硫酸 | 7664-93-9

• 分子结构分类: 无机化合物 - 均质非金属化合物 - 非金属氧阴离子化合物
• 中文名称: 硫酸
• 中文别名: 硫酸（易制毒）；发烟硫酸；电瓶酸；浓硫酸；蓄电池硫酸
• 英文名称: sulfuric acid
• 英文别名: sulphuric acid；H₂SO₄；conc. H₂SO₄；concentrated H₂SO₄；Hydron;sulfate
• CAS: 7664-93-9
• 化学式: H₂O₄S
• 分子量: 98.0795
• InChiKey: QAOWNCQODCNURD-UHFFFAOYSA-N

物化性质

• 稳定性/保质期：
  1. 硫酸在空气中迅速吸收水分，也能夺取有机物如糖、木中的水分子而碳化。冷却时能凝成结晶，在10.37℃熔化。液态硫酸易形成过冷液体。纯硫酸在290℃沸腾，98.3%的硫酸为恒沸物，沸点为330℃。浓硫酸有强烈的吸水性，是良好的干燥剂。 2. 硫酸与水混溶，并对一些无机和有机化合物有一定的溶解能力，虽然可作某些反应的溶剂使用，但长时间在高温下处于稳定状态的化合物较少见。例如己烷、庚烷、辛烷等在室温下与硫酸不反应，但在接近硫酸沸点的温度下会发生磺化反应。乙烯被硫酸吸收后生成乙烯硫酸酯；丙烯更易被硫酸吸收，生成丙烯硫酸酯及其他各种化合物。硫酸吸收乙炔后生成磺酸酯。浓硫酸可以溶解聚酰胺，例如具有特定结构的聚酰胺在浓度为80%~100%的硫酸中溶解，在95%以上的硫酸中室温下稳定性能良好。甚至含6%~7%SO3的发烟硫酸也常用作这类聚合物的溶剂。 3. 硫酸加热到290℃时开始分解，释放三氧化硫；在317℃形成共沸混合物，并转变成98.54%的水溶液。浓硫酸与水混合会产生大量热量。浓硫酸对多种化合物都有脱水作用，例如蔗糖、纸等因脱水而游离出碳。乙醇与浓硫酸一起加热时会脱水生成乙烯。一般有机化合物在浓硫酸的作用下会发生加成反应、氧化反应和磺化反应等。与金属反应时，因其浓度、温度及金属种类的不同，可生成H2、H2S、SO2、S以及金属硫化物等。硫酸与金属氧化物生成硫酸盐。冷的浓硫酸与铁、铝不作用。苯与浓硫酸煮沸20~30分钟后会生成苯磺酸。醇类一般发生酯化反应，烯丙醇与60%硫酸作用生成烯丙醇硫酸酯。硫酸可以与水以任何比例混合并放出大量热量，因此在混合时应将酸缓慢倒入水中，切不可将水加入浓酸中以免局部过热引起酸液喷溅。硫酸是无机强酸，腐蚀性强，几乎能溶解所有金属。它具有较强的吸水性和氧化性，能使棉布、纸张、木材等脱水炭化或使有机物磺化、硫酸化。接触皮肤会导致严重灼伤。 4. 稳定 5. 禁配物：碱类、强还原剂、易燃或可燃物、电石、高氯酸盐、雷酸盐、硝酸盐、苦味酸盐、金属粉末等 6. 避免接触的条件：水 7. 聚合危害：不聚合 8. 分解产物：氧化硫

计算性质

• 辛醇/水分配系数(LogP)：
  -1.4
• 重原子数：
  5
• 可旋转键数：
  0
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  83
• 氢给体数：
  2
• 氢受体数：
  4

ADMET

代谢

硫酸的吸收量中有一部分（6%到8%）以硫酸盐和氢离子的形式在肝脏中与血浆池中的代谢物如酚、甲酚、吲哚和粪臭素结合。

Some (6 to 8%) of the sulfuric acid absorbed as sulfate and hydrogen ions is conjugated in the liver from the plasma pool with such metabolites as phenol, cresol, indole, and skatole.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

