CN107129440A - 一种天然产物(+)‑负霉素的全合成方法 - Google Patents
一种天然产物(+)‑负霉素的全合成方法 Download PDFInfo
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- CN107129440A CN107129440A CN201710469598.2A CN201710469598A CN107129440A CN 107129440 A CN107129440 A CN 107129440A CN 201710469598 A CN201710469598 A CN 201710469598A CN 107129440 A CN107129440 A CN 107129440A
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- Prior art keywords
- tert
- base
- butyl
- tertiary butyl
- methyl
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- IKHFJPZQZVMLRH-RNFRBKRXSA-N 2-[[[(3r,5r)-3,6-diamino-5-hydroxyhexanoyl]amino]-methylamino]acetic acid Chemical compound OC(=O)CN(C)NC(=O)C[C@H](N)C[C@@H](O)CN IKHFJPZQZVMLRH-RNFRBKRXSA-N 0.000 title claims abstract description 41
- IKHFJPZQZVMLRH-UHFFFAOYSA-N negamycin Natural products OC(=O)CN(C)NC(=O)CC(N)CC(O)CN IKHFJPZQZVMLRH-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000006257 total synthesis reaction Methods 0.000 title claims abstract description 14
- 229930014626 natural product Natural products 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 18
- 229920001084 poly(chloroprene) Polymers 0.000 claims abstract description 14
- 125000004494 ethyl ester group Chemical group 0.000 claims abstract description 13
- GWJSQKNYHPYZRN-UHFFFAOYSA-N 2-methylpropane-2-sulfonamide Chemical compound CC(C)(C)S(N)(=O)=O GWJSQKNYHPYZRN-UHFFFAOYSA-N 0.000 claims abstract description 7
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical group [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000001540 azides Chemical class 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000002585 base Substances 0.000 claims description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- -1 Propoxyl group Chemical group 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- ALBYIUDWACNRRB-UHFFFAOYSA-N hexanamide Chemical compound CCCCCC(N)=O ALBYIUDWACNRRB-UHFFFAOYSA-N 0.000 claims description 11
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- WHNQTHDJEZTVHS-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-yl)propanoic acid Chemical compound C1=CC=C2SC(CCC(=O)O)=NC2=C1 WHNQTHDJEZTVHS-UHFFFAOYSA-N 0.000 claims description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 7
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- 239000011630 iodine Substances 0.000 claims description 7
