CN114478663A - Preparation method of fondaparinux sodium impurity - Google Patents
Preparation method of fondaparinux sodium impurity Download PDFInfo
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- CN114478663A CN114478663A CN202011260455.9A CN202011260455A CN114478663A CN 114478663 A CN114478663 A CN 114478663A CN 202011260455 A CN202011260455 A CN 202011260455A CN 114478663 A CN114478663 A CN 114478663A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000012535 impurity Substances 0.000 title claims abstract description 31
- XEKSTYNIJLDDAZ-JASSWCPGSA-F fondaparinux sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C(O)=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-F 0.000 title claims abstract description 19
- 229960003661 fondaparinux sodium Drugs 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000000126 substance Substances 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 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 claims description 10
- -1 sulfate compound Chemical class 0.000 claims description 10
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000006277 sulfonation reaction Methods 0.000 claims description 9
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical group [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 7
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 7
- 229910001415 sodium ion Inorganic materials 0.000 claims description 7
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 239000003729 cation exchange resin Substances 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000005342 ion exchange Methods 0.000 claims description 6
- 239000011347 resin Substances 0.000 claims description 6
- 229920005989 resin Polymers 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 125000005258 alkyl aryl acyl group Chemical group 0.000 claims description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 4
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000005251 aryl acyl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 238000006264 debenzylation reaction Methods 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 2
- 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 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000004451 qualitative analysis Methods 0.000 abstract 1
- 238000004445 quantitative analysis Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 239000013558 reference substance Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- 239000003480 eluent Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000009987 spinning Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N beta-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of fondaparinux sodium impurity, which is simple and convenient to operate and stable in process, and the obtained impurity has high purity and can be synthesized in large quantity. The compound can be used as a reference substance for qualitative and quantitative analysis of related substances of fondaparinux sodium, is used for impurity research of fondaparinux sodium raw material medicines and preparations, and improves the safety of products.
Description
Technical Field
The invention relates to a preparation method of fondaparinux sodium impurity, belonging to the technical field of medicines.
Background
Fondaparinux sodium is a new generation antithrombotic agent jointly developed by Xenoffine and the company of Ougangno, is an artificially synthesized pentose substance, and specifically inhibits Xa factor in blood coagulation cascade to finally show anticoagulant effect. The chemical name of fondaparinux sodium is: methyl O- (2-deoxy-6-O-sulfonic acid group-2-sulfonylamino group- α -D-glucopyranose) - (1 → 4) -O- (β -D-glucopyranose-uronic acid) - (1 → 4) -O- (2-deoxy-3, 6-O-disulfonic acid group-2-sulfonylamino group- α -D-glucopyranose) - (1 → 4) -O- (2-O-sulfonic acid group- α -L-iduronic acid) - (1 → 4) -2-deoxy-6-O-sulfonic acid group-2-sulfonylamino group- α -D-glucopyranoside decasodium salt, the structural formula is as follows:
the fondaparinux sodium and AT III are specifically combined, and inhibit the activity of blood coagulation factor Xa to prevent the formation of thrombus. The blood clearance t1/2 is 13-21 h, and the injection is given 1 time per day. Patients typically do not require routine monitoring of coagulation during injection. The fondaparinux sodium injection is approved by EMA 12 months in 2001 and approved by FDA in the United states to be put on the market in the early 2002.
The chemical name of the fondaparinux sodium impurity compound I is methyl (2-deoxy-2-sodium sulfamate-6-O-sodium sulfonate-alpha-D-glucopyranose) - (1 → 4) - (beta-D-sodium glucopyranosate) - (1 → 4) - (2-deoxy-2-sodium sulfamate-3, 6-di-O-sodium sulfonate-alpha-D-glucopyranose) - (1 → 4) - (2, 3-di-O-sodium sulfonate-alpha-L-sodium pyranoiduronate) -2-deoxy-2-sodium sulfamate-6-O-sodium sulfonate-alpha-D-glucopyranoside, the structural formula is as follows:
impurity compound i has an Rrt of 0.93 in the united states pharmacopeia relative to fondaparinux sodium. The impurities are usually separated and purified from the fondaparinux sodium reaction liquid or crude product, but the content of the impurities in the reaction liquid or the crude product is low, the difficulty of obtaining a large amount of impurities is high, and the cost is high. However, the existing synthesis method of the impurity compound I has no report, and the existence of the impurity is directly related to the quality and safety of the medicine, so that the synthesis and identification of the impurity compound I have important significance for the quality control of the product.
