WO2023227723A1 - An improved process for the preparation of aramchol and salts thereof - Google Patents
An improved process for the preparation of aramchol and salts thereof Download PDFInfo
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- WO2023227723A1 WO2023227723A1 PCT/EP2023/064071 EP2023064071W WO2023227723A1 WO 2023227723 A1 WO2023227723 A1 WO 2023227723A1 EP 2023064071 W EP2023064071 W EP 2023064071W WO 2023227723 A1 WO2023227723 A1 WO 2023227723A1
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- Prior art keywords
- formula
- aramchol
- group
- chloride
- mixtures
- Prior art date
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- SHKXZIQNFMOPBS-OOMQYRRCSA-N (4r)-4-[(3s,5s,7r,8r,9s,10s,12s,13r,14s,17r)-7,12-dihydroxy-3-(icosanoylamino)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound O[C@H]1C[C@@H]2[C@@]3(C)CC[C@H](NC(=O)CCCCCCCCCCCCCCCCCCC)C[C@H]3C[C@@H](O)[C@H]2[C@@H]2CC[C@H]([C@H](C)CCC(O)=O)[C@]21C SHKXZIQNFMOPBS-OOMQYRRCSA-N 0.000 title claims abstract description 37
- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- -1 aramchol methyl ester Chemical class 0.000 claims description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003586 protic polar solvent Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 abstract description 4
- NHXTZGXYQYMODD-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCCCC(O)=O NHXTZGXYQYMODD-UHFFFAOYSA-N 0.000 abstract 1
- 150000004702 methyl esters Chemical class 0.000 description 12
- 239000012535 impurity Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- BXZBGYJQEFZICM-UHFFFAOYSA-N icosanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCCCC(Cl)=O BXZBGYJQEFZICM-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 208000010706 fatty liver disease Diseases 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003858 bile acid conjugate Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 2
- NDQQRRVKUBPTHQ-QBIQUQHTSA-N (2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO NDQQRRVKUBPTHQ-QBIQUQHTSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- AAMWFMOHRYFSEU-UHFFFAOYSA-N methanol;propan-2-one;hydrate Chemical compound O.OC.CC(C)=O AAMWFMOHRYFSEU-UHFFFAOYSA-N 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- SIARJEKBADXQJG-LFZQUHGESA-N stearoyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCCCCCCCCCCCCCCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 SIARJEKBADXQJG-LFZQUHGESA-N 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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
- 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
- C07J41/0011—Unsubstituted amino radicals
Definitions
- the present invention relates to a process for the preparation of Aramchol of formula (I) and its pharmaceutically acceptable salts.
- AramcholTM is an amide conjugate of arachidic acid and 3-aminocholic acid, effective in reducing liver fat content as well as improving metabolic parameters associated with fatty liver disease. It is an oral, liver-targeted, fatty acid-bile acid conjugate that down- regulates stearoyl CoA type 1 desaturase. It belongs to a family of synthetic Fatty- Acid/Bile-Acid Conjugates (FABACs) and is being developed as a potentially disease modifying treatment for fatty liver disease and Non-Alcoholic Steatohepatitis (NASH).
- FABACs Fatty- Acid/Bile-Acid Conjugates
- Aramchol is chemically named as (3p)-Arachidylamido-7a,12a-dihydroxy-5[3-cholan-24- oic acid.
- the Israeli company, Galmed pharmaceuticals has developed a FABACs fatty liver treatment drug Aramchol, which is a compound in which cholic acid is coupled to arachidic acid via an amide bond. It is now under clinical studies, and this drug has been proven to have the potential to treat cholesterol gallstones and atherosclerosis.
