WO2021140480A1 - Procédé de préparation d'aramchol - Google Patents

Procédé de préparation d'aramchol Download PDF

Info

Publication number
WO2021140480A1
WO2021140480A1 PCT/IB2021/050127 IB2021050127W WO2021140480A1 WO 2021140480 A1 WO2021140480 A1 WO 2021140480A1 IB 2021050127 W IB2021050127 W IB 2021050127W WO 2021140480 A1 WO2021140480 A1 WO 2021140480A1
Authority
WO
WIPO (PCT)
Prior art keywords
cholan
compound
methyl
acid
oate
Prior art date
Application number
PCT/IB2021/050127
Other languages
English (en)
Inventor
Gianluca Galdi
Nagnnath KOKARE
Original Assignee
Ice S.P.A.
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 Ice S.P.A. filed Critical Ice S.P.A.
Publication of WO2021140480A1 publication Critical patent/WO2021140480A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0027—Azides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention relates to a method for the preparation of a compound of formula (I), 3 ⁇ -arachidylamido- 7 ⁇ ,12 ⁇ -dihydroxy-5 ⁇ -cholan-24-carboxylic acid, commonly known as Aramchol.
  • Aramchol 3 ⁇ -arachidylamido-7 ⁇ ,12 ⁇ -dihydroxy-5 ⁇ -cholan-24- carboxylic acid
  • Aramchol is derived from 3 ⁇ -amino cholic acid and arachidic acid.
  • Aramchol is molecule being developed by Galmed Pharmaceuticals for treatment of nonalcoholic steatohepatitis (NASH) which is a more advanced condition of non-alcoholic fatty liver disease (US6384024,
  • Aramchol affects liver fat metabolism and has been shown in a Phase Ila clinical study to significantly reduce liver fat content as well as to improve metabolic parameters associated with fatty liver disease. Furthermore, it has been shown to be safe for use, and with no severe adverse effects. It is also reported treating cholelithiasis through the delay of the crystalline growth velocity of cholesterol and the facilitation of the dissolution of formed cholesterol crystals.
  • Aramchol is being studied as an oral therapy for the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis in Phase III/IV with a recommended daily dose of 600mg or 300mg twice.
  • Phase II study showed good results from efficacy and safety data point of view.
  • the synthetic route of Aramchol disclosed in US6384024 comprises the reaction of methyl 3 ⁇ - amino-7 ⁇ ,12 ⁇ -dihydroxy-5 ⁇ -cholan-24-one reacted with arachidic acid chloride followed by hydrolysis using sodium hydroxide in methanol.
  • Medica discloses another method for preparation of Aramchol shown in Scheme 2.
  • Cholic acid is acylated using mesyl chloride/tosyl chloride/trifluoro mesyl chloride to provide selectively 3-hydroxy protected compound. It is further reacted with sodium azide followed by reduction reaction using 10% Pd/C to yield 3 ⁇ -amino cholic acid. The last reaction is the conjugation of 3 ⁇ -amino cholic acid with arachidyl chloride to provide Aramchol.
  • This synthetic route has poor selectivity in acylation reaction towards 3-hydroxy group of cholic acid using mesyl chloride/tosyl chloride/trifluoro mesyl chloride and leads to the formation of diacylated and triacylated impurities.
  • these impurities yield makes purification of intermediates and final active principle very difficult with simple solvent purifications.
  • the presence of impurities affects also the overall yield of Aramchol and cost effectiveness of the process.
  • Aramchol preparation (Scheme 3). This procedure discloses a new approach to prepare methyl 3 ⁇ -amino cholic acid through a Mitsunobu reaction using pthalimide or succinimide and its use for Aramchol synthesis.
  • CN106496300 discloses that the purity of the prepared products can reach up to 98.00%. This clearly indicates that the procedure is not capable of producing pure Aramchol as per ICH Q3A guidelines. In addition, the overall yields based on examples provided are poor.
  • This procedure also exhibits disadvantages of poor selectivity of methyl cholate reaction with pthalimide/succinimide and results in the formation of di- and tri-substituted impurities.
  • the presence of these impurities along with additional impurities generated during the deprotection of pthalimide/succinimide to form amine intermediate make this procedure difficult to produce Aramchol with a quality complying with ICH guidelines.
  • silica gel column chromatography purification is required to get pure intermediates and final product as well which makes procedure too lengthy and not suitable for industrial production of Aramchol.
