1-(3,5-二甲基苯基)-1-[(1S,4S)-1,7,7-三甲基双环[2.2.1]庚烷-2-基]肼的合成工艺改进

以3,5-二甲基苯胺和2-莰酮为起始原料,在微波促进下,经缩合反应制得N-(3,5-二甲基苯基)-1-(1S,4S)-1,7,7-三甲基二环[2.2.1]庚烷-2-亚胺(1);1经硼氢化钠还原后再与羟胺-O-磺酸经胺化反应合成了1-(3,5-二甲基苯基)-1-[(1S,4S)-1,7,7-三甲基双环[2.2.1]庚烷-2-基]肼,总收率70.4%,其结构经1H NMR和ESI-MS确证。     

(3S,6S)-及(3S,6R)-3-苄氧甲基-6-甲基-吗啉-2,5-二酮的 制备及其晶体结构

以2-溴丙酸和N-叔丁氧羰基-O-苄基-L-丝氨酸为起始试剂首先制得N-(2-溴丙基)-O-苄基-L-丝氨酸(BPBS), 在N,N-二甲基甲酰胺(DMF)/三乙胺(Et3N)溶剂中80 ℃经9 h后BPBS发生分子内环化反应生成(3S,6S)-3-苄氧甲基-6-甲 基-吗啉-2,5-二酮[(3S,6S)-BMMD]及(3S,6R)-BMMD共存体, 产率70%. 将所制得的共存体以乙酸乙酯为重结晶溶剂, 采用微分重结晶法, 经4次“溶解-部分重结晶”操作循环制得两种纯光学构型的(3S,6S)-BMMD和(3S,6R)-BMMD. 将两种光学纯双手性中心的BMMD分别溶于乙酸乙酯, 室温下培养得(3S,6S)-BMMD和(3S,6R)-BMMD的单晶体, 以X射线衍射法测定上述两种BMMD的分子结构.     

珊瑚色诺卡氏菌全细胞催化（RS）-4-氟苯甘氨酸去消旋化为（S）-4-氟苯甘氨酸

珊瑚色诺卡氏菌CGMCC 4.1037 全细胞能够催化4-氟苯甘氨酸的（R）-对映体立体反转为（S）-对映体,相反方向的反应不能发生。研究了反应条件对（R）-4-氟苯甘氨酸立体反转的影响。在最优反应条件下,5mmol/L（R）-4-氟苯甘氨酸和10mmol/L（RS）-4-氟苯甘氨酸分别立体反转和去消旋化为（S）-4-氟苯甘氨酸,产率为52%和63%,ee为99.5%和99.2% 。（RS）-4-氟苯甘氨酸的去消旋化过程是通过珊瑚色诺卡氏菌CGMCC 4.1037 全细胞中的两个酶催化反应实现的。（R）-氨基酸氧化酶催化（R）-4-氟苯甘氨酸氧化脱氨形成4-氟苯甲酰甲酸,（S）-氨基酸转移酶催化4-氟苯甲酰甲酸转氨化为（S）-4-氟苯甘氨酸。讨论了4-氟苯甘氨酸两个对映体的代谢途径。     

A concise synthesis of a very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via reductive etherification

This contribution describes a concise synthesis to ethyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate of very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1). The synthesis employs a reductive etherification as a key reaction using (2S,4S)-1-benzyloxycarbonyl-4-methoxypyrrolidine-2-carboxyaldehyde (12) and trans-4-triethylsilyloxycyclohexanecarboxilic acid ethyl ester (13b). This synthesis provides 2b in 6 steps with 38% overall yield from commercially available starting material.     

Synthesis and Crystal Structure of 2-[（4-Methoxy- 6-methylthio-2-pyrimidinyl）aminocarbonyl- aminosulfonyl] Benzoic Acid Methyl Ester

1 INTRODUCTION The sulfonylurea herbicides are characterized by broad-spectrum weed control at very low use rates (c.2~75g ai ha-1), good crop selectivity and very low acute and chronic animal toxicity (acute oral LD50 to rat >4000 mg/kg)[1]. They are e…     

Novel stable fluorophore, 6-methoxy-4-quinolone, with strong fluorescence in wide pH range of aqueous media, and its application as a fluorescent labeling reagent