- Aramchol is disclosed in U.S. patent No. 6,395,722 B1 and its acid addition salts in U.S. patent No. US 10,849,911 B2. Further, US ‘722 B1 describes the preparation of Aramchol by reaction of 3p-Amino-7a,12a-dihydroxy-5[3-cholan-24-oic methyl ester with Arachidoyl chloride in the presence of DMF/TEA to produce Aramchol methyl ester, which is further hydrolyzed with sodium hydroxide in methanol to produce Aramchol. The process is represented in the following scheme I:
- acylation of 3p-Amino-7a,12a-dihydroxy-5[3-cholan-24-oic methyl ester with Arachidoyl chloride leads the formation of impurities which are very difficult to eliminate by means of purification steps.
- the impurities formed during intermediate stages are carried forward in subsequent steps, also up to final API.
- the Arachidoyl chloride is moisture sensitive and forms Arachidic acid during N-acylation reaction and its removal from the process is more difficult.
- CN 110981933 A describes the process for preparation of Aramchol, which comprises: Arachidic acid is first refluxed with thionyl chloride (SOCI 2 ) for 3 hours.
- the technical problem is solved by the present invention to overcome the disadvantages of the above prior art preparation methods of Aramchol and its pharmaceutically acceptable salts, such as, high production cost, unsuitable for industrial production, etc.
- the present invention for the preparation of Aramchol and its pharmaceutically acceptable salts has resulted better yields and quality. All this results in a simple, economical, safe and industrially viable process, which provides substantially pure Aramchol and its salts with high yield.
- the main objective of the present invention is to provide a process for the preparation of Aramchol and its pharmaceutically acceptable salts with high purity and good yield, on commercial scale and substantially free of impurities.
- the present invention provides a process for the preparation of Aramchol of a compound of Formula (I) or its pharmaceutically acceptable salts: Formula I which comprises: reaction of Arachidic acid of formula (V)
- R is a aliphatic alkyl group or O-alkyl group, whereas said alkyl group comprises: methyl, ethyl, tert-butyl or isopropyl.
- the present invention provides a simple, efficient, cost-effective process for the preparation of Aramchol or its pharmaceutically acceptable salts with high purity and good yield.
- the present invention provides a process for the preparation of Aramchol of Formula (I) or its pharmaceutically acceptable salts:
- R is a aliphatic alkyl group or O-alkyl group, whereas alkyl group comprises: methyl, ethyl, tert-butyl and isopropyl ii.
- Formula I iv. optionally converting Aramchol of formula (I) to its pharmaceutically acceptable salts.
- R is an aliphatic alkyl group or O-alkyl group, whereas alkyl group comprises methyl, ethyl, tert-butyl & isopropyl.
- the Arachidic acid is reacted with acid chloride reagent to form mixed anhydride compound in the presence of a solvent and base, which is further condensed with 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester to produce 3(3- arachidylamido-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester (Aramchol methyl ester).
- the mixed anhydride reaction is carried out at below 30°C, preferably below 20°C, more preferably below 10°C and the condensation of 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24- oic methyl ester (Aramchol methyl ester) compound is carried out at ambient temperature.
- reaction mass is washed with water and concentrated the reaction mass to get the 3[3-arachidylamido-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester (Aramchol methyl ester).
- the solvent used in the reaction step (i) is selected from polar aprotic solvents, comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1 ,4-dioxane, acetonitrile, acetone, and/or mixtures thereof; and non-polar solvents comprising hexane, toluene, diisopropyl ether, methyl f-butyl ether, methylene chloride (CH2CI2) ethyl acetate and/or mixtures thereof.
- polar aprotic solvents comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1 ,4-dioxane, acetonitrile, acetone, and/or mixtures thereof.
- non-polar solvents comprising hexane, toluene, diisopropyl ether, methyl
- the base used in the reaction step (i) is organic base.
- the organic base comprises triethylamine, diisopropylamine, diisopropylethylamine, pyridine, dimethylamino pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.
- acid chloride reagent is selected from acetyl chloride, pivaloyl chloride, propionyl chloride, isobutyryl chloride, methyl chloroformate and ethyl chloroform ate.
- the mixed anhydride approach by using acid chloride reagent is advantageous as the Aramchol methyl ester is produced substantially free of impurities and with higher yields.
