WO2023223346A1 - An improved process for the preparation of edoxaban intermediate - Google Patents
An improved process for the preparation of edoxaban intermediate Download PDFInfo
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- WO2023223346A1 WO2023223346A1 PCT/IN2023/050454 IN2023050454W WO2023223346A1 WO 2023223346 A1 WO2023223346 A1 WO 2023223346A1 IN 2023050454 W IN2023050454 W IN 2023050454W WO 2023223346 A1 WO2023223346 A1 WO 2023223346A1
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- formula
- boc
- amino
- amide
- pyridine
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 229960000622 edoxaban Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 title claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- -1 5-chloropyridin-2-yl Chemical group 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims 1
- PSMMNJNZVZZNOI-SJILXJHISA-N edoxaban tosylate hydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 PSMMNJNZVZZNOI-SJILXJHISA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- LSQWUGYWDZRKNW-UHFFFAOYSA-N ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate Chemical compound CCOC(=O)C(=O)NC1=CC=C(Cl)C=N1 LSQWUGYWDZRKNW-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- ZLFZITWZOYXXAW-QXXZOGQOSA-N edoxaban tosylate Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 ZLFZITWZOYXXAW-QXXZOGQOSA-N 0.000 description 2
- 229960005378 edoxaban tosylate Drugs 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YJDLJNAWLBVIRF-AEGPPILISA-N tert-butyl n-[(1r,2s,5s)-2-[[2-[(5-chloropyridin-2-yl)amino]-2-oxoacetyl]amino]-5-(dimethylcarbamoyl)cyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)N(C)C)CC[C@@H]1NC(=O)C(=O)NC1=CC=C(Cl)C=N1 YJDLJNAWLBVIRF-AEGPPILISA-N 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
- 108010074860 Factor Xa Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- RIRGRLHCMHZKCO-UHFFFAOYSA-N carbamic acid;oxalic acid Chemical compound NC(O)=O.OC(=O)C(O)=O RIRGRLHCMHZKCO-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229940127216 oral anticoagulant drug Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 229940011622 savaysa Drugs 0.000 description 1
- JCHIBKSSZNWERE-GARJFASQSA-N tert-butyl n-[(1r,2s,5s)-2-amino-5-(dimethylcarbamoyl)cyclohexyl]carbamate Chemical compound CN(C)C(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1 JCHIBKSSZNWERE-GARJFASQSA-N 0.000 description 1
- IERZZGXDUZIMSC-PBDVDRNWSA-N tert-butyl n-[(1r,2s,5s)-2-amino-5-(dimethylcarbamoyl)cyclohexyl]carbamate;oxalic acid Chemical class OC(=O)C(O)=O.CN(C)C(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1 IERZZGXDUZIMSC-PBDVDRNWSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present invention relates to an improved process for the preparation of Edoxaban intermediate.
- Edoxaban (sold by trade names Savaysa, Lixiana) is an oral anticoagulant drug that exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and is useful as a preventive and/or therapeutic drug for thrombotic diseases.
- U.S. Patent No. 7,365,205 B2 disclosed Edoxaban and its pharmaceutical acceptable salts. US’205 also disclosed process for the preparation of Edoxaban, wherein the process involves the use of t-Butyl ⁇ (lR,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate.
- U.S. Patent No. 8,357,808B2 disclosed a process for the preparation of Edoxaban intermediate tert-butyl (1R, 2S, 5S)-2-( ⁇ (2-[5-chloro pyridine-2-yl) amino]-2-oxoacetyl]amino)-5- (dimethylamino)carbonyl)-cyclohexane carbamate involves, reacting tert-butyl ⁇ (1R,2S,5S)- 2-amino-5-[(dimethylamino) carbonyl] cyclohexyl ⁇ carbamate oxalate salt with hydrochloride salt of ethyl 2- ( (5-chloropyridin-2-yl) amino) -2-oxoacetate in the presence of with a tertiary amine in a solvent.
- U.S. Patent No. 9,44,7118B2 disclosed a process for the preparation of Edoxaban intermediate [tert-butyl N- ((1R, 2S, 5S)-2- ((2- ((5-chloropyridin-2-yl )amino) -2-oxoacetyl )amino) -5- (dimethylcarbamoyl )cyclohexyl )carbamate] involves, reacting tert-butyl N- ( (1R, 2S, 5S) - 2-amino-5-(dimethylcarbamoyl ) cyclohexyl ) carbamate oxalate salt with hydrochloride salt of ethyl 2- ( (5-chloropyridin-2-yl) amino) -2-oxoacetate in the presence of base and solvent.
