WO2021053476A1 - Process for preparation of diroximel fumarate - Google Patents
Process for preparation of diroximel fumarate Download PDFInfo
- Publication number
- WO2021053476A1 WO2021053476A1 PCT/IB2020/058454 IB2020058454W WO2021053476A1 WO 2021053476 A1 WO2021053476 A1 WO 2021053476A1 IB 2020058454 W IB2020058454 W IB 2020058454W WO 2021053476 A1 WO2021053476 A1 WO 2021053476A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- solvent
- fumarate
- reaction
- Prior art date
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- YIMYDTCOUQIDMT-SNAWJCMRSA-N diroximel fumarate Chemical compound COC(=O)\C=C\C(=O)OCCN1C(=O)CCC1=O YIMYDTCOUQIDMT-SNAWJCMRSA-N 0.000 title claims abstract description 99
- 229950008803 diroximel fumarate Drugs 0.000 title claims abstract description 98
- 238000000034 method Methods 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 239000007962 solid dispersion Substances 0.000 claims abstract description 30
- 239000003937 drug carrier Substances 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
- 239000000203 mixture Substances 0.000 claims description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 239000002904 solvent Substances 0.000 claims description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 49
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 48
- NKHAVTQWNUWKEO-UHFFFAOYSA-N fumaric acid monomethyl ester Natural products COC(=O)C=CC(O)=O NKHAVTQWNUWKEO-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 40
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 36
- NKHAVTQWNUWKEO-NSCUHMNNSA-N monomethyl fumarate Chemical compound COC(=O)\C=C\C(O)=O NKHAVTQWNUWKEO-NSCUHMNNSA-N 0.000 claims description 32
- 229940005650 monomethyl fumarate Drugs 0.000 claims description 32
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 30
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000012535 impurity Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 150000002148 esters Chemical class 0.000 claims description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 19
- -1 HBTU Chemical compound 0.000 claims description 19
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 17
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 17
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 16
- 150000002170 ethers Chemical class 0.000 claims description 15
- 239000001530 fumaric acid Substances 0.000 claims description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 14
- 150000008282 halocarbons Chemical class 0.000 claims description 14
- NKHAVTQWNUWKEO-IHWYPQMZSA-N methyl hydrogen fumarate Chemical compound COC(=O)\C=C/C(O)=O NKHAVTQWNUWKEO-IHWYPQMZSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- 150000002825 nitriles Chemical class 0.000 claims description 12
- 229930195733 hydrocarbon Natural products 0.000 claims description 11
- 150000002430 hydrocarbons Chemical class 0.000 claims description 11
- 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 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 9
- 239000007822 coupling agent Substances 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 229960000549 4-dimethylaminophenol Drugs 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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- 150000002576 ketones Chemical class 0.000 claims description 7
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000001856 Ethyl cellulose Substances 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 229920001249 ethyl cellulose Polymers 0.000 claims description 6
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 229920000858 Cyclodextrin Polymers 0.000 claims description 5
- RDWDVLFMPFUBDV-PXMDEAMVSA-N [(e)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-tripyrrolidin-1-ylphosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(O/N=C(C(=O)OCC)\C#N)N1CCCC1 RDWDVLFMPFUBDV-PXMDEAMVSA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 239000012296 anti-solvent Substances 0.000 claims description 5
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 claims description 4
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 claims description 3
- OOWSDKUFKGVADH-UHFFFAOYSA-N 1-diphenylphosphoryloxy-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 OOWSDKUFKGVADH-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims 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 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- KPFBUSLHFFWMAI-HYRPPVSQSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-6-formyl-3-methoxy-10,13-dimethyl-1,2,7,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1C[C@@H]2[C@](CCC(OC)=C3)(C)C3=C(C=O)C[C@H]2[C@@H]2CC[C@](OC(C)=O)(C(C)=O)[C@]21C KPFBUSLHFFWMAI-HYRPPVSQSA-N 0.000 claims description 3
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 claims description 3
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims description 3
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 3
- 239000012973 diazabicyclooctane Substances 0.000 claims description 3
- 150000002191 fatty alcohols Chemical class 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 229920000591 gum Polymers 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 3
- 229960003194 meglumine Drugs 0.000 claims description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 229940069328 povidone Drugs 0.000 claims description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 150000005846 sugar alcohols Polymers 0.000 claims description 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 3
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 claims description 2
- 239000012317 TBTU Substances 0.000 claims description 2
- 241000289690 Xenarthra Species 0.000 claims description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 2
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims 1
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
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- 239000007787 solid Substances 0.000 description 20
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- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 12
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 10
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- TWYIPMITVXPNEM-UHFFFAOYSA-N 1-(2-hydroxyethyl)pyrrolidine-2,5-dione Chemical compound OCCN1C(=O)CCC1=O TWYIPMITVXPNEM-UHFFFAOYSA-N 0.000 description 8
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 7
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- 239000012044 organic layer Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
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- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
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- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 229960002317 succinimide Drugs 0.000 description 6
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
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- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 4
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
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- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 3
- 229940113088 dimethylacetamide Drugs 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- MOWUWAPJWBBZTN-ARJAWSKDSA-N (Z)-4-[2-(2,5-dioxopyrrolidin-1-yl)ethoxy]-4-oxobut-2-enoic acid Chemical compound O=C1N(C(CC1)=O)CCOC(\C=C/C(=O)O)=O MOWUWAPJWBBZTN-ARJAWSKDSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- NXRGKFVQYZGDIY-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1.CC1=CC=CC(C)=N1 NXRGKFVQYZGDIY-UHFFFAOYSA-N 0.000 description 2
- LPBHYOYZZIFCQT-UHFFFAOYSA-N 2-methylpropyl 2-(2-methylpropoxy)-2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC(C)C)C(OCC(C)C)C=CC2=C1 LPBHYOYZZIFCQT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FPQVGDGSRVMNMR-MXZHIVQLSA-N [[(e)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N\OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-MXZHIVQLSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940097362 cyclodextrins Drugs 0.000 description 2
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- RJQRCOMHVBLQIH-UHFFFAOYSA-N pentane-1-sulfonic acid Chemical compound CCCCCS(O)(=O)=O RJQRCOMHVBLQIH-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 1
- HJBLUNHMOKFZQX-UHFFFAOYSA-N 3-hydroxy-1,2,3-benzotriazin-4-one Chemical compound C1=CC=C2C(=O)N(O)N=NC2=C1 HJBLUNHMOKFZQX-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- 229920002535 Polyethylene Glycol 1500 Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 1
- 229920003082 Povidone K 90 Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HBQDCKPPSIWZLY-UHFFFAOYSA-M [dimethylamino-(2-oxopyridin-1-yl)oxymethylidene]-dimethylazanium;trifluoroborane;fluoride Chemical compound [F-].FB(F)F.CN(C)C(=[N+](C)C)ON1C=CC=CC1=O HBQDCKPPSIWZLY-UHFFFAOYSA-M 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- LCFXLZAXGXOXAP-QPJJXVBHSA-N ethyl (2e)-2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=N\O)\C#N LCFXLZAXGXOXAP-QPJJXVBHSA-N 0.000 description 1
- LCFXLZAXGXOXAP-DAXSKMNVSA-N ethyl (2z)-2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=N/O)\C#N LCFXLZAXGXOXAP-DAXSKMNVSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- XCJJBOLVQRGEQJ-SQQVDAMQSA-N furan-2,5-dione (E)-4-methoxy-4-oxobut-2-enoic acid Chemical compound O=C1OC(=O)C=C1.COC(=O)\C=C\C(O)=O XCJJBOLVQRGEQJ-SQQVDAMQSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 238000010951 particle size reduction Methods 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- VUYXVWGKCKTUMF-UHFFFAOYSA-N tetratriacontaethylene glycol monomethyl ether Chemical compound COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO VUYXVWGKCKTUMF-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
Definitions
- the present invention relates to a process for the preparation of diroximel fumarate.