- the condensation reaction in the reaction step (ii) may be carried out in presence of a solvent, whereas solvent is selected from polar aprotic solvents, comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1 ,4-dioxane, acetonitrile, acetone, and/or mixtures thereof; and non-polar solvents comprising toluene, diisopropyl ether, methyl f-butyl ether, methylene chloride (CH 2 CI 2 ), ethyl acetate and/or mixtures thereof.
- the base used in the reaction step (ii) is inorganic or organic base.
- the inorganic base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, and/or potassium bicarbonate.
- the organic base comprises triethylamine, diisopropylamine, diisopropylethylamine, pyridine, Dimethylamino pyridine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.
- the hydrolysis reaction may be carried out in presence of a base.
- the base comprises an inorganic base.
- the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and caesium hydroxide.
- the hydrolysis reaction in the reaction step (iii) may be carried out in presence of a solvent.
- the solvent comprises a polar protic solvent comprising water, methanol, ethanol, isopropyl alcohol, n-butanol, and/or mixtures thereof.
- Aramchol (I) is converted to its pharmaceutically acceptable salt by treating Aramchol (I) with appropriate amine in presence of a suitable solvent, selected from the group comprising water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, acetonitrile, methylene chloride or mixtures thereof.
- a suitable solvent selected from the group comprising water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, acetonitrile, methylene chloride or mixtures thereof.
- the amine is selected from the group consisting of lysine, N- methylglucamine (meglumine) and tromethamine salts.
- Aramchol meglumine salt is prepared by treating Aramchol with N-methyl-D-glucamine in methanol-water-acetone.
- Example-1 Process for the preparation of Aramchol methyl ester (II)
- the temperature of the reaction mass is raised to 35 ⁇ 3°C and stirred for 2-4 hours to complete the reaction, after completion of the reaction, organic layer is washed with water and distilled the solvent completely under vacuum to get Aramchol methyl ester.
- the crude methyl ester is purified by Acetonitrile followed by mixture of toluene & acetonitrile.
- Pivaloyl chloride (3.4 g, 1.3 moles) is added to the mixture of Arachidic acid (6.8 g, 1.0 mole), Toluene (50 mL), Triethylamine (3.4 g, 1.5 moles) at 0-10°C. The resulting reaction mixture is stirred for 1 hour at 0-10°C. The temperature of reaction mass is raised to 25-35°C and charged Triethylamine (4.4 g, 2.5 moles).
- Aramchol methyl ester (23 g, 1.0 mole) is hydrolysed by using methanol (230 mL), water (92 mL) and sodium hydroxide (3.85 g, 3.0 moles) at 40-45°C.
- the reaction mass is distilled under vacuum, charged water (230 mL) and washed with ethyl acetate twice (115 mL).
- the Aramchol is isolated by adjusting aqueous layer pH with dilute HCI.
- Aramchol methyl ester (10 g, 1.0 mole) is hydrolysed by using ethanol (50 mL), water (20 mL) and sodium hydroxide (1.6 g, 3.0 moles) at 40-45°C.
- the reaction mass is distilled under vacuum, charged water (100 mL) and washed with ethyl acetate twice (100 mL).
- the Aramchol is isolated by adjusting aqueous layer pH with dilute HCI.
Abstract
The present invention relates to an improved process for the preparation of Aramchol and its pharmaceutically acceptable salts comprising the reaction of the corresponding 3. beta. -amine compound with a mixed anhydride of arachidic acid (Eicosanoic acid).
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF ARAMCHOL AND SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Aramchol of formula (I) and its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Aramchol™ is an amide conjugate of arachidic acid and 3-aminocholic acid, effective in reducing liver fat content as well as improving metabolic parameters associated with fatty liver disease. It is an oral, liver-targeted, fatty acid-bile acid conjugate that down- regulates stearoyl CoA type 1 desaturase. It belongs to a family of synthetic Fatty- Acid/Bile-Acid Conjugates (FABACs) and is being developed as a potentially disease modifying treatment for fatty liver disease and Non-Alcoholic Steatohepatitis (NASH).
