(m, 10H), 1.528(m, 2H), 1.748-1.792(m,2H), 2.535-2.578(m, 4H), 3.512-3.525(d, 4H), 5.373-5.398(t, 2H), 7.10(s, 4H), 7.84(s , 3H). 13C NMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.95(1 C), 22.08(lC) 27.93(1C)7 28.66" (1C), 28.82(1C), 31.04(1C), 31.27(1G), 33.16(1C), 34.75(1C),. 60.10(2C), 60.83(2C), 128;05(2C), 128.25(2C), 138,81(1 C), 139. 81(1 C). Mass: 344.2 [M+1]
Figure imgf000030_0001
N- [3 -hydroxy- 1, l-bis-hydroxymethyl-3-(4-octyl-phenyl)-propyli-acetamide (15.0 g, 0.041 mol) and 300 ml of acetone were charged into a 1 L4 necked round bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket, addition funnel, condenser. Stirred the mass for 15 fnin. Then 16.80g (0.167mol) of concentrated hydrochloric acid was added to the reaction mass and maintained the mass temperature at 25-30°C for 2 hours. Acetone was completely distilled under vacuum at mass temperature not crossing 35°C. 100 ml tetrahydrofuran was added to reaction mass and distilled off the solvent under vacuum at mass temperature not crossing 35°C to obtain 15.50 g of oily compound (98.3% yield).
1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.866 (t, 3H), 1.23-1.26(m, 10H), 1.54 (m, 2H), 1.87(s, 3H), 2.38 (m, 2H), 2.533-2.572(m, 2H), 3.762-3.793 (d, 4H), 4.75 (t,lH), 7.10(d, 2H),7.38(d,2H),8.47 (s , 3H). 13C NMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.86(lC), 21.G1(1C), 22.08(1C), 28.60(1 C), 28.76 (1C), 28.82(1C), 31.21(1C), 34.78(1C), 41.0(1C), 41.7(1C), 62.10(1C), 64.1(1C), 72.3 (1C), 80.0 (1 C), 126.05(2C), 128.1(2C), 138.2(1C), 141.7(1C), 171.8 (1C). Mass: 382.3[M"1].
Example-2b:
Preparation of N-[l, 1-bis (hydroxymethyl)-3-(4-octylphenylj propyl] acetamide
Figure imgf000031_0001
and condenser. 5.0 g of 5% palladium on carbon was charged. Hydrogen gas was bubbled for 3. hours at room temperature. Filtered the catalyst and washed with 100 ml of methanol. - The solvent was completely distilled off under vacuum at mass temperature not crossing 65°C to obtain 12.20g of low melting solid (89.3% yield).
1 _HNMR (400 MHz, DMSO-d6) δ- Value (ppm): ). 1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.866 (t, 3H), 1.23-1.26(m, 10H), 1.54 (m, 2H), 1.87(s, 3H), 2.38 (m, 2H), 2.533-2.572(m, 4H), 3.762-3.793(d, 4H), 7.10(d, 2H),7.38(d,2H),8.47 (s,3H). 13C NMR ~ (400 MHz, DMSO-d6) δ- Value (ppm): 13.86(lC), 21,01(1 C), 22.08(1C), 28.'60(1C), 28.76 (1C), 28.82(1 C), 31.21(1 C), 34.78(1 C), 41.0(1C), 41.7(1C), 62.10(1 C), 64.1(1C), 72.3 (1C), 80.0 (1C), 126.05(2C), 128.1(2C), 138.2(1C), 141.7(1C), 171.8 (1C). Mass: 351.43[M+2], 350.43^']
Figure imgf000031_0002
25-30°C for 30 min. Reaction mass temperature was raised to reflux and maintained for 2 hours. Methanol was completely distilled under vacuum below 60°C. Remaining mass_ ~ was cooled to 25-30°C. Compound was extracted with 300 ml of ethyl acetate. Organic layer was washed with. 100 ml of brine solution and dried with sodium sulphate. Sodium sulphate was filtered and ethyl acetate was completely distilled under vacuum at below 70°C. Remaining crude mass was crystallized in 50 ml of hexane. Stirred the mass 30 min at 25-30°C. Filtered the solid and washed with 20 ml of hexane. Compound was dried at 50-55°C. Obtained solid weight: 6.50g. (Yield, 73.94 %). Purity by HPLC:
99.7%
FT-IR (KBr) (Cm-": 3351. 1, 2926.3, 2854.2, 1575.7, 1513.9, 1466.0, 1018.6, 965.6, 920.1 1 HNMR (400 MHz, CDC13) δ- Value (ppm): 0.857-0:890 (t, 3H), 1.26-1.29(m, lOH), 1.57(m, 2H), 1.68-1.70(m, 2H), 1.90-2.30 (broad s, 4H), 2.535-2.62(m, 4H), 3.49- 3.525(d, 2H),3.59-3.62(d,2H), 7.10(s, 4H) 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.22(1C), 22.34(1C), 28.75 (lC), 28.91 (1C), 29.08(1 C), 31.34(1 C), 31.53(1C), 35.01(1C), 36.92 (1C), 55.52(2C), 65.33(2C), 128.39(4C), 139.57(1C), 140.67(1C). Mass: 309.51 [M+2], 308.5 [M+l]
Example (2d):
Preparation of 2-amino-2-[2-(4-octylphenyl) ethyl] propane- 1, 3-diol Hydrochloride [Fingolimod hydrochloridej(l)
