WO2022101931A1 - Process for the preparation of eribulin and its intermediates - Google Patents
Process for the preparation of eribulin and its intermediates Download PDFInfo
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- WO2022101931A1 WO2022101931A1 PCT/IN2021/051053 IN2021051053W WO2022101931A1 WO 2022101931 A1 WO2022101931 A1 WO 2022101931A1 IN 2021051053 W IN2021051053 W IN 2021051053W WO 2022101931 A1 WO2022101931 A1 WO 2022101931A1
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- Prior art keywords
- compound
- formula
- eribulin
- preparation
- stirred
- Prior art date
Links
- 229960003649 eribulin Drugs 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 title claims abstract 4
- 239000000543 intermediate Substances 0.000 title abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 42
- 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 15
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 13
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 12
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical compound OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 claims description 10
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 7
- VGGNVBNNVSIGKG-UHFFFAOYSA-N n,n,2-trimethylaziridine-1-carboxamide Chemical group CC1CN1C(=O)N(C)C VGGNVBNNVSIGKG-UHFFFAOYSA-N 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 5
- ZCOGQSHZVSZAHH-UHFFFAOYSA-N n,n-dimethylaziridine-1-carboxamide Chemical compound CN(C)C(=O)N1CC1 ZCOGQSHZVSZAHH-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 239000010410 layer Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000012458 free base Substances 0.000 description 11
- 229960000439 eribulin mesylate Drugs 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 3
- -1 TBS ethers Chemical class 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000002051 biphasic effect Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- ZXDVQYBUEVYUCG-UHFFFAOYSA-N dibutyltin(2+);methanolate Chemical compound CCCC[Sn](OC)(OC)CCCC ZXDVQYBUEVYUCG-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- SJVGFKBLUYAEOK-SFHVURJKSA-N 6-[4-[(3S)-3-(3,5-difluorophenyl)-3,4-dihydropyrazole-2-carbonyl]piperidin-1-yl]pyrimidine-4-carbonitrile Chemical compound FC=1C=C(C=C(C=1)F)[C@@H]1CC=NN1C(=O)C1CCN(CC1)C1=CC(=NC=N1)C#N SJVGFKBLUYAEOK-SFHVURJKSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QHYIGPGWXQQZSA-UHFFFAOYSA-N azane;methanesulfonic acid Chemical compound [NH4+].CS([O-])(=O)=O QHYIGPGWXQQZSA-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 1
- 238000005907 ketalization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- KMIOJWCYOHBUJS-HAKPAVFJSA-N vorolanib Chemical compound C1N(C(=O)N(C)C)CC[C@@H]1NC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C KMIOJWCYOHBUJS-HAKPAVFJSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
Definitions
- the present invention relates to the process for the preparation of Eribulin and Eribulin Mesylate.
- the present invention involves less expensive solvents and the process conditions can be easily adopted for commercial scale.
- Eribulin is a synthetic macrocyclic analogs of halichondrin B, and is represented by structural formula as shown in below.
- Eribulin is marketed as Eribulin Mesylate under the brand name HALAVEN® and it is indicated for the treatment of patients with metastatic breast cancer.
- U.S. patent No 6214865 discloses Eribulin.
- PCT application WO 2005/118565 discloses process for the synthesis of Eribulin Mesylate. The reported process suffer from major disadvantages, including low yield, low purity and formation of Eribulin isomers which are difficult to remove using conventional purification methods.
- US9303039 discloses process for the preparation of Eribulin intermediate ER-811475 from ER- 118046 by reacting with tetrabutyl ammonium fluoride in a amide solvent like N, N-dimethylacetamide solvent.
- the main object of the present invention is to provide a process for the preparation of Eribulin.
- Yet another object of the present invention is to provide an Eribuhn intermediate compound of formula IIA.
- the process is useful in the synthesis of Eribulin and Eribulin mesylate.