Aramchol is chemically named as (3p)-Arachidylamido-7a,12a-dihydroxy-5[3-cholan-24- oic acid. The Israeli company, Galmed pharmaceuticals has developed a FABACs fatty liver treatment drug Aramchol, which is a compound in which cholic acid is coupled to arachidic acid via an amide bond. It is now under clinical studies, and this drug has been proven to have the potential to treat cholesterol gallstones and atherosclerosis.
Aramchol is disclosed in U.S. patent No. 6,395,722 B1 and its acid addition salts in U.S. patent No. US 10,849,911 B2. Further, US ‘722 B1 describes the preparation of Aramchol by reaction of 3p-Amino-7a,12a-dihydroxy-5[3-cholan-24-oic methyl ester with
Arachidoyl chloride in the presence of DMF/TEA to produce Aramchol methyl ester, which is further hydrolyzed with sodium hydroxide in methanol to produce Aramchol. The process is represented in the following scheme I:
(Aramchol)
In the above process acylation of 3p-Amino-7a,12a-dihydroxy-5[3-cholan-24-oic methyl ester with Arachidoyl chloride leads the formation of impurities which are very difficult to eliminate by means of purification steps. The impurities formed during intermediate stages are carried forward in subsequent steps, also up to final API. The Arachidoyl chloride is moisture sensitive and forms Arachidic acid during N-acylation reaction and its removal from the process is more difficult. CN 110981933 A describes the process for preparation of Aramchol, which comprises: Arachidic acid is first refluxed with thionyl chloride (SOCI2) for 3 hours. The Arachidoyl chloride is isolated by distillation of thionyl chloride completely under vacuum. The resulting product is dissolved in dichloromethane and slowly added dropwise to the mixture of 3p-Amino-7a,12a-dihydroxy-5[3-cholan-24-oic methyl ester, DMF and triethylamine to produce Aramchol methyl ester, which is further hydrolyzed with sodium hydroxide in methanol to produce Aramchol. The process is represented in the following scheme-11:
The major disadvantage of the above prior art process is back conversion of Arachidoyl chloride to Arachidic acid during isolation due to its sensitiveness to atmospheric moisture and also the formation of many unidentified impurities. The product Aramchol methyl ester obtained as a brown color gummy residue by this process, which affected the description of final API. Furthermore, it has been observed that, Arachidic acid and all other impurities are very difficult to remove in further stages even after repeated purifications. Hence the overall yield is drastically reduced which results in the increase of the manufacturing cost and subsequently final API cost.
The impurities formed during intermediate stages are carried forward in subsequent steps and furthermore, the removal of these impurities requires tedious purification techniques such as column chromatography or repeated crystallizations that lead to loss of yield and makes the process of Aramchol very expensive.
None of the prior art references disclose the process for the preparation of Aramchol methyl ester by mixed anhydride approach.
The technical problem is solved by the present invention to overcome the disadvantages of the above prior art preparation methods of Aramchol and its pharmaceutically acceptable salts, such as, high production cost, unsuitable for industrial production, etc. The present invention for the preparation of Aramchol and its pharmaceutically acceptable salts has resulted better yields and quality. All this results in a simple, economical, safe and industrially viable process, which provides substantially pure Aramchol and its salts with high yield.
In view of this, inventors have developed the present invention; and it has now surprisingly been found that the pure Aramchol or its pharmaceutically acceptable salts have numerous advantages over the reported processes.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for the preparation of Aramchol and its pharmaceutically acceptable salts with high purity and good yield, on commercial scale and substantially free of impurities.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of Aramchol of a compound of Formula (I) or its pharmaceutically acceptable salts:
Formula I which comprises: reaction of Arachidic acid of formula (V)
Formula V with acid chloride reagent in presence of solvent and base to produce a Arachidic acid anhydride compound of Formula (IV);
Formula IV wherein R is a aliphatic alkyl group or O-alkyl group, whereas said alkyl group comprises: methyl, ethyl, tert-butyl or isopropyl. ii. condensation of compound of formula (IV) with a compound of formula (III)
Formula (II);
iii. hydrolysis of Aramchol methyl ester of Formula (II) in the presence of base and solvent to get Aramchol of formula (I)
iv. optionally converting Aramchol of formula (I) to its pharmaceutically acceptable salts.