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
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- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical group [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
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- ISWQCIVKKSOKNN-UHFFFAOYSA-L Tiron Chemical compound [Na+].[Na+].OC1=CC(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C1O ISWQCIVKKSOKNN-UHFFFAOYSA-L 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- FLALGSYYVIWTFQ-UHFFFAOYSA-K propan-2-olate;titanium(4+);trichloride Chemical class [Cl-].[Cl-].[Cl-].CC(C)O[Ti+3] FLALGSYYVIWTFQ-UHFFFAOYSA-K 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 238000005520 cutting process Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 3
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
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- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 2
- GMRIOAVKKGNMMV-UHFFFAOYSA-N tetrabutylazanium;azide Chemical compound [N-]=[N+]=[N-].CCCC[N+](CCCC)(CCCC)CCCC GMRIOAVKKGNMMV-UHFFFAOYSA-N 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 2
- FDNAPBUWERUEDA-UHFFFAOYSA-N silicon tetrachloride Chemical compound Cl[Si](Cl)(Cl)Cl FDNAPBUWERUEDA-UHFFFAOYSA-N 0.000 claims 2
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- PHVXVOXVDMKTJF-UHFFFAOYSA-N C(C)(C)(C)OC(C)=O.NC(=N)N Chemical compound C(C)(C)(C)OC(C)=O.NC(=N)N PHVXVOXVDMKTJF-UHFFFAOYSA-N 0.000 claims 1
- UHBXGHADNVDXMM-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Li] Chemical group C(C)(C)N(C(C)C)CC[Li] UHBXGHADNVDXMM-UHFFFAOYSA-N 0.000 claims 1
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical group [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 claims 1
- LTEDQKPGOZDGRZ-UHFFFAOYSA-L propan-2-olate;titanium(4+);dichloride Chemical compound Cl[Ti+2]Cl.CC(C)[O-].CC(C)[O-] LTEDQKPGOZDGRZ-UHFFFAOYSA-L 0.000 claims 1
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- C07C241/04—Preparation of hydrazides
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
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Abstract
本发明属于有机合成技术领域,具体为一种天然产物(+)‑负霉素的全合成方法。该方法采用曼尼奇(Mannich)反应构建C3位手性中心,将叠氮官能团的引入放在合成路线后期来实现,以避免易爆剧毒品叠氮化物的大量使用;采用(R)‑(+)‑3‑羟基‑4‑氯丁酸乙酯为原料,以Ellman试剂(R)‑(+)‑叔丁基亚磺酰胺和曼尼奇反应构建C4位手性中心,通过简单的8步反应实现该全合成,总产率达到30%。本发明合成路线简短、后处理简单,为基于(+)‑负霉素的抗生素药物开发提供原料来源。