Disclosure of Invention
The invention aims to provide a preparation method of a fondaparinux sodium impurity compound I, which has the advantages of reasonable process design, stable and controllable reaction process and higher purity of the obtained compound and has important significance for the quality research of fondaparinux sodium and preparations.
The invention provides a preparation method of a fondaparinux sodium impurity compound I, which comprises the following steps:
step 1: preparation of Compound IV
Reacting the compound II with the compound III under the action of a coupling catalyst to obtain a compound IV;
step 2: preparation of Compound V
Hydrolyzing the compound IV under an alkaline condition, and adjusting the pH value to be acidic by hydrochloric acid to obtain a compound V;
and step 3: preparation of Compound VI
Reacting the compound V with a sulfonation reagent A to generate a sulfate compound, and performing sodium ion exchange on the sulfate compound to obtain a compound VI;
and 4, step 4: preparation of Compound VII
The compound VI is subjected to reduction and debenzylation reaction under the action of a catalyst to obtain a compound VII;
and 5: preparation of impurity Compound I
Reacting the compound VII with a sulfonation reagent B to generate a sulfonate compound, and performing sodium ion exchange on the sulfonate compound and purifying to obtain an impurity compound I;
in compounds II or IV, aR is as described1、R2、R3Each independently is any one of benzoyl, alkyl acyl, aryl acyl, alkyl aryl acyl or alkyl aryl acyl substituted by halogen, ethoxy carbonyl, tert-butoxy carbonyl, allyl oxy carbonyl and carbonic ester protecting group.
Further, in the step 1, the molar ratio of the compound II to the compound III to the coupling catalyst is preferably 1:0.9 to 1.1:0.8 to 1.2.
Further, preferably, in step 1, the coupling catalyst is one or a mixture of two or more of TBDMSOTf, TMSOTf and AgOTf.
Further, in the step 1, the reaction temperature is preferably-20 to-40 ℃, and the reaction time is preferably 2 to 6 hours.
Further, preferably, in step 2, the alkaline condition is provided by an alkaline substance, and the alkaline substance is one or a mixture of any of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate; the reaction temperature is 10-60 ℃, and preferably 20-30 ℃; the reaction solvent adopted in the hydrolysis reaction can be a mixed system of one or more of methanol, ethanol, tetrahydrofuran and dioxane and water; the reaction also comprises a recrystallization step, and the recrystallization system can be ethyl acetate/n-hexane, ethyl acetate/petroleum ether.
Further, preferably, in step 3, the sulfonating agent A may be trimethyl ammonium sulfur trioxide copolymer (SO)3NMe3) Sulfur trioxide pyridine complex (SO)3Py), chlorosulfonic acid and sulfamic acid or a mixture of any more of them; the sulfonation reagent A is 15-20 molar equivalents of the compound V.
Further, preferably, in the step 3, the reaction temperature is 40-80 ℃, preferably 50-70 ℃.
Further, in step 3, preferably, 732 cation exchange resin, Dowex 50WX4 resin, or one or more of sodium hydroxide and sodium carbonate can be used for sodium ion exchange.
Further, preferably, in the step 4, the catalyst may be one or a mixture of several of palladium carbon, palladium hydroxide, palladium acetate and palladium black; the mol ratio of the compound VI to the catalyst is 1: 0.1 to 2; the reaction solvent can be one or a mixture of ethanol, methanol and purified water; the reaction temperature can be 10-60 ℃, and the hydrogen pressure is 0.5-4 MPa; in order to improve the safety in the preparation process, purified water or purified water/alcohol greater than 70/30(v/v) is preferably used as a reaction solvent, the hydrogen pressure is 1.0-1.5 MP, and the reaction temperature is 20-30 ℃.
