WO2015059679A1 - Procédé amélioré pour la préparation d'éliglustat - Google Patents

Procédé amélioré pour la préparation d'éliglustat Download PDF

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WO2015059679A1
WO2015059679A1 PCT/IB2014/065631 IB2014065631W WO2015059679A1 WO 2015059679 A1 WO2015059679 A1 WO 2015059679A1 IB 2014065631 W IB2014065631 W IB 2014065631W WO 2015059679 A1 WO2015059679 A1 WO 2015059679A1
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eliglustat
acid
crystalline
free base
methyl
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PCT/IB2014/065631
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English (en)
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Iqbal Javed
Vilas Hareshwar Dahanukar
Srinivas ORUGANTI
Bhaskar KANDAGATLA
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Dr. Reddy's Laboratories Limited
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Publication of WO2015059679A1 publication Critical patent/WO2015059679A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Definitions

  • the present application relates to an improved process for the preparation of eliglustat to salts thereof.
  • Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.
  • Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2', 3'-dihydro- benzo [1 , 4] dioxin-6'-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.
  • Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders.
  • Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy.
  • Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside.
  • the first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] - glucosylceramide glucosyl transferase).
  • Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase.
  • U.S. patent No. 7,196,205 (herein described as US'205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof.
  • eliglustat was synthesized via a seven-step process involving steps in that sequence: (i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate, (ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone, (iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine, (iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from
  • U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.
  • U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.
  • the present application provides an improved process for the preparation of eliglustat free base, which comprises: a) reacting S-(+)-phenyl glycinol with phenyl-a-bromoacetate to obtain a compound of formula II,
  • HA is an acid residue
  • the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction (PXRD) pattern with peaks located at about 6.06, 16.29, 18.96, 21 .77 and 24.03 ⁇ 0.2 degrees 2 ⁇ .
  • An aspect of the present application provides a crystalline eliglustat free base form R1 having PXRD pattern with additional peaks located at about 13.07, 16.93 and 28.30 ⁇ 0.2 degrees 2 ⁇ .
  • Another aspect of the present application provides a crystalline eliglustat free base form R1 having PXRD pattern with further peaks located at about 12.65 and 26.41 ⁇ 0.2 degrees 2 ⁇ .
  • the present application provides a crystalline eliglustat free base form R1 having PXRD pattern substantially as illustrated by figurel .
  • the present application provides a crystalline eliglustat free base form R1 having thermal events at about 71 .98 in differential scanning calorimetry (DSC) thermogram.
  • DSC differential scanning calorimetry
  • the present application provides a crystalline eliglustat free base form R1 having differential scanning calorimetry (DSC) thermogram as illustrated by figure 2.
  • DSC differential scanning calorimetry
  • the present application provides a process for preparation of crystalline eliglustat free base form R1 , which comprises: a) providing a solution of eliglustat free base in a solvent;
  • step (a) adding an anti-solvent to the solution obtained in step (a);
  • the present application provides a process for the preparation of crystalline eliglustat free base form R1 , which comprises:
  • HA is an acid residue
  • the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern with peaks located at about 5.58, 6.90, 14.84, 18.71 and 28.98 ⁇ 0.2 degrees 2 ⁇ .
  • An aspect of the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern with additional peaks located at about 8.13, 21.08 and 23.96 ⁇ 0.2 degrees 2 ⁇ .
  • Another aspect of the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern with further peaks located at about 15.24 and 21 .60 ⁇ 0.2 degrees 2 ⁇ .
  • the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern substantially as illustrated by figure 3.
  • the present application provides a process for the preparation of crystalline oxalic acid salt of eliglustat, which comprises:
  • Figure 1 is an illustration of a PXRD pattern of crystalline form R1 of eliglustat free base as obtained from example 6.
  • Figure 2 is an illustration of a DSC thermogram of crystalline form R1 of eliglustat free base as obtained from example 6.
  • Figure 3 is an illustration of a PXRD pattern of crystalline oxalic acid salt of eliglustat as obtained from example 7.
  • the present application provides an improved process for the preparation of eliglustat free base, which comprises:
  • HA is an acid residue
  • Step (a) of the first embodiment involves reacting S-(+)-phenyl glycinol with phenyl-a-bromoacetate in the presence of a base to obtain 5-phenyl morpholine-2- one.
  • 5-phenyl morpholine-2-one was isolated as a solid as per the procedure described in the US patent No 7,196,205 using column chromatography which is tedious and commercially not viable.
  • 5- phenyl morpholine-2-one was isolated as an acid addition salt thereby providing a process which is simple, cost effective and commercially viable.
  • the base that can be used for the said reaction includes, organic base such as DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1 ,5-Diazabicyclo[4.3.0]non-5- ene), DABCO (1 ,4-diaza-bicyclo[2.2.2]octane), ABCO (1 -azabicyclo [2,2,2]octane), TBD (1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene) or DMAP (4-dimethylaminopyridine), TEA (Triethylamine), DIPEA ( ⁇ , ⁇ -diisopropylethylamine), DIEA (Diethylamine), N-methyl morpholine, lutidine, pyridine or collidine; inorganic base like hydroxides of alkali metals such as sodium hydroxide, lithium hydroxide or potassium hydroxide; carbonates of alkali metals such as sodium carbonate
  • HA of formula II is an acid residue, which includes, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid, hypophosphorous acid, propionic acid, butyric acid, formic acid and the like, and organic acids such as p-toluenesulfonic acid, methane sulfonic acid, trifluoromethane sulphonic acid, succinic acid, citric acid, benzoic acid, acetic acid, trifluoroacetic acid and the like.
  • An aspect of the present application is to convert 5-phenyl morpholine-2-one in to an acid addition salt to obtain a compound of formula II.
  • Suitable acids that can be used to form acid addition salts are from HA described above.
  • Step (b) of the first embodiment involves converting a compound of Formula II in one or more steps in to eliglustat to provide a solution of crude eliglustat free base.
  • Any process known in the art may be followed for providing a solution of crude eliglustat free base.
  • the process that is reported in example-2 of the US patent document No 7,196,205 may be followed to obtain crude eliglustat free base except that instead of free base of formula II, the acid addition salt of formula II is used.
  • the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) peaks located at about 6.06, 16.29, 18.96, 21 .77 and 24.03 ⁇ 0.2 degrees 2 ⁇ .
  • the aspect of the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) having additional peaks located at about 13.07, 16.93 and 28.30 ⁇ 0.2 degrees 2 ⁇ .
  • the aspect of the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) having further peaks located at about 12.65 and 26.41 ⁇ 0.2 degrees 2 ⁇ .
