CN114591379A - 一种磺达肝癸钠甲酰化杂质的制备方法 - Google Patents
一种磺达肝癸钠甲酰化杂质的制备方法 Download PDFInfo
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- 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 13
- 239000012535 impurity Substances 0.000 title claims abstract description 13
- 229960003661 fondaparinux sodium Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 230000022244 formylation Effects 0.000 title abstract description 6
- 238000006170 formylation reaction Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical compound CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 150000004678 hydrides Chemical class 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 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 abstract description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- 230000021235 carbamoylation Effects 0.000 abstract 2
- 238000006277 sulfonation reaction Methods 0.000 abstract 2
- 150000001540 azides Chemical class 0.000 abstract 1
- 238000006264 debenzylation reaction Methods 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 238000002347 injection Methods 0.000 abstract 1
- 239000007924 injection Substances 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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 3
- 229940079593 drug Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 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 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 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
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002316 cosmetic surgery Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Abstract
本发明公开了一种磺达肝癸钠甲酰化杂质的制备方法,包括化合物II为起始原料,经叠氮还原,氨基保护,氨基甲酰化,羟基磺化,氢化脱苄基和氨基磺化以形成氨基甲酰化杂质I的步骤。所述方法操作简单,易于放大规模制备等优点,为磺达肝癸钠注射液的质量研究和控制奠定了良好的基础。
Description
技术领域
本发明涉及一种磺达肝癸钠甲酰化杂质的制备方法,属于医药技术领域。
背景技术
磺达肝癸钠(Fondaparinux sodium)由Choay,S.A.研发,用于预防整形外科手术中病人的静脉血栓的形成,也可用于治疗静脉血栓和肺栓塞,其化学名称为:氧-[2-脱氧-6-氧-磺酸基-2-(磺胺基)-α-D-吡喃葡萄糖基]-(1→4)-氧-(β-D-吡喃葡萄糖醛酸)-(1→4)-氧-[2-脱氧-3,6-二-氧-磺酸基-2-(磺胺基)-α-D-吡喃葡萄糖]-(1→4)-氧-(2-氧-磺酸基-α-L-吡喃艾杜糖醛酸)-(1→4)-氧-[2-脱氧-1-氧-甲基-6-氧-磺酸基-2-(磺胺基)-α-D-吡喃葡萄糖苷]十钠盐,结构式如下:
药物研究人员发现一种磺达肝癸钠甲酰化杂质,化学名为:氧-[2-脱氧-2-甲酰基氨基-6-氧-磺酸基-2-(磺胺基)-α-D-吡喃葡萄糖基]-(1→4)-氧-(β-D-吡喃葡萄糖醛酸)-(1→4)-氧-[2-脱氧-3,6-二-氧-磺酸基-2-(磺胺基)-α-D-吡喃葡萄糖]-(1→4)-氧-(2-氧-磺酸基-α-L-吡喃艾杜糖醛酸)-(1→4)-氧-[2-脱氧-1-氧-甲基-6-氧-磺酸基-2-(磺胺基)-α-D-吡喃葡萄糖苷]十钠盐,具体结构如下:
对药物研究人员来说,主要工作不仅仅在于如何获得高质量的原料药、开发高效的合成工艺,更重要的是研究原料药中杂质种类、来源以及如何控制工艺杂质的产生。为此,药物研究人员需开发制备磺达肝癸钠甲酰化的合成路线,以便获得大量杂质对照品,进而开展磺达肝癸钠的质量研究。
在一些实施方案中,所述氢化物源选自氢气/金属催化剂。在另一些实施方案中,所述金属催化剂选自钯、氢氧化钯或钯炭。在一些实施方案中,所述金属催化剂选自5%或10%钯炭。
另一方面,一些实施方案中,式V化合物与三氧化硫三甲胺复合物反应的摩尔比为1:20-50,优选1:30。
在另一些实施方案中,式V化合物与三氧化硫三甲胺复合物的反应温度为40-70℃。
进一步地,制备式I化合物(甲酰化杂质)的方法还包括式II化合物与硫化氢反应以形成式III化合物,随后式III化合物苄氧羰酰氯反应以形成式IV化合物,