6-Methoxy-4-quinolone (6-MOQ, 1), an oxidation product derived from 5-methoxyindole-3-acetic acid, is a novel fluorophore, which has several useful characteristics for biomedical analysis. Compound 1 has strong fluorescence with a large Stokes' shift in aqueous media, and the maximum fluorescence excitation and emission wavelengths are 243 nm and 374 nm, respectively. The molar absorptivity at the maximum excitation wavelength and fluorescence quantum yield in aqueous 10% (v/v) methanol are 32 600 L mol(-1) cm(-1) and 0.38, respectively. The fluorescence intensity of 1 is scarcely affected by changing the medium pH, showing strong fluorescence from pH 2.0 to 11.0. In addition, 1 is highly stable against light and heat, and no degradation was observed at 60 degrees C for 3 days with exposure to daylight. As a fluorescent labeling reagent, [(6-methoxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl]amine (6-MOQ-NH2, 2) was synthesized, and determination of carboxylic acids was demonstrated; 50 pmol of standard propionic acid and isobutyric acid were derivatized, and the obtained S/N ratios for 10 fmol (injection amount) of these two acids were 206 and 164, respectively.     

Family of mixed-valence oxovanadium(IV/V) dinuclear entities incorporating N4O3-coordinating heptadentate ligands: synthesis, structure, and EPR spectra

Dinuclear (V(IV)V(V)) oxophenoxovanadates of general formula [V2O3L] have been synthesized in excellent yields by reacting bis(acetylacetonato)oxovanadium(IV) with H3L in a 2:1 ratio in acetone under an N2 atmosphere. Here L3- is the deprotonated form of 2,6-bis[{{(2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L1), 2,6-bis[{{(5-methyl-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L2), 2,6-bis[{{(5-tert-butyl-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L3), 2,6-bis[{{(5-chloro-2-hydroxybenzyl)(N',N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol(H3L4), 2,6-bis[{{(5-bromo-2-hydroxybenzyl)(N'N'-(dimethylamino)ethyl)}amino}methyl]-4-methylphenol (H3L5), or 2,6-bis[{{(5-methoxy-2-hydroxybenzyl)(N'N'-(dimethylamino)ethyl)}methyl]-4-methylphenol (H3L6). In [V2O3L1], both the metal atoms have distorted octahedral geometry. The relative disposition of two terminal V=O groups in the complex is essentially cis. The O=V...V=O torsion angle is 24.6(2) degrees . The V-O(oxo)-V and V-O(phenoxo)-V angles are 117.5(4) and 93.4(3) degrees , respectively. The V...V bond distance is 3.173(5) A. X-ray crystallography, IR, UV-vis, and 1H and 51V NMR measurements show that the mixed-valence complexes contain two indistinguishable vanadium atoms (type III). The thermal ellipsoids of O2, O4, C10, C14, and C15 also suggests a type III complex in the solid state. EPR spectra of solid complexes at 77 K display a single line indicating the localization of the odd electron (3d(xy)1). Valence localization at 77 K is also consistent with the 51V hyperfine structure of the axial EPR spectra (3d(xy)1 ground state) of the complexes in frozen (77 K) dichloromethane solution: S = 1/2, g(parallel) approximately 1.94, g(perpendicular) approximately 1.98, A(parallel) approximately 166 x 10(-4) cm(-1), and A(perpendicular) approximately 68 x 10(-4) cm(-1). In contrast isotropic room-temperature solution spectra of the family have 15 hyperfine lines (g(iso) approximately 1.974 and A(iso) approximately 50 x 10(-4) cm(-1)) revealing that the unpaired electron is delocalized between the metal centers. Crystal data for the [V2O3L1].CH2Cl2 complex are as follows: chemical formula, C32H43O6N4Cl2V2; crystal system, monoclinic; space group, C2/c; a = 18.461(4), b = 17.230(3), c = 13.700(3) A; beta = 117.88(3) degrees ; Z = 8.     

四氢糠酸的拆分工艺改进

利用非对映异构体盐在溶剂中溶解度的不同,以(1S,2R)-1-氨基-2-茚醇(1)为手性拆分剂,拆分四氢糠酸［(RS)-THFA, (RS)-2］获得高光学纯的(S)-2,其结构经¹H NMR, ¹³C NMR和HPLC确证。探究了不同溶剂量和投料比对拆分效果的影响。结果表明较佳拆分条件为：以4-甲基-2-戊酮(3)作溶剂,n［(RS)-2］: n(1)=2.2 : 1,一次拆分得91.7% ee (S)-2;再以n［91.7% ee (S)-2］: n(1)=6 : 5进行二次拆分得99.0% ee (S)-2。拆分剂的回收率提高至92.0%,同时对拆分母液中的非目标对映体成功地进行消旋化,回收率为89.0%,实现了四氢糠酸的循环拆分。     

Zinc (II), palladium (II) and cadmium (II) complexes containing 4‐methoxy‐N‐(pyridin‐2‐ylmethylene) aniline derivatives: Synthesis,characterization and methyl methacrylate polymerization