  • CN109503693 further describes a procedure using tosyl chloride for the selective 3-OH acylation of cholic acid which seems to be similar to the procedure disclosed in US20120277448 .
  • the disadvantage of this procedure is that p- toluene sulfonyl chloride reacts both with the carboxyl group of the bile acid and the hydroxy group thus, the reaction selectivity is not good and causes a wide side reaction. Therefore, the intermediate purification is not easy and the final product Aramchol yield is low.
  • CN109503693 describes another synthetic route as shown in Scheme 5.
  • the yield of the procedure is very low (based on the total yield is 12.7% Aramchol to cholic acid) and it is suitable only for synthesis of small quantity of Aramchol in a laboratory.
  • the aim of the present invention is to provide a new method for the synthesis of Aramchol with high yield of pure product that is easy and industrially scalable.
  • a method for the preparation of 3 ⁇ -arachidylamido- 7 ⁇ ,12 ⁇ -dihydroxy-5 ⁇ -cholan-24-carboxylic acid comprising the step of: d) reacting a compound (IV) with methane sulphonyl chloride to obtain methyl 7 ⁇ ,12 ⁇ -diacetyloxy-3 ⁇ -mesyloxy-5 ⁇ - cholan-24-oate (V).
  • the present invention provides an easy, high yield, cost effective and industrially scalable process for Aramchol preparation.
  • a further advantage of the present invention is the selectivity of the acylation of 3-hydroxy group of methyl cholate using mesyl chloride.
  • the method of the present invention comprises, after step d), the steps of: e) reacting compound (V) with sodium azide to provide methyl 3 ⁇ -azido-7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate (VI);
  • the method of the present invention further comprises, after step e), the following steps: f) reduction of compound (VI) using a reducing agent followed by salt formation with an acid and obtaining the free amine in the presence of a base to yield methyl 3 ⁇ - azido-7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate (VII); g) treating compound (VII) with arachidic acid in the presence of a coupling agent and HOBt/HOAt to form methyl 3 ⁇ -arachidylamido-7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate h) hydrolysing compound (VIII) using a base to get 3 ⁇ - arachidylamido-7 ⁇ ,12 ⁇ -dihydroxy-5 ⁇ -cholan-24-carboxylic acid (IX).
  • the method of the present invention comprises, before step d), the steps of: a) treating cholic acid (I) with an esterification reagent to provide compound (II);
  • the preparation methyl cholate (compound (II)) is performed starting from cholic acid.
  • the reaction can be performed in methanol solvent using an esterification reagent selected from the group consisting of methane sulfonic acid, para-toluene sulfonic acid, acetyl chloride, sulfuric acid, thionyl chloride.
  • the preferred and cost effective esterification reagents are acetyl chloride and methane sulphonic acid.
  • Step a) is performed within a wide range of temperature from 30-80°C, preferably 50-70°C. After complete conversion of the starting material, the product is isolated by filtration at acidic pH.
  • Compound (II) is treated with an acylation reagent, such as acetic anhydride, an organic base and DMAP to yield methyl 3 ⁇ ,7 ⁇ ,12 ⁇ -triacetyloxy-5 ⁇ -cholan-24-oate (III).
  • the organic base can be selected from the group consisting of triethylamine, pyridine, N-methyl morphine, and diisoproylethyl amine; preferably trimethylamine or N-methyl morpholine.
  • Step b) can be performed in wide range of temperature from 40-120°C; preferably 80-120°C.
  • a semisolid compound III is obtained which can be isolated as a solid through the treatment with suitable solvents selected from the group consisting of diisopropyl ether, diethyl ether, heptane, and pentane.
  • suitable solvents selected from the group consisting of diisopropyl ether, diethyl ether, heptane, and pentane.
  • semisolid compound (III) can be used directly in the next step of hydrolysis.
  • the semisolid compound (III) is selectively hydrolyzed using a base selected from the group consisting of sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tertiary butoxide and sodium tertiary butoxide; preferably sodium carbonate.
  • This reaction can be performed in polar protic solvents selected from the group consisting of methanol, ethanol, propanol, water and butanol at temperature range of 0-50°C.
