WO2023157015A1 - An improved process for the preparation of eribulin intermediates - Google Patents
An improved process for the preparation of eribulin intermediates Download PDFInfo
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- WO2023157015A1 WO2023157015A1 PCT/IN2023/050108 IN2023050108W WO2023157015A1 WO 2023157015 A1 WO2023157015 A1 WO 2023157015A1 IN 2023050108 W IN2023050108 W IN 2023050108W WO 2023157015 A1 WO2023157015 A1 WO 2023157015A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- preparation
- eribulin
- intermediates
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229960003649 eribulin Drugs 0.000 title abstract description 12
- 239000000543 intermediate Substances 0.000 title abstract description 8
- 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 abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 34
- 238000000746 purification Methods 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 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 7
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 5
- 238000002953 preparative HPLC Methods 0.000 claims description 5
- 238000003818 flash chromatography Methods 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 21
- 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 12
- 239000000243 solution Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- -1 dimethoxytrityl Chemical group 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000003480 eluent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 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
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960000439 eribulin mesylate Drugs 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 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
- IZZWJPQHPPRVLP-UHFFFAOYSA-N hexane;2-methoxy-2-methylpropane Chemical compound CCCCCC.COC(C)(C)C IZZWJPQHPPRVLP-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 1
- AYOOGWWGECJQPI-NSHDSACASA-N n-[(1s)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-(3-propan-2-yloxy-1h-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine Chemical compound N1C(OC(C)C)=CC(N2C3=NC(N[C@@H](C)C=4N=CC(F)=CN=4)=CC=C3N=C2)=N1 AYOOGWWGECJQPI-NSHDSACASA-N 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 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
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
Definitions
- Eribulin is a synthetic macrocyclic analog of halichondrin B, and is represented by structural formula as shown in below.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to process for the preparation of intermediates of Eribulin and process for the preparation of the same. The process of the present invention involves less expensive reagents, solvents and the process conditions can be easily adopted for commercial scale.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF ERIBULIN
INTERMEDIATES
Field of the invention:
The present invention relates to a process for the preparation of intermediates of Eribulin. The present invention involves less expensive reagents, solvents and the process conditions can be easily adopted for commercial scale.
Background of the Invention:
Eribulin, is a synthetic macrocyclic analog of halichondrin B, and is represented by structural formula as shown in below.
Eribulin
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. compound of formula A is used as one of the intermediate.
Formula A
During development of the process, we observed some disadvantageous with the above compound of formula-A. The final two steps of the process involve two cryogenic conditions at -20 °C and -78 °C. which are not commercially viable. Hence, there remains a need to provide an alternative process for the preparation of Eribulin Intermediates.
Summary of the Invention:
According to a first aspect of the present invention, there is provided a process for the preparation of Eribulin Intermediates.
One aspect of the present invention provides a compound of formula I.
Yet another aspect of the present invention is to provide a process for the preparation of a compound of formula IA comprising the steps of: a) reacting the compound of formula - II with a base to get the compound of formula-IA, b) optionally purifying the compound of formula -IA.
Wherein R1 is - SO2Ph or SO2PhMe and R2 is an alcohol - protecting group.
Y et another aspect of the present invention is to provide a process for the preparation of a compound of formula I comprising the steps of: a) reacting the compound of formula - II with a base to get the compound of formula-I, b) optionally purifying the compound of formula -I.
Detailed description of the Invention:
The present invention is related to a process for the preparation intermediates of Eribulin.
One embodiment of the present invention provides a compound of formula I.
Yet another embodiment of the present invention is to provide a process for the preparation of a compound of formula I comprising the steps of: a) reacting the compound of formula - II with a base to get the compound of formula-IA, b) optionally purifying the compound of formula -IA.
Wherein R1 is - SO2Ph or SO2PhMe and R2 is an alcohol - protecting group.
Yet another embodiment of the present invention is to provide a process for the preparation of a compound of formula I comprising the steps of: a) reacting the compound of formula - II with a base to get the compound of formula-I, b) optionally purifying the compound of formula -I.
The invention according to above embodiments is shown in below scheme (Scheme-
1).
Scheme-1
According to the present embodiment, wherein base used in step a) is selected from, Sodium methoxide, sodium ethoxide, potassium tertiary butoxide and sodium tertiary butoxide, preferably Sodium methoxide.
According to the present embodiment, wherein purification of compound of formula-I in step b) is carried out using preparative HPLC, flash chromatography.
According to the present invention alcohol protecting group is selected from mesylate, tosylate, acetyl, benzoyl, benzyl, P-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, allyl ether, t-butyl ether, pivaloyl, trityl, silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxy ethyl ether (EE), or any suitable alcohol protecting group known in the art.