  • the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) substantially as illustrated by fig.1 .
  • PXRD powder x-ray diffraction pattern
  • the present application provides a crystalline eliglustat free base form R1 having thermal events at about 71 .98 ° C in differential scanning calorimetry (DSC) thermogram.
  • the present application provides a crystalline eliglustat free base form R1 having differential scanning calorimetry (DSC) thermogram as illustrated by fig.2.
  • DSC differential scanning calorimetry
  • the present application provides a process for the preparation of crystalline eliglustat free base form R1 , which comprises:
  • step (a) adding an anti-solvent to the solution obtained in step (a);
  • step (b) and step (c) of the first embodiment all the disclosures of which are incorporated herein by reference, can be used for step (a) and step (b) respectively of the sixth embodiment.
  • Step (a) of the sixth embodiment involves providing a solution of eliglustat free base in a solvent.
  • a solution of crude eliglustat free base may be obtained during the course of its synthesis, for example by a process described above from the US patent document No 7,196,205 or alternatively a solution of crude eliglustat free base may be obtained by dissolving crude eliglustat free base in a suitable solvent.
  • Suitable solvent that may be used for providing a solution of crude eliglustat free base includes, but not limited to: ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane, or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate or the like; aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, methylcydohexane
  • Step (b) of sixth embodiment involves adding an anti-solvent to the solution obtained in step (a).
  • US patent No 7,196,205 involves repeated dissolution of eliglustat free base in 5% ethyl acetate in heptane under reflux condition and isolates pure eliglustat free base on cooling thereby resulting in 39% yield.
  • the crude eliglustat free base is dissolved in a solvent and isolated by adding an antisolvent there by resulting in high yield.
  • Anti-solvent refers to a solvent in which eluglustat is poorly soluble when compared to a solvent that is used in step (a) for providing a solution of eliglustat.
  • Suitable anti-solvent include, but not limited to: aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, methylcydohexane or the like; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2- methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate or the like; nitromethane; halogenated hydrocarbon
  • Step (c) of the sixth embodiment involves isolating crystalline eliglustat free base form R1 .
  • the separated crystalline eliglustat free base form R1 can be isolated by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids.
  • the recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.
  • the present application provides a process for the preparation of crystalline eliglustaxt free base form R1 , which comprises:
  • HA is an acid residue
  • steps (a) through (d) of the seventh embodiment may be similar to the similar processes described for first and sixth embodiments, which are incorporated herein by reference.
  • the separated crystalline eliglustat free base form R1 can be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids.
  • the recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.
  • the present application provides crystalline oxalic acid salt of eliglustat having powder x-ray diffraction pattern (PXRD) peaks located at about 5.58, 6.90, 14.84, 18.71 and 28.98 ⁇ 0.2 degrees 2 ⁇ .
  • the aspect of the present application provides crystalline oxalic acid salt of eliglustat having powder x- ray diffraction pattern (PXRD) having additional peaks located at about 8.13, 21 .08 and 23.96 ⁇ 0.2 degrees 2 ⁇ .
  • the aspect of the present application provides crystalline oxalic acid salt of eliglustat having powder x-ray diffraction pattern (PXRD) having further peaks located at about 15.24 and 21 .60 ⁇ 0.2 degrees 2 ⁇ .
  • the present application provides a crystalline oxalic acid salt of eliglustat having powder x-ray diffraction pattern (PXRD) substantially as illustrated by figure 3.
  • PXRD powder x-ray diffraction pattern
  • the present application provides a process for the preparation of crystalline oxalic acid salt of eliglustat, which comprises:
  • Suitable solvents that may be used for the preparation of eliglustat oxalate include, but not limited to esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, 1 ,4-dioxane, and the like; aliphatic or alicyclic hydrocarbons, such as, for example, hexane, heptane, pentane, cy
  • the isolation of crystalline eliglustat oxalic acid salt can be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids.
  • the recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.
  • the present invention addresses the short comings of the prior art by providing an improved process for preparing pure eliglustat (1 R, 2R)-2-amino -1 -(2, 3-dihydro-benzo [1 , 4] dioxin-6-yl)-3-pyrrolidin-1 -yl-propan-1 -ol) in high yield.
  • the present application also provides alternate forms of eliglustat and its pharmaceutically acceptable salt.
  • Solid states of eliglustat or oxalic acid salt there of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A, and were obtained using a PanAlytical, Powder X-ray Diffractometer. DSC was taken using PanAlytical instrument.
  • C1 -C6 alcohols include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
  • aliphatic hydrocarbon is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds.
  • a liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.”
  • C5-C8 aliphatic or aromatic hydrocarbons include, but are not limited to, isopentane, neopentane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3- methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3- methylheptane, neooctane, is
  • C3-C6 esters include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
  • ether is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms.
  • C2-C6 ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
  • halogenated hydrocarbon is an organic compound containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
  • C3-C6 ketones include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
  • a “nitrile” is an organic compound containing a cyano -(C ⁇ N) bonded to another carbon atom.
  • C2-C6 Nitriles include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like. All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise.
  • “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited.
  • the terms “having” and “including” are also to be construed as open ended.
  • Example 2 Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2',3'-dihydro-benzo[1 ,4] dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.
  • 5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30 ° C.
  • toluene (2500ml) under nitrogen atmosphere at 25-30 ° C.
  • ,4- benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105 ° C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25 ° C to get a residue.
  • reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude.
  • the obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography.
  • methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml).
  • Example 4 Preparation of (1 R,2R,1 "S)-1-(2',3'-(Dihydro-benzo[1 ,4]dioxin-6'- yl)2-hydroxy-2-(2"-hydroxy-1 '-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.
  • reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C.
  • Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate.
  • Example 5 Preparation of (1 R, 2R)-2-Amino-1-(2', 3'-dihydro-benzo [1 , 4] dioxin-6'-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.
  • Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere.
  • Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h.
  • White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] +> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %

