9-芴甲氧羰基-对甲磺酰氨-(L)-苯丙氨酸的全合成

(L)-苯丙氨酸经硝化、酯化、叔丁氧羰基(Boc)保护α氨基、Pd/C还原对位硝基、对甲磺酰氯(MSCl)保护对位氨基、经水解反应后,在酸性条件下脱去叔丁氧羰基(Boc)基团,碱性条件下引入9-芴甲氧羰基琥珀酰亚胺(Fmoc-osu),最终生成标题化合物,并且所合成标题化合物进行了HNMR结构确证。     

阿片肽链中L-苯丙氨酸的保护全合成及表征

L-苯丙氨酸经硝化、酯化、叔丁氧羰基(Boc)保护α-氨基、Pd/C还原对位硝基、对甲磺酰氯(MSC1)保护对位氨基、经水解反应后,在酸性条件下脱去叔丁氧羰基(Boc)基团,碱性条件下引入9-芴甲氧羰酰琥珀酰亚胺(Fmocosu),最终生成标题化合物,并且对所合成标题化合物进行了HNMR结构确证。     

2-(2-(6-氯己氧基)乙氧基)乙氨的合成

2-(2-氨基乙氧基)乙醇溶于乙醇,用叔丁氧羰基酸酐(Boc2O)进行氨基保护得,N-叔丁氧羰基-2-(2-氨基乙氧基)乙醇,与1-氯-6-溴己烷在正已烷及50% NaOH和四丁基溴化铵作用下缩合,得N-叔丁氧羰基-2-(2-(6-氯己氧基)乙氧基)乙氨,最后在二氯甲烷及三氟乙酸混合液中脱保护,得标题化合物,总收率11...     

1'-叔丁氧羰基-5-氟-螺-(吲哚啉-3,4'-哌啶)的合成

采用有效的方法合成了标题化合物.首先用三氟乙酸酐对1-N进行保护,然后用钯碳(Pd/C)还原1'-N的Cbz,并用Boc酸酐将1'-N加以保护得到1-三氟乙酰基-1'-叔丁氧羰基-5-氟-螺-(吲哚啉-3,4'-哌啶),最后,在碱性条件下,1-三氟乙酰基-1'-叔丁氧羰基-5-氟-螺-(吲哚啉-3,4'-哌啶)选择性的离去1-N保护基三氟乙酸酐得到标题化合物.     

N,N′-二叔丁氧基羰基-1H-吡唑-1-甲脒的合成

1H-吡唑-1-甲脒盐酸盐在碳酸钾存在下和二碳酸二叔丁酯反应制备了N-叔丁氧基羰基-1H-吡唑-1-甲脒(PB),PB和二碳酸二叔丁酯在4-二甲氨基吡啶的催化下反应制备了N,N,N′-三叔丁氧基羰基-1H-吡唑-1-甲脒(PT),PT和高氯酸镁六水合物反应制备了标题化合物。反应条件温和,总收率65.9%,产品纯度大于99.0%,产品结构经熔点、核磁和质谱确定。     

N,N'-二叔丁氧基羰基-1H-吡唑-1-甲脒的合成

1H-吡唑-1-甲脒盐酸盐在碳酸钾存在下和二碳酸二叔丁酯反应制备了N-叔丁氧基羰基-1H-吡唑-1-甲脒(PB),PB和二碳酸二叔丁酯在4-二甲氨基吡啶的催化下反应制备了N,N,N'-三叔丁氧基羰基-1H-吡唑-1-甲脒(PT),PT和高氯酸镁六水合物反应制备了标题化合物.反应条件温和,总收率65.9%,产品纯度大于99.0%,产品结构经熔点、核磁和质谱确定.     