Further, preferably, in step 5, the sulfonating agent B may be sulfur trioxide and sulfur trioxide derivatives such as trimethyl ammonium sulfur trioxide copolymer (SO)3NMe3) Sulfur trioxide pyridine complex (SO)3Py), chlorosulfonic acid and sulfamic acid; preferably, the sulfonation reagent B is 6-10 molar equivalents of the compound VII; the reaction pH is 8-12, preferably 9-10; the reaction temperature is 6-14 ℃, and the preferable temperature is 8-12 ℃; the exchange process adopts exchange resin: 732 cation exchange resin, Dowex 50WX4 resin, or one or more of sodium hydroxide and sodium carbonate.
Compared with the prior art, the invention has the beneficial effects that:
the synthesis method provided by the invention has the advantages of simple operation and post-treatment, mild reaction conditions, stable process, high yield and good reproducibility, makes up for the blank that the impurity I has no preparation method, and lays a good foundation for the quality research and control of fondaparinux sodium.
Drawings
FIG. 1: MS (ESI) spectrum of impurity compound I;
FIG. 2: of impurity compound I1H NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to preferred examples, but the present invention is not limited thereto.
Examples 1-6 were all synthesized using compound ii to give compound v:
examples 7-8 were all synthesized using the following procedure to give compound vi:
examples 9-10 were all synthesized using the following procedure to give compound vii:
examples 11-12 were all synthesized using the following procedure to provide compound i:
example 1: preparation of Compound V
2.00g of Compound II-1 and 3.00g of Compound III were dissolved in 50ml of anhydrous dichloromethane, and 0.5ml of TBDMSOTf was added dropwise thereto at-20 ℃ and the reaction was continued for 2 hours. After stirring and quenching with triethylamine at-20 ℃ for 2 hours, the mixture was filtered and concentrated, and the obtained sample was chromatographed on 200-mesh 300-mesh silica gel using ethyl acetate/n-hexane (v/v. 1/3) as an eluent, to give 2.34g of compound IV-1 with a yield of 50.4%.
2.20g of compound IV-1 are added to 44ml of THF/H2O (v/v ═ 2/1) was dissolved with stirring, 22ml of 1N NaOH solution was added and the reaction was carried out at 20 ℃ for 12 hours, after completion of the reaction, the pH was adjusted to 3 with 1N HCl, extraction was carried out with dichloromethane, the organic phase was washed with saturated brine to neutrality, and dried over anhydrous sodium sulfate and dried by spinning to obtain 1.92g of a crude product. The crude product was dissolved in 7.7ml ethyl acetate and 3.8ml n-hexane was added dropwise, stirred for 3 hours, filtered and dried at 40 ℃ under vacuum to give 1.46g of compound V, 81.5% yield.
Example 2: preparation of Compound V
2.00g of Compound II-1 and 2.90g of Compound III were dissolved in 50ml of anhydrous dichloromethane, and 0.5ml of TMSOTf was added dropwise at-30 ℃ and the reaction was continued for 5 hours. After stirring and quenching with triethylamine at-30 ℃ for 2 hours, the mixture was filtered and concentrated, and the obtained sample was chromatographed on 200-mesh 300-mesh silica gel using ethyl acetate/n-hexane (v/v. 1/3) as an eluent, to give 2.16g of compound IV-1 in 46.5% yield.
2.10g of compound IV-1 are added to 42ml of THF/H2O (v/v ═ 2/1) was dissolved with stirring, 21ml of 1N KOH solution was added and the reaction was carried out at 25 ℃ for 12 hours, after completion, the pH was adjusted to 3 with 1N HCl, extraction was carried out with dichloromethane, the organic phase was washed with saturated brine to neutrality, and dried over anhydrous sodium sulfate and dried by spinning to obtain 1.71g of a crude product. The crude product was dissolved in 6.8ml of ethyl acetate, 3.4ml of n-hexane were added dropwise, stirred for 3 hours, crystallized, filtered and dried at 40 ℃ under vacuum to give 1.33g of compound V, yield 77.7%.