在一些实施方案中,式III化合物与苄氧羰酰氯的摩尔比1:0.8-1.5,优选1:1。在另一些实施方案中,酰反应温度-70~-30℃,包括但不限于-60℃、-50℃、-40℃、-35℃或任意两数之间值。
在一些实施方案中,所述酰反应中还含有碱,所述碱选自三乙胺、N,N-二异丙基乙基胺或1,8-二氮杂二环十一碳-7-烯(DBU)中的一种或多种。在一些实施方案中,酰化反应中碱的使用量为式III化合物的摩尔量的2倍。
在一些实施方案中,式II化合物与硫化氢反应溶液选自吡啶和水混合溶液,优选吡啶与水的体积比2:1。
一些实施方案提供制备式I化合物(甲酰化杂质)的方法,包括:
步骤1:式II化合物与硫化氢反应以形成式III化合物,
步骤2:式III化合物与苄氧羰酰基反应以形成式IV化合物,
步骤3:式IV化合物与甲酸甲酯反应以形成式V化合物
步骤4:式V化合物与三氧化硫三甲胺复合物反应以形成式VI化合物,
步骤5:式VI化合物与氢化物源反应以形成式VII化合物,以及式VII转化为式I化合物,
本发明所述制备方法还包括括离心(过滤)、洗涤、干燥或柱层析纯化的步骤。
术语“以形成”和“转化为”并不特指两个底物间的转化反应为单步骤的,可为两个底物间的单步骤或多步骤的反应。如中间体含有氨基保护基,所述中间体经过一步脱氨基保护剂,随后再与相应底物反应以获得相应目标产物。
具体实施方式
以下将结合实施例更详细地解释本发明,本发明的实施例仅用于说明本发明的技术方案,本发明的实质和范围并不局限于此。
实施例1:
取化合物II(7.5g)溶于100mL吡啶和50mL水中,通入硫化氢气体使压力为0.1MPa,搅拌反应24h,浓缩除去溶剂,加30ml无水甲醇溶解,过滤后浓缩,得到化合物III(7.2g,产率99%)。
实施例2:
取化合物III(5g,3.2mmol)和三乙胺(0.65g,6.4mmol,2eq)溶于400mL无水甲醇中,-40℃条件下,滴加苄氧羰酰氯CbzCl(0.54g,1eq),搅拌反应1小时后停止反应,浓缩得到粘稠状物,柱层析分离提纯得到化合物IV(3.3g,产率61%)。
实施例3:
取化合物IV(2.5g)和甲酸甲酯(30ml)置于100ml耐压反应瓶中,加热至50-60℃反应10小时,浓缩得到化合物V(2.5g,产率98%)。
ESI-MS,m/z:1704.65(M+H+).
实施例4:
取化合物V(2g,1.2mmol)溶于DMF 3ml和乙腈30ml中,氮气保护条件下加三氧化硫三甲胺复合物(5g,36mmol),加热至50℃反应1天,冰水浴条件下滴加3mL甲醇淬灭反应,过滤后浓缩,制备纯化得到化合物VI(2.3g,产率87%)。
实施例5:
取化合物VI(1.6g,0.7mmol)溶于50ml水和15ml叔丁醇中,加10%钯碳催化剂(1.6g),室温下通入氢气氢化反应1天,过滤除去催化剂,浓缩至粘稠状,加30ml水溶清,搅拌条件下再滴加30ml甲醇,固体析出,过滤得到化合物VII(0.7g,产率68%)。
实施例6:
取化合物VII(0.7g,0.5mmol)和碳酸钠(2.5g,24mmol)溶于50ml水中,冰水浴条件下,加入三氧化硫吡啶复合物(2.5g,15mmol),加完升至室温反应3小时,浓缩,制备纯化得到甲酰化杂质I(0.48g,产率60%)。
1HNMR(D2O,ppm)δ3.35(dd,1H),3.40-3.56(m,5H),3.59-4.13(m,10H),4.21(dd,4H),4.32(d,1H),4.36-4.50(m,5H),4.55(d,2H),4.69(d,1H),4.91(s,1H),5.08(d,1H),5.28(s,1H),5.53(dd,2H),8.24(s,1H).ESI-MS,m/z:1675.56(M+Na+).
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,式IV化合物与甲酸甲酯摩尔比为1:200,反应温度为50~60℃。
4.根据权利要求3所述的制备方法,其特征在于,所述金属催化剂选自钯、氢氧化钯或钯碳。
5.根据权利要求4任一项所述的制备方法,其特征在于,式V化合物与三氧化硫三甲胺复合物摩尔比为1:20-50,优选1:30。
7.根据权利要求6所述的制备方法,其特征在于,式III化合物与苄氧羰酰氯的摩尔比1:0.8-1.5,优选1:1,酰反应温度-70~-30℃。
8.根据权利要求7所述的制备方法,其特征在于,所述酰反应中还含有碱,所述碱选自三乙胺、N,N-二异丙基乙基胺或1,8-二氮杂二环十一碳-7-烯(DBU)中的一种或多种。
9.根据权利要求6所述的制备方法,其特征在于,式II化合物与硫化氢反应溶液选自吡啶和水混合溶液,优选吡啶与水的体积比2:1。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN104098618A (zh) * | 2014-07-25 | 2014-10-15 | 河北常山生化药业股份有限公司 | 磺达肝癸钠中间体及其中间体和磺达肝癸钠的制备方法 |
CN104910217A (zh) * | 2015-06-19 | 2015-09-16 | 天津红日药业股份有限公司 | 用于磺达肝癸钠质量控制的参比化合物 |
CN109734757A (zh) * | 2019-03-11 | 2019-05-10 | 淮北师范大学 | 一种磺达肝癸钠注射液有关物质b的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN104098618A (zh) * | 2014-07-25 | 2014-10-15 | 河北常山生化药业股份有限公司 | 磺达肝癸钠中间体及其中间体和磺达肝癸钠的制备方法 |
CN104910217A (zh) * | 2015-06-19 | 2015-09-16 | 天津红日药业股份有限公司 | 用于磺达肝癸钠质量控制的参比化合物 |
CN109734757A (zh) * | 2019-03-11 | 2019-05-10 | 淮北师范大学 | 一种磺达肝癸钠注射液有关物质b的制备方法 |
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