3-三氟甲基-5,6,7,8-四氢-1,2,4-三唑[4,3-α]吡嗪盐酸盐的合成

乙二胺与氯乙酸乙酯经取代、环合反应制得2-哌嗪酮,2-哌嗪酮与Boc酸酐进行氨基保护反应后,再与五硫化二磷进行硫代反应制得4-(N-叔丁氧羰基)-2-哌嗪硫酮,其与三氟乙酰肼经取代、环合、脱叔丁氧羰基成盐,得标题化合物,总收率为45.7%(以氯乙酸乙酯计)。为磷酸西他列汀中间体的工业化生产提供了一条较理想的工艺路线。     

艾代拉里斯中间体(S)-2-(1-氨基丙基)-5-氟-3-苯基-4(3H)-喹唑啉酮三氟乙酸盐的合成及晶体结构表征

以2-氨基-6-氟苯甲酸和L-2-(叔丁氧羰基氨基)丁酸为起始原料,经环合反应,得到(S)-(1-(5-氟-4-氧代-4H-苯并[d][1,3]-嗪-2-基)-丙基)氨基甲酸叔丁酯;再与苯胺发生胺酯交换反应,得到(S)-(1-(5-氟-4-氧代-苯基-3,4-二氢喹唑啉-2-基)-丙基)氨基甲酸叔丁酯;最后在三氟乙酸的作用下,脱Boc保护基、成三氟乙酸盐,即得标题化合物。其结构通过红外光谱、核磁共振氢谱、X-单晶衍射分析进行表征。     

1′-叔丁氧羰基-5-氟-螺-(吲哚啉-3,4′-哌啶)的合成

采用有效的方法合成了标题化合物。首先用三氟乙酸酐对1-N进行保护,然后用钯碳（Pd／C）还原1′-N的cbz,并用Boc酸酐将1′-N加以保护得到1-三氟乙酰基-′-叔丁氧羰基-5-氟-螺-（吲哚啉-3,4′-哌啶）,最后,在碱性条件下-1-三氟乙酰基-′-叔丁氧羰基-5-氟-螺-（吲哚啉-3,4′-哌啶）选择性的离去1-N保护基三氟乙酸酐得到标题化合物。     

N~1-(4-氨基丁基)-N~4-(9-蒽甲基)-1,4-丁二胺的合成

以N-叔丁氧羰基-1,4-丁二胺和N-(4-溴丁基)邻苯二甲酰亚胺为原料,经取代及保护两步反应合成N1-(4-邻苯二甲酰亚胺)丁基-N1,N4-二叔丁氧羰基-1,4-丁二胺(Ⅳ),然后肼解得N1-氨基丁基-N1,N4-二叔丁氧羰基-1,4-丁二胺(Ⅴ),3步反应总收率38%;Ⅴ与9-蒽甲醛缩合后用NaBH4还原,产物提纯后脱保护得目标产物N1-(4-氨基丁基)-N4-(9-蒽甲基)-1,4-丁二胺盐酸盐(Ⅶ),3步反应总收率约7 5%。化合物Ⅳ~Ⅶ的结构经13CNMR,1HNMR和ESI-MS确证,并对反应条件进行了初步优化。     

Side chain functionality dominated the chromatography of N‐protected amino acid on molecularly imprinted polymer

Molecularly imprinted polymer (MIP) with N^α‐protected amino acid as the print molecule was prepared and used as the stationary phase for the chromatographic study of molecular recognition. Particles of MIP were prepared by photopolymerization of 4‐vinylpyridine in the presence of tert‐butyloxycarbonyl‐L ‐tyrosine (Boc‐L ‐Tyr) and packed into a column for the chromatographic resolution of Boc‐L ‐Tyr and tert‐butyloxycarbonyl‐L ‐phenylalanine (Boc‐L ‐Phe). These two N^α‐protected amino acids that differ from each other in the side chain with one hydroxyl group on the benzene ring could be well separated on the MIP. A separation factor of about two was achieved by using a mixture of acetonitrile (99.5 v/v %) and acetic acid (0.5 v/v %) as the mobile phase. Results suggest that the interaction between hydroxyl group in the side chain of amino acid and pyridine in the polymer dominated the selective adsorption of print molecule on the MIP. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007     

1-N-Boc-4-甲氨甲基哌啶合成方法

以4-哌啶甲酸为原料,经酯化、还原、(Boc)2O保护、溴代、甲胺化五步反应,以72%的总收率合成了重要药物中间体1-N-Boc-4-甲氨甲基哌啶。合成方法操作简单、收率高。     

A Protection Strategy Substantially Enhances Rate and Enantioselectivity in ω‐Transaminase‐Catalyzed Kinetic Resolutions