- One Aspect of the present invention is to provide a process for the preparation an intermediate in the synthesis of Eribulin, said method comprising reacting a compound of formula compound of formula - 1 with fluoride source in a cyclic urea-based solvent to produce the intermediate compound of formula IIA.
- the present invention is related to a process for the preparation of Eribulin and Eribulin mesylate, whereas the present process uses the cyclic urea-based solvent to produce the intermediate compound of formula IIA from compound of formula I intermediate.
- One embodiment of the present invention is to provide a process for the preparation an intermediate in the synthesis of Eribulin, said method comprising reacting a compound of formula-I with fluoride source in a cyclic urea-based solvent to produce the intermediate compound of formula IIA.
- a cyclic urea-based solvent is N, N- Dimethylpropyleneurea (DMPU) and N, N-Dimethylethyleneurea (DMEU).
- the fluoride source is tetrabutylammonium fluoride.
- Eribulin intermediate compound of formula I used in the present invention is prepared by the prior art process.
- Cyclic urea-based solvents such as is N, N-Dimethylpropyleneurea (DMPU) and N, N-Dimethylethyleneurea (DMEU) are highly effective for converting compound of formula I to compound of formula IIA even at low temperatures such as 5-10 °C.
- Example-1 Preparation of compound of formula I via Dess-martin oxidation:
- reaction mass is diluted with 15.0 mL of 5% aqueous sodium bicarbonate solution, 15.0 mL of 20% aqueous sodium sulphite solution and 20 mL of dichloromethane. After stirring the biphasic mass for 10 minutes, separated the organic and aqueous layers.
- Aqueous layer is extracted with 30.0 mL of dichloromethane. Combined organic layers are washed with 40 mL of DM water. Solvent is evaporated under reduced pressure at 30 °C to afford white colored foamy solid or thick oil. Charged 2x20 mL of n-heptane to the foamy solid and distilled out completely to get 1.99 g of compound of formula I as white foamy solid.
- reaction mass is diluted with 900 mL of 20% aqueous NaCl solution and 900 mL of ethyl acetate and stirred for 20 min. Layers are separated and aqueous layer is re-extracted with 288 mL of ethyl acetate. Solvent is evaporated under reduced pressure at 35 °C to afford brown colored oil (25.87 g).
- Brown residue thus obtained is co-distilled twice with MeCN/Water (6: 1), MeCN (2 x 10 V) and methylene chloride (3x20 V) to furnish compound of formula IIA crude (24.65 g) as brown colored oil which is used for compound of formula II formation (Example- V) without any further characterization.
- Example-3 Preparation of compound of formula IIA: compound of formula IIA: Deprotection of TBS ethers employing Imidazole.HCL in a cyclic urea based solvent DMPU:
- reaction mass is diluted with 50 mL of DM water and 50 mL of ethyl acetate and stirred for 15-20 min. Layers are separated and aqueous layer is reextracted with 16 mL of ethyl acetate. Solvent is evaporated under reduced pressure at 30 °C to afford brown colored oil. Brown residue thus obtained is co-distilled with (2x10 mL) of MeCN to furnish compound of formula IIA crude (0.8 g) as brown colored oil.
- compound of formula IIA Crude HPLC result: compound of formula IIA -66.06% compound of formula IIA Isomer-6.15%
- Example-4 Preparation of compound of formula IIA: compound of formula IIA: Deprotection of TBS ethers employing Imidazole.HCL in a cyclic urea based solvent DMEU:
- reaction mass is stirred for 4-7 h at the same temperature and the progress of the reaction is monitored by HPLC. After the consumption of starting material (compound of formula IIA content judged by HPLC), reaction mass is diluted with 900.0 mL of DM water and 900 mL of MTBE. After stirring the biphasic mass for 10-15 minutes, separated the organic and aqueous layers. Aqueous layer is extracted with 2x900 mL of MTBE.
