2,3,5,6-四氟苄醇和4-甲基-2,3,5,6-四氟苄醇合成路线图解

2,3 ,5 ,6-四氟苄醇 (1 )和 4-甲基 -2 ,3 ,5 ,6-四氟苄醇 (2 )分别是拟除虫菊酯类新型杀虫剂四氟菊酯(transfluthrin)和七氟菊酯 (tefluthrin)的主要中间体 [1 ,2 ] ,其合成方法归纳如下。,5 ,6-四氟苄醇 (1 )的合成 (图 1 )图 1　 1的合成路线1 .1　 2 ,3 ,5 ,6-四氟对苯二甲腈 (3 )经水解 [3]、脱羧[4 ] 得到 2 ,3 ,5 ,6-四氟苯甲酸 (4 ) ,4在无水乙醚中以氢化铝锂还原即得 1 ,收率 46.7% [5]。 4也可经酯化或酰卤化后再以 Na BH4 还原得到 1。此法开发较早 ,除 4的还原收率较低外 ,其它各步收率都在85 %以上。1 .2　 3以 5 % Pd-C催化…     

4-氨基-2-氯吡啶的合成

4-氨基-2-氯吡啶(1)是医药及农药中间体[1～3],主要有以下3条合成路线:(1)2-氯-4-乙酰基吡啶与盐酸羟胺反应生成相应的肟,经Beckmann重排得到的2-氯-4-乙酰胺基吡啶再经水解制得,总收率77.8%[4,5].(2)2-氯-4-氨甲酰基吡啶在PhI(OAc)2作用下进行Hofmann重排制得,总收率85.4%[6].     

1-脱氮腺苷的改良合成法

腺苷类似物1-脱氮腺苷(1)具有广泛的生物活性,有抑制血小板凝聚和腺苷脱氨酶的作用。本文介绍1的新合成方法。合成路线如方程式所示。化合物2与硝酸-三氟醋酸混合物反应生成7-硝基咪唑并[4.5-6]吡啶4-氧化物(3)。和PCl_3处理3,生成脱氧衍生物4。在催化量的SnCl_4作用下,4再与等摩尔的1,2,3,5-四-O-乙酰基-β- D映喃核糖(TAR)进行反应,得到7-硝基-3-(2,3,5-三-O-乙酰基-β-D-呋喃核糖)-3H咪唑并[4,5-b]吡啶(5),收率82%。在化合物5的甲醇溶液中通入氨气,脱去保护基,生成化合物6,收率86%。用Pd/C加压氢化,     

(1-苯乙基哌啶-4-基)苯胺的制备

(1-苯乙基哌啶-4-基)苯胺(1)是合成阿片类镇痛药芬太尼(fentanyl)的重要中间体[1,2].文献[3]以β-苯乙胺和丙烯酸甲(乙)酯为原料,经Michael加成、Dieckmann缩合及酸性水解得N-苯乙基-4-哌啶酮(4),再与苯胺反应生成亚胺后由四氢锂铝还原得到1,总收率为30.5％～37.5％.4也可经三乙酰氧基硼氢化钠还原氨化[4]得到1.本研究改用雷尼镍催化下还原氨化,收率89.5％.改进后的总收率可提高至77.7％,且成本降低.1的合成路线见图1.     

乙酰阿魏酰氯的合成

乙酰阿魏酰氯(1)可用作医药、农药、化妆品和食品添加剂的中间体[1,2],可由阿魏酸经乙酰化、氯化制得[3].阿魏酸可由香草醛和丙二酸在吡啶、哌啶或苯胺催化下,在吡啶、吡啶和苯或甲苯的混合溶剂中缩合制得[4,5].本研究改用香草醛在乙酸钠作用下直接和乙酸酐反应得到乙酰阿魏酸(2),再经氯化即可制得1,反应周期短,操作简便,总收率79%.反应式如下:     