  • semisolid compound (IV) is obtained, which can be isolated as solid by treating it with suitable solvents selected from the group consisting of diisopropyl ether, diethyl ether, heptane, and pentane. To make the procedure easy, short and convenient, semisolid compound (IV) can be used as such in the next step.
  • the semisolid compound (IV) is reacted with methane sulphonyl chloride in the presence of a suitable base to provide methyl 7 ⁇ ,12 ⁇ -diacetyloxy-3 ⁇ -mesyloxy-5 ⁇ -cholan-24- oate (V).
  • the reaction can be performed in a solvent selected from the group consisting of ethyl acetate, dichloromethane, toluene, chloroform, tetrahydrofuron, methylisobutyl ketone and mixture therof; preferably ethyl acetate and dichloromethane.
  • the base can be selected from the group consisting of triethyl amine, pyridine, diisopropyl ethylamine, N-methyl morpholine, sodium carbonate, potassium carbonate, sodium bicarbonate and sodium acetate; preferably triethyl amine.
  • Compound (V) is reacted with sodium azide to get methyl 3 ⁇ -azido-7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate (VI).
  • the solvent can be selected from the group consisting of DMF, DMSO, DMAc, acetonitrile, ethanol, and methanol.
  • azide nucleophile reacts from opposite side of the mesylate group, which provides the inversion of the stereochemistry of position 3.
  • Mole ratio of sodium azide in respect to compound V ranges from 1.0 to 4.5.
  • Reduction of compound (VI) can be performed using a reducing reagent and then performing the purification/isolation through the formation of an acid salt followed by obtaining the free amine to yield pure 3 ⁇ -amino- 7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate (VII).
  • the present reaction can be performed in solvents selected from the group consisting of methanol, tetrahydrofuron, isopropyl alcohol, n-propanol, 2-butanol and ethanol; preferably in methanol or isopropyl alcohol.
  • solvents selected from the group consisting of methanol, tetrahydrofuron, isopropyl alcohol, n-propanol, 2-butanol and ethanol; preferably in methanol or isopropyl alcohol.
  • different reducing reagents can be used under hydrogen atmosphere selected from the group consisting of Pd/C, Pt/C and Raney Nickel.
  • Triphenyl phosphine may also be used for said reaction.
  • the most suitable reducing agent found to be 10% Pd/C under hydrogen pressure in the range of 1 - 5kg.
  • the catalyst is separated by filtration and the collective filtrate is evaporated to get crude amine intermediate (VII), which contains isomer impurity (X) in range of 0.5% to 3%.
  • the preferred acid for salt formation is tartaric acid which helps to eliminate maximum of isomer impurity up to 0.05%.
  • the isolated tartaric acid salt of amine intermediate purified with suitable solvent leads to control isomer impurity up to 0.01%. Furthermore, the wet salt as such is processed to obtain the free base using a mild base and to isolate substantial pure amine intermediate (VII).
  • the salt formation can be performed using a suitable solvent selected from the group consisting of propanol, methanol, ethanol, ethyl acetate, methyl isobutyl ketone, acetone, isopropyl alcohol and mixture thereof; preferably ethyl acetate or propanol.
  • a suitable solvent selected from the group consisting of propanol, methanol, ethanol, ethyl acetate, methyl isobutyl ketone, acetone, isopropyl alcohol and mixture thereof; preferably ethyl acetate or propanol.
  • the coupling reagent is selected from the group consisting of dicyclohexyl carbodiimide (DCC), N- (3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (EDC. HC1), Diethyl cyanophosphonate, 2- ( 1H-benzotriazole-l-yl)-1,1,3,3-tetra- methylaminium-tetra-fluroborate (TBTU), carbonyl di- imidazole (CDI).
  • DCC dicyclohexyl carbodiimide
  • EDC. HC1 N- (3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride
  • Diethyl cyanophosphonate 2- ( 1H-benzotriazole-l-yl)-1,1,3,3-tetra- methylaminium-tetra-fluroborate (TBTU), carbonyl di- imi
  • N-(3-Dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride (EDC.HC1) and TBTU can be used to provide better results.
  • EDC.HC1 N-(3-Dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride
  • TBTU ethylcarbodiimide hydrochloride
  • the more preferable and cost effective reagent suitable for this reaction was EDC.HC1.
