CN112430243B - 一种制备硫酯类化合物的方法 - Google Patents
一种制备硫酯类化合物的方法 Download PDFInfo
- Publication number
- CN112430243B CN112430243B CN201910786371.XA CN201910786371A CN112430243B CN 112430243 B CN112430243 B CN 112430243B CN 201910786371 A CN201910786371 A CN 201910786371A CN 112430243 B CN112430243 B CN 112430243B
- Authority
- CN
- China
- Prior art keywords
- following groups
- thioester
- group
- reaction
- iii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 24
- -1 thioester compound Chemical class 0.000 title claims abstract description 16
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000005499 phosphonyl group Chemical group 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 44
- 239000002994 raw material Substances 0.000 abstract description 3
- 229910052710 silicon Inorganic materials 0.000 abstract description 3
- 239000010703 silicon Substances 0.000 abstract description 3
- 150000003951 lactams Chemical class 0.000 abstract description 2
- 150000007970 thio esters Chemical class 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 7
- 229920001184 polypeptide Polymers 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 229930014626 natural product Natural products 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- BUIGLPNXWMXPGK-UHFFFAOYSA-N 3-(9h-fluoren-9-ylmethoxycarbonylamino)-2-sulfopropanoic acid Chemical compound C1=CC=C2C(COC(=O)NCC(C(=O)O)S(O)(=O)=O)C3=CC=CC=C3C2=C1 BUIGLPNXWMXPGK-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 125000006575 electron-withdrawing group Chemical group 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- IMUSLIHRIYOHEV-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-methylsulfanylbutanoic acid Chemical compound CSCCC(C(O)=O)NC(=O)OC(C)(C)C IMUSLIHRIYOHEV-UHFFFAOYSA-N 0.000 description 1
- YGSRAYJBEREVRB-UHFFFAOYSA-N 5-[(2-methylpropan-2-yl)oxy]-2-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound CC(C)(C)OC(=O)CCC(C(O)=O)NC(=O)OC(C)(C)C YGSRAYJBEREVRB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 229940122767 Potassium sparing diuretic Drugs 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229940092229 aldactone Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical compound C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 description 1
- 229960005229 ceftiofur Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002898 organic sulfur compounds Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000003286 potassium sparing diuretic agent Substances 0.000 description 1
- 229940097241 potassium-sparing diuretic Drugs 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/38—Polysiloxanes modified by chemical after-treatment