The kinetic resolution of 3‐aminopyrrolidine (3AP) and 3‐aminopiperidine (3APi) with ω‐transaminases was facilitated by the application of a protecting group concept. 1‐N‐Cbz‐protected 3‐aminopyrrolidine could be resolved with >99% ee at 50% conversion, the resolution of 1‐N‐Boc‐3‐aminopiperidine yielded 96% ee at 55% conversion. The reaction rate was up to 50‐fold higher by using protected substrates. Most importantly, enantioselectivity increased remarkably after carbamate protection compared to the unprotected substrates (86 vs. 99% ee). Surprisingly, benzyl protection of 3AP had no influence on enantioselectivity. A possible explanation for this observation could be the different flexibility of the benzyl‐ or carbamate‐protected 3AP as confirmed by NMR spectroscopy.     

保护氨基酸Fmoc-His(Trt)-OH的合成方法优化

在肽合成中,为了得到理想的目的肽,首先需要对氨基酸的活性基团加以封闭或保护。叔丁氧羰基(Boc)和9-芴甲氧羰基(Fmoc)是固相合成中首选的-αNH2保护基,由此形成了多肽固相合成方法中的两大类:Boc方法和Fmoc方法。组氨酸(His)是多肽合成中问题最大的氨基酸之一,需要对其α-氨基及侧链上的咪唑环加以保护。由于Fmoc保护基的一些独特优点,如对碱的不稳定性、易检测性等,因此,我们选择Fmoc为其-αNH2保护基。在Fmoc策略合成过程中,三苯甲基(Trt)对缩合以及脱保护条件都很稳定,它可被稀乙酸在稍高的温度条件下,或TFA在室温脱除,因而选用Trt封闭咪唑环上的活性官能团。实验通过中心曲面实验设计方法和正交实验设计方法对His的两步保护反应条件进行优化,使得最终两步反应收率分别都达到80%以上,产品纯度达到95%以上。     

齐多夫定合成工艺改进

以β-胸苷为起始原料,5’-伯羟基采用对甲氧基苯甲酸保护,并在DEAD/PPh3体系中经过mitsuobu反应形成氧桥化合物,再与叠氮化钠发生叠氮化反应,最后脱对甲氧基苯甲酸保护基后获得目标产物齐多夫定,总收率62%。     

Practical Syntheses of Both Enantiomers of Cyclopropylglycine and of Methyl 2‐Cyclopropyl‐2‐N‐Boc‐iminoacetate

A facile three‐step synthesis of racemic cyclopropylglycine in multigram quantities from inexpensive cyclopropyl methyl ketone has been elaborated. Enzymatic hydrolysis of the N‐Boc‐protected methyl ester of cyclopropylglycine 9 with the inexpensive enzyme papain from Carica papaya affords both enantiomers of cyclopropylglycine ( 8 ) with enantiomeric excesses of 99 % or better after deprotection under acidic conditions. Furthermore, the new cyclopropyl group‐containing building block methyl 2‐cyclopropyl‐2‐N‐Boc‐iminoacetate ( 13 ) was prepared by N‐chlorination and subsequent dehydrochlorination with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). Addition of nucleophiles to 13 offers a ready access to an unusual, orthogonally bisprotected α,α‐diamino acid derivative and interesting components of rigid peptide backbones.     

Synthesis of Non‐Natural O‐Glycosylamino Acids Derived from n‐Pentenyl Glycosides; Model Studies and Proof of Principle for Glycopeptide Synthesis

Model studies on the transformation of the olefinic unit contained in n‐pentenyl glycosides (NPGs) to glycoamino acids is described. The methodology involves a Horner‐Emmons olefination with a protected glycine derived phosphonate, followed by asymmetric hydrogenation using Du‐PHOS catalyst system. A variety of protecting group schemes have been investigated and their stereoselectivity in the hydrogenation reaction determined. With N‐Boc and C‐TSE ester protection, the diastereoselectivity in the reaction was measured by ¹H NMR analysis with “racemic” product as a comparison. These modified glycoamino acids are also useful for peptide synthesis. The methodology appears to be general and was extended to include the synthesis a glycoamino acid containing the complex hexasaccharide Globo‐H.