  • Organic bases are selected from the group consisting of triethyl amine (TEA), diisopropyl ethyl amine, Diethyl amine, N-methyl morpholine, n-methyl pyrrolidine. Triethyl amine and n-Methyl morpholine can be used for said reaction in combination with EDC.HC1 to provide better results.
  • TAA triethyl amine
  • HOBt and HOAt reagents can be used effectively.
  • the reaction was performed in a solvent selected from the group consisting of methylene dichloride, ethyl acetate, chloroform, tetrahydrofuran, acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, 1,4-dioxane or in a mixture thereof.
  • the preferred solvents are ethyl acetate and methylene dichloride.
  • the present reaction can be performed in wide range of temperature from -20°C to 80°C, preferably -10°C to 50°C. Reaction conversion is completed in 3-20 hrs.
  • the starting material is quenched with a suitable diluted aqueous solution of a base like sodium bicarbonate or sodium carbonate.
  • a suitable diluted aqueous solution of a base like sodium bicarbonate or sodium carbonate.
  • the excess of arachidic acid is removed by washing with an aqueous solution of inorganic base like but not limited to sodium bicarbonate, sodium carbonate, potassium carbonate etc.
  • a solution of sodium bicarbonate can be used to get better results.
  • Further unreacted amine content is removed by washing with a diluted aqueous acid, preferably selected from the group consisting of hydrochloric acid, sulphuric acid, citric acid, acetic acid and phosphoric acid.
  • VIII semisolid methyl 3 ⁇ - arachidylamido-7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate (VIII).
  • Compound (VIII) can be isolated as solid with suitable solvents preferably selected from the group consisting of cyclohexane, toluene, diisopropyl ether and diethyl ether.
  • the hydrolysis can be performed in the presence of a base preferably selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, sodium methoxide and sodium ethoxide; more preferably sodium hydroxide or potassium hydroxide.
  • the hydrolysis reaction can be performed in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, butanol, acetone, methyl etheyl ketone and mixtures thereof; preferably alcoholic solvent and water. It can be performed in wide range of temperature from -10°C to 110°C; preferably 0-100°C. After complete conversion of starting materials, aqueous work up can be performed to isolate Aramchol at acidic pH.
  • the isolated Aramchol can be further purified using ester solvents preferably selected from the group consisting of ethyl acetate, methyl acetate, tert-butyl acetate or ketone solvents preferably selected from the group consisting of acetone, methylisobutyl ketone, ethylmethyl ketone and mixtures thereof with water to provide pure Aramchol .
  • ester solvents preferably selected from the group consisting of ethyl acetate, methyl acetate, tert-butyl acetate or ketone solvents preferably selected from the group consisting of acetone, methylisobutyl ketone, ethylmethyl ketone and mixtures thereof with water to provide pure Aramchol .
  • purification is performed using mixtures of alcohol solvents like methanol, ethanol, propanol, isopryl alchohol along with water to provide pure Aramchol.
  • the preferred solvent combination is a mixture of ethyl acetate and water in different ratio.
  • the preferred ratio organic solvent/water varies from 0.5% to 99.5%.
  • the ratio organic solvent/water varies from 50-50%. In another embodiment, the preferred ratio was 30-70% to get better results .
  • the method of the present invention comprises eight stages, wherein each and every stage is very simple, easy to perform, high yielding and provides good quality of intermediates and final active principle.
  • intermediates II and III can be used as such in thenext respective steps without isolation.
  • intermediate VIII can be used as such. Therefore, the procedure can be performed to have only five isolating steps and without affecting the quality of intermediates and final product. This makes the procedure of present invention short, cost effective, high yielding and industrially scalable.
  • one of the differences between the present invention and the synthetic method illustrated in CN109503693 is the use of 7 ⁇ ,12 ⁇ -diacetyloxy-3 ⁇ -mesyloxy-5 ⁇ - cholan-24-oate (V) to prepare azide intermediate (VI) instead of methyl 7 ⁇ ,12 ⁇ -diacetyloxy-3 ⁇ -tosyloxy-5 ⁇ -cholan- 24-oate.