- the present invention relates to amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation.
- Diroximel fumarate also known as, 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate, is represented by the structure of formula I.
- Diroximel fumarate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS).
- the present invention provides a process for the preparation of diroximel fumarate, a compound of formula I, the process comprising: (a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV; (b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and (c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III, to give diroximel fumarate, the compound of formula I.
- the present invention provides an amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier.
- the present invention provides a process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising: (a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and (b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a).
- Figure 1 is a characteristic XRPD of crystalline diroximel fumarate as obtained in Example 3.
- Figure 2 is a DSC thermogram of crystalline diroximel fumarate as obtained in Example 3.
- Figure 3 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and polyvinyl pyrrolidone as obtained in Example 4.
- Figure 4 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and hydroxypropyl methylcellulose phthalate as obtained in Example 5.
- Figure 5 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and hydroxypropyl methylcellulose phthalate as obtained in Example 6.
- Figure 6 is a characteristic XRPD of crystalline diroximel fumarate as obtained in Example 11.
- the present invention provides a process for the preparation of diroximel fumarate, a compound of formula I, the process comprising: (a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV; (b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and (c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III, to give diroximel fumarate, the compound of formula I.
- room temperature means a temperature of about 25°C to about 30°C.
- maleic anhydride is reacted with methanol to give monomethyl maleate, the compound of formula IV.
- the reaction of maleic anhydride with methanol occurs in the presence of a solvent.
- the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
- the solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; and mixtures thereof.
- hydrocarbons such as toluene,
- the reaction of maleic anhydride with methanol occurs in the presence of a solvent, wherein the solvent is toluene. [0021] In one embodiment, the reaction of maleic anhydride with methanol occurs in the absence of a solvent. [0022] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 4. [0023] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 3. [0024] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 2.5.
- the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 2. [0026] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 1, about 1 to 1.05, about 1 to 1.1, about 1 to 1.15, about 1 to 1.2, about 1 to 1.25, about 1 to 1.3, about 1 to 1.35, about 1 to 1.4, about 1 to 1.45, about 1 to 1.5, about 1 to 1.55, about 1 to 1.6, about 1 to 1.65, about 1 to 1.7, about 1 to 1.75, about 1 to 1.8, about 1 to 1.85, about 1 to 1.9, about 1 to 1.95, about 1 to 2, about 1 to 2.05, about 1 to 2.1, about 1 to 2.15, about 1 to 2.2, about 1 to 2.25, about 1 to
- the molar ratio of maleic anhydride to methanol is in the range of about 1 to 1 to about 1 to 4. [0028] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 3. [0029] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 2. [0030] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C.
- the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C, about 25°C to about 80°C, about 30°C to about 80°C, about 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 70°C, about 50°C to about 65°C.
- the reaction of maleic anhydride with methanol occurs at a temperature of about 40°C to about 75°C.
- the reaction of maleic anhydride with methanol occurs at a temperature of about 50°C to about 70°C.
- the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 12 hours. [0035] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 6 hours. [0036] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 4 hours. [0037] In one embodiment, monomethyl maleate, the compound of formula IV obtained in step (a) is isolated. [0038] In one embodiment, the compound of formula IV obtained in step (a) is isolated by removing the solvent. [0039] In one embodiment, removal of solvent may be accomplished by substantially complete evaporation of the solvent.
- the solvent may be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.
- the compound of formula IV is reacted with thionyl chloride to give monomethyl fumarate, the compound of formula II.
- the compound of formula IV obtained in step (a) is isolated and then reacted with thionyl chloride.
- the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent.
- the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
- the solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate,
- the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent, wherein the solvent is toluene.
- the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 1.
- the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01, about 1 to 0.015, about 1 to 0.02, about 1 to 0.025, about 1 to 0.03, about 1 to 0.035, about 1 to 0.04, about 1 to 0.045, about 1 to 0.05, about 1 to 0.055, about 1 to 0.06, about 1 to 0.065, about 1 to 0.07, about 1 to 0.075, about 1 to 0.08, about 1 to 0.085, about 1 to 0.09, about 1 to 0.095, about 1 to 0.10, about 1 to 0.15, about 1 to 0.20, about 1 to 0.25, about 1 to 0.30, about 1 to 0.35, about 1 to 0.40, about 1 to 0.45, about 1 to 0.50, about 1 to 0.55, about 1 to 0.60, about 1 to 0.65, about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95
- the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 0.1.
- the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C.
- the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C, about 60°C to about 100°C, about 60°C to about 90°C, about 70°C to about 90°C, about 75°C to about 90°C.
- the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 70°C to about 100°C. [0052] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 75°C to about 95°C. [0053] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 80°C to about 90°C. [0054] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 24 hours.
- the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 12 hours. [0056] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 8 hours. [0057] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 6 hours. [0058] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is isolated by crystallization from a solvent selected from ethyl acetate, toluene, methanol, water, or mixtures thereof.
- monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.15%.
- monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.10%.
- monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.05%.
- monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.15%.
- monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.10%.
- monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.05%.
- step (c) of the process for the preparation of diroximel fumarate monomethyl fumarate
- the compound of formula II is reacted with the compound of formula III to give diroximel fumarate.
- monomethyl fumarate the compound of formula II obtained in step (b) in a purity of at least 99.0% with the level of fumaric acid or dimethyl fumarate less than 0.15%, is reacted with the compound of formula III to give diroximel fumarate.
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent.
- the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof.
- the solvent is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, n-propyl
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent, wherein the solvent is dichloromethane.
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent selected from the group consisting of TsCl (p-toluenesulfonyl chloride), HBTU (N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1- yl)uronium hexafluorophosphate), EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), HOBt (hydroxybenzotriazole hydrate), COMU ((1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate),
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent, wherein the coupling agent is EDCI.
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent, wherein the coupling agent is TsCl.
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from organic base or inorganic base.
- the organic base includes but is not limited to diisopropylethylamine, trimethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, oxyma (ethyl cyanohydroxyiminoacetate), or mixtures thereof.
- the inorganic base includes but is not limited to lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or mixtures thereof.
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8- diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-
- the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base, wherein the coupling agent is DMAP, sodium carbonate, or mixtures thereof.
- the diroximel fumarate obtained in step (c) is isolated from a solvent selected from the group consisting of esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; water; and mixtures thereof.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of impurity A is less than 0.15%.
- monomethyl fumarate, the compound of formula II obtained in step (b) in a purity of at least 99.0% with the level of fumaric acid less than 0.15% is reacted with the compound of formula III to give diroximel fumarate in a purity of 399.0% with the level of impurity A less than 0.15%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of impurity is less than 0.10%. [0084] In one embodiment, the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of impurity A is less than 0.05%. [0085] In one embodiment, the diroximel fumarate is obtained in a purity of 399.0% and wherein the impurity A is not detected. [0086] In one embodiment, the diroximel fumarate is obtained in a purity of 399.5% and wherein the level of impurity A is less than 0.15%.
- the diroximel fumarate is obtained in a purity of 399.5% and wherein the level of impurity A is less than 0.10%. [0088] In one embodiment, the diroximel fumarate is obtained in a purity of 399.5% and wherein the level of impurity A is less than 0.05%. [0089] In one embodiment, the diroximel fumarate is obtained in a purity of 399.8% and wherein the level of impurity A is less than 0.15%. [0090] In one embodiment, the diroximel fumarate is obtained in a purity of 399.8% and wherein the level of impurity A is less than 0.10%.
- the diroximel fumarate is obtained in a purity of 399.8% and wherein the level of impurity A is less than 0.05%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of impurity B is less than 0.15%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.15%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.10%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.05%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of compound of III or monomethyl fumarate is less than 0.15%.