Example 3: preparation of Compound V
8.50g of Compound II-2 and 12.00g of Compound III were dissolved in 205ml of anhydrous dichloromethane, and 2ml of TBDMSOTf was added dropwise at-20 ℃ and the reaction was continued for 2 hours. After stirring and quenching with triethylamine at-20 ℃ for 2 hours, the mixture was filtered and concentrated, and the obtained sample was chromatographed on 200-mesh 300-mesh silica gel using ethyl acetate/n-hexane (v/v. 1/3) as an eluent, to give 10.61g of compound IV-2 with a yield of 56.1%.
10g of compound IV-2 are added to 200ml of THF/H2O (v/v ═ 2/1) was dissolved with stirring, 100ml of 1N NaOH solution was added and the reaction was carried out at 25 ℃ for 12 hours, after completion of the reaction, the pH was adjusted to 3 with 1N HCl, extraction was carried out with dichloromethane, the organic phase was washed with saturated brine to neutrality, and dried over anhydrous sodium sulfate and dried by spinning to obtain 9.12g of a crude product. The crude product was dissolved in 36.4ml ethyl acetate, 18.2ml n-hexane was added dropwise, stirred for 3 hours, filtered and dried under vacuum at 40 ℃ to give 6.60g of compound V, 83.7% yield.
Example 4: preparation of Compound V
4.00g of Compound II-2 and 6.00g of Compound III were dissolved in 100ml of anhydrous dichloromethane, and 1ml of TBDMSOTf was added dropwise at-20 ℃ and the reaction was continued for 4 hours. After stirring and quenching with triethylamine at-20 ℃ for 2 hours, the mixture was filtered and concentrated, and the obtained sample was chromatographed on 200-mesh 300-mesh silica gel using ethyl acetate/n-hexane (v/v. 1/3) as an eluent, to give 4.65g of compound IV-2 with a yield of 52.2%.
4.6g of compound IV-2 are added to 92ml of THF/H2O (v/v ═ 2/1) was dissolved with stirring, 46ml of 1N NaOH solution was added and the reaction was carried out at 25 ℃ for 12 hours, after completion of the reaction, the pH was adjusted to 3 with 1N HCl, extraction was carried out with dichloromethane, the organic phase was washed with saturated brine to neutrality, and dried over anhydrous sodium sulfate and dried by spinning to obtain 4.3g of a crude product. The crude product was dissolved in 17.2ml ethyl acetate and 8.6ml n-hexane was added dropwise, stirred for 3 hours, filtered and dried under vacuum at 40 ℃ to give 3.06g of compound V, 84.4% yield.
Example 5: preparation of Compound V
1.00g of Compound II-3 and 1.50g of Compound III were dissolved in 25ml of anhydrous dichloromethane, and 0.25ml of TBDMSOTf was added dropwise thereto at-20 ℃ and the reaction was continued for 2 hours. After stirring and quenching with triethylamine at-20 ℃ for 2 hours, the mixture was filtered and concentrated, and the obtained sample was chromatographed on 200-mesh 300-mesh silica gel using ethyl acetate/n-hexane (v/v. 1/3) as an eluent, to give 1.16g of compound IV-3 with a yield of 50.0%.
1.10g of compound IV-3 are added to 22ml of THF/H2O (v/v ═ 2/1) was dissolved with stirring, and 11ml of 1N NaOH solution was added to the solution and reacted at 20 ℃ for 12 hours, after completion of the reaction, the pH was adjusted to 3 with 1N HCl, extraction was performed with dichloromethane, the organic phase was washed with saturated brine to neutrality, and dried over anhydrous sodium sulfate and dried by spinning to obtain 0.90g of a crude product. The crude product was dissolved in 3.6ml of ethyl acetate, 1.8ml of n-hexane was added dropwise, stirred for 3 hours, crystallized, filtered and dried under vacuum at 40 ℃ to give 0.72g of compound V, yield 80.4%.
