CN101250172B - 精氨酸双保护制备工艺 - Google Patents
精氨酸双保护制备工艺 Download PDFInfo
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- arginine
- pentamethyl
- alkylsulfonyl
- dihydrofuran
- fluorenylmethyloxycarbonyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims description 22
- 239000004475 Arginine Substances 0.000 title abstract description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 title abstract description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims abstract description 11
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical class Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 11
- 230000000903 blocking effect Effects 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- JFBSXHCYJQMNAT-NRFANRHFSA-N (2s)-2-amino-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonyl)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)[C@@](N)(C(O)=O)CCCN=C(N)N)C3=CC=CC=C3C2=C1 JFBSXHCYJQMNAT-NRFANRHFSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229960002317 succinimide Drugs 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003929 acidic solution Substances 0.000 claims description 5
- -1 t-butoxycarbonyl protecting group Chemical group 0.000 claims description 5
- 150000002220 fluorenes Chemical class 0.000 claims description 4
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- FTHUKEBATJXQFL-UHFFFAOYSA-N formic acid;hydrochloride Chemical compound Cl.OC=O FTHUKEBATJXQFL-UHFFFAOYSA-N 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- KWTQSFXGGICVPE-PGMHMLKASA-N (2r)-2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@H](N)CCCN=C(N)N KWTQSFXGGICVPE-PGMHMLKASA-N 0.000 claims description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 claims description 2
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 claims description 2
- RHLBRQUUVYXKLA-UHFFFAOYSA-N 2-methylpropan-1-ol;hydrochloride Chemical compound Cl.CC(C)CO RHLBRQUUVYXKLA-UHFFFAOYSA-N 0.000 claims description 2
- KWTQSFXGGICVPE-WCCKRBBISA-N Arginine hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCCN=C(N)N KWTQSFXGGICVPE-WCCKRBBISA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- ISWIXOPWSBGVNF-UHFFFAOYSA-N Cl.COC=O Chemical compound Cl.COC=O ISWIXOPWSBGVNF-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004989 dicarbonyl group Chemical group 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- SOJSYOXMFGDLHY-UHFFFAOYSA-N methyl acetate;hydrochloride Chemical compound Cl.COC(C)=O SOJSYOXMFGDLHY-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 claims description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 9
- 238000007327 hydrogenolysis reaction Methods 0.000 abstract description 7
- 230000003197 catalytic effect Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 235000009697 arginine Nutrition 0.000 abstract description 4