Advantages of the present invention:
1. Less expensive chemicals were used in the process.
2. Most of the reactions are taken insitu to subsequent stages without purification.
3. This sequence does not involve any cryogenic condition at low temperatures of -25 °C and -78°C.
4. The overall yield up to preparative purification stage from compound of formula- VI is 58%.
5. The above invention has one purification step less than the prior art process.
6. The above invention has one step less than the prior art process.
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-V
Compound- VI
To a stirred solution of Compound- VI (18.0 g) in THF (54.0 mL), charged 54.0 mL of 5% K2HPO4 aqueous solution (prepared by dissolving 2.7 g of K2HPO4 in 54.0 mL of
DM water and adjusted its PH from 9.3 to 7.4 by the gradual addition of 1 N HC1 (4.0 mL)). Subsequently, 17.8 g of sodium periodate was added to the reaction mass at once and stirred the reaction mass for 4-5 h at room temperature while maintaining the PH of the reaction mass at above 4.0 throughout the maintenance of the reaction. After completion of the reaction, reaction mass is filtered over Buchner funnel, washed the filtered cake with ethyl acetate (450.0 mL). Separated the organic and aqueous layers, washed the organic layer with 10% sodium thiosulphate solution (450.0 mL), 5% sodium bicarbonate solution (450.0 mL), 10% sodium chloride solution (450 mL). Organic layer is dried over sodium sulphate (90.0 g) and solvent is evaporated under reduced pressure to afford 15.7 g of compound-V as a light yellow coloured viscous liquid.
Purity by HPLC: 96.92%.
Example-2: Preparation of compound of formula-III
Compound- IV
Compound- III
To a stirred and pre-cooled (-30±5 °C) solution of compound-IV (15.26 g) in THF (75.0 mL), charged 9.0 mL of triethylamine and stirred for 5-10 min at the same temperature. Subsequently, 3.7 mL of methanesulfonyl chloride was introduced into the reaction mass dropwise at the same temperature. The resulting mass was stirred for 20-30 min at -30±5 °C, after completion of the reaction, reaction mass was diluted with 210.0 mL of 20% sodium chloride solution and 210.0 mL of n-heptane, stirred for 10 minutes. Separated the organic and aqueous layers, extracted the aqueous layer with 105.0 mL of n-heptane. Combined organic layers are dried over sodium sulphate (70.0 g) and the solvent is evaporated under reduced pressure at 28 °C to afford 17.8 g of compound- ill as a light brown coloured oil.
Purity by HPLC; 87.92%
Example-3: Preparation of compound of formula-II
Compound-A (20.26 g) was transferred into an appropriately sized flask and dissolved it in 280.0 mL of tetrahydrofuran. 8.4 g of chromium (II) chloride was introduced into
the flask and reaction mass was warmed up to attain a temperature of 33.5±1.5 °C. 9.5 mL of triethylamine was added drop wise to the reaction mass and the resultant intense green coloured mass was stirred at the same temperature for 3.0 h. To the Compound- A-Chromium complex thus obtained, 0.35 g of Nickel (II) chloride is charged at 0±5 °C. Separately, mixture of Compound-V (14.0 g) + compound-III (17.8 g) was dissolved in 112.0 mL of tetrahydrofuran, and added drop wise to the reaction mass at the same temperature and maintained for 15-20min min. Reaction mass was gradually allowed to attain a temperature of 23-26 °C and stirred it for 8 h at the same temperature after the completion of reaction, reaction mass is cooled to 0±5 °C and quenched by the addition of 13.5 mL of ethylenediamine. After stirring the quenched solution of reaction mass for 1 h at 0±5 °C, it is diluted with 650.0 mL of DM water, 840.0 mL of n-heptane and stirred for 20 min at room temperature. Separated the aqueous and organic layers, extracted the aqueous layer with 420.0 mL of n-heptane. Combined organic layers are washed with 840.0 mL of 20% sodium chloride solution, dried over sodium sulphate (70.0 g), evaporated the solvent under reduced pressure. Resulting residue is diluted with 560.0 mL of n-heptane, cooled to 0±5 °C, stirred for 1 h, filtered over Buchner funnel for the removal of compound-A. Residue obtained (31.0 g) after distillation is carried to the next reaction without any further purification.
Mass: m/Z: 1062.39 (M+NH4 +).
Example-4: Preparation of compound of formula-I
To a stirred solution of compound-II (31.0 g) in THF (310.0 mL), charged 20.0 mL of 25% sodium methoxide at 25±5 °C. Reaction mass was stirred for 1-2 h at the same temperature. After completion of the reaction, reaction mass was cooled to 15±5 °C. Subsequently, reaction mass was diluted with 310.0 mL of DM water and 620.0 mL of n-heptane, stirred for 10 minutes. Separated the organic and aqueous layers, extracted the aqueous layer with 310.0 mL of n-heptane. Combined organic layers are washed with 640.0 mL of 5% ammonium chloride solution and 640.0 mL of 5% sodium chloride solution respectively. Dried the organic layer over sodium sulphate (155.0 g), evaporated the solvent under reduced pressure. The residue thus obtained (22.56 g) was purified by flash chromatography using 22-27 % ethyl acetate and hexane as the eluent to afford 11.4 g of compound-I which was found to be an inseparable mixture of compound-I, compound-LC-27 and Compound-LC-34 isomers; hence it was subjected to preparative HPLC purification to get rid of aforementioned undesired isomers.