4—氨基吡啶合成的改进

4-氨基吡啶 (1 )是合成抗生素类药物 4-乙酰胺基哌啶醋酸盐等的中间体 ,也是制备强心剂、灭菌剂、抗心律失常药、抗溃疡药等的中间体。文献[1～ 3 ]报道的合成方法通常是以吡啶 (2 )为原料 ,经 N-氧化制得氧化吡啶 (3) ,再以混酸硝化制得 4-硝基氧化吡啶 (4) ,4在醋酸介质中 ,经铁粉还原制得 1。此法收率虽高 ,但还原时需消耗大量的溶剂 ,且后处理过程繁琐 ,并产生较多的废水和废渣。我们以 Raney镍为催化剂 ,在室温常压下对 4进行催化还原合成1 ,收率较高 ,且后处理操作简便 ,三废也少 (图 1 )。实验部分吡啶 N-氧化物 (3)按文献[3 ] 制…     

苯磺酸贝他斯汀的不对称合成

用（S）-[Ru（BINAP）Cl2]2（NEt3）作催化剂，不对称氢化还原（4-氯苯基）-（吡啶-2-基）-甲酮得到（S）-（＋）-（4-氯苯基）-（吡啶-2-基）-甲醇，与4-（4-溴哌啶-1-基）丁酸乙酯缩合，再经水解、成盐得到抗过敏药苯磺酸贝他斯汀，总收率57%。     

5-HT1A受体拮抗剂WAY-100635的合成

2-氨基吡啶和2-氯乙酰氯经酰胺化、与N'-(邻甲氧基苯基)哌嗪缩合、氢化铝锂还原得4-(邻甲氧基苯基)-1-[2-[(2-吡啶基)氨基]乙基]哌嗪,再与环己甲酰氯缩合得到5-HT1A受体拮抗剂WAY-100635,总收率35%.     

5-HT_(1A)受体拮抗剂WAY-100635的合成

2-氨基吡啶和2-氯乙酰氯经酰胺化、与N'-(邻甲氧基苯基)哌嗪缩合、氢化铝锂还原得4-(邻甲氧基苯基)-1-[2-[(2-吡啶基)氨基]乙基]哌嗪,再与环己甲酰氯缩合得到5-HT1A受体拮抗剂WAY-100635,总收率35%。     

科研文摘

β-酮酸酯和伯(仲)胺用4-二甲胺基吡啶(DMAP)催化在氩气保护下于甲苯中回流反应16～48 h,可一步制得β-酮酸酰胺,10例收率70～94％。 [俞雄摘]     

氧化还原法结合络和法测定锌铜溶液中硫酸铜和硫酸锌的含量

目的建立锌铜溶液的含量测定方法。方法采用氧化还原滴定法测定硫酸铜的含量;以硫脲为掩蔽剂,EDTA络和滴定法测定硫酸锌的含量。结果硫酸铜和硫酸锌的平均回收率分别为101.1%(RSD=0.80%)和102.4%(RSD=0.85%)。结论用该法测定硫酸铜和硫酸锌的含量,方法简便、重复性好,适用于锌铜溶液的质量控制。     

Effect of galactose density on asialoglycoprotein receptor-mediated uptake of galactosylated liposomes

Galactosylated (Gal) liposomes containing various molar ratios of cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)formamide (Gal-C4-Chol) as a ligand for asialoglycoprotein receptors were prepared to study the effect of the galactose content of Gal-liposomes labeled with [3H]cholesteryl hexadecyl ether on their targeted delivery to hepatocytes. The uptake characteristics of Gal-liposomes having Gal-C4-Chol of 1.0%, 2.5%, 3.5%, 5.0%, and 7.5% were evaluated. The uptake and internalization by HepG2 cells was enhanced by the addition of Gal-C4-Chol to the Gal-liposomes. In the presence of excess galactose, the uptake of Gal-liposomes having Gal-C4-Chol of 3.5%, 5.0%, and 7.5% was inhibited suggesting asialoglycoprotein receptor mediated uptake. After intravenous injection, Gal-liposomes having Gal-C4-Chol of 3.5%, 5.0%, and 7.5%, rapidly disappeared from the blood and exhibited rapid liver accumulation with up to about 80% of the dose within 10 min whereas Gal-liposomes having low Gal-C4-Chol (1.0% and 2.5%) showed a slight improvement in liver accumulation compared with bare-liposomes. Gal-liposomes with high Gal-C4-Chol are preferentially taken up by hepatocytes and the highest uptake ratio by parenchymal cells (PC) and nonparenchymal cells (NPC) (PC/NPC ratio) was observed with Gal-liposomes having of 5.0% Gal-C4-Chol. We report here that the galactose density of Gal-liposomes prepared by Gal-C4-Chol is important for both effective recognition by asialoglycoprotein receptors and cell internalization.     