- WO2019158550 disclosed a process for the preparation of Edoxaban intermediate [tert-butyl N- ((1R, 2S, 5S)-2- ((2- ((5-chloropyridin-2-yl )amino) -2-oxoacetyl )amino) -5- (dimethylcarbamoyl )cyclohexyl )carbamate] involves, reacting tert-butyl N- ( (1R, 2S, 5S) - 2-amino-5-(dimethylcarbamoyl ) cyclohexyl ) carbamate with ethyl 2- ( (5-chloropyridin-2-yl) amino) -2-oxoacetate in the presence of base and solvent.
- the present inventors developed an improved process for the preparation of tert-butyl (1R, 2S, 5S)-2-( ⁇ (2- [5-chloro pyridine-2-yl) amino] -2-oxoacetyl ⁇ amino)-5-(dimethylamino)carbonyl) - cyclohexane carbamate [BOC pyridine amide], an intermediate of Edoxaban tosylate, which can be easily scalable commercially with good yield and purity.
- the principal aspect of the present invention provides an improved process for the preparation of Tertiary butyl-(lR,2S,5S)-2- ⁇ (2-[(5-Chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5- (dimethylamino)-carbonyl]-cyclohexyl carbamate[BOC pyridine amide] or a salt represented by the formula 1.
- Another aspect of the present invention provides process for the preparation of Tertiary butyl- (lR,2S,5S)-2- ⁇ (2-[(5-Chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5-(dimethylamino)- carbonyl] -cyclohexyl carbamate[BOC pyridine amide] or a salt comprising the steps of: a) reacting compound of formula 2 [BOC amino amide]
- Boc represents a tert-butoxycarbonyl group
- compound of formula 3 [Chloro pyridine acid Hydrochloride] in presence of a solvent and with or without base.
- Yet another aspect of the present invention provides the compound of formula I prepared according to the present invention is converted to Edoxaban and/or its pharmaceutically acceptable salts.
- the BOC pyridine amide of Formula 1, prepared according to the present invention has a purity of about 99.6% with a yield of about 85%.
- Yet another aspect of the present invention provides compound of formula or its pharmaceutically acceptable salts.
- the main embodiment of the present invention relates to an improved process for the preparation of Tertiary butyl-(lR,2S,5S)-2- ⁇ (2-[(5-Chloropyridin-2-yl) amino] -2-oxoacetyl ⁇ - amino)-5-(dimethylamino)-carbonyl]-cyclohexyl carbamate [BOC pyridine amide] or a salt represented by the formula 1.
- Another embodiment of the present invention relates to process for the preparation of Tertiary butyl-( lR,2S,5S)-2- ⁇ (2- [(5-Chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5-
- compound of the formula 2 [BOC amino amide] may be taken in a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added compound formula 3 [Chloro pyridine acid Hydrochloride] followed by addition of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [EDAC] hydrochloric acid at room temperature and reaction may be maintained for about 20 hours at same temperature. After completion of reaction, water may be added and stirred for 2 hours at same temperature.
- a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added compound formula 3 [Chloro pyridine acid Hydrochloride] followed by addition of Hydr
- compound of the formula 2 [BOC amino amide] may be taken in a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added Chloro pyridine acid followed by addition of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide [EDAC] hydrochloric acid at room temperature and reaction may be maintained for about 20 hours at same temperature. After completion of reaction, water may be added and stirred for 2 hours at same temperature. Obtained crude was filtered and dried to get BOC pyridine amide. Further crude may be added with triethylamine in water solution or purified in acetonitrile and water. The solid obtained may be filtered and dried to obtain pure compound of the formula 1[BOC pyridine amide].
- a solvent selected from group consisting of Acetonitrile,
- compound of the formula 2 [BOC amino amide] may be taken in a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added compound formula 3 [Chloro pyridine acid Hydrochloride] followed by addition of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [EDAC] hydrochloric acid and base selected from the group consisting of triethylamine or diisopropyl ethyl amine at room temperature and reaction maintained for 20 hours at same temperature.
- a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added compound formula 3 [Chloro pyridine acid Hydrochlor
- the BOC pyridine amide of Formula 1, prepared according to the present invention has a purity of about 99.6% with a yield of about 85%.