Figure imgf000032_0001
ol) was dissolved in 60_ ml of methanol at 50-55°C. Cooled to 25-30°C._ 38.8 g of 2N hydrochloride solution was added and maintained for 30 min. 200 ml of ethyl acetate was added and stirred the mass for 15 min. Water , ethanol and ethyl acetate was completely distilled under vacuum below 70°C. Remaining crude mass was dissolved in 30 ml methanol at 50-55°C. 150 ml of ethyl acetate was added at 50-55°C and stirred the mass for 15 min. Cooled to 25-30°C and maintained for 1 hour. Solid was filtered and Washed with 25 ml of ethyl acetate. Compound was dried at 50-55°C. Obtained' solid weight: 6.30g. (Yield, 93.88 %).
FT-IR ( Br) (Cm-1'; 3371.9, 3266.6, 2922.3, 2851.4, 1601.8, 1069.6
1 HNMR (400 MHz, DMSO-d6) 6- Value (ppm): 0.833-0.867 (t,3H), L24-1.26(m, 10H), 1.528(m, 2H), 1.748-1.792(m,2H), 2.535-2.578(m, 4H), 3.512-3.525(d, 4H), 5.373- 5.398(t, 2H), 7.10(s, 4H), 7.84(s , 3H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.95(1C), 22.08(1C), 27.93(1C), 28.66 (1G), 28.82(1 C), 31.04(1C), 31.27(1"C), 33.16(1C), 34.75(1C), 60.10(2C), 60.83(2C), 128.05(2C), 128.25(2C), 138.81(1C), 139.81 (1 C). Mass: 344.2 [M+l], 342.2 [M-l]
Example-3a:
Preparation of 1, 1-Bis (hydroxymethyl)-3-(4-octylphenyl) allyl] acetamide (9a)
3 and
Figure imgf000033_0001
300.0 ml of methanol were charged into a 500 ml 4 necked round bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket condenser, additional funnel1 . 1.0 g of methanesulfonic acid (0.0104 mol) was added at 25-30°C .Reaction mass temperature was raised to reflux by azeotrope system and maintained for 2 hours.1.4ml of water was collected. Toluene was completely distilled under vacuum below 90°C. Remaining mass was cooled to 25-30°C and released vacuum. Obtained oily compound_weight^28.30 g. (yield, 99.22 %).
1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.834-0.866(t, 3H), 1.24-1.26(m, JOH), 1.53(d, 2H), 2.1 1 (s, 2H), 2.31(s,3H), 2.54-2.543(t,2H), 3.81-3.84(d,lH),"4.02-4.05 (d,lH). 4.23-4.24(d,lH), 4.32-4.35(d,lH), 4.85-4.89 (m,"lH) , 7.18-7.20 d,2H), 7.31- 7.33(d,2H), 8.29 (s, 2H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm):14.04(lC), 20.71(1C), 22.18 (1C), 28.77(1C), 28.92(2C), 31.08(1C), 31.38(1C),34.95(1C), 42.01(1C), 62.08(1C), 64.8J(1C), 72.60(1C),80.08(1C), 126.02(1C), 126.37(1C), 128.30(1C), 128.41(IC), 137.65(1C), 142.18(1C), 170.42 (1C) . Mass: 349.25[M+2], 348.26 [M+l] " . chloride (7g)
Figure imgf000034_0001
bottom flask, connected to a mechanical stirrer, equipped with thermo meter socket, addition, funnel, and condenser. 8.0 g (0.0230 mol) of 1, 1-Bis (hydroxymethyl)-3-(4-octylphenyl) allyl] acetamide. Raised the mass temperature to reflux. Maintained the mass temperature at reflux for 20 min. 68.0 g of isopropyl alcohol-HCl [chemical assay: 15.0 % w/w] was added at reflux temperature. Maintained the. mass temperature at reflux for 5 hours. Isopropyl alcohol was completely distilled under vacuum at below 80 °C. Finally applied high vacuum for to completely remove the traces of solvent at below 80 °C. Cooled the mass temperature to 25-30°C. Obtained crude solid was slurried in 20 ml of acetone. Filtered the solid and washed the solid with 10 ml of acetone. Compound was dried at 25- 30 °C under vacuum. Obtained dry compound weight: 4.80 g (yields 60.9 %).
Purity by HPLC: 98.50 %
FT-IR (KBr) (Cm-0: 3343.0, 2924.6, 2852.2, 1654.7, 1604.1, 1505.3, 1467.0, 1070.0, 823.9, 672.1, 574.8. 1 :HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833.-0.866 (t,3H), 1.23-1.26(m,- 10H), X54(s, 2H), 1.84-1.85 (m, 1H), 2.36- (d,lH), -2.53(d,2H), 3.57(s,lH), 3.64(t,lH), 3.76(d,lH), 3.97-4.06(m,lH), 4.78-4.82(m,lH), 5.07 (d,lH), 5.70-5.74 (m,lH),7.16- 7.18(d,2H), 7.22 ( d,lH), 7.32-7.34(d,2H)78.35 (broad s, 3H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 14.10(1 C), 22.26(1 C), 28.85(1C), 31.46(1C), 35.04(1C), 41.80(1C), -62.80(1C), 63.53(1C), 64.08(1 C), 64.19(1C), 72.44(1C), 79.52(1 C), 80.3(1C), 126.03(1 C), 126.51(1C), 128.30(1C), 128.42(1C),