Description
技术领域
本发明属于有机合成技术领域,特别涉及一种天然产物(+)-负霉素的全合成方法。
背景技术
(+)-负霉素(或称耐格霉素,英文名(+)-negamycin,化学结构见下式)是从绛红褐链霉菌(Streptomyces purpeofuscus)的培养基中分离得到的一种含氮的抗生素,其对耐药性较强的革兰氏阳性菌和革兰氏阴性菌都有较好的抗性且毒性较低(J.Antibiotics1970,23,170)。同时,负霉素也是一种特异性蛋白质合成抑制剂,在原核细胞中显示出提前终止密码子(PTCs)的通读作用,使蛋白质编码出错(J.Antibiotics 1970,23,581;J.Antibiotics1970,23,589)。此外,负霉素在杜氏肌营养不良症(DMD)小鼠模型显示出抑制抗肌营养不良蛋白无意义突变的作用(J.Biochem.2003,134,751;Molecular Cell2014,56,541;ACS Med.Chem.Lett.2015,6,930)。
目前,自负霉素的结构和生理活性报道以来,已有20多条负霉素全合成路线的报道,其中涉及不对称全合成主要包括以下几个课题组的研究工作:
Shibahara于1972年首次报道(+)-负霉素及其对映异构体的全合成,从半乳糖醛酸出发共15步,初步研究了(+)-负霉素及对映异构体的生理活性(J.Am.Chem.Soc.1972,94,4353)。1982年,Ohno从已知手性半酯化合物出发,经过Wittig反应以及碘代环化反应构建C5位手性中心,以11步合成(+)-负霉素(16%,Am.Chem.Soc.1982,104,6465)。1986年,Kibayashi从古洛糖酸内酯出发,利用关键的一步不对称1,3-偶极环加成反应引进两个手性中心,以13步合成(+)-负霉素(17%,J.Am.Chem.Soc.1986,108,4647)。1988年,Weigele从葡萄糖出发,采用先引入甲基肼片段,再通过葡萄糖片段的还原衍生化策略,以9步合成(+)-负霉素(6.8%,Tetrahedron Lett.1988,29,4077)。同年Tanner从(R)-(+)-苹果酸出发,通过已知文献合成丙酮叉保护的trans-α,β-不饱和酯基化合物,利用Sharpless不对称环氧化引入C3位手性中心,以14步合成(+)-负霉素(20%,Tetrahedron Lett.1988,29,2373)。1992年,Maycock从金鸡纳酸出发,利用氧化开环衍生化以23步合成(+)-负霉素(13%,Tetrahedron Lett.1992,33,4633)。同年Schmidt从(R)-(+)-2,2-二甲基-1,3-二氧戊环-4-甲醛出发,利用不对称氢化反应引入C3位手性氨基,随后通过Wolff重排反应将α-氨基酸转化为β-氨基酸,以21步合成(+)-负霉素(2.8%,Synthesis 1992,482)。1993年,Hegedus从已知手性氨基甲酸盐出发,经过Pd(II)催化的烷基化/羰基插入偶联串联反应引入C3位手性中心,底物控制立体选择性还原建立C5位手性中心,以15步合成(+)-负霉素(16%,J.Org.Chem.1993,58,4547)。Davies小组曾多次开展负霉素的全合成工作,其中1996年Davies从4-氯乙酰乙酸乙酯出发,首先经过不对称氢化还原建立C5位手性中心,之后通过试剂控制的不对称Michael加成反应引入C3位手性中心,以13步合成(+)-负霉素(27%,Tetrahedron Asymmetry 1996,7,1919;Tetrahedron 2011,67,216)。2002年Williams从商业易得的(2S,3R)-(+)-N-Z-6-氧代-2,3-二苯基吗啉出发,首先经过Wittig反应与氢化反应构建所需热力学稳定的C5位手性中心,随后利用金属螯合下底物控制的不对称烯丙基化反应引入C3位手性中心,以11步合成(+)-负霉素(27%,J.Org.Chem.2002,67,6361)。2003年,Raju从商业易得的叔丁氧羰基保护烯丙基甘氨酸出发,经过碘代内酯化并开环引入C5位羟基(1:1),利用柱层析分离所需异构体,以9步合成(+)-负霉素(13%,Bioorg.Med.Chem.Lett.2003,13,2413)。2007年,Kumar从消旋的环氧氯丙烷出发,利用Jacobsen发展的手性动力学拆分得到手性环氧化合物,接受烯基格氏试剂进攻环氧开环构建C5位手性中心,继而再次利用Jacobsen的手性动力学拆分得到手性环氧,并再次接受烯基格氏试剂进攻引入C3位手性中心,以13步合成(+)-负霉素(4.6%,TetrahedronLett.2007,48,3793)。2008年,Hayashi等人以N-叔丁氧羰基-2-氨基乙醛为原料,通过不对称烯丙基化反应建立C5位手性中心,进而利用不对称Michael加成反应引入氨基并同时建立C3位手性中心,以9步反应实现了(+)-负霉素的全合成(46.5%,Chem.Commun.2008,2379);2010年,Hayashi小组使用市售可得的(R)-(+)-3-羟基4-氯-丁酸乙酯为原料,同样以不对称Michael加成反应构建关键C3位手性中心,通过13步反应实现了(+)-负霉素的全合成(31%,Tetrahedron2010,66,314);2014年,Bates从手性环氧氯丙烷出发,经过烯基格氏试剂环氧开环建立C5位手性中心,随后利用Sakurai反应引入C3手性中心,以10步合成(+)-负霉素(23%,Org.Biomol.Chem.2014,12,4879)。