- Example-6 Preparation of Eribulin free base from compound of formula II via selective tosylation by employing Dibutyldimethoxy tin:
- reaction mass is stirred for 20-25 h at the same temperature and the progress of the reaction is monitored by HPLC. After the consumption of starting material (judged by HPLC), reaction mass is evacuated to get the crude. Subsequently, the crude is diluted with 7.0 mL of methylene chloride and aqueous solution of sodium bicarbonate and sodium carbonate (0.1 g of sodium bicarbonate and 0.1 g of sodium carbonate dissolved in 2.0 mL of DM water). After stirring the biphasic mass for 15 minutes, separated the organic and aqueous layers.
- Enbulin free base crude (0.134 g).
- Enbulin free base crude is purified by flash chromatography using acetonitrile and aqueous ammonium acetate as the eluent to afford 0.065 g of Eribulin free base as a white foamy solid. Purified sample is characterized by HPLC for its purity.
- Example-8 Preparation of Eribulin mesylate from Eribulin PTSPA salt via
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of Eribulin Intermediates. The present invention involves less expensive solvents and the process conditions can be easily adopted for commercial scale.
Description
PROCESS FOR THE PREPARATION OF ERIBULIN AND ITS
INTERMEDIATES
Field of the invention: The present invention relates to the process for the preparation of Eribulin and Eribulin Mesylate. The present invention involves less expensive solvents and the process conditions can be easily adopted for commercial scale.
Background of the Invention: Eribulin, is a synthetic macrocyclic analogs of halichondrin B, and is represented by structural formula as shown in below.
Eribulin mesylate (II)
Eribulin is marketed as Eribulin Mesylate under the brand name HALAVEN® and it is indicated for the treatment of patients with metastatic breast cancer. U.S. patent No 6214865 discloses Eribulin.
PCT application WO 2005/118565 discloses process for the synthesis of Eribulin Mesylate. The reported process suffer from major disadvantages, including low yield, low purity and formation of Eribulin isomers which are difficult to remove using conventional purification methods.
US9303039 discloses process for the preparation of Eribulin intermediate ER-811475 from ER- 118046 by reacting with tetrabutyl ammonium fluoride in a amide solvent like N, N-dimethylacetamide solvent.
Hence, there remains a need to provide an alternative process for the preparation of high pure Eribulin and Eribulin Mesylate.
Objects of the Invention:
The main object of the present invention is to provide a process for the preparation of Eribulin.
Yet another object of the present invention is to provide an Eribuhn intermediate compound of formula IIA.
Summary of the Invention:
According to a first aspect of the present invention, the process is useful in the synthesis of Eribulin and Eribulin mesylate.
One Aspect of the present invention is to provide a process for the preparation an intermediate in the synthesis of Eribulin, said method comprising reacting a compound of formula compound of formula - 1 with fluoride source in a cyclic urea-based solvent to produce the intermediate compound of formula IIA.
Detailed description of the Invention:
The present invention is related to a process for the preparation of Eribulin and Eribulin mesylate, whereas the present process uses the cyclic urea-based solvent to produce the intermediate compound of formula IIA from compound of formula I intermediate.
One embodiment of the present invention is to provide a process for the preparation an intermediate in the synthesis of Eribulin, said method comprising reacting a compound of formula-I with fluoride source in a cyclic urea-based solvent to produce the intermediate compound of formula IIA.
According to the present invention a cyclic urea-based solvent is N, N- Dimethylpropyleneurea (DMPU) and N, N-Dimethylethyleneurea (DMEU).
According to the present invention the fluoride source is tetrabutylammonium fluoride.
The Present invention is further illustrated in detail with reference to following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the invention in any way.
According to the present invention, Eribulin intermediate compound of formula I used in the present invention is prepared by the prior art process.
Advantages of the Present Invention:
1. Cyclic urea-based solvents such as is N, N-Dimethylpropyleneurea (DMPU) and N, N-Dimethylethyleneurea (DMEU) are highly effective for converting compound of formula I to compound of formula IIA even at low temperatures such as 5-10 °C.