- the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of compound of III or monomethyl fumarate is less than 0.10%. [0099] In one embodiment, the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of impurity C or impurity D or impurity E or impurity F is less than 0.15%. [0100] In one embodiment, the diroximel fumarate is obtained in a purity of 399.0% and wherein the level of impurity C or impurity D or impurity E or impurity F is less than 0.10%.
- the present invention provides diroximel fumarate obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below: [0104] Reagents and Solvents: Perchloric acid (AR grade), Pentane-1-sulfonic acid Na salt (AR grade), Methanol (Gradient Grade), Water (Milli Q or equivalent), Acetonitrile (Gradient Grade) [0105] Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
- the compound of formula III is prepared by reacting succinimide with ethylene carbonate.
- the compound of formula III is prepared by reacting succinimide with ethylene carbonate in the presence of a base.
- the reaction of succinimide with ethylene carbonate occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, DMAP (4- (dimethylamino)pyridine), and mixtures thereof.
- the compound of formula III is isolated.
- the compound of formula III is isolated by removing the solvent. [0111] In one embodiment, the compound of formula III is isolated as a residue. [0112] In one embodiment, the compound of formula III is not isolated. [0113] In one embodiment, the compound of formula III is dissolved in a solvent selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof. [0114] In one embodiment, the compound of formula III dissolved in a solvent is reacted with the compound of formula II to give diroximel fumarate.
- the present invention provides an amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier is selected from a group consisting of one or more of a povidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose-acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids.
- Useful pyrrolidones include, but are not limited to homopolymers or copolymers of N-vinylpyrrolidone. Such polymers can form complexes with a variety of compounds.
- the water-soluble forms of N-vinylpyrrolidone are available in a variety of viscosity and molecular weight grades such as but not limited to PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-90, PVP K-120 and crospovidone.
- Polyethylene glycols, condensation polymers of ethylene oxide and water are commercially available from various manufacturers in average molecular weights ranging from about 300 to about 10,000,000 Daltons.
- the grades that are useful in the present invention include, but are not limited to, PEG 1500, PEG 4000, PEG 6000, PEG 8000.
- the pharmaceutically acceptable carrier is polyvinyl pyrrolidone.
- the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose phthalate.
- the present invention provides an amorphous solid dispersion comprising diroximel fumarate with polyvinyl pyrrolidone.
- the present invention provides an amorphous solid dispersion comprising diroximel fumarate with polyvinyl pyrrolidone which is substantially in accordance with Figure 2. [0124] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate. [0125] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate which is substantially in accordance with Figure 3. [0126] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate which is substantially in accordance with Figure 4.
- the present invention provides a process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising: (a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and (b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a).
- the step (a) of providing a solution or mixture of diroximel fumarate or salt thereof for the preparation of amorphous solid dispersion involves mixing with at least one pharmaceutically acceptable carrier as described herein above with a suitable solvent.
- the solvent is selected from the group consisting of ethers, ketones, esters, halogenated hydrocarbons, amides, alcohols, water, and mixtures thereof.
- the solvent is selected from the group consisting of ethers such as such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; amides such as dimethylformamide, dimethyl acetamide and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol,
- the step (b) of obtaining the amorphous solid dispersion comprises: (i) removing the solvent from the solution or mixture obtained in (a); or (ii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
- the removal of solvent in (b) (i) may be carried out by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.
- removal of solvent in (b) (i) may be carried out by spray drying.
- removal of solvent in (b) (i) may be carried out by solvent distillation, preferably under vacuum.
- the anti-solvent used in (b) (ii) is a solvent which on addition to the solution of step (a) causes precipitation of amorphous solid dispersion of diroximel fumarate with at least one pharmaceutically acceptable carrier.
- the anti-solvent is selected from the group consisting of ethers such as such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; amides such as dimethylformamide, dimethyl acetamide and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propan
- the amorphous solid dispersion of diroximel fumarate with at least one pharmaceutically acceptable carrier prepared using the process of the present invention contains diroximel fumarate in amorphous form together with at least one pharmaceutically acceptable carrier.
- the present invention provides an amorphous diroximel fumarate.
- the present invention provides pharmaceutical compositions comprising diroximel fumarate or salt thereof obtained by the processes herein described, having a D 90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
- the present invention provides pharmaceutical compositions comprising diroximel fumarate or salt thereof obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
- the particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state diroximel fumarate or salt thereof into any of the foregoing desired particle size range.
- the examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
- EXAMPLE 1 Preparation of monomethyl fumarate Maleic anhydride (20g) was added in toluene (40mL) and methanol (13.05g) by maintaining temperature at about 42°C to about 55°C. The reaction mixture was maintained at about 50°C to about 60°C for about 2h. The solvent was distilled out and the reaction mixture was stripped out with toluene. To the obtained residue, toluene (80mL) was added, followed by thionyl chloride (2.43g). The reaction mixture was maintained at about 80°C to about 90°C for about 2h. The reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered.
- EXAMPLE 2 Preparation of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione A mixture of ethylene carbonate (10g), succinimide (10.06g) and triethylamine (2g) was heated at about 90°C to about 100°C for about 6h. Traces of triethylamine were distilled out. Ethyl acetate and cyclohexane were added to the reaction mixture. The reaction mixture was stirred and filtered. The solid obtained was dried.
- EXAMPLE 3 Preparation of diroximel fumarate To a mixture of monomethyl fumarate (12g), 1-(2-hydroxyethyl)-2,5-pyrrolidinedione (17.1g) and DMAP (0.6g) in dichloromethane (120mL), cooled to about below 10°C, EDC.HCl (18.4g) was added. The reaction mixture was stirred and heated to about 20°C to about 30°C for about 150min. Water was added to the reaction mixture and the two layers were separated. The organic layer was washed with sodium bicarbonate solution followed with dilute hydrochloric acid solution.
- the reaction mixture was cooled to about 20°C to about 30°C and toluene (50mL) was added to it.
- Acetyl chloride (0.45g) was added to the reaction mixture which was heated to about 80°C to about 85°C for about 5h.
- the reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered.
- the solid was washed with toluene and dried under vacuum at about 60°C for about 6h. Yield: 10.1g HPLC Purity: 97.32%; Fumaric acid content in monomethyl fumarate: 2.35%
- a mixture of the obtained solid (4g) in ethyl acetate (20mL) was heated at about 65°C to about 75°C for about 1h.
- the solution was filtered for particle free solution.
- the solvent was removed from the obtained solution by spray dryer.
- the solid obtained was dried in air tray dryer (ATD) at about 40°C for about 30 minutes. Yield: 85% Spray drying parameters: Carrier nitrogen flow 2.0kg/cm 2 , inlet temperature 48°C, outlet temperature 75°C, feed rate 16rpm, aspirator 1700rpm and vacuum 250mm Hg.
- EXAMPLE 5 Preparation of amorphous solid dispersion of diroximel fumarate with hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) Diroximel fumarate (0.25g) and hydroxypropyl methylcellulose phthalate (1.5g) were dissolved in methanol and dichloromethane (1:1v/v) solvent mixture (50mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The obtained clear solution was distilled off under high vacuum at about 50°C using rotavapour. The solid obtained was dried on rotavapour at about 50°C for about 30 minutes.
- HPMC-Phthalate hydroxypropyl methylcellulose phthalate
- EXAMPLE 6 Preparation of amorphous solid dispersion of diroximel fumarate with hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) Diroximel fumarate (0.25g) and hydroxypropyl methylcellulose phthalate (0.75g) were dissolved in methanol and dichloromethane (1:1v/v) solvent mixture (50mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The obtained clear solution was distilled off under high vacuum at about 50°C using rotavapour. The solid obtained was dried on rotavapour at about 50°C for about 30 minutes.