同年,Olivier等人以(R)-(+)-3-羟基-4-氯丁酸乙酯为原料,经过TBS保护羟基、叠氮化反应以及选择性还原反应得到相应的醛,随后与Ellman试剂(R)-(+)-叔丁亚磺酰胺缩合构建亚胺,进而通过Mannich反应制备β-氨基酸骨架并构建C3位手性中心,通过9步反应实现了(+)-负霉素的全合成(9%,Proc.Natl.Acad.Sci.USA.2014,111,16274)。总结已有的合成路线,仍存在着大部分合成路线冗长、手性中心构建时受限与部分化学反应立体选择性不高而需多次的柱层析分离纯化,使用昂贵的过渡金属催化剂以及合成初期就使用易爆剧毒品如叠氮化钠等问题,因此已有合成路线一般均无法大量合成所需目标化合物和结构衍生物,影响后续的构效关系研究所需的大量样品提供,极大地限制了(+)-负霉素的药物化学研究。另外已有合成路线对所获得的目标结构进一步衍生化也会受制于分子中原有官能团的影响。因此,发展新颖高效的合成路线仍然十分迫切与必要。
发明内容
为了克服现有技术的不足,本发明的目的在于提供一种操作简便的天然产物(+)-负霉素的全合成方法。
本发明采用曼尼奇(Mannich)反应构建C3位手性中心,将叠氮官能团的引入放在合成路线后期来实现,以避免易爆剧毒品叠氮化钠的大量使用;以(R)-(+)-3-羟基-4-氯丁酸乙酯为原料,以Ellman试剂(R)-(+)-叔丁基亚磺酰胺和Mannich反应构建C4位手性中心,通过简单、易操作的8步反应,总产率30%实现该全合成。本发明的技术方案具体介绍如下。
一种天然产物(+)-负霉素的全合成方法,具体步骤如下:
A)(R)-(+)-3-羟基-4-氯丁酸乙酯和氯化硅试剂在碱A作用下发生羟基保护反应得到(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯;
B)将(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯和二异丁基氢化铝在-78℃的温度下发生还原反应,得到(R)-3-叔丁基二甲基硅氧基-4-氯丁醛;
C)冰浴条件下,将(R)-3-叔丁基二甲基硅氧基-4-氯丁醛、(R)-(+)-叔丁基亚磺酰胺和钛试剂混合,混合后自然恢复到室温,搅拌反应得到(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺;
D)将碱性试剂B的四氢呋喃溶液冷至-78℃后,依次加入乙酸酯的四氢呋喃溶液、三异丙氧基氯化钛以及(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺的四氢呋喃溶液搅拌反应,反应结束后后处理得到(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯;
E)冰浴条件下,将(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯溶解在甲醇中,用碱性试剂C水溶液水解,得到(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸;
F)将(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸、N-甲基-N-氨基甘氨酸叔丁酯和溶剂在冰浴下冷却,之后加入碱D和缩合试剂,加完后自然恢复至室温反应,得到N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯;
G)取N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯、无机碘试剂和叠氮化物在溶剂中反应,得到N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯;
H)首先,室温下,将N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯溶于甲醇或乙醇,在Pd/C催化剂作用下,在氢气气氛中进行还原反应得到叠氮还原产物;然后,将叠氮还原产物溶于稀盐酸中室温搅拌反应,反应结束后加水,用有机溶剂萃取水相,浓缩水相得到(+)-负霉素。
优选的,步骤A)中,氯化硅试剂是叔丁基二甲基氯化硅、叔丁基二苯基氯化硅或三乙基氯化硅;碱A是咪唑、三乙胺与4-二甲氨基吡啶或1,8-二氮杂二环十一碳-7-烯;(R)-(+)-3-羟基-4-氯丁酸乙酯、氯化硅试剂和碱A的摩尔比为1:(0.95~1.05):(1.5~3.50)。
优选的,步骤B)中,所述(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯和二异丁基氢化铝的摩尔比为1:1~1:1.1。
优选的,步骤C)中,钛试剂是四氯化钛、四乙氧基钛、四异丙氧基钛、二异丙氧基二氯化钛或三异丙氧基氯化钛。
优选的,(R)-3-叔丁基二甲基硅氧基-4-氯丁醛、(R)-(+)-叔丁基亚磺酰胺和钛试剂的摩尔比为1:(0.95~1.05):(1.1~3.3)。