- the present invention relates to compound of formula or its pharmaceutically acceptable salts.
- the present invention relates to process for the preparation of Edoxaban using compound of formula 1 prepared according to the present invention comprising the steps of
- Edoxaban prepared according to the above scheme may be further converted into its pharmaceutically acceptable salts.
- composition comprising Edoxaban tosylate prepared according to the present invention and a pharmaceutically acceptable excipient.
- Example-1 To a stirred solution of Boc aminoamide (5g) in Acetonitrile (50ml) was added Chloro pyridine acid Hydrochloride (4.55g), Hydroxybenzotriazole [HOBT] (2.71g) and EDAC HC1 (4.2g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water( 100ml) was added and stirred for 2 hours at same temperature. Obtain white precipitate filtered and dried under vacuum oven to get BOC pyridine amide crude product(7.6g).
- Example -2 To a stirred solution of Boc aminoamide (5g) in Dichloromethane (50ml) was added
- Example-3 To a stirred solution of Boc aminoamide (10g) in Acetonitrile (100ml) was added Chloro pyridine acid Hydrochloride (8.71g), HOBT (5.4g) and EDAC HC1 (8.39g) and Triethylamine (5.3g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water(200ml) was added and stirred for 2 hours at same temperature. Obtain white precipitate filtered and wash with Acetonitrile and water (1:2 mixture) (3x10ml) then dry the wet product under hot air oven for 6h at 55 °C to obtain pure Boc pyridine amide (10g, 60.9%).
- Example-4 To a stirred solution of Boc aminoamide (5g) in Acetonitrile (50ml) was added Chloro pyridine acid (4.55g), Hydroxy benzotriazole [HOBT] (2.71g) and EDAC HC1 (4.2g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water(lOOml) was added and stirred for 2 hours at same temperature. Obtain white precipitate filtered and dried under vacuum oven to get BOC pyridine amide crude product(7.6g).
Abstract
The present invention relates to an improved process for the preparation of Edoxaban intermediate and further preparation of Edoxaban or its pharmaceutically acceptable salts.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF EDOXABAN INTERMEDIATE
CROSS-REFERENCE TO RELATED APPLICATIONS:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN202241028041 filed on May 16, 2022; the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Edoxaban intermediate.
BACKGROUND OF THE INVENTION:
Edoxaban (sold by trade names Savaysa, Lixiana) is an oral anticoagulant drug that exhibits an inhibitory effect on activated blood coagulation factor X (FXa) and is useful as a preventive and/or therapeutic drug for thrombotic diseases.
It is chemically known as N'-(5-chloropyridin-2-yl)-N-[(lS,2R,4S)-4-(dimethylcarbamoyl)-2- [(5-methyl-6,7 -dihydro-4H- [1,3] thiazolo [5 ,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide p-toluene sulfonate monohydrate represented by the following formula (A).
Formula-A
U.S. Patent No. 7,365,205 B2 disclosed Edoxaban and its pharmaceutical acceptable salts. US’205 also disclosed process for the preparation of Edoxaban, wherein the process involves the use of t-Butyl {(lR,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate. Further it disclosed, reacting tert-butyl {(lR,2S,5S)-2-amino-5-[(dimethylamino)
carbonyl]cyclohexyl}carbamate with lithium salt of ethyl 2- ( (5-chloropyridin-2-yl) amino) - 2-oxoacetate to obtain tertiary butyl-(lR,2S,5S)-2-{(2-[(5-Chloropyridin-2-yl) amino]-2- oxoacetyl}-amino)-5-(dimethylamino)-carbonyl]-cyclohexyl carbamate.
U.S. Patent No. 8,357,808B2 disclosed a process for the preparation of Edoxaban intermediate tert-butyl (1R, 2S, 5S)-2-({(2-[5-chloro pyridine-2-yl) amino]-2-oxoacetyl]amino)-5- (dimethylamino)carbonyl)-cyclohexane carbamate involves, reacting tert-butyl {(1R,2S,5S)- 2-amino-5-[(dimethylamino) carbonyl] cyclohexyl} carbamate oxalate salt with hydrochloride salt of ethyl 2- ( (5-chloropyridin-2-yl) amino) -2-oxoacetate in the presence of with a tertiary amine in a solvent.