- C08G77/382—Polysiloxanes modified by chemical after-treatment containing atoms other than carbon, hydrogen, oxygen or silicon
- C08G77/392—Polysiloxanes modified by chemical after-treatment containing atoms other than carbon, hydrogen, oxygen or silicon containing sulfur
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
Abstract
本发明提供了一种制备硫酯类化合物的方法，所述方法的主要步骤是：由硅基取代的内炔酰胺与单硫代羧酸在有机溶剂中反应，得到目标产物，其反应式为(1)。本发明的方法具有条件温和、原料简单易得、应用前景广泛等优点。
Description
技术领域
本发明涉及有机化学领域，尤其涉及一种制备硫酯类化合物的方法。
背景技术
硫酯是一类活泼的酯类衍生物，该结构分子在多肽合成中具有重要作用，也存在于许多药物分子以及天然产物分子中，是众多天然产物和具有生物活性化合物的重要骨架之一。在多肽合成方面，1994年由Kent组提出的自然连接法(Science 1994,266,776–779)，是由C端为硫酯的多肽片段与N端连有半胱氨酸的多肽片段进行偶联。在硫醇为添加物的作用下，经过S到N的酰基转移形成新的天然酰胺键。该方法是当前化学合成蛋白最有效的方法。在药物中，第二次世界大战期间发现了磺胺药和青霉素，这两种含硫药物为有机硫化合物的研究开创了历史新篇章。除了上述两种药物外，还有很多其他的含硫药物如预防高血压和充血性心力衰竭的保钾利尿药螺内酯(Aldactone)，治疗动物敏感菌所致感染性疾病的头孢噻呋(Ceftionfur)以及抗高血压药物佐芬普利(Zofenopril)等都含有硫酯结构；同时，许多含有硫酯单元的天然产物也具有多种多样的生物活性。由于在多肽合成和医药领域的重要应用价值，硫酯类化合物的合成也一度成为有机合成工作者的研究热点。
当前，多肽硫酯合成占主导的方法是采用固相掩蔽的方式合成硫酯如分子内可逆的O-S、N-S迁移法，多肽骨架C端连接臂活化法等方法。但是连接臂结构复杂合成困难和硫酯化效率低仍然困扰着上述方法的使用。普通硫酯衍生物的合成方法大体可以分为以下三大类：(1)以硫醇或硫酚为底物的合成法；(2)以二硫醚为底物的合成法；(3)羰化法合成。这些方法存在着所用还原剂或催化剂昂贵、酰化试剂不稳定、反应条件较苛刻等缺点。
发明内容
本发明提供一种以硅基取代的内炔酰胺、单硫代羧酸为原料，一步合成硫酯类化合物的方法。
本发明的一种制备硫酯类化合物的方法，包括以下步骤：
在有机溶剂中，式I所示的单硫代羧酸与式II所示的炔酰胺于0℃～50℃反应，得到式III所示的硫酯类化合物；
式中，R1选自C1～C7的烷基、烯基、炔基、C3～C10的杂环基、芳基、取代的芳基、N端保护的氨基酸去除一个羧基的残基、N端保护的肽链残基、N端保护的蛋白质残基；
R2选自烷基或芳基
R3选自三取代的硅基；
EWG(吸电子基团)选自烷磺酰基、芳磺酰基、芳酰基、烷酰基、硝基、睛基、膦酰基、磺酰亚胺等；
其中，所述的取代的苯基、取代的苯磺酰基、三取代的硅基中的取代基独立地选自C1～C4的烷基、C1～C4的烷氧基、卤素、硝基、氰基。
在一些优选的实施例中，R1选自甲基、乙基、正丙基、异丙基、正庚基、对氯苯基、苯甲基、苯乙基，或下列基团中的一种：
其中PG为Fmoc、Boc、Cbz或Ac，R4选自甲基、异丙基、苄基等氨基酸侧链基团；
R2选自下列基团中的一种：
R3选自下列基团中的一种：
在一些优选的实施例中，R1选自甲基、乙基，或下列基团中的一种：
R2选自下列基团中的一种：
R3为三甲基硅基。
在一些优选的实施例中，有机溶剂为二氯甲烷(DCM)。
由上述技术方案可知，本发明提供一种由硅基取代的内炔酰胺与单硫代羧酸反应制备硫酯类化合物的方法。该方法具有选择性高、反应条件温和、底物易得、适应性广和产物具有多样性等优点；该方法原料简单易得，反应高效，反应条件温和且不需要任何添加剂。基于这些优点，本发明将会为硫酯类化合物的合成提供一条更为简洁可行，应用前景广泛的途径。
具体实施方式
下面结合实施例1～11来对本发明作进一步说明，帮助阅读者更好地理解本发明的实质，但不能对本发明的实施和保护范围构成任何限定。
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，均可从商业途径获得。
实施例1
(E)-S-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinylethanethioate(III-1)
在干净的反应管中加入硫代乙酸I-1(15mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在0℃下反应6小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-1，淡黄色液体，收率90％。
1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.2Hz,2H),7.20(d,J＝8.0Hz,2H),6.10(s,1H),2.73(s,3H),2.34(s,3H),2.08(s,3H),0.17(s,9H).
13C NMR(101MHz,CDCl3)δ193.5,154.3,144.7,137.3,135.7,130.4,129.1,36.9,31.0,22.4,0.0.
HRMS(ESI)calcd for C15H23NO3S2Si(M+Na)+:380.0781,found 380.0786.