- HPMC-Phthalate hydroxypropyl methylcellulose phthalate
- EXAMPLE 7 Preparation of diroximel fumarate A mixture of ethylene carbonate (47.38g), succinimide (49.5g) and triethylamine (10.11g) was heated at about 85°C to about 95°C for about 6h. The reaction mixture was cooled to about 50°C to about 60°C and concentrated. To the obtained residue, dichloromethane (150mL) was added (solution of 1-(2-hydroxyethyl)-2, 5-pyrrolidinedione in dichloromethane).
- EXAMPLE 9 Preparation of impurity B To a mixture of 1-(2-hydroxyethyl)-2, 5-pyrrolidinedione (50g) in acetone (150mL), was added maleic anhydride (34.93g) followed by triethylamine (1.45g). The reaction mixture was heated to about 40°C to about 45°C for about 6h.
- EXAMPLE 10 Preparation of diroximel fumarate A mixture of ethylene carbonate (9.4g), succinimide (9.9g) and triethylamine (2g) was heated at about 80°C to about 85°C for about 12h. After the reaction was completed, the reaction mixture was cooled to about 60°C to about 65°C and concentrated under vacuum NLT 650 mmHg at about below 65°C for about 30min to obtain residue.
- dichloromethane (4mL) was added (solution of 1-(2-hydroxyethyl)-2, 5-pyrrolidinedione in dichloromethane).
- solution of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione in dichloromethane and dimethyl amino pyridine (0.5g) was added at about 20°C to about 30°C temperature.
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Abstract
The present invention relates to a process for the preparation of diroximel fumarate, a compound of formula I. The present invention relates to amorphous solid dispersion comprising diroximel fumarate, a compound of formula I or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation.
Description
PROCESS FOR PREPARATION OF DIROXIMEL FUMARATE PRIORITY [0001] This application claims the benefit of Indian Provisional Applications 201921037120 filed on September 16, 2019 and 201921042111 filed on October 17, 2019, entitled “PROCESS FOR PREPARATION OF DIROXIMEL FUMARATE”, the contents of which are incorporated herein by reference. FIELD OF THE INVENTION [0002] The present invention relates to a process for the preparation of diroximel fumarate. The present invention relates to amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation. BACKGROUND OF THE INVENTION [0003] Diroximel fumarate, also known as, 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl fumarate, is represented by the structure of formula I.
[0004] Diroximel fumarate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). SUMMARY OF THE INVENTION [0005] The present invention provides a process for the preparation of diroximel fumarate, a compound of formula I,
the process comprising: (a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV;
(b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and
(c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III,
to give diroximel fumarate, the compound of formula I. [0006] In another embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier. [0007] In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising: (a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and (b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a). BRIEF DESCRIPTION OF THE DRAWINGS [0008] Figure 1 is a characteristic XRPD of crystalline diroximel fumarate as obtained in Example 3.
[0009] Figure 2 is a DSC thermogram of crystalline diroximel fumarate as obtained in Example 3. [0010] Figure 3 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and polyvinyl pyrrolidone as obtained in Example 4. [0011] Figure 4 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and hydroxypropyl methylcellulose phthalate as obtained in Example 5. [0012] Figure 5 is a characteristic XRPD of amorphous solid dispersion comprising diroximel fumarate and hydroxypropyl methylcellulose phthalate as obtained in Example 6. [0013] Figure 6 is a characteristic XRPD of crystalline diroximel fumarate as obtained in Example 11. DETAILED DESCRIPTION OF THE INVENTION [0014] The present invention provides a process for the preparation of diroximel fumarate, a compound of formula I,
the process comprising: (a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV;
(b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and
(c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III,
to give diroximel fumarate, the compound of formula I. [0015] In the present application, the term “room temperature” means a temperature of about 25°C to about 30°C. [0016] In (a) of the process for the preparation of diroximel fumarate, maleic anhydride is reacted with methanol to give monomethyl maleate, the compound of formula IV. [0017] In one embodiment, the reaction of maleic anhydride with methanol occurs in the presence of a solvent. [0018] In one embodiment, the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof. [0019] In one embodiment, the solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; and mixtures thereof. [0020] In one embodiment, the reaction of maleic anhydride with methanol occurs in the presence of a solvent, wherein the solvent is toluene. [0021] In one embodiment, the reaction of maleic anhydride with methanol occurs in the absence of a solvent. [0022] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 4. [0023] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 3. [0024] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 2.5.
[0025] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 2. [0026] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 1, about 1 to 1.05, about 1 to 1.1, about 1 to 1.15, about 1 to 1.2, about 1 to 1.25, about 1 to 1.3, about 1 to 1.35, about 1 to 1.4, about 1 to 1.45, about 1 to 1.5, about 1 to 1.55, about 1 to 1.6, about 1 to 1.65, about 1 to 1.7, about 1 to 1.75, about 1 to 1.8, about 1 to 1.85, about 1 to 1.9, about 1 to 1.95, about 1 to 2, about 1 to 2.05, about 1 to 2.1, about 1 to 2.15, about 1 to 2.2, about 1 to 2.25, about 1 to 2.3, about 1 to 2.35, about 1 to 2.4, about 1 to 2.45, about 1 to 2.5, about 1 to 2.6, about 1 to 2.7, about 1 to 2.8, about 1 to 2.9, about 1 to 3, about 1 to 4. [0027] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 1 to about 1 to 4. [0028] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 3. [0029] In one embodiment, the molar ratio of maleic anhydride to methanol is in the range of about 1 to 2. [0030] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C. [0031] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C, about 25°C to about 80°C, about 30°C to about 80°C, about 40°C to about 75°C, about 45°C to about 70°C, about 50°C to about 70°C, about 50°C to about 65°C. [0032] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 40°C to about 75°C. [0033] In one embodiment, the reaction of maleic anhydride with methanol occurs at a temperature of about 50°C to about 70°C. [0034] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 12 hours.
[0035] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 6 hours. [0036] In one embodiment, the reaction of maleic anhydride with methanol occurs over a period of about 1 hour to about 4 hours. [0037] In one embodiment, monomethyl maleate, the compound of formula IV obtained in step (a) is isolated. [0038] In one embodiment, the compound of formula IV obtained in step (a) is isolated by removing the solvent. [0039] In one embodiment, removal of solvent may be accomplished by substantially complete evaporation of the solvent. The solvent may be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg. [0040] In (b) of the process for the preparation of diroximel fumarate, monomethyl maleate, the compound of formula IV is reacted with thionyl chloride to give monomethyl fumarate, the compound of formula II. [0041] In one embodiment, the compound of formula IV obtained in step (a) is isolated and then reacted with thionyl chloride. [0042] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent. [0043] In one embodiment, the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof. [0044] In one embodiment, the solvent is selected from the group consisting of hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ethylene dichloride, and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; and mixtures thereof. [0045] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent, wherein the solvent is toluene.
[0046] In one embodiment, the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 1. [0047] In one embodiment, the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01, about 1 to 0.015, about 1 to 0.02, about 1 to 0.025, about 1 to 0.03, about 1 to 0.035, about 1 to 0.04, about 1 to 0.045, about 1 to 0.05, about 1 to 0.055, about 1 to 0.06, about 1 to 0.065, about 1 to 0.07, about 1 to 0.075, about 1 to 0.08, about 1 to 0.085, about 1 to 0.09, about 1 to 0.095, about 1 to 0.10, about 1 to 0.15, about 1 to 0.20, about 1 to 0.25, about 1 to 0.30, about 1 to 0.35, about 1 to 0.40, about 1 to 0.45, about 1 to 0.50, about 1 to 0.55, about 1 to 0.60, about 1 to 0.65, about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 0.10, about 1 to 0.15, about 1 to 0.20, about 1 to 0.25, about 1 to 0.30, about 1 to 0.35, about 1 to 0.40, about 1 to 0.45, about 1 to 0.50, about 1 to 0.55, about 1 to 0.60, about 1 to 0.65, about 1 to 0.70, about 1 to 0.75, about 1 to 0.80, about 1 to 0.85, about 1 to 0.90, about 1 to 0.95, about 1 to 1. [0048] In one embodiment, the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 0.1. [0049] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C. [0050] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C, about 60°C to about 100°C, about 60°C to about 90°C, about 70°C to about 90°C, about 75°C to about 90°C. [0051] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 70°C to about 100°C. [0052] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 75°C to about 95°C. [0053] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 80°C to about 90°C. [0054] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 24 hours. [0055] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 12 hours.