In one aspect, the present invention provides a simple, efficient, cost-effective process for the preparation of Aramchol or its pharmaceutically acceptable salts with high purity and good yield.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of Aramchol of Formula (I) or its pharmaceutically acceptable salts:
Formula V with acid chloride reagent in presence of solvent and base to produce a Arachidic acid anhydride compound of Formula (IV);
Formula IV wherein R is a aliphatic alkyl group or O-alkyl group, whereas alkyl group comprises: methyl, ethyl, tert-butyl and isopropyl ii. condensation of compound of formula (IV) with a compound of formula (III)
Formula III in presence of solvent and base to produce Aramchol methyl ester of Formula
Formula II iii. hydrolysis of Aramchol methyl ester of Formula (II) in the presence of base and solvent to get Aramchol of formula (I)
Formula I iv. optionally converting Aramchol of formula (I) to its pharmaceutically acceptable salts.
In another embodiment R is an aliphatic alkyl group or O-alkyl group, whereas alkyl group comprises methyl, ethyl, tert-butyl & isopropyl.
In another embodiment, the Arachidic acid is reacted with acid chloride reagent to form mixed anhydride compound in the presence of a solvent and base, which is further condensed with 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester to produce 3(3- arachidylamido-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester (Aramchol methyl ester).
The mixed anhydride reaction is carried out at below 30°C, preferably below 20°C, more preferably below 10°C and the condensation of 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24- oic methyl ester (Aramchol methyl ester) compound is carried out at ambient temperature.
After completion of the reaction, reaction mass is washed with water and concentrated the reaction mass to get the 3[3-arachidylamido-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester (Aramchol methyl ester).
In another embodiment, the solvent used in the reaction step (i) is selected from polar aprotic solvents, comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1 ,4-dioxane, acetonitrile, acetone, and/or mixtures thereof; and non-polar solvents comprising hexane, toluene, diisopropyl ether, methyl f-butyl ether, methylene chloride (CH2CI2) ethyl acetate and/or mixtures thereof.
In still another embodiment, the base used in the reaction step (i) is organic base. The organic base comprises triethylamine, diisopropylamine, diisopropylethylamine, pyridine, dimethylamino pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.
In still another embodiment, acid chloride reagent is selected from acetyl chloride, pivaloyl chloride, propionyl chloride, isobutyryl chloride, methyl chloroformate and ethyl chloroform ate.
The mixed anhydride approach by using acid chloride reagent is advantageous as the Aramchol methyl ester is produced substantially free of impurities and with higher yields.
In another embodiment, in the reaction step (ii) the condensation reaction may be carried out in presence of a solvent, whereas solvent is selected from polar aprotic solvents, comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), 1 ,4-dioxane, acetonitrile, acetone, and/or mixtures thereof; and non-polar solvents comprising toluene, diisopropyl ether, methyl f-butyl ether, methylene chloride (CH2CI2), ethyl acetate and/or mixtures thereof.
In still another embodiment, the base used in the reaction step (ii) is inorganic or organic base. The inorganic base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, and/or potassium bicarbonate. The organic base comprises triethylamine, diisopropylamine, diisopropylethylamine, pyridine, Dimethylamino pyridine, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof.
In another embodiment, in the reaction step (iii) the hydrolysis reaction may be carried out in presence of a base. The base comprises an inorganic base. The inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and caesium hydroxide.
In another embodiment, in the reaction step (iii) the hydrolysis reaction may be carried out in presence of a solvent. The solvent comprises a polar protic solvent comprising water, methanol, ethanol, isopropyl alcohol, n-butanol, and/or mixtures thereof.