Example 6: preparation of Compound V
1.00g of Compound II-3 and 1.50g of Compound III were dissolved in 25ml of anhydrous dichloromethane, and 0.25ml of TBDMSOTf was added dropwise thereto at-20 ℃ and the reaction was continued for 2 hours. After stirring and quenching with triethylamine at-20 ℃ for 2 hours, the mixture was filtered and concentrated, and the obtained sample was chromatographed on 200-mesh 300-mesh silica gel using ethyl acetate/n-hexane (v/v. 1/3) as an eluent, to give 1.20g of compound IV-3 in 51.7% yield.
1.10g of compound IV-3 are added to 22ml of THF/H2O (v/v-2/1) was dissolved with stirring, and 11ml of 1N N was addedThe reaction was completed by adjusting the pH to 3 with 1N HCl after the reaction was completed, extracting with dichloromethane, washing the organic phase with saturated brine to neutrality, drying over anhydrous sodium sulfate and spin-drying to obtain 0.94g of a crude product. The crude product was dissolved in 3.6ml of ethyl acetate, 1.8ml of petroleum ether was added dropwise, stirred for 3 hours, crystallized, filtered and dried under vacuum at 40 ℃ to give 0.69g of compound V, yield 77.0%.
Example 7: preparation of Compound VI
6.50g of compound V, 10g of SO3NMe3Adding the mixture into 65ml of DMF, heating to 60 ℃ for reaction for 12 hours, concentrating the reaction solution under reduced pressure to obtain an oily substance, adding 13ml of dichloromethane/methanol to dissolve the oily substance (v/v-1/1), removing inorganic salts from the obtained solution by LH20 chromatography with dichloromethane/methanol (v/v-1/1) as an eluent, concentrating the chromatography solution under reduced pressure, dissolving the concentrated solution by using a proper amount of methanol/water (v/v-1/1), exchanging the concentrated solution by a 732 cation exchange resin with methanol/water (v/v-1/1) as an eluent, and concentrating to obtain 8.02g of a compound VI with the yield of 85.9%.
Example 8: preparation of Compound VI
3.00g of compound V, 5.00g of SO3NMe3Adding the mixture into 32ml of DMF, heating to 50 ℃ for reaction for 12 hours, adding ml of 4N sodium hydroxide solution after the reaction is finished, stirring for 2 hours, filtering, concentrating the filtrate under reduced pressure to obtain oily matter, adding 10ml of dichloromethane/methanol to dissolve the oily matter (v/v-1/1), removing inorganic salt by LH20 chromatography by taking dichloromethane/methanol (v/v-1/1) as an eluent to obtain 2.78g of compound VI by concentrating the chromatographic solution, wherein the yield is 64.5%.
Example 9: preparation of Compound VII
The hydrogenation reactor was charged with 7.80g of compound vi, 5.6g of 10% Pd/C, 156ml of ethanol/purified water (v/v: 3/7), and the reaction was carried out under a hydrogen pressure of 1.0MPa at 25 ℃ for 48 hours, and after completion of the reaction, 3.81g of compound vii was obtained by filtration and spin-drying, with a yield of 69.3%.
Example 10: preparation of Compound VII
The hydrogenation vessel was charged with 2.70g of Compound VI, 0.2g Pd (OAc)254ml of purified water, the pressure of hydrogen is 1.5MPa, the reaction is carried out for 64 hours at 40 ℃, and after the reaction is finished, the reaction is carried outFiltration and spin-drying gave 1.30g of compound VII, yield 68.3%.
Example 11: preparation of impurity Compound I
Dissolving 3.70g of compound VII in 74ml of purified water, controlling the temperature at 9-10 ℃, adjusting the pH of the solution to 9-10 by using 2N NaOH, and slowly adding 3.70g of SO3Py, maintaining the pH value of 9-10, reacting for 6 hours, after the reaction is finished, carrying out G25 chromatography on the reaction liquid by using purified water as an eluent, and concentrating under reduced pressure until the reaction liquid is dried to obtain an impurity compound I crude product. The crude product was purified by column separation to give 1.78g of impurity compound I, 40.1% yield, 97.1% purity.