实施例2
(E)-S-1-(N,4-dimethyl phenylsulfonamido)-2-(trimethyl silyl)vinyl 4-chlorobenzothioate(III-2)
在干净的反应管中加入对氯硫代苯乙酸I-2(34mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在10℃下反应5小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-2，淡黄色油状物，收率87％。
1H NMR(400MHz,CDCl3)δ7.54(d,J＝8.2Hz,2H),7.50(d,J＝8.6Hz,2H),7.21(d,J＝8.6Hz,2H),7.13(d,J＝8.2Hz,2H),6.21(s,1H),2.77(s,3H),2.26(s,3H),0.17(s,9H).
13C NMR(100MHz,CDCl3)δ189.0,155.4,144.7,140.9,136.5,135.6,135.4,130.4,129.8,129.6,129.1,37.3,22.4,0.0.
HRMS(ESI)calcd for C20H24ClNO3S2Si(M+Na)+:476.0548,found 476.0543.
实施例3
(E)-S-1-(N,4–dimethylphenylsulfonamido)-2-(trimethylsilyl)vinylbenzothioate(III-3)
在干净的反应管中加入硫代苯乙酸I-3(28mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在20℃下反应4小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-3，得无色油状物，收率87％。
1H NMR(400MHz,CDCl3)δ7.59(t,J＝8.1Hz,4H),7.43(t,J＝7.4Hz,1H),7.27(t,J＝7.8Hz,2H),7.16(d,J＝8.1Hz,2H),6.26(s,1H),2.82(s,3H),2.29(s,3H),0.21(s,9H).
13C NMR(101MHz,CDCl3)δ190.0,155.1,144.6,137.1,136.9,135.6,134.5,130.3,129.4,129.1,128.2,37.2,22.3,0.0.
HRMS(ESI)calcd for C20H25NO3S2Si(M+Na)+:420.1118,found 420.1113.
实施例4
(S,E)-S-1-(N,4-dimethyl phenylsulfonamido)-2-(trimethylsilyl)vinyl2-(tert-butoxycarbon ylamino)propanethioate(III-4)
在干净的反应管中加入硫代2-(叔丁氧基羰基氨基)丙酸I-4(41mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在30℃下反应5小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-4，得无色油状物(化合物III硫酯III-4)，收率87％。
1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.9Hz,2H),7.05(d,J＝8.0Hz,2H),5.96(s,1H),4.62(d,J＝5.5Hz,1H),3.99(s,1H),2.57(s,3H),2.19(s,3H),1.14(s,9H),1.00(d,J＝7.0Hz,3H),0.03(s,9H).
13C NMR(101MHz,CDCl3)δ199.8,155.5,154.7,144.7,136.5,135.7,130.4,129.1,81.0,57.2,36.8,29.1,22.4,19.5,0.0.
HRMS(ESI)calcd for C21H34N2O5S2Si(M+Na)+:509.1571,found 509.1571.
实施例5
(S,E)-S-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinyl2-(tert-butoxycarbonyl amino)-4-(methylthio)butanethioate(III-5)
在干净的反应管中加入硫代2-(叔丁氧基羰基氨基)-4-(甲硫基)丁酸I-5(53mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，30℃下反应6小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-5，无色油状物，收率89％。
1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),6.21(s,1H),4.99(d,J＝7.6Hz,1H),4.35(s,1H),2.82(s,3H),2.45(s,4H),2.05(s,3H),1.40(s,9H),0.28(s,9H).
13C NMR(100MHz,CDCl3)199.0,155.0,144.8,136.4,135.6,130.5,129.1,81.3,60.7,36.9,32.8,30.8,30.5,29.1,22.5,16.2,0.0.
HRMS(ESI)calcd for C23H38N2O5S3Si(M+Na)+:569.1620,found 569.1604.