A series of Zn (II), Pd (II) and Cd (II) complexes, [(L) _n MX ₂ ] _m (L = L‐a–L‐c; M = Zn, Pd; X = Cl; M = Cd; X = Br; n, m = 1 or 2), containing 4‐methoxy‐N‐(pyridin‐2‐ylmethylene) aniline ( L‐a ), 4‐methoxy‐N‐(pyridin‐2‐ylmethyl) aniline ( L‐b ) and 4‐methoxy‐N‐methyl‐N‐(pyridin‐2‐ylmethyl) aniline ( L‐c ) have been synthesized and characterized. The X‐ray crystal structures of Pd (II) complexes [L ₁ PdCl ₂ ] (L = L‐b and L‐c) revealed distorted square planar geometries obtained via coordinative interaction of the nitrogen atoms of pyridine and amine moieties and two chloro ligands. The geometry around Zn (II) center in [(L‐a)ZnCl ₂ ] and [(L‐c)ZnCl ₂ ] can be best described as distorted tetrahedral, whereas [(L‐b) ₂ ZnCl ₂ ] and [(L‐b) ₂ CdBr ₂ ] achieved 6‐coordinated octahedral geometries around Zn and Cd centers through 2‐equivalent ligands, respectively. In addition, a dimeric [(L‐c)Cd(μ ‐ Br)Br] ₂ complex exhibited typical 5‐coordinated trigonal bipyramidal geometry around Cd center. The polymerization of methyl methacrylate in the presence of modified methylaluminoxane was evaluated by all the synthesized complexes at 60°C. Among these complexes, [(L‐b)PdCl ₂ ] showed the highest catalytic activity [3.80 × 10⁴ g poly (methyl methacrylate) (PMMA)/mol Pd hr^?1], yielding high molecular weight (9.12 × 10⁵ g mol^?1) PMMA. Syndio‐enriched PMMA (characterized using ¹H‐NMR spectroscopy) of about 0.68 was obtained with T_g in the range 120–128°C. Unlike imine and amine moieties, the introduction of N‐methyl moiety has an adverse effect on the catalytic activity, but the syndiotacticity remained unaffected.     

Bischler-Napieralski Reaction of 2-(3,4-Dimethoxy-2-nitrophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-[(S)-1-phenylethyl] acetamide Accompanied by Elimination of Chiral Auxiliary

Chiral 1-benzyltetrahydroisoquinoline alkaloids can be asymmetrically synthesized via Bischler-Napieralski (B-N) cyclization followed by stereoselective NaBH4 reduction (Polniaszek抯 method) of the N- (2-phenylethyl)-2-phenylacetamides bearing chiral auxiliary such as (S)-1-phenylethyl group on the nitrogen atom1-4. Recently Y. Ohishi and co-workers found an unusual B-N reaction on the carbon at 2-position of the A ring, which bears a bromine atom5, 6. They indicated that the steric ef…     

Phthalazinone in Heterocyclic Synthesis: Synthesis of Some s-Triazole,s-Triazolothiadiazine,s-Triazolothiadiazine,and s-Triazolothiadiazole Derivatives as Pharmaceutical Interest

1(2H)-Oxophthalazine-2-acetic acid ethyl ester was allowed to react with various reagents under different conditions to yield compounds 2-[(4-substituted-5-mercaptotriazol-3-yl) methyl]-1 (2H)-oxophthalzines 5 and 7 which acted as starting materials for the preparation of some new s-triazolo[5,1-b][1,3]thiazine (8), s-triazolo[3,4-b][1,3,4]thiadiazine 9,12,14,20, and s-triazolo[3,4-b][1,3,4]thiadiazole 18,21 derivatives.

     

新型苯并二氢呋喃合二酮酸类化合物的合成及其与整合酶分子对接研究

以阿魏酸甲酯为原料,通过氧化偶联构建2-芳基苯并二氢呋喃骨架,再经傅克酰基化和酯缩合反应依次制得(E)-3-［2-(4-羟基-3-甲氧基-5-乙酰基)苯基-3-甲氧羰基-7-甲氧基-2,3-二氢苯［b］并呋喃-5-基］丙烯酸甲酯（3）和(E)-3-［2-(4-羟基-3-甲氧基-5-甲氧羰基乙酰基)苯基-3-甲氧羰基-7-甲氧基-2,3二氢苯并［b］呋喃-5-基］丙烯酸甲酯（4）; 4经水解反应合成3-【2-羟基-3-甲氧基-5-｛5-［2-（甲氧基羰基）乙烯基］-7-甲氧基-3-甲氧羰基-2,3-二氢苯并［b］呋喃-2-｝基】苯基-3-氧丙酸（5）,化合物3~5未见文献报道,其结构经¹H NMR, ¹³C NMR和MS(ESI)表征。采用分子对接软件Autodock vina对化合物2~5与HIV-1整合酶核心部位高度同源的PFV IN（PDB: 3L2V）进行对接,计算结果显示该类化合物能与整合酶形成稳定的复合物,具有1,3-二酮基团的化合物3, 4和5能与整合酶中金属离子产生螯合作用,其中化合物5的结合作用最强。     