138.39(1C), 142.12(1C). Mass: 340.31 [M"1]. acetamide
Figure imgf000035_0001
1, 1-Bis (hydroxymethyl)-3-(4-octylphenyl) allyl] acetamide (8.0 g, 0.023 mol) was dissolved in 100 ml of methanol and Reaction mass was transferred in 0.5L hydrogenator kettle. 2.0 g of 5% palladium carbon was-charged. Hydrogen gas was feeding up to 50-60 psi till the completion of consumption. 5% palladium carbon was filtered on hyflow bed and washed the bed with 50 ml of methanol. Methanol was completely distilled under vacuum below 60 °C. Compound weight: 7.80 g (yield, 97.0 %). 1 HNMR (400 MHz, DMSO-d6) 6- Value (ppm): ).
1 HNMR (400 MHz, DMSO-d6) δ- Value (ppm): 0.833-0.866 (t, 3H), 1.23-1.26(m, ίΟΗ), 1.54 (m, 2H), 1.87(s, 3H), 2.38 (m, 2H), 2.533-2.572(m, 4H), 3.762-3.793(d, 4H), 7.10(d, 2H),7.38(d,2H),8.47 (s,3H). 13C NMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.86(lC), 21.01(1C), 22.08(1C), 28.60(1C), 28.76 (1C), 28.82(1 C), 31.21(1C),
Figure imgf000035_0002
mechanical stirrer, equipped with thermo meter socket, addition funnel, condenser. 88.0 ml of 2N Lithium hydroxide solution was added to reaction mass for 30 min. Raised the mass temperature to reflux. Maintained the mass temperature at reflux for 2 hours. Methanol was completely distilled under vacuum below 60 °C. Finally applied high vacuum to completely remove the traces of solvent below 60 °C. Remaining crude mass was cooled to 25-30°C. 250 ml of ethyl acetate was added to remaining crude mass and stirred the mass for 15 min. 100 ml of saturated brine solution was added. Stirred the mass for 15 min. Organic layer was separated. Organic layer was dried with 20.0 g sodium sulphate. Filtered the sodium sulphate and washed with 50 ml of ethyl-acetate. Ethyl acetate was completely distilled under vacuum below 70 °C. Obtained crude mass was crystallized in 50 ml of hexane. Stirred the mass" for 30 min. Filtered the solid and washed the solid with 20 ml of hexane. Compound was dried at50- 55°C under vacuum. Obtained dry compound weight: 2.80 g (yield 39.82%).
FT-IR (KBr) (Cm-0: 3329.7, 3288.6, 2925.3, 2852÷2, 1675.8, 1592.0, 1512.2, 1468.6, 1070.8 1 HNMR (400 MHz, CDC13) δ- Value (ppm): 0.831-0.865 (t, 3H), 1.23-1.26(m, lOH), 1.52-1.57 (m, 2H), 1.69(s, 2H) ,3.38 (s,lH), 3.56 (d, 2H),3.66(d,2H), 4.79 (s,lH), 4.86(s, 2H), 7.10(d, 4H), 7.24 (d,2H). 13 CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 14.05(1C), 22.25(1C), 28.86 (IC), 29.02(1 C), 31120(1 C), 31.45(1 C), 35.02(2C), 45.85(1C), 62.58(1C), 66.68(1C), 76.62(1C), 80.14(1C), 125.92(2C), 128.14(2C), 140.78(1 C), 141.21(1C). Mass: 307.38 [M+2], 306.37 [M+l].
Example-4b:
Figure imgf000036_0001
dissolved in 100 ml of methanol and Reaction mass was transferred in 0.5 L hydrogenator kettle. 1.0 g of 5% palladium carbon was charged. Hydrogen gas was feeding upto 50-60 psi till the completion of consumption. 5% palladium carbon was filtered on hyflow bed and washed the bed with 50 ml of methanol. Methanol was completely distilled under vacuum below 60 °C. Obtained criide mass was crystallized in 50 ml of hexane. Stirred the mass for 30 min. Filtered the solid and washed the solid with 20 ml of hexane.. Compound was dried at 50- 55°C under vacuum. Obtained dry compound weight: 1.10 g (yield, 54.72 %). FT-IR (KBr) (Cm-0: 3351. 1, 2926.3, 2854.2, 1575.7, 1513.9,. 1466.0, 1018.6, 965.6, 920.1. 1 HNMR (400 MHz, CDC13) δ- Value (ppm): 0.857-0.890 (t, 3H), 1.26-1.29(m, 10H), 1.57(m, 2H), 1.68-1.70(m, 2H), 1.90-2.30 (broad s, 4H), 2.535-2.62(m, 4H), 3.49- 3.525(d, 2H),3.59-3.62(d,2H), 7.10(s, 4H). 13CNMR (400 MHz, DMSO-d6) δ- Value (ppm): 13.22(1C), 22.34(1C), 28.75 (IC), 28.91 (lC), 29.08(1C), 31.34(1C), 31.53(1C), 35.01QC), 36.92 (IC), 55.52(2C), 65.33(2C), 128.39(4C), 139J7(1C), 140.67(lC).Mass: 309.5-1 [M+2], 308.5 [M+l]