In another embodiment, Aramchol (I) is converted to its pharmaceutically acceptable salt by treating Aramchol (I) with appropriate amine in presence of a suitable solvent, selected from the group comprising water, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, acetone, acetonitrile, methylene chloride or mixtures thereof.
In another embodiment, the amine is selected from the group consisting of lysine, N- methylglucamine (meglumine) and tromethamine salts.
In still another embodiment, Aramchol meglumine salt is prepared by treating Aramchol with N-methyl-D-glucamine in methanol-water-acetone.
The process is as shown in Scheme-Ill below:
Scheme III
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES:
Example-1: Process for the preparation of Aramchol methyl ester (II)
A mixture of Pivaloyl chloride (8.6 g, 1.3 moles) and Toluene (25 mL) is added to the mixture of Arachidic acid (17 g, 1.0 mole), Toluene (125 mL), Triethylamine (19.3 g, 3.5 moles) at 0-10°C. The resulting reaction mixture is stirred for 1 hour at 0-10°C.
To the above reaction mass, 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester hydrochloride (25 g, 1.0 mole) is added in lot wise at 25-35°C. The temperature of the reaction mass is raised to 35±3°C and stirred for 2-4 hours to complete the reaction, after completion of the reaction, organic layer is washed with water and distilled the solvent completely under vacuum to get Aramchol methyl ester. Yield: 80%, Purity by HPLC: 92%.
Example-2: Process for the preparation of Aramchol methyl ester (II)
A mixture of methyl chloroformate (2.6 g, 1.3 moles) and Toluene (10 mL) is added to the mixture of Arachidic acid (6.4 g, 0.95 mole), Toluene (50 mL), Triethylamine (7.8 g, 3.5 moles) at 0-10°C. The resulting reaction mixture is stirred for 1 hour at 0-10°C.
To the above reaction mass, 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester hydrochloride (10 g, 1.0 mole) is added in lot wise at 25-35°C. The temperature of the reaction mass is raised to 35±3°C and stirred for 2-4 hours to complete the reaction, after completion of the reaction, organic layer is washed with water and distilled the solvent completely under vacuum to get Aramchol methyl ester. The crude methyl ester is purified by Acetonitrile followed by mixture of toluene & acetonitrile.
Yield: 68 %, Purity by HPLC: 87%.
Example-3: Process for the preparation of Aramchol methyl ester (II)
A mixture of Pivaloyl chloride (3.4 g, 1.3 moles) and THF (10 mL) is added to the mixture of Arachidic acid (6.4 g, 0.95 mole), DBU (11.6 g, 3.5 moles) and THF (50 mL) at 0- 10°C. The resulting reaction mixture is stirred for 1 hour at 0-10°C.
To the above reaction mass, 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester hydrochloride (10 g, 1.0 mole) is added in lot wise at 25-35°C. The temperature of the reaction mass is raised to 35±3°C and stirred for 2-4 hours to complete the reaction, after completion of the reaction, organic layer is washed with water and distilled the solvent completely under vacuum to get Aramchol methyl ester. The crude methyl ester is purified by Acetonitrile followed by mixture of toluene & acetonitrile.
Yield: 68%, Purity by HPLC: 86%.
Example-4: Process for the preparation Aramchol methyl ester (II)
Pivaloyl chloride (3.4 g, 1.3 moles) is added to the mixture of Arachidic acid (6.8 g, 1.0 mole), Toluene (50 mL), Triethylamine (3.4 g, 1.5 moles) at 0-10°C. The resulting reaction mixture is stirred for 1 hour at 0-10°C. The temperature of reaction mass is raised to 25-35°C and charged Triethylamine (4.4 g, 2.5 moles).
To the above reaction mass 3[3-amino-7a,12a-dihyroxy-5[3-cholan-24-oic methyl ester hydrochloride (10 g, 1.0 mole) is added in lot wise at 25-35°C and stirred for 1-2 hours. After completion of the reaction, the organic layer is washed with water and distilled the solvent completely under vacuum to get Aramchol methyl ester. The crude methyl ester is purified by Acetonitrile followed by mixture of toluene & acetonitrile.