实施例6
(S,E)-tert-butyl4-(tert-butoxycarbonylamino)-5-(1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinylthio)-5-oxopentanoate(III-6)
在干净的反应管中加入硫代5-叔丁氧基-2-(叔丁氧基羰基氨基)-5-氧代戊酸I-6(64mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在30℃下反应4小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-6，淡黄色油状物，收率93％。
1H NMR(400MHz,CDCl3)δ7.40(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),5.96(s,1H),4.81(d,J＝8.0Hz,1H),3.95(s,3H),2.57(s,3H),2.20(s,2H),2.13–1.89(m,1H),1.78–1.70(m,1H),1.18(s,9H),1.14(s,9H),0.03(s,9H).
13C NMR(100MHz,CDCl3)δ199.1,172.9,155.8,154.7,144.7,136.5,135.7,130.5,129.0,81.9,81.1,61.3,36.8,32.4,29.1,28.9,28.2,22.4,0.0.
HRMS(ESI)calcd for C27H44N2O7S2Si(M+Na)+:623.2251,found 623.2256.
实施例7
(S,E)-S-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinyl2-(tert-butoxycarbonylamino)-3-methylbutanethioate(III-7)
在干净的反应管中加入硫代2-(叔丁氧基羰基氨基)-3-甲基丁酸I-7(46mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在40℃下反应6小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-7，无色油状物，收率76％。
1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.2Hz,2H),7.31(d,J＝8.0Hz,2H),6.20(s,1H),4.82(d,J＝9.0Hz,1H),4.15(m,4.5Hz,1H),3.48(s,3H),2.82(s,1H),2.45(s,3H),1.48(s,3H),1.41(s,9H),0.90(d,J＝6.8Hz,3H),0.77(d,J＝6.7Hz,3H),0.28(s,9H).
13C NMR(100MHz,CDCl3)156.1,154.9,144.7,136.6,135.6,130.4,129.1,81.0,66.3,36.8,31.9,29.1,22.4,20.1,17.8,0.0.
HRMS(ESI)calcd for C23H38N2O5S2Si2(M+Na)+:537.1884,found 537.1887.
实施例8
(S,E)-S-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinyl2-(benzyloxycarbonylamino)-4-methylpentanethioate(III-8)
在干净的反应管中加入硫代2-(苄氧基羰基氨基)-4-甲基戊酸I-8(56mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在40℃下反应3小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-8，淡黄色固体，收率82％。
1H NMR(400MHz,CDCl3)δ7.57(d,J＝7.9Hz,1H),7.34–7.23(m,4H),7.20(d,J＝7.7Hz,2H),6.16(s,1H),5.09–4.95(m,2H),4.94–4.87(m,1H),4.34–4.14(m,1H),2.75(s,3H),2.32(s,3H),1.65–1.49(m,1H),1.48–1.20(m,2H),0.80(s,3H),0.79(s,3H),0.20(s,9H).
13C NMR(100MHz,CDCl3)199.2,156.4,155.0,144.8,136.9,136.4,135.6,130.4,129.4,129.2,129.1,128.8,68.1,60.5,42.8,37.0,25.6,23.8,22.4,0.0.
HRMS(ESI)calcd for C27H38N2O5S2Si(M+Na)+:585.1884,found 585.1888.
实施例9
(E)-S-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinyl2-(benzyloxycarbonylamino)et hanethioate(III-9)
在干净的反应管中加入硫代2-(苄氧基羰基氨基)丙酸I-9(45mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在40℃下反应4小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-9，无色油状物，收率92％。
1H NMR(400MHz,CDCl3)δ7.55(d,J＝7.9Hz,2H),7.26(d,J＝7.8Hz,4H),7.20(d,J＝8.1Hz,2H),6.12(d,J＝34.9Hz,1H),5.18(s,1H),5.00(s,2H),3.90(d,J＝5.8Hz,2H),2.75(s,3H),2.34(s,3H),0.20(s,9H).