  • methyl 7 ⁇ ,12 ⁇ -diacetyloxy-3 ⁇ - mesyloxy-5 ⁇ -cholan-24-oate is used to make substantial pure amine intermediate (VII) and subsequently Aramchol with comparatively very high yield and better quality.
  • the overall yield of Aramchol as per the method of the present invention is about 65% based on cholic acid which is fivefold more than the procedure disclosed in CN109503693 (12.7% only).
  • the procedure disclosed in CN109503693 is not capable of producing good quality of Aramchol, whereas the method of the present invention allows the production of pure Aramchol and control of impurities as per ICH Q3 guidelines.
  • the procedure is capable of producing Aramchol having optical purity up to 99.9%.
  • the procedure disclosed in CN109503693 is suitable for the preparation of small quantities of Aramchol only and is not industrially scalable, whereas the procedure of present invention has been developed considering safety aspects and operation ease for each stage which make this procedure industrially scalable in production plants.
  • the method is capable of producing bulk quantity of Aramchol up to hundreds kg scale which makes it suitable for commercial mass production.
  • a pure amine intermediate (VII) having HPLC chromatography purity greater than 99.5 % is provided.
  • Yet another aspect of the present invention relates to the preparation of substantially pure amine intermediate (VII) having HPLC chromatography purity up to 99.9% and isomer impurity of formula (X) controlled up to 0.01%.
  • Yet another aspect of the present invention relates to preparation of pure Aramchol having HPLC chromatography purity greater than 99.5%.
  • Yet another aspect the present invention relates to preparation of substantially pure Aramchol having optical purity up to 99.9% and isomer impurity of formula (XI) controlled up to 0.01%.
  • Methyl cholate (100gm, 0.237mol) is taken in dry and clean RBF containing methyl isobutyl ketone (500 ml).
  • acetic anhydride (96.6 gm, 0.946 mol)
  • trimethylamine 95.76 g, 0.946 mol
  • DMAP (1.44 g, 0.0118 mol
  • Reaction mass is maintained at reflux until complete conversion.
  • the reaction is quenched with water (950 ml) and top organic layer is separated at about 65°C. The organic layer is distilled completely under reduced pressure below 60°C to get semisolid residue.
  • the mass is cooled to 0-5°C and stirred for 2 hours to obtain product precipitation.
  • the mass is filtered on buchner funnel, washed with chilled methanol and dried under vacuum below 50°C to provide the desired product.
  • Methyl 3 ⁇ -azido-7 ⁇ , 12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate (93 g, 0.175 mol), 10% Pd/C (9.3 g) and methanol (900 ml) are charged into a hydrogen pressure reactor.
  • the reaction mass is flushed with nitrogen and hydrogen twice and then is maintained under 3 kg hydrogen pressure under stirring at 25-30°C for 10 hours. After complete conversion, the mass is filtered through a celite bed at and washed with methanol.
  • Arachidic Acid 33.35 g, 0.106 mol
  • ethyl acetate (13.5vol) are taken in clean and dry RBF and stirred at 25- 30°C to get complete dissolution.
  • the mass is cooled to 10°C- 15°C and HOBt (14.4gm, 0.106mol) and triethylamine (21.5gm, 0.21mol) are added to the reaction mass.
  • Methyl 3 ⁇ -amino- 7 ⁇ ,12 ⁇ -diacetyloxy-5 ⁇ -cholan-24-oate 65 g, 0.128 mol
  • EDC.HC1 24.55 g, 0.128 mol
  • the organic layer is separated, washed with water (510 ml) twice and distilled under reduced pressure below 50°C.
  • Ethyl acetate (510ml) and water (510ml) are added to the mass at 20-25°C, heated to 80-85°C and maintained 1 hour to obtain a clear solution. Then, the mass is cooled to 25- 30°C and maintained 4 hour at the same temperature to precipitate the product. The precipitated product filtered on buchner funnel, is washed with a mixture of ethyl acetate + water (1:1 ratio) and the wet cake is dried under vacuum below 60°C to provide Aramchol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'acide 3β-arachidylamido-7α,12α-dihydroxy-5β-cholan-24-carboxylique comprenant l'étape consistant à : d) faire réagir le composé (IV) avec du méthane sulfochloré pour obtenir du 7α,12α-diacétyloxy-3α-mésyloxy-5β-cholan-24-oate de méthyle (V).
PCT/IB2021/050127 2020-01-10 2021-01-08 Procédé de préparation d'aramchol WO2021140480A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102020000000328A IT202000000328A1 (it) 2020-01-10 2020-01-10 Metodo di preparazione dell'aramchol
IT102020000000328 2020-01-10