Synthesis,Structure,and Magnetic Property of One Snake-shaped Copper（Ⅱ）-organic Compound：Cu[Cu_2（PP）_2]（CBPC）_2]·2（H_2O）

One novel copper(II)-organic compound,namely Cu[Cu2(PP)2](CBPC)2]·2(H2O)(1,H2CBPC = 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-propylimidazole-4-carboxylic acid,HPP = 3-(2-pyridyl)pyrazole),was designed and synthesized under hydrothermal conditions.X-ray diffraction analysis reveals that two Cu(II)ions in the quasi-planar dimmer of [Cu2(PP)2] are linked by the carboxylate oxygen atoms on the phenyl ring and the imidazole ring,respectively,yielding one snake-shaped structure.Magnetic measurements reveal that compound 1 shows the strongly antiferromagnetic property.Crystal data of 1:C58H52Cu3N10O10,Mr = 1239.72,monoclinic,P21/c,a = 14.900(7),b = 15.029(7),c = 12.308(6),β = 102.519(9)o,V = 2691(2)3,Z = 2,Dc = 1.530 g/cm3,F(000)= 1274,μ = 1.246 mm-1,R = 0.0416,wR = 0.0780(I > 2σ(I))and S = 0.999.     

Quantification of polyamines in human erythrocytes using a new near-infrared cyanine 1-(epsilon-succinimidyl-hexanoate)-1'-methyl-3,3,3',3'-tetramethyl-indocarbocyanine-5,5'-disulfonate potassium with CE-LIF detection

A novel near-infrared (NIR) cyanine 1-(epsilon-succinimidyl-hexanoate)-1'-methyl-3,3,3',3'-tetramethyl-indocarbocyanine-5,5'-disulfonate potassium (MeCy5-OSu) has been developed in our laboratory. Simultaneous determination of MeCy5-OSu-derivatized polyamines spermine (Spm), spermidine (Spd), cadaverine (Cad), and putrescine (Put) based on the separation by CE combined with diode LIF detection has been accomplished. The highest derivatization efficiency was achieved in 0.2 mol/L borate buffer (pH 8.8) for 20 min at 25 degrees C. Polyamine derivatives were separated within 14 min in the phosphate running buffer (pH 3) containing 50 mmol/L phosphoric acid, 40 mmol/L SDS, and 35% methanol v/v. Linearity of response was obtained in the range of 10-200 nmol/L. The detection limits (S/N = 3) for Spm, Spd, Cad, and Put were 0.8, 1, 3, and 2 nmol/L, respectively. The proposed method has been successfully applied to the analysis of polyamines in erythrocytes of two healthy persons and one cancer patient. Average recoveries for erythrocyte samples were 93.6-106% and coefficients of variation ranged from 1.8 to 5.4%. The analysis of polyamines in erythrocytes can be used for studying the relationship between their changes and the carcinogenesis process involved in erythrocytes.     

Chiral Pyridine-Based Macrobicyclic Clefts: Synthesis and Enantiomeric Recognition of Ammonium Salts

An achiral (3) and two chiral pyridine-based macrobicyclic clefts (4 and 5) have been prepared by treating 2,6-bis[[2',6'-bis(bromomethyl)-4'-methylphenoxy]methyl]pyridine (2) with the appropriate achiral and chiral glycols. Starting 2 was prepared by first treating 2,6-bis(hydroxymethyl)-4-methylphenol with 2,6-[(tosyloxy)methyl]pyridine followed by phosphorus tribromide. Achiral macrobicyclic cleft 3 formed a complex at 25 degrees C in 50% CH(3)OH/50% CHCl(3) (v/v) with a primary ammonium salt (log K = 3.15) as evidenced by a significant change in the (1)H NMR spectrum. Highly organized (S,S,S,S)-4, prepared by treating 2 with (1S,5S)-3-oxapentane-1,5-diol, exhibited recognition at 25 degrees C in 20% C(2)H(5)OH/80% 1,2-C(2)H(4)Cl(2) (v/v) for the (S)-enantiomer of alpha-(1-naphthyl)ethylammonium perchlorate (NapEt) over its (R)-form (Delta log K = 0.85). This high recognition factor probably reflects an increase in molecular rigidity by the introduction of a second macro ring on the monocyclic pyridinocrown ligand.     