2. Selectivity between compound of formula IIA and compound of formula IIA isomer induced by DMPU is as high as 20: 1.
3. Since, DMPU and DMEU are highly soluble in water, it could be easily removed by extractive work-up with aqueous sodium chloride.
The Present invention is further illustrated in detail with reference to following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the invention in any way.
Examples:
Example-1: Preparation of compound of formula I via Dess-martin oxidation:
To a stirred and pre-cooled (10-20 °C) solution of compound of formula IA (2.0 g) in dichloromethane (40 mL), charged 0.96 g of Dess-Martin Periodinane. The resulting white slurry is stirred for 2-4 h at the same temperature and the progress of the reaction is monitored by HPLC. After the consumption of starting material (judged by HPLC), reaction mass is diluted with 15.0 mL of 5% aqueous sodium bicarbonate solution, 15.0 mL of 20% aqueous sodium sulphite solution and 20 mL of dichloromethane. After stirring the biphasic mass for 10 minutes, separated the organic and aqueous layers. Aqueous layer is extracted with 30.0 mL of dichloromethane. Combined organic layers are washed with 40 mL of DM water. Solvent is evaporated under reduced pressure at 30 °C to afford white colored foamy solid or thick oil. Charged 2x20 mL of n-heptane to the foamy solid and distilled out completely to get 1.99 g of compound of formula I as white foamy solid.
HPLC Purity: 97.74%
’H NMR 400 MHz, CDC13: 5 7.305-7.250 (m, 1 H), 6.35 (d, 1H, 7=15.6 Hz), 5.026- 5.005 (m, 2H), 4.897-4.788 (m, 3H), 1.053 (bs, 1H), 4.083-4.036 (m, 3H), 3.916-3.780
(m, 5H), 3.704 (m, 1H), 3.535 (ddd, 3H, 7=15.6, 10.4, 5.6 Hz), 3.43 (d, 2H, 7=2.8 Hz), 3.314 (s, 3H), 2.963-2.939 (m, 1H), 2.862 (dd, 1H, 7=15.6, 7.2 Hz), 2.760-2.625 (m, 4H), 2.547-2.433 (m, 3H), 2.309-2.271 (m, 2H), 2.081-2.030 (m, 1H), 1.984-1.885 (m, 2H), 1.832-1.671 (m, 7H), 1.471-1.403 (m, 1H), 1.354-1.307 (m, 2H), 1.26 (bs, 3H), 1.091-1.029 (m, 4H), 0.982-0.946 (m, 17H), 0.891-0.881 (m, 26H), 0.203 (bs, 3H), 0.146-0.133 (m, 9H), 0.076 to -0.037 (m, 21H).
Example-2: Preparation of compound of formula HA:
Deprotection of TBS ethers employing TBAF and Imidazole.HCL in a cyclic urea based solvent DMPU:
Weighed 0.884 g of imidazole hydrochloride in an inert atmosphere Glove box and transferred into an appropriate flask. Charged 17.8 mL of tetrabutylammonium fluoride (1.0 M solution in THF), to the flask containing imidazole hydrochloride and stirred at room temperature for 10-15 minutes. Subsequently, Tetrahydrofuran in the reaction mass was evaporated completely by connecting the reaction flask to a vacuum port. The thick mass thus obtained was cooled to 5-10 °C and was charged with N,N- Dimethylpropyleneurea (DMPU) solution of compound of formula I (3.6 g dissolved in 90.0 mL of DMPU). The resulting solution is stirred at the same temperature for 12- 20 h until the completion of reaction (monitored by HPLC). Following the completion of reaction, reaction mass is diluted with 900 mL of 20% aqueous NaCl solution and 900 mL of ethyl acetate and stirred for 20 min. Layers are separated and aqueous layer is re-extracted with 288 mL of ethyl acetate. Solvent is evaporated under reduced pressure at 35 °C to afford brown colored oil (25.87 g). Brown residue thus obtained is
co-distilled twice with MeCN/Water (6: 1), MeCN (2 x 10 V) and methylene chloride (3x20 V) to furnish compound of formula IIA crude (24.65 g) as brown colored oil which is used for compound of formula II formation (Example- V) without any further characterization.