Example 12: preparation of impurity Compound I
Dissolving 1.00g of compound VII in 20ml of purified water, controlling the temperature at 8-9 ℃, adjusting the pH of the solution to 10-11 by using 2N NaOH, and slowly adding 0.8g of SO3Py, maintaining the pH value of 10-11 for 6 hours, after the reaction is finished, carrying out G25 chromatography on the reaction liquid by using purified water as an eluent, and concentrating under reduced pressure until the reaction liquid is dried to obtain an impurity compound I crude product. The crude product was dissolved in an appropriate amount of methanol/water (v/v-1/1), concentrated by cation exchange resin exchange with 732 using methanol/water (v/v-1/1) as eluent, and then purified by column separation to give 0.43g of impurity compound i in 35.8% yield with a purity of greater than 96.7%.
Molecular structural information for compound i:
the molecular formula is as follows: c31H42N3Na11O52S9
Exact Mass：1828.7095
MS(ESI)m/z:937.3467＝[(M+2Na)/2]+,
926.3549＝[(M+Na+H)/2]+
1H NMR(D2O,ppm)δ：5.52(d,1H),5.25(s,1H),5.23(d,1H),4.91(d,1H),4.83(s,1H),4,75(s,1H),4.54(d,1H),4.42-4.24(m,5H),4.20-4.10(m,3H),4.06(d,3H),3.95-3.80(m,3H),3.80-3.65(m,4H),3.65-3.55(m,2H),3.55-3.45(m,2H),3.33(dd,1H),3.35-3.25(m,4H),3.20-3.10(m,2H)。
Claims (17)
1. A preparation method of fondaparinux sodium impurity is characterized by comprising the following steps: the method comprises the following steps:
step 1: preparation of Compound IV
Reacting the compound II with the compound III under the action of a coupling catalyst to obtain a compound IV;
step 2: preparation of Compound V
Hydrolyzing the compound IV under an alkaline condition, and adjusting the pH value to be acidic by hydrochloric acid to obtain a compound V;
and step 3: preparation of Compound VI
Reacting the compound V with a sulfonation reagent A to generate a sulfate compound, and performing sodium ion exchange on the sulfate compound to obtain a compound VI;
and 4, step 4: preparation of Compound VII
The compound VI is subjected to reduction and debenzylation reaction under the action of a catalyst to obtain a compound VII;
and 5: preparation of impurity Compound I
Reacting the compound VII with a sulfonation reagent B to generate a sulfonate compound, and performing sodium ion exchange on the sulfonate compound and purifying to obtain an impurity compound I;
in the compounds II or IV, R is1、R2、R3Each independently is any one of benzoyl, alkyl acyl, aryl acyl, alkyl aryl acyl or alkyl aryl acyl substituted by halogen, ethoxy carbonyl, tert-butoxy carbonyl, allyl oxy carbonyl and carbonic ester protecting group.
2. The method of claim 1, wherein: in the step 1, the molar ratio of the compound II to the compound III to the coupling catalyst is 1: 0.9-1.1: 0.8-1.2.
3. The method of claim 1, wherein: in the step 1, the coupling catalyst is one or the combination of two or more of TBDMSOTf, TMSOTf and AgOTf.
4. The method of claim 1, wherein: in the step 1, the reaction temperature is preferably-20 to-40 ℃, and the reaction time is preferably 2 to 6 hours, and more preferably 5 hours.
5. The method of claim 1, wherein: in the step 2, the alkaline condition is provided by an alkaline substance, and the alkaline substance is one or a mixture of any more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate.
6. The method of claim 1, wherein: in the step 2, the reaction temperature is 10-60 ℃, and preferably 20-30 ℃.
7. The method of claim 1, wherein: in the step 2, the reaction solvent adopted in the hydrolysis reaction can be one or a mixture of several of methanol, ethanol, tetrahydrofuran and dioxane and water.