[0056] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 8 hours. [0057] In one embodiment, the reaction of the compound of formula IV with thionyl chloride occurs over a period of about 1 hour to about 6 hours. [0058] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is isolated by crystallization from a solvent selected from ethyl acetate, toluene, methanol, water, or mixtures thereof. [0059] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.15%. [0060] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.10%. [0061] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.05%. [0062] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.15%. [0063] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.10%. [0064] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of monomethyl maleate or dimethyl maleate or dimethyl fumarate is less than 0.05%. [0065] In (c) of the process for the preparation of diroximel fumarate, monomethyl fumarate, the compound of formula II is reacted with the compound of formula III to give diroximel fumarate.
[0066] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) in a purity of at least 99.0% with the level of fumaric acid or dimethyl fumarate less than 0.15%, is reacted with the compound of formula III to give diroximel fumarate. [0067] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent. [0068] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof. [0069] In one embodiment, the solvent is selected from the group consisting of halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; nitriles such as acetonitrile, benzonitrile and the like; amides such as dimethylformamide, dimethyl acetamide and the like; sulfoxides such as dimethyl sulfoxide; and mixtures thereof. [0070] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent, wherein the solvent is dichloromethane. [0071] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent selected from the group consisting of TsCl (p-toluenesulfonyl chloride), HBTU (N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1- yl)uronium hexafluorophosphate), EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), HOBt (hydroxybenzotriazole hydrate), COMU ((1-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate), TBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TATU (O- (7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate), Oxyma (ethyl (hydroxyimino)cyanoacetate), PyBOP ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), HOTT (S-(1-oxido-2-pyridyl)-N,N,N',N'-tetramethylthiuronium hexafluorophosphate), FDPP (pentafluorophenyl diphenylphosphinate), T3P (propylphosphonic anhydride), DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium tetrafluoroborate), PyOxim ([ethyl cyano(hydroxyimino)acetato-
O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), TSTU (N,N,N,N-tetramethyl-O- (N-succinimidyl)uronium tetrafluoroborate), TDBTU (O-(3,4-dihydro-4-oxo-1,2,3- benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TPTU (O-(2-oxo-1 (2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), TOTU (O- [(ethoxycarbonyl)cyanomethylenamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate), IIDQ (isobutyl 1,2-dihydro-2-isobutoxy-1-quinolinecarboxylate), PyCIU (chlorodipyrrolidinocarbenium hexafluorophosphate), DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), TOTT (N,N,N',N'-tetramethyl-S-(1-oxido-2- pyridyl)thiouronium tetrafluoroborate), EEDQ (N-Ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline), HDMC (N-[(5-Chloro-3-oxido-1H-benzotriazol-1-yl)-4- morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate), HCTU (2-(6- chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), PyOxim (ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate), PyAOP ((7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), HOOBt (hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine), HOSu (N-hydroxysuccinimide), HOAt (1-hydroxy-7-azabenzotriazole), TFFH (tetramethylfluoroformamidinium hexafluorophosphate), and mixtures thereof. [0072] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent, wherein the coupling agent is EDCI. [0073] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent, wherein the coupling agent is TsCl. [0074] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from organic base or inorganic base. [0075] The organic base includes but is not limited to diisopropylethylamine, trimethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN
(1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'-tetramethyl-1,8-naphthalenediamine, oxyma (ethyl cyanohydroxyiminoacetate), or mixtures thereof. [0076] The inorganic base includes but is not limited to lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or mixtures thereof. [0077] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine (2,6-dimethylpyridine), collidine (2,4,6-trimethylpyridine), imidazole, DMAP (4-(dimethylamino)pyridine), DABCO (1,4-diazabicyclo[2.2.2]octane), DBU (1,8- diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), N,N,N',N'- tetramethyl-1,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. [0078] In one embodiment, the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base, wherein the coupling agent is DMAP, sodium carbonate, or mixtures thereof. [0079] In one embodiment, the diroximel fumarate obtained in step (c) is isolated from a solvent selected from the group consisting of esters such as methyl acetate, ethyl acetate, n- propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile and the like; water; and mixtures thereof. [0080] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity A is less than 0.15%.
[0081] The presence of fumaric acid impurity in monomethyl fumarate, the compound of formula II, leads to the formation of impurity A in step (c) of the preparation of diroximel fumarate.
[0082] In one embodiment, monomethyl fumarate, the compound of formula II obtained in step (b) in a purity of at least 99.0% with the level of fumaric acid less than 0.15%, is reacted with the compound of formula III to give diroximel fumarate in a purity of ³99.0% with the level of impurity A less than 0.15%. [0083] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity is less than 0.10%. [0084] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity A is less than 0.05%. [0085] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the impurity A is not detected. [0086] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.5% and wherein the level of impurity A is less than 0.15%. [0087] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.5% and wherein the level of impurity A is less than 0.10%. [0088] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.5% and wherein the level of impurity A is less than 0.05%. [0089] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.8% and wherein the level of impurity A is less than 0.15%. [0090] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.8% and wherein the level of impurity A is less than 0.10%. [0091] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.8% and wherein the level of impurity A is less than 0.05%. [0092] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity B is less than 0.15%.
[0093] The presence of monomethyl maleate in monomethyl fumarate, the compound of formula II, leads to the formation of impurity B in step (c) of the preparation of diroximel fumarate. [0094] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.15%. [0095] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.10%. [0096] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of fumaric acid or dimethyl fumarate is less than 0.05%. [0097] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of compound of III or monomethyl fumarate is less than 0.15%. [0098] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of compound of III or monomethyl fumarate is less than 0.10%. [0099] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity C or impurity D or impurity E or impurity F is less than 0.15%.
[0100] In one embodiment, the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity C or impurity D or impurity E or impurity F is less than 0.10%. [0101] The presence of fumaric acid impurity in monomethyl fumarate, the compound of formula II, leads to the formation of impurity C in step (c) of the preparation of diroximel fumarate.
[0102] The presence of succinic acid impurity in monomethyl fumarate, the compound of formula II, leads to the formation of impurity D in step (c) of the preparation of diroximel fumarate. [0103] The present invention provides diroximel fumarate obtained by above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below: [0104] Reagents and Solvents: Perchloric acid (AR grade), Pentane-1-sulfonic acid Na salt (AR grade), Methanol (Gradient Grade), Water (Milli Q or equivalent), Acetonitrile (Gradient Grade) [0105] Chromatographic Conditions: Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software. Column: Zorbax SB C8250 X 4.6 mm, 5µ; Column temperature: 40°C Sample Cooler temperature: 10°C Mobile phase A = Buffer: Methanol (980:20, V/V); Buffer: Add 1.0 mL perchloric acid and 0.4 g of Pentane-1-sulfonic acid Na salt in 1000 mL of water Mobile Phase B: Buffer: Methanol (500:500, V/V)
Diluent: Water: Acetonitrile (980:20, V/V) Flow Rate: 1.0 mL/minute Detection: UV 210 nm Injection Volume: 40µL Run time: 120 minutes Needle wash: Acetonitrile (100%) The retention time of diroximel fumarate is about 58.0 minutes under these conditions.