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Abstract

La présente invention porte sur un procédé amélioré pour la préparation d'éliglustat en sels de ce dernier. La présente invention concerne également une forme épurée d'éliglustat cristallin R1.
PCT/IB2014/065631 2013-10-25 2014-10-27 Procédé amélioré pour la préparation d'éliglustat WO2015059679A1 (fr)

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CN105646442A (zh) * 2015-10-27 2016-06-08 北京凯莱天成医药科技有限公司 一种依利格鲁司他的制备方法
CN106349210A (zh) * 2016-08-24 2017-01-25 北京阳光诺和药物研究有限公司 一种制备酒石酸艾力骨司坦的方法
WO2017068496A1 (fr) * 2015-10-20 2017-04-27 Dr. Reddy' S Laboratories Limited Procédé amélioré pour la préparation d'éliglustat et de ses sels
CN108822072A (zh) * 2017-04-11 2018-11-16 中国医学科学院药物研究所 一种制备伊力格鲁司他的方法
WO2020194138A1 (fr) * 2019-03-22 2020-10-01 Piramal Enterprises Limited Procédé amélioré pour la préparation d'éliglustat et de son intermédiaire
WO2023083293A1 (fr) * 2021-11-12 2023-05-19 曙方(上海)医药科技有限公司 Sel pharmaceutiquement acceptable d'éliglustat et forme cristalline de celui-ci

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
WO2017068496A1 (fr) * 2015-10-20 2017-04-27 Dr. Reddy' S Laboratories Limited Procédé amélioré pour la préparation d'éliglustat et de ses sels
CN105646442A (zh) * 2015-10-27 2016-06-08 北京凯莱天成医药科技有限公司 一种依利格鲁司他的制备方法
CN106349210A (zh) * 2016-08-24 2017-01-25 北京阳光诺和药物研究有限公司 一种制备酒石酸艾力骨司坦的方法
CN108822072A (zh) * 2017-04-11 2018-11-16 中国医学科学院药物研究所 一种制备伊力格鲁司他的方法
CN108822072B (zh) * 2017-04-11 2021-01-12 中国医学科学院药物研究所 一种制备伊力格鲁司他的方法
WO2020194138A1 (fr) * 2019-03-22 2020-10-01 Piramal Enterprises Limited Procédé amélioré pour la préparation d'éliglustat et de son intermédiaire
WO2023083293A1 (fr) * 2021-11-12 2023-05-19 曙方(上海)医药科技有限公司 Sel pharmaceutiquement acceptable d'éliglustat et forme cristalline de celui-ci

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