8. The method of claim 1, wherein: in the step 2, the reaction further comprises a recrystallization step, and the recrystallization system can be ethyl acetate/n-hexane or ethyl acetate/petroleum ether.
9. The method of claim 1, wherein: in the step 3, the sulfonation reagent A can be one or a mixture of any more of trimethyl ammonium sulfur trioxide copolymer, sulfur trioxide pyridine complex, chlorosulfonic acid and sulfamic acid; the sulfonation reagent A is 15-20 molar equivalents of the compound V.
10. The method of claim 1, wherein: in the step 3, the reaction temperature is 40-80 ℃, and preferably 50-70 ℃.
11. The method of claim 1, wherein: in step 3, 732 cation exchange resin, Dowex 50WX4 resin, or one or more of sodium hydroxide and sodium carbonate can be used for sodium ion exchange to obtain sodium salt compound vi.
12. The method of claim 1, wherein: in the step 4, the catalyst can be one or a mixture of several of palladium carbon, palladium hydroxide, palladium acetate and palladium black; the mol ratio of the compound VI to the catalyst is 1: 0.1 to 2.
13. The method of claim 1, wherein: in the step 4, the reaction solvent may be one or a mixture of ethanol, methanol and purified water.
14. The method of claim 1, wherein: in the step 4, the reaction temperature can be 10-60 ℃, and the hydrogen pressure is 0.5-4 MPa; preferably purified water or purified water/alcohol greater than 70/30(v/v) is used as a reaction solvent, the hydrogen pressure is 1.0-1.5 MP, and the reaction temperature is 20-30 ℃.
15. The method of claim 1, wherein: in step 5, the sulfonating agent B can be sulfur trioxide and sulfur trioxide derivatives such as trimethyl ammonium sulfur trioxide copolymer (SO)3NMe3) Sulfur trioxide pyridine complex (SO)3Py), chlorosulfonic acid and sulfamic acid; preferably, the sulfonation reagent B is 6-10 molar equivalents of the compound VII.
16. The method of claim 1, wherein: in the step 5, the reaction pH is 8-12, preferably 9-10; the reaction temperature is 6-14 ℃, and preferably 8-12 ℃.
17. The method of claim 1, wherein: in step 5, the exchange process adopts exchange resin: 732 cation exchange resin, Dowex 50WX4 resin, or one or more of sodium hydroxide and sodium carbonate, and mixing to obtain sodium salt compound impurity A.
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|---|---|---|---|---|
| US20050020536A1 (en) * | 2003-02-27 | 2005-01-27 | Jean-Francois Branellec | Highly pure fondaparinux sodium composition, process for preparing said composition and pharmaceutical compositions containing it as active principle |
| US20120116066A1 (en) * | 2009-10-30 | 2012-05-10 | Reliable Biopharmaceutical Corporation | Efficient and scalable process for the manufacture of fondaparinux sodium |
| US20150031866A1 (en) * | 2013-07-25 | 2015-01-29 | Scinopharm Taiwan, Ltd. | Process for the production of fondaparinux sodium |
| CN105473602A (en) * | 2013-07-25 | 2016-04-06 | 台湾神隆股份有限公司 | Process for the production of fondaparinux sodium |
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| US20050020536A1 (en) * | 2003-02-27 | 2005-01-27 | Jean-Francois Branellec | Highly pure fondaparinux sodium composition, process for preparing said composition and pharmaceutical compositions containing it as active principle |
| US20120116066A1 (en) * | 2009-10-30 | 2012-05-10 | Reliable Biopharmaceutical Corporation | Efficient and scalable process for the manufacture of fondaparinux sodium |
| US20150031866A1 (en) * | 2013-07-25 | 2015-01-29 | Scinopharm Taiwan, Ltd. | Process for the production of fondaparinux sodium |
| CN105473602A (en) * | 2013-07-25 | 2016-04-06 | 台湾神隆股份有限公司 | Process for the production of fondaparinux sodium |
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