HPLC result: compound of formula IIA -56.49% compound of formula IIA Isomer-2.57%.
Example-3: Preparation of compound of formula IIA: compound of formula IIA: Deprotection of TBS ethers employing Imidazole.HCL in a cyclic urea based solvent DMPU:
Weighed 0.048 g of imidazole hydrochloride in an inert atmosphere Glove box and transferred into an appropriate flask containing 1.0 mL of N,N-Dimethylpropyleneurea (DMPU). Subsequently, charged 0.308 g of solid tetrabutylammonium fluoride trihydrate (TBAF.3H2O) to the above flask and stirred at room temperature for 10-15 minutes. The resulting solution thus obtained was cooled to 5-10 °C and was charged with N,N-Dimethylpropyleneurea (DMPU) solution of compound of formula I (0.2 g dissolved in 5.0 mL of DMPU). The resulting solution is stirred at the same temperature for 5 h until the completion of reaction (monitored by HPLC). Following the completion of reaction, reaction mass is diluted with 50 mL of DM water and 50 mL of ethyl acetate and stirred for 15-20 min. Layers are separated and aqueous layer is reextracted with 16 mL of ethyl acetate. Solvent is evaporated under reduced pressure at 30 °C to afford brown colored oil. Brown residue thus obtained is co-distilled with
(2x10 mL) of MeCN to furnish compound of formula IIA crude (0.8 g) as brown colored oil. compound of formula IIA Crude HPLC result: compound of formula IIA -66.06% compound of formula IIA Isomer-6.15%
Example-4: Preparation of compound of formula IIA: compound of formula IIA: Deprotection of TBS ethers employing Imidazole.HCL in a cyclic urea based solvent DMEU:
Weighed 0.024 g of imidazole hydrochloride in an inert atmosphere Glove box and transferred into an appropriate flask. Charged 0.49 mL of tetrabutylammonium fluoride (1.0 M solution in THF), to the flask containing imidazole hydrochloride and stirred at room temperature for 10-15 minutes. The resulting solution thus obtained was cooled to 15-20 °C and was charged with N,N-Dimethylethyleneurea (DMEU) solution of compound of formula - 1 (0.1 g dissolved in 2.5 mL of DMEU). The resulting solution is stirred at the same temperature for 12 h until the completion of reaction (monitored by HPLC). Formation of the product is confirmed by HPLC.
HPLC result: compound of formula - IIA: 49.17% compound of formula - IIA Isomer-5.43%
Example-5: Preparation of compound of formula II employing PPTS for ketalization of compound of formula IIA:
Mi
To a stirred and pre-cooled (15-20 °C) solution of compound of formula IIA crude (24.6 g) in dichloromethane (90.0 mL), charged methylene chloride solution of PPTS (3.43 g of PPTS in 18 mL of MDC). Reaction mass is stirred for 4-7 h at the same temperature and the progress of the reaction is monitored by HPLC. After the consumption of starting material (compound of formula IIA content judged by HPLC), reaction mass is diluted with 900.0 mL of DM water and 900 mL of MTBE. After stirring the biphasic mass for 10-15 minutes, separated the organic and aqueous layers. Aqueous layer is extracted with 2x900 mL of MTBE. Combined organic layers are washed with 3x900 mL of aqueous 10% sodium chloride solution. Organic layer is dried over sodium sulphate and solvent is evaporated under reduced pressure at 30 °C to afford compound of formula II crude as thick oil (1.7 g). compound of formula II crude was purified by flash chromatography at first for the removal of DMPU and subsequently by Prep-HPLC for the removal of compound of formula IIA isomer to afford 0.82g of pure compound of formula II.