[0106] In one embodiment, the compound of formula III is prepared by reacting succinimide with ethylene carbonate. [0107] In one embodiment, the compound of formula III is prepared by reacting succinimide with ethylene carbonate in the presence of a base. [0108] In one embodiment, the reaction of succinimide with ethylene carbonate occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, DMAP (4- (dimethylamino)pyridine), and mixtures thereof. [0109] In one embodiment, the compound of formula III is isolated. [0110] In one embodiment, the compound of formula III is isolated by removing the solvent. [0111] In one embodiment, the compound of formula III is isolated as a residue. [0112] In one embodiment, the compound of formula III is not isolated. [0113] In one embodiment, the compound of formula III is dissolved in a solvent selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof. [0114] In one embodiment, the compound of formula III dissolved in a solvent is reacted with the compound of formula II to give diroximel fumarate. [0115] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier. [0116] In one embodiment, the pharmaceutically acceptable carrier is selected from a group consisting of one or more of a povidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose-acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids. [0117] Useful pyrrolidones include, but are not limited to homopolymers or copolymers of N-vinylpyrrolidone. Such polymers can form complexes with a variety of compounds. The
water-soluble forms of N-vinylpyrrolidone are available in a variety of viscosity and molecular weight grades such as but not limited to PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-90, PVP K-120 and crospovidone. [0118] Polyethylene glycols, condensation polymers of ethylene oxide and water, are commercially available from various manufacturers in average molecular weights ranging from about 300 to about 10,000,000 Daltons. Some of the grades that are useful in the present invention include, but are not limited to, PEG 1500, PEG 4000, PEG 6000, PEG 8000. [0119] Among various cyclodextrins a-, b-, g- and e-cyclodextrins or their methylated or hydroxyalkylated derivatives may be used. [0120] In one embodiment, the pharmaceutically acceptable carrier is polyvinyl pyrrolidone. [0121] In one embodiment, the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose phthalate. [0122] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with polyvinyl pyrrolidone. [0123] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with polyvinyl pyrrolidone which is substantially in accordance with Figure 2. [0124] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate. [0125] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate which is substantially in accordance with Figure 3. [0126] In one embodiment, the present invention provides an amorphous solid dispersion comprising diroximel fumarate with hydroxypropyl methylcellulose phthalate which is substantially in accordance with Figure 4. [0127] In one embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising: (a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and
(b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a). [0128] In one embodiment, the step (a) of providing a solution or mixture of diroximel fumarate or salt thereof for the preparation of amorphous solid dispersion, involves mixing with at least one pharmaceutically acceptable carrier as described herein above with a suitable solvent. [0129] In one embodiment, the solvent is selected from the group consisting of ethers, ketones, esters, halogenated hydrocarbons, amides, alcohols, water, and mixtures thereof. [0130] In one embodiment, the solvent is selected from the group consisting of ethers such as such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; amides such as dimethylformamide, dimethyl acetamide and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; water; and mixtures thereof. [0131] In one embodiment, the step (b) of obtaining the amorphous solid dispersion comprises: (i) removing the solvent from the solution or mixture obtained in (a); or (ii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture. [0132] In one embodiment, the removal of solvent in (b) (i) may be carried out by solvent distillation, concentration, spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying. [0133] In one embodiment, removal of solvent in (b) (i) may be carried out by spray drying. [0134] In one embodiment, removal of solvent in (b) (i) may be carried out by solvent distillation, preferably under vacuum.
[0135] In one embodiment, the anti-solvent used in (b) (ii) is a solvent which on addition to the solution of step (a) causes precipitation of amorphous solid dispersion of diroximel fumarate with at least one pharmaceutically acceptable carrier. [0136] In one embodiment, the anti-solvent is selected from the group consisting of ethers such as such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, dioxane and the like; ketones such as acetone, methyl isobutyl ketone, ethyl methyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; amides such as dimethylformamide, dimethyl acetamide and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol and the like; water; and mixtures thereof. [0137] In one embodiment, the amorphous solid dispersion of diroximel fumarate with at least one pharmaceutically acceptable carrier prepared using the process of the present invention, contains diroximel fumarate in amorphous form together with at least one pharmaceutically acceptable carrier. [0138] In one embodiment, the present invention provides an amorphous diroximel fumarate. [0139] In one embodiment, the present invention provides pharmaceutical compositions comprising diroximel fumarate or salt thereof obtained by the processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns. [0140] In one embodiment, the present invention provides pharmaceutical compositions comprising diroximel fumarate or salt thereof obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
[0141] The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state diroximel fumarate or salt thereof into any of the foregoing desired particle size range. [0142] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES [0143] EXAMPLE 1: Preparation of monomethyl fumarate Maleic anhydride (20g) was added in toluene (40mL) and methanol (13.05g) by maintaining temperature at about 42°C to about 55°C. The reaction mixture was maintained at about 50°C to about 60°C for about 2h. The solvent was distilled out and the reaction mixture was stripped out with toluene. To the obtained residue, toluene (80mL) was added, followed by thionyl chloride (2.43g). The reaction mixture was maintained at about 80°C to about 90°C for about 2h. The reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered. The solid was washed with toluene and dried under vacuum at about 60°C for about 6h. HPLC Purity: 99.01%; Fumaric acid content in monomethyl fumarate: 0.09% A mixture of the obtained solid in ethyl acetate (60mL) was heated to about 70°C to about 80°C for about 30min and then cooled to about 5°C to about 10°C, stirred for about 2h and filtered. The solid obtained was recrystallized with ethyl acetate and dried. Yield: 16.5g HPLC purity 99.96%; Fumaric acid content in monomethyl fumarate: 0.04% [0144] EXAMPLE 2: Preparation of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione A mixture of ethylene carbonate (10g), succinimide (10.06g) and triethylamine (2g) was heated at about 90°C to about 100°C for about 6h. Traces of triethylamine were distilled out. Ethyl acetate and cyclohexane were added to the reaction mixture. The reaction mixture was stirred and filtered. The solid obtained was dried. Yield: 11g; HPLC Purity: 98.97% [0145] EXAMPLE 3: Preparation of diroximel fumarate To a mixture of monomethyl fumarate (12g), 1-(2-hydroxyethyl)-2,5-pyrrolidinedione (17.1g) and DMAP (0.6g) in dichloromethane (120mL), cooled to about below 10°C, EDC.HCl (18.4g) was added. The reaction mixture was stirred and heated to about 20°C to about 30°C for about 150min. Water was added to the reaction mixture and the two layers were separated. The organic layer was washed with sodium bicarbonate solution followed
with dilute hydrochloric acid solution. The organic layer was concentrated and the solid obtained was crystallized in ethyl acetate. Yield: 16.5g HPLC Purity: 100%; Impurity A content in diroximel fumarate: Not detected A mixture of diroximel fumarate (7g) in acetone (35mL) was heated to about 40°C to about 45°C and filtered through micron filter. The filtrate was concentrated and the solid obtained was crystallized with ethyl acetate. The solid obtained was dried in VTD under vacuum NLT 650 mmHg at about 50°C to about 55°C. Yield: 5.85g HPLC Purity: 100%; Impurity A content in diroximel fumarate: Not detected XRPD table of crystalline diroximel fumarate:
[0146] COMPARATIVE EXAMPLE 1: Preparation of monomethyl fumarate (using acetyl chloride)