13C NMR(100MHz,CDCl3)195.3,156.9,155.3,145.,136.9,135.7,135.5,130.5,129.4,129.2,129.1,128.9,68.2,51.3,37.0,22.5,0.0.
HRMS(ESI)calcd for C23H30N2O5S2Si(M+Na)+:529.1258,found 529.1265.
实施例10
(E)-S-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinyl3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanethioate(III-10)
在干净的反应管中加入硫代3-(((9H-芴-9-基)甲氧基)羰基氨基)丙酸I-10(66mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在30℃下反应6小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-10，得白色固体，收率90％。
1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.5Hz,2H),7.61(d,J＝8.0Hz,2H),7.54(d,J＝7.4Hz,2H),7.39(t,J＝7.4Hz,2H),7.32–7.22(m,4H),6.23(s,1H),5.36–5.00(m,1H),4.35(d,J＝6.9Hz,2H),4.16(t,J＝6.8Hz,1H),3.45–3.27(m,2H),2.82(s,3H),2.66(t,J＝5.8Hz,2H),2.39(s,3H),0.30(s,9H).
13C NMR(100MHz,CDCl3)196.2,157.0,154.6,144.8,144.6,142.1,136.3,135.3,130.4,128.9,128.5,127.8,125.7,120.8,67.5,48.0,44.2,37.5,36.9,22.4,0.0.
HRMS(ESI)calcd for C31H36N2O5S2Si(M+H)+:609.1908,found 609.1913.
实施例11
(2S,3R)-S-((E)-1-(N,4-dimethylphenylsulfonamido)-2-(trimethylsilyl)vinyl)2-acetamido-3-meth ylpentanethioate(III-11)
在干净的反应管中加入硫代2-乙酰氨基-3-甲基戊酸I-11(38mg，0.2mmol)、炔酰胺II-1(62mg，0.22mmol)、DCM溶剂2mL，在50℃下反应8小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-11，无色液体，收率82％。
1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.2Hz,2H),7.33(d,J＝8.0Hz,2H),6.22(s,1H),5.87–5.68(m,1H),4.54(dd,J＝9.0,5.0Hz,1H),2.82(s,3H),2.47(s,3H),1.95(s,4H),1.27(s,2H),1.11–0.96(m,2H),0.87(s,1H),0.85(d,J＝1.0Hz,1H),0.29(s,9H).
13C NMR(100MHz,CDCl3)198.1,170.6,155.3,144.9,136.3,135.5,130.5,129.11,64.2,38.7,36.9,3.45,23.9,22.4,16.5,12.4,0.0.
HRMS(ESI)calcd for C21H34N2O4S2Si(M+Na)+:493.1621,found 493.1629.
实施例12
在干净的反应管中加入硫代3-(((9H-芴-9-基)甲氧基)羰基氨基)丙酸I-12(65mg，0.2mmol)、炔酰胺II-2(62mg，0.22mmol)、DCM溶剂2mL，在40℃下反应6小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-11，无色液体，收率81％。
1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.5Hz,2H),7.57–7.51(m,2H),7.33(t,J＝7.5Hz,2H),7.23(t,J＝7.3Hz,2H),7.12(d,J＝7.7Hz,2H),6.14(s,1H),5.08(d,J＝7.7Hz,1H),4.27(d,J＝9.6Hz,2H),4.09(t,J＝6.6Hz,1H),2.74(s,3H),2.24(s,3H),1.21(d,J＝7.0Hz,1H),0.96(t,J＝7.8Hz,9H),0.76(q,J＝15.6,7.7Hz,6H).
13C NMR(101MHz,CDCl3)δ198.3,155.3,152.6,144.0,143.7,141.3,136.0,134.5,129.6,128.3,127.9,127.1,125.0,120.1,67.2,56.7,47.2,36.2,21.485,19.1,7.4,3.7.
HRMS(ESI)calcd for C31H36N2O5S2Si(M+Na)+:558.1361,found 558.1351.