HPLC Purity of compound of formula II Crude: compound of formula II -66.05%; compound of formula IIA -Isomer- 1.65%
HPLC Purity of compound of formula II punned by Prep-HPLC: compound of formula II: 99.88% compound of formula IIA Isomer: Not detected. compound of formula II: 0.08%
’H NMR 400 MHz, CD3OD: 5 5.142 (d, 1H, 7=1.2 Hz), 5.029 (bs, 1H), 4.83 (d, 1H, 7=1.2 Hz), 4.711 (t, 1H, 7=4.8 Hz), 4.615 (t, 1H, 7=4.4 Hz), 4.484 (d, 1H, 7=10.8 Hz), 4.329-4.269 (m, 2H), 4.183 (dd, 1H, 6.4, 4.4 Hz), 4.118 (dd, 1H, 7=6.0, 4.0 Hz), 4.077 (bs, 1H), 3.987 (t, 1H, 7=10.4 Hz), 3.886-3.839 (m, 3H), 3.744-3.656 (m, 2H), 3.49 (ddd, 2H, 7=19.6, 11.2, 4.4 Hz), 3.422 (s, 3H), 3.355 (d, 1H, 7=4.0 Hz), 3.211 (s, 2H), 2.947-2.918 (m, 2H), 2.764-2.648 (m, 2H), 2.475-2.301 (m, 5H), 2.207-(m, 4H), 2.032- 1.957 (m, 3H), 1.902-1.857 (m, 2H), 1.794-1.690 (m, 4H), 1.601-1.291 (m, 7H), 1.111 (d, 3H, 7=6.4 Hz), 1.069-0.979 (m, 1H).
13C NMR 100 MHz, CD3OD:
5 208.184, 154.310, 153.122, 111.051, 105.148, 105.017, 87.889, 83.950, 82.527, 82 .031,
79.464, 78.521, 77.988, 77.781, 75.975, 75.504, 75.312, 74.671, 74.473, 74.324, 74.2 83, 71.297, 69.798, 67.389, 57.365, 44.988, 44.869, 40.036, 39.563, 36.795, 36.306, 33.065, 32.694, 32.103, 31.213, 29.822, 27.200, 18.433.
Example-6: Preparation of Eribulin free base from compound of formula II via selective tosylation by employing Dibutyldimethoxy tin:
To a stirred solution of compound of formula II (0.1 g) in acetonitrile (1.5 mL), charged an acetonitrile solution (0.2 mL) of dibutyldimethoxytin (2 mg) and N, N- diisopropylethylamine (72 pL). After stirring the above mass for 10 minutes at ambient temperature, charged an acetonitrile solution (0.5 mL) of para-toluenesulfonyl chloride (0.077 g). The resulting mass is stirred for 4-6 h at the room temperature and the progress of the reaction is monitored by HPLC. After the consumption of starting material (compound of formula II content judged by HPLC), reaction mass is diluted with isopropyl alcohol (11 mL) and transferred into an appropriately sized flask for transforming it to the subsequent stages without any further characterization.
To the above stirred solution of reaction mass in isopropyl alcohol (11 mL), charged 12.6 mL of ammonia solution at room temperature. Reaction mass is stirred for 20-25 h at the same temperature and the progress of the reaction is monitored by HPLC. After the consumption of starting material (judged by HPLC), reaction mass is evacuated to get the crude. Subsequently, the crude is diluted with 7.0 mL of methylene chloride and aqueous solution of sodium bicarbonate and sodium carbonate (0.1 g of sodium bicarbonate and 0.1 g of sodium carbonate dissolved in 2.0 mL of DM water). After stirring the biphasic mass for 15 minutes, separated the organic and aqueous layers. Aqueous layer is extracted with 4.0 mL of dichloromethane. Solvent is evaporated
under reduced pressure at 30 C to afford Enbulin free base crude (0.134 g). Enbulin free base crude is purified by flash chromatography using acetonitrile and aqueous ammonium acetate as the eluent to afford 0.065 g of Eribulin free base as a white foamy solid. Purified sample is characterized by HPLC for its purity.