Publications (1)

Publication Number Publication Date
WO2021140480A1 true WO2021140480A1 (fr) 2021-07-15

Family

ID=70009335

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/050127 WO2021140480A1 (fr) 2020-01-10 2021-01-08 Procédé de préparation d'aramchol

Country Status (2)

Country Link
IT (1) IT202000000328A1 (fr)
WO (1) WO2021140480A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6384024B1 (en) 1998-04-08 2002-05-07 Galmed International Limited Bile salt conjugates
US20120277448A1 (en) 2009-12-30 2012-11-01 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Preparation method for 3beta-arachidylamido-7alpha, 12alpha, 5beta-cholan-24-carboxylic acid
CN106496300A (zh) 2016-10-19 2017-03-15 上海博志研新药物技术有限公司 花生胆酸及其中间体的制备方法
CN109503693A (zh) 2018-12-12 2019-03-22 合肥工业大学 一种利用胆酸和花生酸为原料高效合成Aramchol的新工艺

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6384024B1 (en) 1998-04-08 2002-05-07 Galmed International Limited Bile salt conjugates
US20120277448A1 (en) 2009-12-30 2012-11-01 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Preparation method for 3beta-arachidylamido-7alpha, 12alpha, 5beta-cholan-24-carboxylic acid
CN106496300A (zh) 2016-10-19 2017-03-15 上海博志研新药物技术有限公司 花生胆酸及其中间体的制备方法
CN109503693A (zh) 2018-12-12 2019-03-22 合肥工业大学 一种利用胆酸和花生酸为原料高效合成Aramchol的新工艺