- HSQIYOPBCOPMSS-ZETCQYMHSA-N (2s)-5-(diaminomethylideneamino)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCN=C(N)N HSQIYOPBCOPMSS-ZETCQYMHSA-N 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract 4
- 229930064664 L-arginine Natural products 0.000 abstract 1
- 235000014852 L-arginine Nutrition 0.000 abstract 1
- 238000003889 chemical engineering Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 229940124280 l-arginine Drugs 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 7
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HLJKUZUILACRPQ-UHFFFAOYSA-N 2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-sulfonyl chloride Chemical compound CC1=C(S(Cl)(=O)=O)C(C)=C2CC(C)(C)OC2=C1C HLJKUZUILACRPQ-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229960003121 arginine Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- CVFXPOKENLGCID-KRWDZBQOSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC1=C(S(=O)(=O)NC(N)=NCCC[C@H](NC(=O)OC(C)(C)C)C(O)=O)C(C)=C2CC(C)(C)OC2=C1C CVFXPOKENLGCID-KRWDZBQOSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000219780 Pueraria Species 0.000 description 1
- HDELGKMVZYHPPB-FJXQXJEOSA-N [(4s)-4-carboxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]butyl]-(diaminomethylidene)azanium;chloride Chemical compound Cl.CC(C)(C)OC(=O)N[C@H](C(O)=O)CCCN=C(N)N HDELGKMVZYHPPB-FJXQXJEOSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
Classifications
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明精氨酸双保护制备工艺,属医药化工技术领域。具体涉及一种NG-(2,2,4,6,7-五甲基苯丙二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸的制备方法。由于本发明Boc-Arg-OH中引入NG-2,2,4,6,7-五甲基苯丙二氢呋喃-5-磺酰基保护基团,即用NG-pbf保护基团制备Nα-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯丙二氢呋喃-5-磺酰基)-精氨酸,然后在氯化氢乙醇饱和溶液中脱除α位保护基,避免使用昂贵催化剂钯-炭及催化氢解操作过程。由于脱α位保护基过程简单,条件易控制,可操作性强,生产成本低,便于工业化生产;另外,由于避免了钯-炭及催化氢解过程,大大降低了环境污染。本发明反应总收率达到63.51%(以L-精氨酸计),产品含量≥99.0%。
Description
技术领域
本发明精氨酸双保护制备工艺,属医药化工技术领域。具体涉及一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸(以下简称Fmoc-Arg(pbf)-OH)的制备方法。
背景技术
现有制备Fmoc-Arg(pbf)-OH双保护氨基酸的方法,如:由许云生、葛邦轮等人发明的制备专利方法(申请号:200410018114.5),该专利提出由2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰氯与Nα-苄氧羰基L-精氨酸在HMPA的非水溶剂体系中以吡啶作为缚酸剂进行缩合反应得到Nα-苄氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)L-精氨酸,以10%钯-炭催化剂催化氢解,得到NG(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)L-精氨酸,再与N-(9-芴甲氧羰基氧)琥珀酰亚胺进行相转移催化反应得到目的产物Fmoc-Arg(pbf)-OH。华东师范大学胡巧斐在其论文《几种氨基酸双保护的工艺研究》中,由Nα-苄氧羰基L-精氨酸引入2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基团时采用加入相转移催化剂四乙基溴化胺(TEBA)而得到Nα-苄氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)L-精氨酸,以10%钯-炭催化剂50℃条件下通氢过夜,滤去催化剂,减压除去溶剂,得到NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)L-精氨酸,再与N-(9-芴甲氧羰基氧)琥珀酰亚胺进行反应得到目的产物Fmoc-Arg(pbf)-OH。上述两种制备方法在脱除α-氨基保护基苄氧羰基时都使用了催化剂钯-炭及氢解过程,一方面钯-炭催化剂价格昂贵,造成生产成本高,另一方面催化氢解等操作步骤繁琐,不利工业化实施。
发明内容:
本发明的目的是克服现有技术中上述缺点,提供一种精氨酸双保护新的制备方法,达到降低生产成本,简化操作步骤,满足工业化生产需要。