HPLC Purity: 90.04%.
Example-7: Preparation of Eribulin PTSPA salt from Eribulin Free Base:
To a stirred solution of acetonitrile (100 ml) was added Eribulin free base (2.0 g) at 20- 30 °C and stirred the mass for 10-15 minutes at 20-30 °C. Dissolved the 2V-(p-Toluene sulfonyl)-L-phenyl alanine (PTSPA) (0.875 g) in acetonitrile (50 mL) and added slowly to the Eribulin free base solution at 20-30 °C. Stirred the reaction mass for 60 minutes at 20-30 °C and filtered the solid and washed the cake with 25 ml of acetonitrile and dried under vacuum at 30-35 °C for 3 hours.
Dry weight: - 2.35 g
Purity by HPLC: - 99.69%
Example-8: Preparation of Eribulin mesylate from Eribulin PTSPA salt via
Eribulin free base (pure)
Preparation of Pure Enbuhn free base
To a stirred Eribulin PTSPA salt (2.74 g) charged dichloromethane (300 ml) at 20-30 °C and charged DM water (150 ml) at 20-30 °C and cooled the reaction mass to 10-15 °C and charged aqueous ammonia solution (3.0 ml) at 10-15 °C and stirred the mass for 20 minutes (pH « 9.7), separated the organic layer and aqueous layer, extracted the aqueous layer with dichloromethane (150 ml), separated the organic layer and aqueous layer, combined the organic layer and washed with DM water (150 ml), distilled the dichloromethane layer under vacuum at below 30 °C to obtain Pure Eribulin free base (1-905 g).
Purity by HPLC: 99.068%
Preparation of Eribulin Mesylate:
To a stirred solution of pure Eribulin free base (1.9 g), charged acetonitrile (70 ml) at 20-30 °C, charged aqueous ammonia solution (3 ml) at 20-30 °C, charged ammonium methane sulfonate (0.3 g) with acetonitrile (10 ml). Stirred the reaction mass for 30 minutes at 20-30 °C. Distilled the reaction mass at below 30 °C and obtained thick oil residue. Co-distilled the reaction mass with acetonitrile (20 ml) under vacuum at below 30 °C and obtained thick solid. Charged 75% dichloromethane in n-Pentane (40 ml) at 20-30 °C. Stirred for 10 minute and filtered the solution. Distilled the filtrate under vacuum at below 30 °C and obtained solid, dissolved the above solid in 50% dichloromethane in n-pentane (40 ml) and filtered the particles, the filtrate was added slowly into n-pentane (225 ml) in another RB flask at 20-30 °C. Stirred the mass for 16 hours at 20-30 °C. Filtered the solid under nitrogen pressure and washed with n- pentane (50 ml), Dried the compound under vacuum at 20-30 °C for 60 minutes.
Dry weight: 1.70 g.
The overall yield of Eribulin mesylate obtained from Eribulin PTSPA salt:-79% Purity by HPLC: 99.416%
Claims
1. A process for the preparation of Eribulin Intermediate Compound of formula- IIA by reacting a compound of formula-I with fluoride source in a cyclic urea-based solvent to produce the intermediate Compound of formula -II A.
2. The process as claimed in claim 1, wherein the cyclic urea-based solvent is selected from N, N-Dimethylpropylene urea (DMPU) and N, N- Dimethylethylene urea (DMEU).
3. The process as claimed in claim 1, wherein the fluoride source is tetrabutylammonium fluoride.
4. The process as claimed in claim 1, wherein the intermediate Compound of formula -II A is further converted to Eribulin.
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