Solvent- and temperature-controlled in situ ligand reactions mediated by Cu(II) and 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-4-biphenylcarboxlic acid

Three new compounds, CuL, CuL', and Cu(2)O(2)L'(2) (H(2)L = 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-4-biphenylcarboxlic acid, H(2)L' = 3'-[(E)-{[(1S,2S)-2-aminocyclohexyl]imino}methyl]-4'-hydroxy-5'-nitro-4-biphenylcarboxlic acid, H(2)L' = 3'-(N,N-dimethylamino methyl)-4'-hydroxy-4-biphenylcarboxlic acid), were selectively synthesized through a controlled in situ ligand reaction system mediated by copper(II) nitrate and H(2)L. Selective nitration was achieved by using different solvent mixtures under relatively mild conditions, and an interesting and economical reductive amination system in DMF/EtOH/H(2) O was also found. All crystal structures were determined by single-crystal X-ray diffraction analysis. Both CuL and CuL' display chiral 1D chain structures, whereas Cu(2)O(2)L'(2) possesses a structure with 13×16?? channels and a free volume of 41.4?%. The possible mechanisms involved in this in situ ligand-controlled reaction system are discussed in detail.     

抗丙肝药物维拉帕维的合成

以7-羟甲基-1-四氢萘酮和1-溴-4-氯-苯甲醛为起始原料,经14步反应合成了抗丙肝新药维拉帕维--甲基（2S）-1-【(2S,5S)-2-【9{2［（2S,4S）-1-（2R)-2-［（甲氧基羰基）氨基］-2-苯乙酰基-4-（甲氧基甲基）吡咯烷-2-基］-1H-咪唑 5 基} 1,11-二氢异色烯［4′,3′ :6,7］萘并［1,2-d］咪唑-2-基-5-甲基吡咯烷-1-基】-3-甲基-1-氧丁烷-2-基】氨基甲酸酯,总产率10.14%,其结构经¹H NMR和ESI-MS确证。     

A novel synthetic approach to very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via tert-butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a key intermediate

This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu?NSO?H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material.     

羰基还原酶CR2重组酶体系不对称合成(S)-N,N-二甲基-3-羟基-3-(2-噻吩)-1-丙胺

构建了羰基还原酶CR2重组酶体系,并优化了相关的酶促催化反应条件.通过在催化体系中添加辅酶NADP+(0.1 mmol/L)和辅底物葡萄糖(120 g/L),在30℃及p H=8.0的条件下反应4 h,CR2重组酶体系不对称还原N,N-二甲基-3-酮-3-(2-噻吩)-1-丙胺(DKTP,10 g/L),合成了高光学纯度(S)-N,N-二甲基-3-羟基-3-(2-噻吩)-1-丙胺[(S)-DHTP,e.e.值99.9%],产率为62%.在酶促催化过程中,由于辅酶循环生成葡萄糖酸导致反应体系p H值下降而影响催化效率.通过调控反应体系p H值,(S)-DHTP的产率提高到68%.不同浓度底物的反应过程表明底物对CR2酶促反应具有抑制作用,且在10 g/L底物浓度下反应的时空产率可达1.3 g·L-1·h-1.     

胶束电动色谱-激光诱导荧光检测法测定肌松弛药巴氯芬

以4-氯-7-硝基苯并-2-氧杂-1,3-二唑(NBD-Cl)为柱前衍生试剂,建立了胶束电动色谱-激光诱导荧光检测法测定肌松弛药巴氯芬(BAL)的新方法。经过实验条件的优化,采用15 mmol/L硼砂、20 mmol/L十二烷基硫酸钠、10%(v/v)乙腈、pH 9.75的缓冲体系,在分离电压为17.5 kV、柱温为25 ℃的条件下,压力进样3.45 kPa(0.5 psi)×3 s,巴氯芬及其内标物的衍生产物在7 min内实现较好的基线分离,线性范围为0.025～25 mg/L,相关系数为0.9999,检出限(S/N=3)和定量限(S/N=10)分别为0.90 μg/L和6.25 μg/L。该方法被应用于巴氯芬制剂及加入巴氯芬对照品的尿液样品分析,回收率范围分别为101.6%～107.9%和107.0%～109.6%。该方法有望应用于巴氯芬药物制剂的质量监控以及为巴氯芬药物代谢的研究提供辅助手段。