U.S. Patent No. 9,44,7118B2 disclosed a process for the preparation of Edoxaban intermediate [tert-butyl N- ((1R, 2S, 5S)-2- ((2- ((5-chloropyridin-2-yl )amino) -2-oxoacetyl )amino) -5- (dimethylcarbamoyl )cyclohexyl )carbamate] involves, reacting tert-butyl N- ( (1R, 2S, 5S) - 2-amino-5-(dimethylcarbamoyl ) cyclohexyl ) carbamate oxalate salt with hydrochloride salt of ethyl 2- ( (5-chloropyridin-2-yl) amino) -2-oxoacetate in the presence of base and solvent.
WO2019158550 disclosed a process for the preparation of Edoxaban intermediate [tert-butyl N- ((1R, 2S, 5S)-2- ((2- ((5-chloropyridin-2-yl )amino) -2-oxoacetyl )amino) -5- (dimethylcarbamoyl )cyclohexyl )carbamate] involves, reacting tert-butyl N- ( (1R, 2S, 5S) - 2-amino-5-(dimethylcarbamoyl ) cyclohexyl ) carbamate with ethyl 2- ( (5-chloropyridin-2-yl) amino) -2-oxoacetate in the presence of base and solvent.
The present inventors developed an improved process for the preparation of tert-butyl (1R, 2S, 5S)-2-( { (2- [5-chloro pyridine-2-yl) amino] -2-oxoacetyl } amino)-5-(dimethylamino)carbonyl) - cyclohexane carbamate [BOC pyridine amide], an intermediate of Edoxaban tosylate, which can be easily scalable commercially with good yield and purity.
OBJECT AND SUMMARY OF THE INVENTION:
The principal aspect of the present invention provides an improved process for the preparation of Tertiary butyl-(lR,2S,5S)-2-{(2-[(5-Chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5- (dimethylamino)-carbonyl]-cyclohexyl carbamate[BOC pyridine amide] or a salt represented by the formula 1.
Formula 1
Another aspect of the present invention provides process for the preparation of Tertiary butyl- (lR,2S,5S)-2-{(2-[(5-Chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5-(dimethylamino)- carbonyl] -cyclohexyl carbamate[BOC pyridine amide] or a salt comprising the steps of: a) reacting compound of formula 2 [BOC amino amide]
Formula 2
(wherein Boc represents a tert-butoxycarbonyl group),) with compound of formula 3 [Chloro pyridine acid Hydrochloride] in presence of a solvent and with or without base.
Formula 3
Yet another aspect of the present invention provides the compound of formula I prepared according to the present invention is converted to Edoxaban and/or its pharmaceutically acceptable salts.
The BOC pyridine amide of Formula 1, prepared according to the present invention has a purity of about 99.6% with a yield of about 85%.
Yet another aspect of the present invention provides compound of formula
or its pharmaceutically acceptable salts.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention relates to an improved process for the preparation of Tertiary butyl-(lR,2S,5S)-2-{(2-[(5-Chloropyridin-2-yl) amino] -2-oxoacetyl}- amino)-5-(dimethylamino)-carbonyl]-cyclohexyl carbamate [BOC pyridine amide] or a salt represented by the formula 1.
Formula 1
Another embodiment of the present invention relates to process for the preparation of Tertiary butyl-( lR,2S,5S)-2-{(2- [(5-Chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5-
(dimethylamino)-carbonyl] -cyclohexyl carbamate[BOC pyridine amide] or a salt comprising the steps of: a) reacting compound of formula 2 [BOC amino amide]
Formula 2
((wherein Boc represents a tert-butoxycarbonyl group),) with compound of formula 3 [Chloro pyridine acid Hydrochloride] in presence of a solvent and with or without base.
Formula 3
According to the present invention, compound of the formula 2 [BOC amino amide] may be taken in a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added compound formula 3 [Chloro pyridine acid Hydrochloride] followed by addition of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [EDAC] hydrochloric acid at room temperature and reaction may be maintained for about 20 hours at same temperature. After completion of reaction, water may be added and stirred for 2 hours at same temperature. Obtained crude was filtered and dried to get BOC pyridine amide. Further crude may be added with triethylamine in water solution or purified in acetonitrile and water. The solid obtained may be filtered and dried to obtain pure compound of the formula 1[BOC pyridine amide].