优选的,步骤D)中,碱性试剂B是二异丙基氨基锂或二(三甲基硅基)氨基钠;乙酸酯是乙酸甲酯、乙酸乙酯或乙酸叔丁酯;(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺、乙酸酯、碱性试剂B和三异丙氧基氯化钛的摩尔比为1:(0.95~4.05):(1.05~4.1):(2.1~5.3)。
优选的,步骤E)中,碱C是氢氧化锂、氢氧化钠或氢氧化钾;(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯和碱C的摩尔比为1:1.4~1:3.6。
优选的,步骤F)中,缩合试剂是二环己基碳二亚胺、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯或O-苯并三氮唑-四甲基脲六氟磷酸酯;碱D是三乙胺、二异丙基乙基胺、4-二甲氨基吡啶或碳酸钾;(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸、N-甲基-N-氨基甘氨酸叔丁酯、缩合试剂和碱D的摩尔比为1:(0.95~1.5):(1.2~2.5):(1.2~4.4)。
优选的,步骤G)中,无机碘试剂是碘化钠或碘化钾;叠氮化物是叠氮化钠、叠氮基三甲基硅烷或四丁基叠氮化铵;N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯、无机碘试剂和叠氮化物的摩尔比为1:(0.15~1.05):(0.95~2.05)。
步骤H)中,Pd/C催化为10wt%催化剂,N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯和10%Pd/C的质量比为3.1:1~3.2:1。
本发明与现有技术相比具有以下优点:
(1)以常见化工原料(R)-(+)-3-羟基-4-氯丁酸乙酯为原料,通过8个步骤的化学全合成,总收率在30%左右,得到目标产物(+)-负霉素。
(2)该全合成制备方法有效解决基于天然产物(+)-负霉素来源的药物开发资源,不破坏生态环境,化合物来源充分,不受自然资源短缺的限制。
(3)化学合成(+)-负霉素,生产周期较短,二到三周即可,经济有效,环保可控。
附图说明
图1为本发明目标产物(+)-负霉素的核磁氢谱(400MHz,D2O)。
具体实施方式
下面结合附图和实施例对本发明的技术方案进行详细阐述。
本发明的合成路线如下所示。
实施例1
步骤A中(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯(2)的合成
将2.72g咪唑溶于20mL DMF中,冰水浴中冷却至0℃后,依次加入3.3g化合物1和3.0g叔丁基二甲基氯化硅,搅拌反应24h后,TLC监测反应(展开剂,石油醚:乙酸乙酯=5:1,v/v),加入5mL饱和碳酸氢钠水溶液淬灭反应,加入20mL水充分搅拌,分离有机相,用乙醚(3×30mL)萃取水相,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析纯化,洗脱剂(石油醚:乙酸乙酯=100:1),得到黄色油状物5.0g,产率90%。
比旋光值[α]D 25 18.0(c 1.03,CHCl3);化合物的核磁共振氢谱谱图数据如下:1HNMR(400MHz,CDCl3):δppm 4.34-4.28(m,1H),4.20-4.08(m,2H),3.55-3.47(m,2H),2.68(dd,J1=15.2,J2=4.8Hz,1H),2.52(dd,J1=15.2,J2=7.2Hz,1H),1.27(t,J=7.2Hz,3H),0.87(s,9H),0.09(d,J=15.6Hz,6H)。
步骤B中(R)-3-叔丁基二甲基硅氧基-4-氯丁醛(3)的合成
取3.28g化合物2溶于100mL甲苯中,并将反应温度降至-78℃,滴加8.5mL二异丁基氢化铝的甲苯溶液,反应1h后,TLC监测反应(展开剂,乙酸乙酯),加入3mL甲醇淬灭反应。恢复至室温,向体系中加入50mL饱和酒石酸钠钾溶液充分搅拌2h。分离有机相,水相用乙醚(3×30mL)萃取,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析纯化,洗脱剂(石油醚:乙酸乙酯=40:1),得到黄色油状化合物2.73g,产率99%。
比旋光值[α]D 23 17.1(c 1.01,CHCl3);化合物的核磁共振氢谱谱图数据如下:1HNMR(400MHz,CDCl3):δppm 9.80(t,J=1.6Hz,1H),4.41-4.37(m,1H),3.54(dd,J1=11.2,J2=4.8Hz,1H),3.47(dd,J1=10.8,J2=6.4Hz,1H),2.81-2.65(m,2H),0.87(s,9H),0.10(d,J=14.4Hz,6H)。
步骤C中(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺(4)的合成
将1.42g(R)-(+)叔丁基亚磺酰胺溶于40mL四氢呋喃中,于冰水浴中冷却至0℃,依次加入2.8g化合物3的THF(12mL)溶液和3mL四乙氧基钛,加料完成后恢复至室温,搅拌至反应完全,TLC监测反应(展开剂,石油醚:乙酸乙酯=10:1,v/v),加入5mL饱和氯化钠水溶液淬灭反应,过滤,浓缩,残余物用乙醚稀释,水相用乙醚(3×20mL)萃取,合并有机相后用无水硫酸钠干燥,过滤,浓缩,柱层析纯化,洗脱剂(石油醚:乙酸乙酯=20:1),得到黄色油状化合物3.58g,产率89%。