HIV感染合并肺结核患者CD4^＋细胞计数与胸部影像特征的相关性研究

目的分析HIV感染合并肺结核患者外周血CD4^＋T淋巴细胞计数与其胸部影像特征的相关性。方法选取220例经Westernblot确诊为HIV感染并合并肺结核患者,抽取外周血进行CD4淋巴细胞计数,同时行正位X胸片或CT检查及PPD实验。结果220例患者中CD4细胞计数〈200者占30％,PPD阳性反应仅2例患者阳性;200～500者占49％,PPD阳性率为28．7％;〉500者占21％,PPD阳性率为80．4％。胸部影像检查显示当CD4细胞数〉500时,肺部病变与普通患者相似,空洞、钙化灶等多见;CD4细胞数在200—500时渗出性实变较多,52％的患者可出现纤维化病灶、空洞等典型症像;CD4细胞数〈200时,以弥漫性的渗出性病变为主。结论HIV感染合并肺结核患者随着机体免疫系统受损,影像表现以渗出性病变为主,有必要与肺部其他病变相鉴别。     

The fate of saccharin impurities. The excretion and metabolism of [14C]toluene-4-sulphonamide and 4-sulphamoyl[14C]benzoic acid in the rat

1. 4-Sulphamoyl[carboxy-14C]benzoic acid was rapidly eliminateda after oral administration to rats (94% dose in 24 h). After 6 days most of the 14C (73-83% dose) was recovered in the urine with significant amounts (18-32% dose) in the faeces due to incomplete absorption. 2. The 14C in the urine and faeces was unchanged 4-sulphamoylbenzoic acid. No 14CO2 was detected in the expired air. 3. After oral administration of [methyl-14C]toluene-4-sulphonamide to rats the label was rapidly eliminated largely in the urine (66-89% dose) with little in the faeces (2-8% dose). The 14C in the faeces was 4-sulphamoylbenzoic acid, which probably originated in the tissues since the gut flora was unable to effect this biotransformation. 4. The urine of rats given [14C]toluene-4-sulphonamide contained 4-sulphamoylbenzoic acid as the major metabolite (93% of the urinary 14C) together with small amounts of unchanged compound (1.5-2.3% of urinary 14C), 4-sulphamoylbenzyl alcohol (2.0-3.9%), 4-sulphamoylbenzaldehyde (0-1.5%) and at higher doses N-acetyltoluene-4-sulphonamide (2.1-2.3%).     

卡介菌多糖核酸对生殖器疱疹病人血CD4~+T细胞细胞因子表达影响

目的:研究卡介菌多糖核酸(BCG-PSN)对复发性生殖器疱疹(RGH)病人外周血CD4+T细胞内白细胞介素12(CD4+T-IL-12),干扰素γ(IFN-γ),白细胞介素4(IL-4)表达的影响。方法:用流式细胞仪检测30例经BCG-PSN治疗、15例未予BCG-PSN治疗的RGH病人与15名正常人外周血CD4+T-IL-12,IFN-γ和IL-4表达。结果:治疗前RGH病人外周血CD4+T-IL-12,IFN-γ表达较正常组下降[(1.8±s0.5)%vs(3.3±1.9)%,(3.5±2.6)%vs(5.3±1.5)%;P<0.01],IL-4表达上升[(3.0±0.5)%vs(2.2±0.8)%,P<0.01]。治疗后BCG-PSN组外周血CD4+T-IL-12和IFN-γ水平升高[(3.1±1.6)%vs(1.8±0.5)%,P<0.01;(5.0±2.6)%vs(3.6±2.6)%,P<0.05],IL-4表达下降[(2.4±0.5)%vs(3.0±0.5)%,P<0.01],Th1/Th2恢复正常。结论:RGH病人存在Th1/Th2失衡和IL-12表达低下;BCG-PSN通过诱导外周血CD4+T-IFN-γ,IL-12表达,下调IL-4表达,纠正病人免疫紊乱而提高临床疗效和预防复发。     

Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects

Aims

The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2).