According to the present invention, compound of the formula 2 [BOC amino amide] may be taken in a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added Chloro pyridine acid followed by addition of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide [EDAC] hydrochloric acid at room temperature and reaction may be maintained for about 20 hours at same temperature. After completion of reaction, water may be added and stirred for 2 hours at same temperature. Obtained crude was filtered and dried to get BOC pyridine amide. Further crude may be added with triethylamine in water solution or purified in acetonitrile and water. The solid obtained may be filtered and dried to obtain pure compound of the formula 1[BOC pyridine amide].
According to the present invention, compound of the formula 2 [BOC amino amide] may be taken in a solvent selected from group consisting of Acetonitrile, Dichloromethane, Ethyl acetate, isopropyl acetate, N,N-dimethylformamide, Tetrahydrofuran and added compound formula 3 [Chloro pyridine acid Hydrochloride] followed by addition of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide [EDAC] hydrochloric acid and base selected from the group consisting of triethylamine or diisopropyl ethyl amine at room temperature and reaction maintained for 20 hours at same temperature. After completion of reaction, water may be added and stirred for 2 hours at same temperature. Obtained crude was filtered and dried to get BOC pyridine amide. Further crude may be purified with acetonitrile in water solution. The solid obtained may be filtered and dried to obtain pure compound of the formula 1[BOC pyridine amide].
The BOC pyridine amide of Formula 1, prepared according to the present invention has a purity of about 99.6% with a yield of about 85%.
In yet another embodiment, the present invention relates to compound of formula
or its pharmaceutically acceptable salts.
Yet another embodiment, the present invention relates to process for the preparation of Edoxaban using compound of formula 1 prepared according to the present invention comprising the steps of
Edoxaban prepared according to the above scheme may be further converted into its pharmaceutically acceptable salts.
Pharmaceutical composition comprising Edoxaban tosylate prepared according to the present invention and a pharmaceutically acceptable excipient.
The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
EXAMPLES:
Example-1: To a stirred solution of Boc aminoamide (5g) in Acetonitrile (50ml) was added Chloro pyridine acid Hydrochloride (4.55g), Hydroxybenzotriazole [HOBT] (2.71g) and EDAC HC1 (4.2g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water( 100ml) was added and stirred for 2 hours at same temperature. Obtain white precipitate filtered and dried under vacuum oven to get BOC pyridine amide crude product(7.6g). Obtained crude product was added Triethylamine (5ml) dilute in water(50ml) solution and stir for 2h at 25°C temperature, filter the solid and solid wash with water then dry the wet product under hot air oven for 6h at 55°C to obtain pure Boc pyridine amide (6.9g, 84%: Purity:99.6%).
Example -2: To a stirred solution of Boc aminoamide (5g) in Dichloromethane (50ml) was added
Chloro pyridine acid hydrochloride (4.55g), HOBT (2.71g) and EDAC HC1 (4.2g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water(lOOml) was added and stirred for 15mins. Separated the layers and organic extracts distilled under atmospheric pressure then vacuum to get crude Boc pyridine amide (8.5g). Obtained crude product was purified in acetonitrile(50ml) and water(lOOml) mixture at 25°C for 2h. filter the solid and solid wash with water then dry the wet product under hot air oven for 6h at 55°C to obtain pure Boc pyridine amide (4.5g, 54%: Purity:95.2%).
Example-3: To a stirred solution of Boc aminoamide (10g) in Acetonitrile (100ml) was added Chloro pyridine acid Hydrochloride (8.71g), HOBT (5.4g) and EDAC HC1 (8.39g) and Triethylamine (5.3g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water(200ml) was added and stirred for 2 hours at same temperature. Obtain white precipitate filtered and wash with Acetonitrile and water (1:2 mixture) (3x10ml) then dry the wet product under hot air oven for 6h at 55 °C to obtain pure Boc pyridine amide (10g, 60.9%).
Example-4: To a stirred solution of Boc aminoamide (5g) in Acetonitrile (50ml) was added Chloro pyridine acid (4.55g), Hydroxy benzotriazole [HOBT] (2.71g) and EDAC HC1 (4.2g) at 25°C temperature and reaction maintained for 20hours at same temperature. After completion of reaction, water(lOOml) was added and stirred for 2 hours at same temperature.
Obtain white precipitate filtered and dried under vacuum oven to get BOC pyridine amide crude product(7.6g). Obtained crude product was added Triethylamine (5ml) dilute in water(50ml) solution and stir for 2h at 25°C temperature, filter the solid and solid wash with water then dry the wet product under hot air oven for 6h at 55°C to obtain pure Boc pyridine amide (6.7g, 80%).