IR(thin film,KBr):νcm-1 2956,2929,2898,2858,1737,1622,1089,838;ESI-LR:[M+H]+340.2;HRMS(ESI)m/z calculated for C14H31O2NCLSSi[M+H]+340.1528,found340.1527;[α]D 25-117.0(c 1.19,CH2Cl2);化合物的核磁共振氢谱、碳谱谱图数据如下:1H NMR(400MHz,CDCl3):δppm 8.12(t,J=4.8Hz,1H),4.30-4.24(m,1H),3.55(dd,J1=10.8,J2=4.8Hz,1H),3.50(dd,J1=11.2,J2=6.4Hz,1H),2.90-2.77(m,2H),1.20(s,9H),0.89(s,9H),0.10(d,J=8.0Hz,6H);13C NMR(100MHz,CDCl3):δppm 166.7,70.1,56.9,48.0,41.2,25.8,22.5,18.1,-4.5,-4.6。
步骤D中(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯(5)的合成
将0.54mL二异丙胺溶于10mL四氢呋喃,并冷却至-78℃,依次滴加1.7mL正丁基锂(2.4M in hexanes),260mg乙酸甲酯的THF(10mL)溶液,7.7mL三异丙氧基氯化钛(1M inhexanes)后滴入1.2g化合物4的THF(7mL)溶液,TLC监测反应(展开剂,石油醚:乙酸乙酯=5:1,v/v),低温下加入3mL甲醇淬灭反应,恢复至室温,加10mL水充分搅拌后过滤,浓缩,残余物用乙醚稀释,水相用乙醚(3×20mL)萃取,合并有机相后用无水硫酸钠干燥,过滤,浓缩后柱层析纯化,洗脱剂(石油醚:乙酸乙酯=4:1),得到黄色油状化合物1.3g,产率89%。
IR(thin film,KBr):νcm-1 3206,2955,2929,2857,1740,1092,1044,837;ESI-LR:[M+H]+414.1;HRMS(ESI)m/z calculated for C17H37O4NClSSi[M+H]+414.1896,found414.1893;[α]D 25-48.3(c 0.33,CH2Cl2);化合物的核磁共振氢谱、碳谱谱图数据如下:1H NMR(400MHz,CDCl3):δppm 4.34(d,J=10.0Hz,1H),4.02-4.00(m,1H),3.68(s,3H),3.46(dd,J1=10.8Hz,J2=3.6Hz,1H),3.39(dd,J1=10.8Hz,J2=6.4Hz,1H),2.96(dd,J1=16.4Hz,J2=5.6Hz,1H),2.62(dd,J1=16.8Hz,J2=4.4Hz,1H),1.99-1.92(m,1H),1.61-1.54(m,1H),1.23(s,9H),0.89(s,9H),0.09(s,6H);13C NMR(100MHz,CDCl3):δppm 172.6,69.4,56.3,51.7,51.0,48.9,41.7,41.0,25.9,22.9,18.1,-4.0,-4.2。
步骤E中(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸(6)的合成
取2.5g化合物5溶于20mL甲醇中,于冰水浴中冷却至0℃后,滴加9mL氢氧化锂水溶液,滴加完成后恢复至室温反应,TLC监测反应(展开剂,石油醚:乙酸乙酯=1:1,v/v),滴加盐酸将反应液pH调至2,用乙醚(4×40mL)萃取,合并有机相用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,浓缩后柱层析纯化,洗脱剂(二氯甲烷:甲醇=50:1),得到白色固体2.13g,产率88%。
IR(thin film,KBr):νcm-1 3212,2956,2929,2857,1718,1255,1197,1094,837;ESI-LR:[M-H]-398.2;HRMS(ESI)m/z calculated for C16H33O4NClSSi[M-H]-398.1594,found398.1591;[α]D 25 7.5(c 1.91,CH2Cl2);化合物的核磁共振氢谱、碳谱谱图数据如下:1H NMR(400MHz,CDCl3):δppm 4.80(d,J=9.2Hz,1H),3.96(s,1H),3.69-3.63(m,1H),3.48-3.37(m,2H),3.06-3.01(m,1H),2.52(d,J=16.4Hz,1H),2.16-2.09(m,1H),1.64-1.57(m,1H),1.28(s,9H),0.89(s,9H),0.09(s,6H);13C NMR(100MHz,CDCl3):δppm 173.8,69.8,57.1,51.7,48.9,41.8,40.5,25.9,23.1,18.1,-3.9,-4.2。
步骤F中N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯(7)的合成