Claims

Claims: We claim
1. The intermediate compounds employed in the preparation of the compound of Formula 1 - '
Figure imgf000038_0001
Formula 8a
Figure imgf000038_0002
A pro
Figure imgf000039_0001
Formula 1
comprising the steps of:
a) reacting octanoyi chloride with benzene in the presence of aluminum chloride and methylene chloride to get n-octanophenone (7a)
Figure imgf000039_0002
b) catalytically reducing n-octanophenone in the presence of 10% palladium on carbon and methanol to get n-octyl benzene(7b)
Figure imgf000039_0003
c) reacting n-octyl benzene with acetyl chloride in presence of aluminium chloride and methylene chloride to obtain 4-octyl acetophenone (7c),
Figure imgf000040_0001
e) reacting the phenaceyl bromide derivative (2a) with diethyl acetamidomalonate in presence of sodium ethoxide to obtain diethyl ester acetamide derivative (2b)
f)
Figure imgf000040_0002
g)
h)
Figure imgf000041_0001
about 20-80°C to get olefin acetamide derivative (9a).
Figure imgf000041_0002
. Formula (8a) . Formula (9a) reacting the olefin acetamide derivative (9a) with hydrochloric acid in isopropyl alcohol or acetone or mixture of aqueous solvents at a temperature of about 20-
Figure imgf000041_0003
of formula 1
PCT/IN2013/000044 2013-01-21 2013-01-21 Intermediates and process for the preparation of high purity fingolimod hydrochloride WO2014111949A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2013/000044 WO2014111949A1 (en) 2013-01-21 2013-01-21 Intermediates and process for the preparation of high purity fingolimod hydrochloride

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2013/000044 WO2014111949A1 (en) 2013-01-21 2013-01-21 Intermediates and process for the preparation of high purity fingolimod hydrochloride

Publications (1)

Publication Number Publication Date
WO2014111949A1 true WO2014111949A1 (en) 2014-07-24

Family

ID=48539338

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2013/000044 WO2014111949A1 (en) 2013-01-21 2013-01-21 Intermediates and process for the preparation of high purity fingolimod hydrochloride