Claims
1. A process for the preparation of Tertiary butyl-(lR,2S,5S)-2-{(2-[(5-chloropyridin-2-yl) amino]-2-oxoacetyl]-amino)-5-(dimethylamino)-carbonyl]-cyclohexyl carbamate [BOC pyridine amide] of formula 1 or a salt comprising the steps of:
Formula 1 a) reacting BOC amino amide, compound of formula 2
Formula 2 wherein Boc represents a tert-butoxycarbonyl group with compound of formula 3 [Chloro pyridine acid hydrochloride] or chloro pyridine acid in presence of Hydroxybenzotriazole [HOBT] and l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide [EDAC] hydrochloric acid.
Formula 3
2. The process as claimed in claim 1, in carried in presence of a solvent selected from acetonitrile, dichloromethane, ethyl acetate, isopropyl acetate, N, N-dimethylformamide or tetrahydrofuran or their mixtures thereof.
3. The process as claimed in claim 1, is carried in presence or absence of a base.
4. The process as claimed in claim 3, wherein the base is selected from triethylamine or diisopropyl ethyl amine.
5. The process as claimed claim 1, wherein the BOC pyridine amide of formula 1 is purified in
acetonitrile and water to obtain pure BOC pyridine amide.
6. The process as claimed claim 1, wherein BOC pyridine amide of formula 1 is further converted into Edoxaban or its pharmaceutically acceptable salts.
7. The BOC pyridine amide of Formula- 1 prepared as claimed in claim 1 have a purity of 99.6% by HPLC.
8. A compound of formula
or its pharmaceutically acceptable salts.
9. The compound as claimed in claim 8, wherein the salt is hydrochloride.
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| IN202241028041 | 2022-05-16 | ||
| IN202241028041 | 2022-05-16 |
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|---|---|---|---|---|
| US7365205B2 (en) | 2001-06-20 | 2008-04-29 | Daiichi Sankyo Company, Limited | Diamine derivatives |
| US8357808B2 (en) | 2009-03-10 | 2013-01-22 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
| CN105399667A (en) * | 2015-12-15 | 2016-03-16 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of edoxaban intermediate |
| US9447118B2 (en) | 2013-03-29 | 2016-09-20 | Daiichi Sankyo Company, Limited | Preparation method of optically active diamine compound |
| WO2019158550A1 (en) | 2018-02-14 | 2019-08-22 | Moehs Iberica, S.L. | Method for preparing tert-butyl n-((1r,2s,5s)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacetyl)amino)-5-(dimethylcarbamoyl)cyclohexyl)carbamate |
| KR20190139463A (en) * | 2018-06-08 | 2019-12-18 | 주식회사 가피바이오 | The fabrication method of intermediate for fabricating edoxabane and the fabrication method of edoxabane |
| CN112321613A (en) * | 2020-11-06 | 2021-02-05 | 江苏华阳制药有限公司 | Preparation method of idoxaban tosylate and isomer thereof |
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2023
- 2023-05-15 WO PCT/IN2023/050454 patent/WO2023223346A1/en unknown
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7365205B2 (en) | 2001-06-20 | 2008-04-29 | Daiichi Sankyo Company, Limited | Diamine derivatives |
| US8357808B2 (en) | 2009-03-10 | 2013-01-22 | Daiichi Sankyo Company, Limited | Process for producing diamine derivative |
| US9447118B2 (en) | 2013-03-29 | 2016-09-20 | Daiichi Sankyo Company, Limited | Preparation method of optically active diamine compound |
| CN105399667A (en) * | 2015-12-15 | 2016-03-16 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of edoxaban intermediate |
| WO2019158550A1 (en) | 2018-02-14 | 2019-08-22 | Moehs Iberica, S.L. | Method for preparing tert-butyl n-((1r,2s,5s)-2-((2-((5-chloropyridin-2-yl)amino)-2-oxoacetyl)amino)-5-(dimethylcarbamoyl)cyclohexyl)carbamate |
| KR20190139463A (en) * | 2018-06-08 | 2019-12-18 | 주식회사 가피바이오 | The fabrication method of intermediate for fabricating edoxabane and the fabrication method of edoxabane |
| CN112321613A (en) * | 2020-11-06 | 2021-02-05 | 江苏华阳制药有限公司 | Preparation method of idoxaban tosylate and isomer thereof |
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