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WO2014111949A1 - Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur - Google Patents

Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur Download PDF

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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
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mass
range
temperature
compound
yield
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PCT/IN2013/000044
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English (en)
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Durga Prasad Konakanchi
Subba Rao PULA
Ramakrishna Pilli
Kali Satya Bhujanga Rao ADIBHATLA
Venkaiah Chowdary Nannapaneni
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Natco Pharma Limited
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Priority to PCT/IN2013/000044 priority Critical patent/WO2014111949A1/fr
Publication of WO2014111949A1 publication Critical patent/WO2014111949A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • 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.

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

Abstract

La présente invention concerne une préparation simple et commercialement réalisable de chlorhydrate de Fingolimod présentant une pureté supérieure à 99, 9%. La présente invention concerne également des nouveaux intermédiaires pour la préparation de chlorhydrate de Fingolimod de formule 1.
PCT/IN2013/000044 2013-01-21 2013-01-21 Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur WO2014111949A1 (fr)

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PCT/IN2013/000044 WO2014111949A1 (fr) 2013-01-21 2013-01-21 Intermédiaires et procédé pour la préparation de chlorhydrate de fingolimod extra pur

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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 (fr) 1999-03-11 2000-09-14 Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd. Procede de preparation d'un 2-[2-(4-benzene alkyl)-ethyl]-2-amino-propadeniol et son produit intermediaire
WO2012041359A1 (fr) * 2010-10-01 2012-04-05 Synthon B.V. Procédé de fabrication du 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 (fr) 1999-03-11 2000-09-14 Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd. Procede de preparation d'un 2-[2-(4-benzene alkyl)-ethyl]-2-amino-propadeniol et son produit intermediaire
WO2012041359A1 (fr) * 2010-10-01 2012-04-05 Synthon B.V. Procédé de fabrication du 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

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