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BIOCHEM. SOC. TRANS., vol. 32, 2004, pages 131 - 133
DEJAN OPSENICA ET AL: "Cholic Acid Derivatives as 1,2,4,5-Tetraoxane Carriers:? Structure and Antimalarial and Antiproliferative Activity 1, +", JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, no. 17, 1 August 2000 (2000-08-01), US, pages 3274 - 3282, XP055332890, ISSN: 0022-2623, DOI: 10.1021/jm000952f *
EUI-HYUN RYU ET AL., TETRAHEDRON, vol. 26, 2006, pages 11178 - 11186
HEPATOLOGY, vol. 38, pages 436442
LETIS ANTONIOS S ET AL: "Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, NL, vol. 25, no. 13, 20 April 2017 (2017-04-20), pages 3357 - 3367, XP085037279, ISSN: 0968-0896, DOI: 10.1016/J.BMC.2017.04.021 *
PATHOBIOLOGY, vol. 70, 2002, pages 215 - 218
STEF DE LOMBAERDE ET AL: "Synthesis, in vitro and in vivo evaluation of 3[beta]-[18F]fluorocholic acid 2 for the detection of drug-induced cholestasis in mice.", SUPPLEMENTARY DATA TO PLOS ONE, 2017, VOL. 12, # 3, ART. NO. E0173529 XP55726110, 1 January 2017 (2017-01-01), pages 1 - 6, XP055726115, Retrieved from the Internet <URL:https://doi.org/10.1371/journal.pone.0173529.s001> [retrieved on 20200831] *
STEF DE LOMBAERDE ET AL: "Synthesis, in vitro and in vivo evaluation of 3[beta]-[18F]fluorocholic acid for the detection of drug-induced cholestasis in mice", PLOS ONE, 1 January 2017 (2017-01-01), United States, pages e0173529 - e0173529, XP055726110, Retrieved from the Internet <URL:https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0173529&type=printable> DOI: 10.1371/journal.pone.0173529 *

Also Published As

Publication number Publication date
IT202000000328A1 (it) 2021-07-10

Similar Documents

Publication Publication Date Title
US8759582B2 (en) Process for the preparation of lacosamide
IL159740A (en) A process for producing three-carbon amino-alcohol salts
JP5781432B2 (ja) ピリピロペン誘導体の製造法
JP5717752B2 (ja) ピリピロペン誘導体の製造法
JP3473976B2 (ja) アラニルグルタミンの製造法
JP2022525662A (ja) 高純度アロプレグナノロンおよびその中間体を調製する方法
TWI634100B (zh) 製備拉科醯胺的方法
EP3227312A1 (fr) Procédé de purification de carfilzomib
WO2021140480A1 (fr) Procédé de préparation d&#39;aramchol
AU2012219096A1 (en) An improved process for preparation of levonorgestrel
EP2598476B1 (fr) Procédé de préparation de lacosamide et de dérivés intermédiaires de n-benzyl-propanamide
KR102255357B1 (ko) 2-아미노-1,3-프로판디올 화합물 및 이의 염의 제조방법
KR100554562B1 (ko) 에리트로마이신 유도체의 제조 방법
KR100743617B1 (ko) 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법
US11498917B2 (en) Process for the preparation of lifitegrast
WO2012117410A1 (fr) Procédé pour la préparation d&#39;ester phénylméthylique de n-[2-[(acétylthio) méthyl]-1-oxo-3-phénylpropyl] glycine et d&#39;intermédiaires de celui-ci
EP2448916B1 (fr) Production de derives d&#39;acide trans-4-aminocyclopent-2-ene-1-carboxylique
US8664443B2 (en) Process for the preparation of (1S, 3S, 5S)-2-[2(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile
WO2012001710A1 (fr) Procédé amélioré pour la préparation de lacosamide
RU2190597C2 (ru) Способ получения антагонистов nmda (n-метил-d-аспартата)
CN111808040A (zh) 多构型2-氧代噁唑烷-4-羧酸类化合物的合成方法
JP2022072636A (ja) アミド化合物の製造方法
JPH08311049A (ja) Ｌ−スレオ−βーヒドロキシアスパラギン酸誘導体および製造法
CZ280793B6 (cs) Způsob přípravy N2-/1(S)-karboxy-3-fenyl-propyl/ L-lysyl-L-prolinu (lisinoprilu)
JPH11116546A (ja) ７−メトキシ−２−アミノテトラリンカーバメート及びその製造方法並びにそれを用いた７−メトキシ−２−アミノテトラリンの光学純度向上方法

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: 21700066

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: 21700066

Country of ref document: EP

Kind code of ref document: A1