为实现上述目的,本发明是这样实施的:一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,其反应式为:
其中:
步骤一中,将精氨酸或其盐溶解在溶剂中,冷却至-50℃~50℃,加入叔丁氧羰基保护基团,反应后得到物质I:Nα-叔丁氧羰基-精氨酸或Nα-叔丁氧羰基-精氨酸盐;
步骤二中,将物质I溶解在溶剂中,冷却至-15~15℃,用5%~25%氢氧化钠溶液调节pH值5~13,另外,将2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基保护基团加入到溶剂中,然后加入前述的氢氧化钠溶液,反应后得到物质II:N-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸;
三、将N-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸溶解在酸性溶液中,在-20~20℃下反应1~15小时,脱除叔丁氧羰基保护基团,反应后得到NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸;
四、将NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸溶解在溶剂中,冰浴条件下加入芴甲氧羰基保护基团,反应后得到目的产品NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸。
在上述方案基础上,所述的精氨酸及其盐为L-精氨酸、D-精氨酸、DL-精氨酸、L-精氨酸盐酸盐、D-精氨酸盐酸盐、DL-精氨酸盐酸盐、L-精氨酸硫酸盐、D-精氨酸硫酸盐和DL-精氨酸硫酸盐之中的一种。
在上述第二步骤中,所述的溶剂为二氧六环、二氧六环-水、丙酮、丙酮-水、四氢呋喃和四氢呋喃-水中的一种或几种的混合。
所述的2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基保护基团为2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰氯。
在上述第三步骤中,所述的酸性溶液为饱和柠檬酸溶液、0.1~1.0M的硫酸溶液、氯化氢乙醇、氯化氢丙醇、氯化氢异丁醇、氯化氢甲酸乙脂、氯化氢甲酸甲脂、氯化氢乙酸乙脂和氯化氢乙酸甲脂之中的一种。
在上述方案基础上,所述的芴甲氧羰基保护基团为芴甲氧羰酰琥珀酰亚胺或芴甲氧羰酰氯。
进一步,本发明:一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,是将L-精氨酸的单盐酸盐按照1∶1.4~1.6的比例加入水和二氧六环混合液中(水∶二氧六环=1∶1),按1∶1~1.5比例加入(Boc)2O,搅拌下不断滴加4N氢氧化钠溶液,控制PH=9-10,直至溶液变橙清且PH值保持不变,再反应2~3小时。减压蒸去二氧六环(水浴50℃),加入水稀释后,在冰浴下用冷3N盐酸调PH=4~5,无水***萃取(2×25mL)除杂。水相继续用3N盐酸调PH=2~3,冷却结晶,得白色固体,即Nα-叔丁氧羰基-L-精氨酸.盐酸盐。
在冰浴条件下(-15~15℃),将Nα-叔丁氧羰基-L-精氨酸.盐酸盐,即Boc-Arg-OH.HCl按照1∶6~7的比例加入二氧六环溶液中,用5~25%氢氧化钠溶液调节PH=5~13。将Pbf-Cl按照1∶4~5的比例溶于二氧六环溶液中,然后冰浴条件下滴加到Nα-叔丁氧羰基-L-精氨酸.盐酸盐二氧六环混合液中。滴加完毕升至室温条件反应3~4小时。反应结束减压除去二氧六环,冷却到室温,用饱和柠檬酸水溶液调PH=3~4,得黄色油状物。黄色油状物加乙酸乙脂萃取,静置分层得到有机相和水相,合并有机相,水和饱和盐水交替洗涤,直至溶液PH=5~6,然后用无水硫酸钠干燥,过滤后浓缩至干,加入石油醚,充分搅拌,过滤,烘干得到Nα-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)L-精氨酸,即Nα-Boc-Arg(pbf)-OH。
在-20~20℃条件下,将Nα-Boc-Arg(pbf)-OH按照1∶5~6的比例用饱和氯化氢乙醇溶解,保温反应1~15小时。反应结束用5~25%氢氧化钠调节PH=3~4,静置分层得有机相和水相,有机相多次水洗,合并水相,用5~25%氢氧化钠继续调节PH=7~8,冷却到0~10℃,结晶、过滤得NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-L-精氨酸,即Arg(pbf)-OH。
将Arg(pbf)-OH按照1∶1~2的比例加入10%碳酸钠溶液及二氧六环中,然后冷却到-5~0℃;将N-(9-芴甲氧羰基氧)琥珀酰亚胺,即Fmoc-OSu按照1∶8~9的比例加入到二氧六环中,并滴加到前述反应体系内,冰浴下反应1~2小时,再室温反应2~3小时,***萃取除去杂质,饱和柠檬酸调节PH=3~4,用乙酸乙脂萃取,分出有机相和水相,合并有机相并用水和饱和盐水洗涤,无水硫酸镁干燥,过滤,减压蒸馏除去大部分溶剂,加入正己烷析出白色产品NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-L-精氨酸,即Fmoc-Arg(pbf)-OH。
本发明与现有同类产品生产方法相比,优点体现在:由于本发明Boc-Arg-OH引入NG-2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基保护基团,即NG-pbf保护基团制备Nα-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸,然后在氯化氢乙醇饱和溶液中脱除α位保护基,避免使用昂贵催化剂钯-炭及催化氢解操作过程。本发明脱α位保护基过程简单,条件易于控制,可操作性强,生产成本低,便于实现工业化生产;另一方面由于避免了钯-炭及催化氢解过程,大大降低了环境污染。本发明反应总收率达到63.51%(以L-精氨酸计),产品含量≥99.0%。
具体实施方式:
实施例1:
将20gL-精氨酸的单盐酸盐及30g水和二氧六环的混合液中(水∶二氧六环=1∶1)加入250mL配有机械搅拌的三口烧瓶中,然后将26.5g(Boc)2O加入混合液中,搅拌下不断滴加4N氢氧化钠溶液,控制PH=9-10,直至溶液变橙清且PH值保持不变,再反应2~3小时。减压蒸去二氧六环(水浴50℃)至干,加入17mL水稀释后,在冰浴下用冷3N盐酸调PH=4~5,无水***萃取(2×25mL)除杂。水相继续用3N盐酸调PH=2~3,冷却结晶,得白色固体,即Nα-叔丁氧羰基-L-精氨酸.盐酸盐26.2g,收率88.50%。