取563mg化合物6,224mg N-氨基-N-甲基甘氨酸叔丁酯对甲磺酸盐和246mg 1-羟基苯并三唑溶于15mL二氯甲烷中,置于冰水浴中冷却至0℃后,滴加0.26mL三乙胺并加入349mg 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐,后恢复至室温反应,TLC监测反应(展开剂,二氯甲烷:甲醇=15:1,v/v),加入30mL 10%柠檬酸水溶液充分搅拌,分离有机相,水相用乙酸乙酯(3×30mL)萃取,合并有机相,依次用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤,无水硫酸钠干燥,浓缩后柱层析纯化,洗脱剂(石油醚:丙酮=5:1),得到黄色油状化合物762mg,产率100%。
IR(thin film,KBr):νcm-13236,2956,2929,2857,1744,1667,1253,1225,1072,837;ESI-LR:[M+H]+542.2;HRMS(ESI)m/z calculated for C23H48O5N3ClNaSSi[M+Na]+564.2665,found 564.2668;比旋光值[α]D 25-4.7(c 0.85,CH2Cl2);化合物的核磁共振氢谱谱图数据如下:1H NMR(400MHz,CDCl3):δppm 5.28-4.96(m,1H),4.02-3.96(m,1H),3.67-3.32(m,5H),3.03-2.84(m,1H),2.71(s,1.8H,major isomer),2.70(s,1.2H,minorisomer),2.23-1.90(m,2H),1.67-1.52(m,1H),1.45(s,9H),1.24(s,5.7H,major isomer),1.21(s,3.8H,minor isomer),0.89(s,3.6H,minor isomer),0.87(s,5.4H,majorisomer),0.09(s,1.2H,minor isomer)0.084(s,1.2H,minor isomer),0.076(s,1.8H,major isomer),0.07(s,1.8H,major isomer);ratio of isomers≈1.5:1。
步骤G中N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯(8)的合成
取279mg化合物7溶于3mL DMF中,加入83mg碘化钾和33mg叠氮化钠,搅拌,核磁(1HNMR)跟踪至原料反应完全,加入5mL水充分搅拌,用乙醚(5×10mL)萃取水相,合并有机相,用饱和氯化钠水溶液洗涤,无水硫酸钠干燥,过滤,浓缩后柱层析纯化,洗脱剂(二氯甲烷:甲醇=50:1),得到黄色油状化合物200mg,产率71%。
ESI-LR:[M+H]+549.2;比旋光值[α]D 25-10.9(c 1.51,CHCl3);化合物的核磁共振氢谱谱图数据如下:1H NMR(400MHz,CDCl3):δppm 5.08-4.97(m,1H),4.05-3.91(m,1H),3.65-3.28(m,4H),3.17-2.86(m,2H),2.72(s,1.7H,major isomer),2.71(s,1.3H,minorisomer),2.24-1.94(m,1H),1.85-1.56(m,1H),1.47(s,3.8H,minor isomer),1.46(s,5.3H,major isomer),1.24(s,5.3H,major isomer),1.22(s,3.8H,minor isomer),0.90(s,3.8H,minor isomer),0.89(s,5.3H,major isomer),0.10(s,3.4H,major isomer),0.08(s,2.5H,minor isomer);ratio of isomers≈1.3:1。
步骤H中(+)-负霉素(9)的合成
将62mg化合物8溶于4mL甲醇中,加入20mg 10%Pd/C,氢气气氛下,室温下搅拌反应4h,反应结束后过滤,浓缩后柱层析纯化,洗脱剂(二氯甲烷:甲醇=10:1),得到叠氮还原产物40mg。然后取该还原产物溶于1.5mL稀盐酸溶液中,室温下继续搅拌2h,反应结束后加入5mL水充分搅拌,分离有机相,用乙酸乙酯(3×10mL)萃取水相,后旋干水相得到天然产物(+)-负霉素19mg,白色固体,收率68%。
ESI-LR:[M-H]-247.2;化合物的核磁共振氢谱谱图数据如下:1H NMR(400MHz,D2O):δppm 4.14-4.08(m,1H),3.93-3.82(m,1H),3.67(s,2H),3.18-3.11(m,1H),3.00-2.94(m,1H),2.70(s,3H),2.67-2.59(m,2H),2.00-1.79(m,2H)。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所做的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
1.一种天然产物(+)-负霉素的全合成方法,其特征在于,具体步骤如下:
A)(R)-(+)-3-羟基-4-氯丁酸乙酯和氯化硅试剂在碱A作用下发生羟基保护反应得到(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯;B)将(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯和二异丁基氢化铝在-78℃的温度下发生还原反应,得到(R)-3-叔丁基二甲基硅氧基-4-氯丁醛;