Yield: 71 %, Purity by HPLC: 99%.
Example-5: Process for the preparation Aramchol
Aramchol methyl ester (23 g, 1.0 mole) is hydrolysed by using methanol (230 mL), water (92 mL) and sodium hydroxide (3.85 g, 3.0 moles) at 40-45°C. The reaction mass is distilled under vacuum, charged water (230 mL) and washed with ethyl acetate twice (115 mL). The Aramchol is isolated by adjusting aqueous layer pH with dilute HCI.
Yield: 90%, Purity by HPLC: 99%.
Example-6: Process for the preparation Aramchol
Aramchol methyl ester (10 g, 1.0 mole) is hydrolysed by using ethanol (50 mL), water (20 mL) and sodium hydroxide (1.6 g, 3.0 moles) at 40-45°C. The reaction mass is
distilled under vacuum, charged water (100 mL) and washed with ethyl acetate twice (100 mL). The Aramchol is isolated by adjusting aqueous layer pH with dilute HCI.
Yield: 90%, Purity by HPLC: 99%. Example-7: Process for the preparation Aramchol Meglumine
The mixture of Aramchol (25 g, 1 mole) and Meglumine (7.0, 1 mole) was dissolved in methanol (100 mL) by maintain the reaction mixture at 60-65°C. The reaction mass is filtered and concentrated under vacuum. The reaction mass residue is dissolved in methanol (25 mL), water (25 mL) at 40-45°C and added acetone (100 mL). Stirred the reaction mass for 1-2 hours at 25-30°C and filtered the product.
Yield: 87%, Purity by HPLC: 99.6%.
Claims
1. A process for the preparation of Aramchol of formula (I) or its pharmaceutically acceptable salts:
Formula V with an acid chloride reagent in the presence of solvent and base to produce arachidic acid anhydride of formula (IV);
Formula IV wherein R is an aliphatic alkyl group or O-alkyl group, whereas each of said alkyl groups comprises a methyl, ethyl, tert-butyl or isopropyl group; ii. condensation of said compound of formula (IV) with a compound of formula (III)
Formula II iii. hydrolysis of said aramchol methyl ester of Formula (II) in the presence of base and solvent to obtain Aramchol of formula (I)
iv. optionally converting Aramchol of formula (I) to a pharmaceutically acceptable salt thereof. The process according to claim 1 , wherein the acid chloride reagent is selected from a group of acid chloride reagents comprising acetyl chloride, pivaloyl chloride, propionyl chloride, isobutyryl chloride, methyl chloroformate and ethyl chloroformate.
The process according to claim 1 or 2, wherein the suitable solvent in step (i) and step (ii) is selected from a group comprising polar aprotic solvents, comprising dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetra hydrofuran (THF), 1 ,4-dioxane, acetonitrile, acetone, and mixtures thereof; and non-polar solvents, comprising hexane, toluene, diisopropyl ether, methyl t-butyl ether, methylene chloride, ethyl acetate and mixtures thereof. The process according to anyone of the preceding claims, wherein the suitable base in step (i) is selected from a group of organic bases, wherein said group of organic bases comprises triethylamine, diisopropylamine, diisopropylethylamine, pyridine, Dimethylamino pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof. The process according to anyone of the preceding claims, wherein the suitable base in step (ii) is selected from a group of inorganic or organic bases, wherein, said inorganic bases comprise sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; and wherein said organic base comprise triethylamine, diisopropylamine, diisopropylethylamine, pyridine, dimethylamino pyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and mixtures thereof. The process according to anyone of the preceding claims, wherein the suitable solvent in step (iii) is selected from a group of polar protic solvents, comprising water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. The process according to anyone of the preceding claims, wherein the suitable base in step (iii) is selected from a group of inorganic bases, comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide and mixtures thereof.
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