取20g Nα-叔丁氧羰基-L-精氨酸.盐酸盐及140mL二氧六环加入500mL配有机械搅拌的三口烧瓶中,放置在冰浴条件下(-5~0℃),启动搅拌混合均匀。搅拌条件下,用10%氢氧化钠溶液调节混合液的PH=10~12。将34.5gPbf-Cl及140mL的二氧六环加入250mL配有机械搅拌的三口烧瓶中,搅拌至完全溶解。在冰浴条件下将配制好的Pbf-Cl-二氧六环溶液滴加到Nα-叔丁氧羰基-L-精氨酸.盐酸盐二氧六环混合液中,滴加过程中用20%氢氧化钠溶液调节反应液的PH=10~12。滴加完毕升至室温反应3.5小时。反应结束减压除去二氧六环,冷却到室温,用饱和柠檬酸水溶液调PH=3~4,得黄色油状物。黄色油状物加乙酸乙脂萃取(5次×150mL),静置分层得到有机相和水相,合并有机相,用水和饱和盐水交替洗涤,直至溶液PH=5~6,然后用无水硫酸钠干燥。干燥后用旋转薄膜蒸发仪在真空条件下浓缩至干,加入200mL石油醚,充分搅拌,过滤,减压烘干得28.38gNα-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)L-精氨酸,薄层层析为一个斑点,收率为83.67%。
在配有机械搅拌的500mL三口烧瓶中加入130g饱和氯化氢乙醇,冷却至-5~0℃,将25g Nα-Boc-Arg(pbf)-OH加入,冰浴条件下反应10小时。反应结束用10%氢氧化钠调节PH=3~4,静置分层得有机相和水相,有机相用水洗涤(4×120mL),合并水相,然后用10%氢氧化钠继续调节PH=7~8,冷却到0~10℃,结晶、过滤得18.78g NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-L-精氨酸,即NG-Arg(pbf)-OH,熔点为154~157℃,薄层层析为一个斑点,收率为92.86%。
在配有机械搅拌的500mL三口烧瓶中加入18g Arg(pbf)-OH,再加入10%碳酸钠溶液30g及二氧六环32g,然后冷却到-5~0℃;边搅拌边加入15.3g N-(9-芴甲氧羰基氧)琥珀酰亚胺与125g二氧六环的混合液,冰浴下反应2小时,再室温反应2.5小时,***萃取除去杂质(100mL×3次),饱和柠檬酸调节PH=3~4,用乙酸乙脂萃取(150mL×4次),分出有机相和水相,合并有机相并用水和饱和盐水洗涤,无水硫酸镁干燥,过滤,用旋转薄膜蒸发器减压蒸馏除去大部分溶剂,加入正己烷析出白色产品25.31g NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-L-精氨酸,即Fmoc-L-Arg(pbf)-OH,薄板层析显示一个斑点,比旋光度[α]D 25=-5.560(c=1DMF),收率92.36%。
实施例2:
除下列工艺参数与例1不同外,其他制备工艺参数及过程均同例1;
1、二氧六环用等量丙酮替代;
2、pbf-cl用量为30g;
3、氯化氢乙醇改为等量氯化氢甲酸乙脂;
4、得到Boc-Arg(pbf)-OH 21.42g,收率为63.15%;
5、得到Arg(pbf)-OH 15.37g,收率为75.99%。
实施例3:
除下列工艺参数与例1不同外,其他制备工艺参数及过程均同例1;
1、二氧六环用等量四氢呋喃替代;
2、pbf-cl用量为40g;
3、氯化氢乙醇改为等量饱和柠檬酸溶液;
4、得到Boc-Arg(pbf)-OH15.62g,收率为46.06%;
5、得到Arg(pbf)-OH 12.78g,收率为63.19%。
Claims (6)
2.根据权利要求1所述的NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,其特征在于:
步骤一中,将精氨酸或其盐溶解在溶剂中,冷却至-50℃~50℃,加入叔丁氧羰基保护基团,反应后得到物质I:Nα-叔丁氧羰基-精氨酸或Nα-叔丁氧羰基-精氨酸盐;
步骤二中,将物质I溶解在溶剂中,冷却至-15~15℃,用5%~25%氢氧化钠溶液调节pH值5~13,另外,将2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基保护基团加入到溶剂中,然后加入前述的氢氧化钠溶液,反应后得到物质II:N-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸;
步骤三、将N-叔丁氧羰基-NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸溶解在酸性溶液中,在-20~20℃下反应1~15小时,脱除叔丁氧羰基保护基团,反应后得到NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸;
步骤四、将NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-精氨酸溶解在溶剂中,冰浴条件下加入芴甲氧羰基保护基团,反应后得到目的产品NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸。
3.根据权利要求2所述的一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,其特征在于:所述的精氨酸及其盐为L-精氨酸、D-精氨酸、DL-精氨酸、L-精氨酸盐酸盐、D-精氨酸盐酸盐、DL-精氨酸盐酸盐、L-精氨酸硫酸盐、D-精氨酸硫酸盐和DL-精氨酸硫酸盐之中的一种。
4.根据权利要求1所述的一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,其特征在于:第二步骤中,所述的溶剂为二氧六环、二氧六环-水、丙酮、丙酮-水、四氢呋喃和四氢呋喃-水中的一种或几种的混合。
5.根据权利要求2所述的一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,其特征在于:所述的2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基保护基团为2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基氯。
6.根据权利要求2所述的一种NG-(2,2,4,6,7-五甲基苯并二氢呋喃-5-磺酰基)-Nα-(9-芴甲氧羰基)-精氨酸双保护制备工艺,其特征在于:所述的芴甲氧羰基保护基团为芴甲氧羰酰琥珀酰亚胺或芴甲氧羰酰氯。
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