实施例13
在干净的反应管中加入硫代3-(((9H-芴-9-基)甲氧基)羰基氨基)丙酸I-12(65mg，0.2mmol)、炔酰胺II-3(62mg，0.22mmol)、DCM溶剂2mL，在30℃下反应4小时(用TLC决定停止反应的时间)；反应结束后，经柱层析分离得到纯的硫酯III-11，无色液体，收率84％。
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.4Hz,2H),7.65(d,J＝3.6Hz,2H),7.59(d,J＝8.0Hz,2H),7.56(d,J＝7.7Hz,2H),7.43–7.34(m,5H),7.30(t,J＝7.1Hz,1H),7.16(d,J＝7.8Hz,2H),6.37(s,1H),5.17(d,J＝7.3Hz,1H),4.34(d,J＝7.1Hz,1H),4.15(t,J＝6.5Hz,1H),2.65(s,3H),2.28(s,3H),1.25(s,3H),0.59(s,6H).
13C NMR(101MHz,CDCl3)δ198.5,155.7,152.7,144.4,144.1,141.7,138.2,137.3,135.0,134.5,130.0,129.6,128.6,128.2,127.5,125.4,120.5,67.5,57.12,47.6,36.2,21.9,19.3,-1.6.
HRMS(ESI)calcd for C36H38N2O5S2Si(M+H)+:670.1991,found 670.1999.
以上所述的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (4)
1.一种制备硫酯类化合物的方法，包括以下步骤：
在有机溶剂中，式I所示的单硫代羧酸与式II所示的炔酰胺于0℃~50℃反应，得到式III所示的硫酯类化合物；
R2选自烷基或芳基；
R3选自三取代的硅基；
EWG吸电子基团选自烷磺酰基、芳磺酰基、芳酰基、烷酰基、硝基、腈基、膦酰基、磺酰亚胺；
其中，所述的取代的芳基、三取代的硅基中的取代基独立地选自C1~C4的烷基、C1~C4的烷氧基、卤素、硝基、氰基。
2.根据权利要求1所述的方法，其特征在于：R1选自甲基、乙基、正丙基、异丙基、正庚基、对氯苯基、苯甲基、苯乙基，或下列基团中的一种：
EWG吸电子基团选自下列基团中的一种：
3.根据权利要求1所述的方法，其特征在于：R1选自甲基、乙基，或下列基团中的一种：
4.根据权利要求1~3任一权利要求所述的方法，其特征在于：有机溶剂为二氯甲烷(DCM)。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910786371.XA CN112430243B (zh) | 2019-08-24 | 2019-08-24 | 一种制备硫酯类化合物的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910786371.XA CN112430243B (zh) | 2019-08-24 | 2019-08-24 | 一种制备硫酯类化合物的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112430243A CN112430243A (zh) | 2021-03-02 |
| CN112430243B true CN112430243B (zh) | 2023-03-21 |
Family
ID=74690531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910786371.XA Active CN112430243B (zh) | 2019-08-24 | 2019-08-24 | 一种制备硫酯类化合物的方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112430243B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017046133A1 (en) * | 2015-09-14 | 2017-03-23 | Universiteit Antwerpen | Process for the catalytic directed cleavage of amide-containing compounds |
| CN107033037A (zh) * | 2017-04-27 | 2017-08-11 | 江西师范大学 | 一种由手性酸催化的光学纯萜类生物碱类似物的不对称合成方法 |
| CN108484461A (zh) * | 2018-04-02 | 2018-09-04 | 江西师范大学 | 炔酰胺介导的硫代酰胺制备方法及其在硫代多肽合成中的应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2891657A1 (en) * | 2014-01-07 | 2015-07-08 | Centre National de la Recherche Scientifique (CNRS) | Ionic liquid supported organotin reagents for the manufacturing of radiopharmaceuticals compounds |
-
2019
- 2019-08-24 CN CN201910786371.XA patent/CN112430243B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017046133A1 (en) * | 2015-09-14 | 2017-03-23 | Universiteit Antwerpen | Process for the catalytic directed cleavage of amide-containing compounds |
| CN107033037A (zh) * | 2017-04-27 | 2017-08-11 | 江西师范大学 | 一种由手性酸催化的光学纯萜类生物碱类似物的不对称合成方法 |
| CN108484461A (zh) * | 2018-04-02 | 2018-09-04 | 江西师范大学 | 炔酰胺介导的硫代酰胺制备方法及其在硫代多肽合成中的应用 |
Non-Patent Citations (2)
| Title |