Crude Purity by HPLC: 66.21%
Purity by HPLC: 91.71%
1HNMR (400 MHz, CDC13):
5 7.83-7.815 (d, 2H, J 8.0 Hz), 7.411-7.391 (m, 2H), 4.943-4.939 (d, 0.1H, J=1.6Hz-
Isomer), 4.920-4.905 (m, 0.78H), 4.889 (bs, 0.12H-Isomer), 4.846 (s, 0.9H), 4.813- 4.802 (m, 0.15H-Isomer), 4.779-4.775 (d, 0.8H, J=1.6 Hz), 4.673-4.668 (d, 0.86 H, J=2.0 Hz), 4.431-4.395 (m, 0.24H-Isomer), 4.311 (m, 0.79H), 4.016-3.952 (m, 1H), 3.848-3.772 (m, 3H), 3.692-3.538 (m, 5H), 3.504-3.465 (dd, 1H, J=10.0, 5.2 Hz), 3.434 (s, 3H), 3.405-3.354 (m, 1H), 3.020-3.00 (m, 2H), 2.655-2.596 (ddd, 1H, J=15.6, 6.4, 1.6 Hz), 2.534-2.500 (m, 1H), 2.464 (s, 3H), 2.274-2.163 (m, 3H), 2.047-1.984 (m, 1H), 1.903-1.799 (m, 2H), 1.767-1.730 (m, 1H), 1.688-1.502 (m, 8H), 1.47-1.388 (m, 2H), 1.306-1.219 (m, 4H), 1.078-1.047 (m, 4H), 0.904-0.860 (m, 22H), 0.101 (s, 3H), 0.095 (s, 3H), 0.051 (s, 3H), 0.045 (s, 3H).
13C NMR(400 MHz, CDCh): 151.12, 150.57, 144.98, 136.76, 130.08, 128.00, 130.08, 128.00, 104.87, 85.76, 80.72, 79.57, 78.28, 77.24, 76.82, 75.32, 71.38, 67.84, 62.80, 58.17, 57.51, 43.44, 42.66, 38.97, 37.51, 35.50, 33.09, 32.27, 31.67, 31.56, 31.25, 29.65, 25.98, 25.94, 22.63, 21.60, 18.37, 18.17, 17.89, -4.08, -4.73, -5.34.
Mass: m/Z: 865.33 (M+H), 887.31 (M+Na).
Example- 5: Purification of compound of formula -I
11.0 g of compound-I admixed with diastereomers (compound- I-C-34, compound-I-C- 27) was purified by preparative HPLC to get 6.98 g of Pure compound-I which is free of diastereomers Pure fractions were eluted in MTBE:Hexane (4:6).
Final weight of pure compound I: 6.98 g (from 15.0 g of compound- V)
Yield: 50% from compound-V
Purity by HPLC: 98.71%.
C-34 Isomer by chiral HPLC: 0.29%
C-27 Isomer: 0.02%
Example- 6: Alternate Purification of compound of formula -I
105.3 g of compound-I crude was purified by flash chromatography using 35% MTBE- Hexane as eluent. Impure fractions from flash purification were reloaded on preparative HPLC to get a combined yield of 21.6 g of pure compound-I using 40% MTBE-Hexane as eluent.
Final weight of pure compound I: 21.6 g
Purity by HPLC: 97.53%.
C-34 Isomer by chiral HPLC: 0.51%.
C-27 Isomer: Not Detected.
Claims
1. A compound of formula I.
compound of formula I.
2. A process for the preparation of a compound of formula IA comprising the steps of: a) reacting the compound of formula - II with a base to get the compound of formula-IA, b) optionally purifying the compound of formula -IA.
Wherein R1 is - SO2Ph or SO2PhMe and R2 is an alcohol - protecting group.
3. A process for the preparation of a compound of formula I comprising the steps of: a) reacting the compound of formula - II with a base to get the compound of formula-I, b) optionally purifying the compound of formula -I.
Compound-ll
Compound-I A process as claimed in claims 2 and 3, wherein base used in step a) is selected from Sodium methoxide, sodium ethoxide, potassium tertiary butoxide and sodium tertiary butoxide. A process as claimed in claims 2 and 3, wherein purification of compound of formula-I in step b) is carried out using preparative HPLC, flash chromatography.
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