Country Status (1)

Country Link
WO (1) WO2014111949A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11518733B2 (en) 2019-02-15 2022-12-06 Shivalik Rasayan Limited Process for preparation of highly pure Fingolimod hydrochloride

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888818A (en) 1972-09-08 1975-06-10 Solvay Thermal stabilization of vinyl resins with derivatives of alpha-phenylindole
US5604229A (en) 1992-10-21 1997-02-18 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
WO2000053569A1 (en) 1999-03-11 2000-09-14 Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd. Method for preparing 2-2[(4-alkylphenyl)-ethyl]-2-amino-propanediol and intermediates useful in such preparation
WO2012041359A1 (en) * 2010-10-01 2012-04-05 Synthon B.V. Process for making fingolimod

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888818A (en) 1972-09-08 1975-06-10 Solvay Thermal stabilization of vinyl resins with derivatives of alpha-phenylindole
US5604229A (en) 1992-10-21 1997-02-18 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
US5719176A (en) 1992-10-21 1998-02-17 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
WO2000053569A1 (en) 1999-03-11 2000-09-14 Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd. Method for preparing 2-2[(4-alkylphenyl)-ethyl]-2-amino-propanediol and intermediates useful in such preparation
WO2012041359A1 (en) * 2010-10-01 2012-04-05 Synthon B.V. Process for making fingolimod

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BISWAJIT KALITA, SYNLETT, 2001, pages 91411
DURANDET, SYNTHESIS, 2000, pages 505 - 506
GUNTER SEIDEL, J.O.C., vol. 69, 2004, pages 3950 - 3952
J.HET. CHEM., vol. 21, 1984, pages 1741
SYNTHESIS, 2000, pages 505 - 506
TETSURO FUJITA, CHEM.PHARM.BULL., vol. 56, no. 4, 2008, pages 595 - 597

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11518733B2 (en) 2019-02-15 2022-12-06 Shivalik Rasayan Limited Process for preparation of highly pure Fingolimod hydrochloride

Similar Documents

Publication Publication Date Title
JP2023002679A (en) Inhibitors of cytochrome p450 monooxygenase, and intermediates involved therein
KR100695964B1 (en) A process for preparing 2-amino malonic acid derivatives
US5225585A (en) Production of fluoxetine and new intermediates
US11352346B2 (en) Process for the preparation of 2-(5-methoxyisochroman-1-yl)-4,5-dihydro-1H-imidazole and the hydrogensulfate salt thereof
US6605732B1 (en) Clean, high-yield preparation of S,S and R,S amino acid isosteres
JP2009522227A (en) Epoxide intermediates in the synthesis of Tamiflu
CA2773064C (en) Novel method for synthesizing ivabradine and the addition salts thereof with a pharmaceutically acceptable acid
EP2807143A2 (en) Process for preparation of fingolimod
WO2014111949A1 (en) Intermediates and process for the preparation of high purity fingolimod hydrochloride
JP4399885B2 (en) Method for producing 4-methyltetrafluorobenzyl alcohol derivative
JP3632979B6 (en) Method for producing 2-aminomalonic acid derivative and 2-amino-1,3-propanediol derivative
JP2009512661A (en) Method for obtaining a valine derivative useful for obtaining a pharmaceutically active compound
JP2002173472A (en) Method for producing optically active 1-(trifluoromethyl mono-substituted phenyl) ethylamine
UA78876C2 (en) Process for production of an acetylenic compound
US20090182150A1 (en) Novel Intermediate for the Preparation of Paliperidone
JP3144921B2 (en) Benzyl ester derivative and method for producing the same
CN114478346A (en) Method for preparing Upacatinib intermediate
JP3144920B2 (en) α-Acylaminoketone derivatives, production method thereof and use thereof
CN114716341A (en) Method for preparing dimethachlor by one-pot method
WO2020194326A1 (en) Process for the preparation of tapentadol and analogs thereof
KR100199042B1 (en) Process for preparation of 2-aminothiazolecarboxylic acid derivative
US20140228582A1 (en) Process for preparation of zolmitriptan
WO2005061478A1 (en) Process for producing 4-alkoxycarbonyltetrahydropyran or tetrahydropyranyl-4-carboxylic acid
CZ9400242A3 (en) N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine and process for preparing thereof
Ye et al. Further studies on the reductive–alkylation of chiral endo-himimide derived from (R)-phenylglycinol

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13726303

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13726303

Country of ref document: EP

Kind code of ref document: A1