C)冰浴条件下,将(R)-3-叔丁基二甲基硅氧基-4-氯丁醛、(R)-(+)-叔丁基亚磺酰胺和钛试剂混合,混合后自然恢复到室温,搅拌反应得到(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺;
D)将碱性试剂B的四氢呋喃溶液冷至-78℃后,依次加入乙酸酯的四氢呋喃溶液、三异丙氧基氯化钛以及(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺的四氢呋喃溶液搅拌反应,反应结束后后处理得到(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯;
E)冰浴条件下,将(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯溶解在甲醇中,用碱性试剂C水溶液水解,得到(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸;
F)将(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸、N-甲基-N-氨基甘氨酸叔丁酯和溶剂在冰浴下冷却,之后加入碱D和缩合试剂,加完后自然恢复至室温反应,得到N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯;
G)取N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯、无机碘试剂和叠氮化物在溶剂中反应,得到N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯;
H)首先,室温下,将N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯溶于甲醇或乙醇,在Pd/C催化剂作用下,在氢气气氛中进行还原反应得到叠氮还原产物;然后,将叠氮还原产物溶于稀盐酸中室温搅拌反应,反应结束后加水,用有机溶剂萃取水相,浓缩水相得到(+)-负霉素。
2.如权利要求1所述的全合成方法,其特征在于,步骤A)中,氯化硅试剂是叔丁基二甲基氯化硅、叔丁基二苯基氯化硅或三乙基氯化硅;碱A是咪唑、三乙胺、4-二甲氨基吡啶或1,8-二氮杂二环十一碳-7-烯;(R)-(+)-3-羟基-4-氯丁酸乙酯、氯化硅试剂和碱A的摩尔比为1:(0.95~1.05):(1.5~3.50)。
3.如权利要求1所述的全合成方法,其特征在于,步骤B)中,所述(R)-3-叔丁基二甲基硅氧基-4-氯丁酸乙酯和二异丁基氢化铝的摩尔比为1:1~1:1.1。
4.如权利要求1所述的全合成方法,其特征在于,步骤C)中,钛试剂是四氯化钛、四乙氧基钛、四异丙氧基钛、二异丙氧基二氯化钛或三异丙氧基氯化钛;
(R)-3-叔丁基二甲基硅氧基-4-氯丁醛、(R)-(+)-叔丁基亚磺酰胺和钛试剂的摩尔比为1:(0.95~1.05):(1.1~3.3)。
5.如权利要求1所述的全合成方法,其特征在于,步骤D)中,碱性试剂B是二异丙基氨基锂或二(三甲基硅基)氨基钠;乙酸酯是乙酸甲酯、乙酸乙酯或乙酸叔丁酯;(R)-N-[(R,E)-3-叔丁基二甲基硅氧基-4-氯丁基亚基]叔丁基亚磺酰胺、乙酸酯、碱性试剂B和三异丙氧基氯化钛的摩尔比为1:(0.95~4.05):(1.05~4.1):(2.1~5.3)。
6.如权利要求1所述的全合成方法,其特征在于,步骤E)中,碱C是氢氧化锂、氢氧化钠或氢氧化钾;(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸甲酯和碱C的摩尔比为1:1.4~1:3.6。
7.如权利要求1所述的全合成方法,其特征在于,步骤F)中,缩合试剂是二环己基碳二亚胺、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐、2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯或O-苯并三氮唑-四甲基脲六氟磷酸酯;碱D是三乙胺、二异丙基乙基胺、4-二甲氨基吡啶或碳酸钾;(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酸、N-甲基-N-氨基甘氨酸叔丁酯、缩合试剂和碱D的摩尔比为1:(0.95~1.5):(1.2~2.5):(1.2~4.4)。
8.如权利要求1所述的全合成方法,其特征在于,步骤G)中,无机碘试剂是碘化钠或碘化钾;叠氮化物是叠氮化钠、叠氮基三甲基硅烷或四丁基叠氮化铵;N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-5-叔丁基二甲基硅氧基-6-氯己酰胺氨基乙酸叔丁酯、无机碘试剂和叠氮化物的摩尔比为1:(0.15~1.05):(0.95~2.05)。
9.如权利要求1所述的全合成方法,其特征在于,步骤H)中,Pd/C催化为10wt%催化剂,N-甲基-N-(3R,5R)-3-(R)-叔丁基亚磺酰氨基-6-叠氮基-5-叔丁基二甲基硅氧基己酰胺氨基乙酸叔丁酯和10%Pd/C的质量比为3.1:1~3.2:1。
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