To a mixture of maleic anhydride (10g) in toluene (40mL), methanol (4.46g) was added. The reaction mixture was stirred at about 60°C to about 65°C for about 2h. The reaction mixture was concentrated under vacuum at about below 60°C and degassed under vacuum at about 50°C to about 60°C for about 1h. The reaction mixture was cooled to about 20°C to about 30°C and toluene (50mL) was added to it. Acetyl chloride (0.45g) was added to the reaction mixture which was heated to about 80°C to about 85°C for about 5h. The reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered. The solid was washed with toluene and dried under vacuum at about 60°C for about 6h. Yield: 10.1g HPLC Purity: 97.32%; Fumaric acid content in monomethyl fumarate: 2.35% A mixture of the obtained solid (4g) in ethyl acetate (20mL) was heated at about 65°C to about 75°C for about 1h. The reaction mixture was cooled to about 5°C to about 10°C and stirred for about 2h. The solid obtained was filtered, washed with ethyl acetate and dried under vacuum at about 40°C to about 45°C for about 12h. Yield: 3.22g HPLC Purity: 99.49%; Fumaric acid content in monomethyl fumarate: 0.51% [0147] EXAMPLE 4: Preparation of amorphous solid dispersion of diroximel fumarate with polyvinyl pyrrolidone (PVP K90) Diroximel fumarate (1g) and polyvinyl pyrrolidone K90 (6g) were dissolved in methanol (80mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The solvent was removed from the obtained solution by spray dryer. The solid obtained was dried in air tray dryer (ATD) at about 40°C for about 30 minutes. Yield: 85% Spray drying parameters: Carrier nitrogen flow 2.0kg/cm2, inlet temperature 48°C, outlet temperature 75°C, feed rate 16rpm, aspirator 1700rpm and vacuum 250mm Hg. [0148] EXAMPLE 5: Preparation of amorphous solid dispersion of diroximel fumarate with hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) Diroximel fumarate (0.25g) and hydroxypropyl methylcellulose phthalate (1.5g) were dissolved in methanol and dichloromethane (1:1v/v) solvent mixture (50mL). The solution
was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The obtained clear solution was distilled off under high vacuum at about 50°C using rotavapour. The solid obtained was dried on rotavapour at about 50°C for about 30 minutes. Yield: 90% [0149] EXAMPLE 6: Preparation of amorphous solid dispersion of diroximel fumarate with hydroxypropyl methylcellulose phthalate (HPMC-Phthalate) Diroximel fumarate (0.25g) and hydroxypropyl methylcellulose phthalate (0.75g) were dissolved in methanol and dichloromethane (1:1v/v) solvent mixture (50mL). The solution was stirred at about room temperature for about 15-20 minutes. The solution was filtered for particle free solution. The obtained clear solution was distilled off under high vacuum at about 50°C using rotavapour. The solid obtained was dried on rotavapour at about 50°C for about 30 minutes. Yield: 85% [0150] EXAMPLE 7: Preparation of diroximel fumarate A mixture of ethylene carbonate (47.38g), succinimide (49.5g) and triethylamine (10.11g) was heated at about 85°C to about 95°C for about 6h. The reaction mixture was cooled to about 50°C to about 60°C and concentrated. To the obtained residue, dichloromethane (150mL) was added (solution of 1-(2-hydroxyethyl)-2, 5-pyrrolidinedione in dichloromethane). To a mixture of monomethyl fumarate (50g) in dichloromethane (350mL), was added sodium carbonate (52.96g), DMAP (2.5g) followed by the solution of 1-(2- hydroxyethyl)-2, 5-pyrrolidinedione in dichloromethane. The reaction mixture was stirred for about 10min and p-toluenesulfonyl chloride (80.60g) was lot wise added to it. The reaction mixture was stirred for about 2h. Water was added to the reaction mixture and the two layers were separated. The organic layer was washed with water, dilute hydrochloric acid solution followed by water. The organic layer was concentrated under vacuum and degassed. To the obtained solid, ethyl acetate was added and the reaction mixture was heated to about 60°C to about 70°C. The reaction mixture was cooled to about 5°C to about 10°C and stirred it for about 3h. The reaction mixture was filtered, washed with ethyl acetate and dried. The solid was crystallized in ethyl acetate-methanol mixture. Yield: 60.9g
HPLC Purity: 100% A mixture of diroximel fumarate (50g) in ethyl acetate (325mL) was heated at about 45°C to about 55°C for about 30min and filtered through micron filter. The filtrate was concentrated under vacuum up to about 150mL to about 160mL. The mixture was heated to about 60°C to about 70°C and stirred for 30min. The mixture was cooled to about 10°C to about 15°C and stirred for about 3h. The solid obtained was filtered, washed with ethyl acetate and dried under vacuum. Yield: 44g HPLC Purity: 100% [0151] EXAMPLE 8: Preparation of diroximel fumarate To a mixture of monomethyl fumarate (17.26g) and 1-(2-hydroxyethyl)-2, 5- pyrrolidinedione (20g) in toluene (200mL) was added p-toluenesulfonic acid (2g). The reaction mixture was heated to about 110°C to about 115°C. The water was removed azeotropically for about 12h. The reaction mixture was cooled to about 20°C to about 30°C. Water was added to the reaction mixture. The reaction mixture was stirred, filtered and washed with water. The solid obtained was dried at about 45°C to about 50°C. Yield: 10g [0152] EXAMPLE 9: Preparation of impurity B To a mixture of 1-(2-hydroxyethyl)-2, 5-pyrrolidinedione (50g) in acetone (150mL), was added maleic anhydride (34.93g) followed by triethylamine (1.45g). The reaction mixture was heated to about 40°C to about 45°C for about 6h. The reaction mixture was cooled, filtered and washed with acetone. The solid was dried to give 52g of (2Z)-4-[2-(2, 5- dioxopyrrolidin-1-yl) ethoxy]-4-oxobut-2-enoic acid. To a mixture of (2Z)-4-[2-(2, 5-dioxopyrrolidin-1-yl) ethoxy]-4-oxobut-2-enoic acid (10g) in dichloromethane (120mL), was added triethylamine (6.93mL). The reaction mixture was cooled to about 0°C to about 5°C. Methyl chloroformate (3.92g) was slowly added to the reaction mixture followed by DMAP (0.5g). The reaction mixture was stirred for about 60min. Water was added to the reaction mixture and the two layers were separated. The organic layer was concentrated under reduced pressure to give impurity B.
[0153] EXAMPLE 10: Preparation of diroximel fumarate A mixture of ethylene carbonate (9.4g), succinimide (9.9g) and triethylamine (2g) was heated at about 80°C to about 85°C for about 12h. After the reaction was completed, the reaction mixture was cooled to about 60°C to about 65°C and concentrated under vacuum NLT 650 mmHg at about below 65°C for about 30min to obtain residue. To the obtained residue, dichloromethane (4mL) was added (solution of 1-(2-hydroxyethyl)-2, 5-pyrrolidinedione in dichloromethane). A mixture of monomethyl fumarate (1.2g) and sodium carbonate (1.05g) was stirred at about 20°C to about 30°C temperature for about 10min to about 15min. To this mixture, solution of 1-(2-hydroxyethyl)-2,5-pyrrolidinedione in dichloromethane and dimethyl amino pyridine (0.5g) was added at about 20°C to about 30°C temperature. To this reaction mixture, p- toluenesulfonyl chloride (16.1g) was added slowly at about 20°C to about 30°C temperature and stirred at about same temperature for about 2h. The reaction mixture was charged water at about 20°C to about 30°C temperature and stirred for about 30min. The two layers were separated and the organic layer was washed with dil. HCl solution. Activated carbon was added to the organic layer, the resulting solution was stirred for about 30min and was filtered through hyflo with dichloromethane washing. The filtrate was concentrated under vacuum at about 45°C and toluene was added to the obtained residue. The resulting mixture was stirred at about 70°C to about 80°C temperature for about 1h. The resulting mixture was cooled to about 20°C to about 30°C temperature and stirred at about the same temperature for about 2h. The resulting mixture was filtered, washed with toluene and dried under vacuum. Yield: 1.45g [0154] EXAMPLE 11: Preparation of diroximel fumarate A mixture of diroximel fumarate (1g) in acetone (4.5mL) was stirred to about 40°C to about 50°C temperature for about 30min. The resulting mixture was filtered through micron filter and washed with acetone (5mL). The filtrate was concentrated under vacuum. To the obtained residue, acetone (2mL) and DM water (8mL) was added at about below 35°C temperature. The resulting mixture was stirred at about 55°C to about 65°C temperature for about 30min. The resulting mixture was cooled to about 25°C to about 35°C temperature and
stirred at about same temperature for about 3h. The resulting mixture was filtered and washed with DM water. The solid obtained was dried in VTD under vacuum NLT 650 mmHg at about 50°C to about 55°C temperature for about 6h. Yield: 0.8g. XRPD table of crystalline diroximel fumarate:
Claims
CLAIMS: 1] A process for the preparation of diroximel fumarate, a compound of formula I, the process comprising:
(a) reacting maleic anhydride with methanol to give monomethyl maleate, a compound of formula IV;
(b) reacting monomethyl maleate, the compound of formula IV with thionyl chloride to give monomethyl fumarate, a compound of formula II; and
(c) reacting monomethyl fumarate, the compound of formula II with a compound of formula III,
to give diroximel fumarate, the compound of formula I. 2] The process of claim 1, wherein the reaction of maleic anhydride with methanol occurs in the presence of a solvent. 3] The process of claim 2, wherein the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof.