|---|
| Functionalization of SBR copolymer by free radical addition of thiols;Romani, F等;《MACROMOLECULAR CHEMISTRY AND PHYSICS》;19990331;第200卷(第3期);第524-530页 * |
| Synthesis of Thiomorpholin-3-ones by a Gold-Catalysed Oxidative Cyclisation-Rearrangement Cascade from Ynamides;Baker, T等;《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》;20190606(第31-32期);第5201-5204页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112430243A (zh) | 2021-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2156236C2 (ru) | Арилтиосоединения, способ лечения и фармацевтическая композиция | |
| AU742928B2 (en) | N-alkanoylphenylalanine derivatives | |
| US20200299226A1 (en) | Mild and efficient preparation method for a-acyloxyenamide compounds and use thereof in synthesis of amide and polypeptide | |
| EP0498665A1 (en) | Hydroxamic acids derivatives, process for their preparation and use thereof | |
| EP1154993A1 (en) | Thioamide derivatives | |
| EP0496836B1 (en) | Synthesis and use of amino acid fluorides as peptide coupling reagents | |
| US6380358B1 (en) | Guanidinylation reagents | |
| CN112430243B (zh) | 一种制备硫酯类化合物的方法 | |
| Sureshbabu et al. | Protection reactions | |
| AU2009201025A1 (en) | Process for preparing intermediates useful to prepare certain antibacterial N-formyl hydroxylamines | |
| EP0968997B1 (en) | Process for S-aryl-L-cysteine and derivatives | |
| HU201005B (en) | Process for producing new n-substituted mercaptopropaneamide derivatives and pharmaceutical compositions comprising such compounds | |
| CN102675165A (zh) | 一种n-苄氧羰基-2-氨基烷基磺酰胺的制备方法 | |
| KR20040029460A (ko) | 폴리아미드를 합성하기 위한 방향족 및 헤테로방향족 산할로겐화물 | |
| US6765109B1 (en) | Preparation of S-aryl-cysteine and its derivatives | |
| US20230312479A1 (en) | Novel amino acid derivatives | |
| WO2017122822A1 (ja) | デプシペプチド類化合物の製造中間体及びその製造方法 | |
| KR20000065816A (ko) | 파라 및/또는 메타-치환 시아노페닐알라닌 유도체의 새로운 합성방법 | |
| CA2427594C (en) | Process for s-aryl-cysteine and derivatives | |
| US7081537B2 (en) | Process for the electrophilic substitution of thiazolidines or oxazolidines | |
| JP3931231B2 (ja) | 非対称ジスルフィド化合物の製造方法 | |
| US20130023696A1 (en) | Process for producing sulfur-containing amino acids | |
| WO2001012594A1 (fr) | Procede de preparation de chlorures de sulfenyle aromatiques et autres | |
| EP1236715A2 (en) | Process for S-Aryl cysteine | |
| MXPA99010786A (es) | Reactivos de guanidinilacion |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231218 Address after: Room 618, No. 11 Yunchuang Street, Huangpu District (Zhongxin Guangzhou Knowledge City), Guangzhou City, Guangdong Province, 510555 (Office only) Patentee after: Guangzhou Xinpeptide Biopharmaceutical Technology Co.,Ltd. Address before: No.99 Ziyang Avenue, Nanchang City, Jiangxi Province 330000 Patentee before: Jiangxi Normal University |