Methods

The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.

Results

Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]).

Conclusions

Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination.     

Notch受体在胰腺癌中的表达及意义

目的探讨Notch1～4在胰腺癌中的表达及其肿瘤生物学意义。方法采用免疫组化检测17例胰腺癌及其癌旁组织中的Notch1～4的表达。结果 Notch1～4在胰腺癌中的表达率分别为17.65%(3/17)、23.53%(4/17)、70.59%(12/17)和100%(17/17),在癌旁组织中的表达率分别为88.24%(15/17)、88.24%(15/17)、58.82%(10/17)和64.71%(11/17)。与癌旁组织中的表达比较,Notch1和Notch2在癌组织中表达下调(P<0.01),Notch4表达明显上调(P<0.01)。结论不同Notch受体家族成员在胰腺癌中的表达不尽相同,Notch1和Notch2可能具有抑制肿瘤生长的作用,而Notch4可能具有促进肿瘤生长的作用。     

溶血磷脂酸和人附睾蛋白4联合检测在卵巢癌诊断中的价值

目的溶血磷脂酸(LPA)和人附睾蛋白4(HE4)联合检测在卵巢癌诊断中的价值。方法 50例卵巢癌患者作为A组,45例卵巢良性病变患者作为B组,100例健康查体者作为C组。测定3组血清LPA和HE4。结果 A组HE4和LPA均高于B组和C组(P<0.01),但血清HE4和LPA在B、C两组之间无明显差异(P>0.05)。LPA诊断卵巢癌敏感度为70.0%,特异度为95.2%,准确度为88.7%;HE4诊断卵巢癌的敏感度为80.0%,特异度为97.2%,准确度为92.8%。联合检测时,诊断卵巢癌的敏感度为94.0%,而特异度为93.1%,准确度为93.3%,高于单项检测的敏感度与准确度(P<0.05)。结论联合测定血清LPA和HE4可以较敏感和准确的诊断卵巢癌。     

4％色甘酸钠滴眼液治疗变应性结膜炎

４％色甘酸钠滴眼液经实验研究证明能明显减轻豚鼠变态反应、推迟发作和缩短症状持续时间。抑制大鼠Ⅰ型变态反应，与剂量呈依赖关系。小鼠ｉｐＬＤ５０为８５－１１７ｍＬ／ｋｇ，对兔和人眼无明显刺激性。变应性结膜炎２２１例（男性１４５例，女性７６例；年龄１２±ｓ８ａ），用４％色甘酸钠，０．１％地塞米松和２％色甘酸钠滴眼液分别治疗３０２，６９和６０只眼，以４％色甘酸钠疗效最佳，且未见不良反应。     

FOLFOX4方案化疗联合射频消融治疗原发性肝癌

目的探讨应用FOLFOX4方案化疗联合射频消融（RFA）治疗伴有门脉癌栓的局部晚期原发性肝癌的疗效。方法 46例经临床确诊伴有门脉癌栓的局部晚期原发性肝癌患者随机分为两组,联合组（n=24）：此组患者先行RFA治疗,每4周治疗1次,共4个疗程,第1次RFA治疗后1周行FOLFOX4方案化疗,14 d为1个周期,共12个周期;单纯射频组（n=22）：此组患者单纯采用射频消融治疗,每4周治疗1次,共4个疗程。观察终点为病情进展。结果联合组患者治疗后1、2、3年无瘤生存率分别为75.2%、51.0%和36.1%,射频组患者治疗后1、2、3年无瘤生存率分别为60.0%、31.2%和15.7%,差异有统计学意义（P=0.024）。结论对于肿瘤直径为3～5 cm的多个病灶结节合并门脉癌栓的原发性肝癌患者,FOLFOX4方案化疗联合射频消融治疗的疗效优于单纯射频消融。