4] The process of claim 1, wherein the reaction of maleic anhydride with methanol occurs in the absence of a solvent. 5] The process of claim 1, wherein in step (a), the molar ratio of maleic anhydride to methanol is in the range of about 1 to 0.70 to about 1 to 4. 6] The process of claim 1, wherein the reaction of maleic anhydride with methanol occurs at a temperature of about 20°C to about 100°C. 7] The process of claim 1, wherein the compound of formula IV obtained in step (a) is isolated and then reacted with thionyl chloride. 8] The process of claim 1, wherein the reaction of the compound of formula IV with thionyl chloride occurs in the presence of a solvent. 9] The process of claim 8, wherein the solvent is selected from the group consisting of hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, and mixtures thereof. 10] The process of claim 1, wherein in step (b), the molar ratio of the compound of formula IV to thionyl chloride is in the range of about 1 to 0.01 to about 1 to 1. 11] The process of claim 1, wherein the reaction of the compound of formula IV with thionyl chloride occurs at a temperature of about 50°C to about 100°C. 12] The process of claim 1, wherein the compound of formula II obtained in step (b) is isolated by crystallization from a solvent selected from ethyl acetate, toluene, methanol, water, or mixtures thereof.
13] The process of claim 1, wherein the compound of formula II obtained in step (b) is in a purity of at least 99.0% and wherein the level of fumaric acid is less than 0.15%, as determined by HPLC. 14] The process of claim 1, wherein the reaction of the compound of formula II with the compound of formula III occurs in the presence of a solvent. 15] The process of claim 14, wherein the solvent is selected from the group consisting of halogenated hydrocarbons, ethers, hydrocarbons, esters, nitriles, amides, sulfoxides, and mixtures thereof. 16] The process of claim 1, wherein the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent selected from the group consisting of TsCl, HBTU, EDCI, HOBt, COMU, TBTU, TATU, Oxyma, PyBOP, HOTT, FDPP, T3P, DMTMM, PyOxim, TSTU, TDBTU, TPTU, TOTU, IIDQ, PyCIU, and mixtures thereof. 17] The process of claim 1, wherein the reaction of the compound of formula II with the compound of formula III occurs in the presence of a coupling agent, wherein the coupling agent is TsCl. 18] The process of claim 1, wherein the reaction of the compound of formula II with the compound of formula III occurs in the presence of a base selected from the group consisting of diisopropylethylamine, trimethylamine, triethylamine, tributylamine, triphenylamine, pyridine, lutidine, collidine, imidazole, DMAP, DABCO, DBU, DBN, N,N,N',N'- tetramethyl-1,8-naphthalenediamine, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.
19] The process of claim 1, wherein the diroximel fumarate obtained in step (c) is isolated from a solvent selected from the group consisting of esters, ketones, nitriles, water, and mixtures thereof. 20] The process of claim 1, wherein the diroximel fumarate is obtained in a purity of ³99.0% and wherein the level of impurity A is less than 0.15%, as determined by HPLC,
21] An amorphous solid dispersion comprising diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier. 22] The amorphous solid dispersion of claim 21, wherein the pharmaceutically acceptable carrier is selected from a group consisting of one or more of a povidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose-acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids. 23] The amorphous solid dispersion of claim 21, wherein the pharmaceutically acceptable carrier is polyvinyl pyrrolidone. 24] The amorphous solid dispersion of claim 21, wherein the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose phthalate.
25] A process for the preparation of an amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier, the process comprising: (a) providing a solution or mixture of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier in a solvent; and (b) obtaining the amorphous solid dispersion of diroximel fumarate or salt thereof together with at least one pharmaceutically acceptable carrier from the solution or mixture of step (a). 26] The process of claim 25, wherein the solvent is selected from the group consisting of ethers, ketones, esters, halogenated hydrocarbons, amides, alcohols, water, and mixtures thereof. 27] The process of claim 25, wherein the step (b) of obtaining the amorphous solid dispersion comprises: (i) removing the solvent from the solution or mixture obtained in (a); or (ii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture. 28] The process of claim 27, wherein the anti-solvent is selected from the group consisting of hydrocarbons, ethers, ketones, esters, haloalkanes, amides, alcohols, water, and mixtures thereof. 29] The process of claim 25, wherein the pharmaceutically acceptable carrier is selected from a group consisting of one or more of a povidone, meglumine, gum, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose- acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethyl cellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, lactose, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, propylene glycol derivative, fatty acid, fatty alcohols, or esters of fatty acids.
30] The process of claim 25, wherein the pharmaceutically acceptable carrier is polyvinyl pyrrolidone. 31] The process of claim 25, wherein the pharmaceutically acceptable carrier is hydroxypropyl methylcellulose phthalate.
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WO2022266082A1 (en) * | 2021-06-15 | 2022-12-22 | Biogen Ma Inc. | Synthetic preparation for diroximel fumarate |
WO2023044031A1 (en) * | 2021-09-17 | 2023-03-23 | Biogen Ma Inc. | Diroximel fumarate particles having improved flow properties and methods of making same |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CA795368A (en) * | 1968-09-24 | Dowbenko Rostyslaw | Isomerization of maleates with thionyl chloride | |
US20160228376A1 (en) * | 2015-02-08 | 2016-08-11 | Alkermes Pharma Ireland Limited | Monomethylfumarate prodrug compositions |
WO2017108960A1 (en) * | 2015-12-22 | 2017-06-29 | Ratiopharm Gmbh | Method for producing monomethyl fumarate compounds |
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---|---|---|---|---|
CA795368A (en) * | 1968-09-24 | Dowbenko Rostyslaw | Isomerization of maleates with thionyl chloride | |
US20160228376A1 (en) * | 2015-02-08 | 2016-08-11 | Alkermes Pharma Ireland Limited | Monomethylfumarate prodrug compositions |
WO2017108960A1 (en) * | 2015-12-22 | 2017-06-29 | Ratiopharm Gmbh | Method for producing monomethyl fumarate compounds |
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WO2022266082A1 (en) * | 2021-06-15 | 2022-12-22 | Biogen Ma Inc. | Synthetic preparation for diroximel fumarate |
WO2023044031A1 (en) * | 2021-09-17 | 2023-03-23 | Biogen Ma Inc. | Diroximel fumarate particles having improved flow properties and methods of making same |
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