硫酸是一种无色、油性的液体。它用于制造肥料、炸药、染料、其他酸类、羊皮纸、胶水、石油净化和金属的酸洗。人类暴露和毒性：硫酸对皮肤、眼睛和粘膜具有腐蚀性。硫酸在人类中并不被认为是通过皮肤接触的过敏原。人类志愿者急性暴露于100微克/立方米的硫酸导致从大近端气道清除颗粒物的粘液纤毛清除率增加；在更高的水平100微克/立方米，则出现相反的情况。在两个水平上，从远端气道的清除都减少了。因接触汽车电池中的硫酸而导致的眼睛损伤已有报道。最常见的伤害是结膜和角膜化学烧伤以及虹膜炎。由于硫酸暴露，皮肤烧伤可能导致死亡。一名意外暴露于高浓度硫酸烟雾的男子报告了成人呼吸窘迫综合征。对十名摄入硫酸的患者进行了研究。通过纤维光学内窥镜和尸检确定了上消化道损伤的程度和严重性。所有患者都有食道和胃的受累，但在大多数情况下十二指肠得以幸免。严重损伤的患者出现了并发症和死亡。几项流行病学研究表明，暴露于含有硫酸的无机酸雾与喉癌发生率增加有关。国际癌症研究机构（IARC）已经得出结论，职业暴露于含有硫酸的强无机雾对人类具有致癌性。动物研究：在不同物种进行的急性吸入研究中观察到的硫酸气溶胶的LC50值较低，这很可能是由于这种化学物质的腐蚀/刺激作用。对于豚鼠，LC50（8小时；粒子大小约1微米）的范围从0.018到0.050毫克/升，取决于动物的年龄。根据暴露时间的不同，大鼠的LC50范围从0.37到0.42毫克/升，小鼠从0.6到0.85毫克/升，家兔从1.47到1.61毫克/升。急性口服毒性研究显示，大鼠的LD50为2140毫克/千克。硫酸对皮肤、眼睛和粘膜具有腐蚀性。在多种物种中，10%的硫酸溶液似乎不会刺激皮肤。在使用10%硫酸进行的眼睛刺激研究中观察到不一致的结果（不刺激或严重刺激），这取决于所使用的协议（OECD/EU或美国）。在多次重复的硫酸气溶胶吸入研究中，毒性局限于呼吸道的结构和功能的变化，这表明它具有局部效应而没有系统性影响。观察到的变化与硫酸的刺激性质有关，很可能是由H+离子引起的。在大鼠吸入硫酸气溶胶的28天研究中，观察到在最低浓度（0.3毫克/立方米）暴露后喉上皮细胞的最小鳞状细胞化生。这种效果是完全可逆的。暴露于1.38毫克/立方米导致更严重的化生并伴有细胞增殖。已经证明，在使用各种菌株的S. typhimurium（pH 4至9）和E. coli（0.002至0.005%）进行的Ames试验中，硫酸没有效果，无论是否进行代谢激活。已经证明它能在CHO细胞（pH 3.5至7.4，无论是否进行代谢激活）和发育海胆胚胎的非标准试验（pH 5 - 不进行代谢激活）中引起染色体畸变。在使用硫酸气溶胶通过吸入进行的致癌性研究中，没有观察到致癌效果。在大鼠和小鼠经口慢性插管或气管内滴注硫酸溶液后，报告了肿瘤发生率的轻微增加，但这些研究无法得出明确的结论。因为硫酸是一种直接作用的毒物，而且它不太可能到达生殖器官，所以哺乳动物在暴露于硫酸后不太可能出现生殖效应。在通过吸入硫酸气溶胶进行的发育毒性/致畸性研究中，小鼠和家兔的母体毒性的NOAEL似乎是20毫克/立方米。在任一物种中都没有观察到胎儿毒性和致畸性。生态毒性研究：硫酸对水生生物的毒性是结果的pH值的函数。pH 4.0导致明显的鳃刺激，3.5导致太阳鱼、鲈鱼和鲤鱼的死亡。导致蓝鳃在96小时内死亡50%的氢离子浓度在3.5到3.0之间。在鱼类中，毒性的主要原因是与钠平衡和呼吸的干扰有关。

IDENTIFICATION AND USE: Sulfuric acid is a colorless, oily liquid. It is used in manufacture of fertilizers, explosives, dyestuffs, other acids, parchment paper, glue, purification of petroleum, pickling of metal. HUMAN EXPOSURE AND TOXICITY: Sulfuric acid is corrosive to the skin, eyes and mucous membranes. Sulfuric acid is not considered as an allergen by skin contact in humans. Acute exposure of human volunteers to 100 ug/cu m of sulfuric acid resulted in increased mucociliary clearance of particles from the large proximal airways; at higher levels 100 ug/cu m, the opposite occurred. Clearance from the distal airways was reduced at both levels. Eye damage as a result of contact with sulfuric acid from car batteries has been reported. The most common injuries were conjunctival and corneal chemical burns, and iritis. Death can occur from dermal burns from sulfuric acid exposure. Adult respiratory distress syndrome was reported in a man accidentally exposed to high concentrations of sulfuric acid fumes. Ten patients with sulfuric acid ingestion were studied. The extent and severity of upper gastrointestinal tract injury was determined by fiberoptic endoscopy and necropsy. All patients had esophageal and gastric involvement but the duodenum was spared in the majority. Complications and mortality occurred in patients with severe injury. Several epidemiological studies have suggested a relationship between exposure to inorganic acid mists containing sulfuric acid and an increased incidence of laryngeal cancer. IARC has concluded that occupational exposure to strong inorganic mists containing sulfuric acid is carcinogenic for humans. ANIMAL STUDIES: The LC50 values for sulfuric acid aerosol observed in acute inhalation studies conducted in different species are low and are most likely due to the corrosive/irritant effect of this chemical. For guinea pigs, the LC50 (8 hours; particle size approximately 1 um) ranges from 0.018 to 0.050 mg/L, depending on the age of the animals. Depending on the duration of exposure, the LC50 ranges from 0.37 to 0.42 mg/L in rats, 0.6 to 0.85 mg/L in mice and 1.47 to 1.61 mg/L in rabbits. Acute oral toxicity study indicated an LD50 of 2140 mg/kg in the rat. Sulfuric acid is corrosive to the skin, eyes and mucous membranes. 10% solutions of sulfuric acid appear not to be irritating to the skin in different species. Conflicting results (not irritating or severely irritating) are observed in eye irritation studies using 10% sulfuric acid, depending on the protocol used (OECD/EU or US). In numerous repeated inhalation studies with sulfuric acid aerosol, toxicity was confined to changes in the structure and function of the respiratory tract, suggesting that it has a local effect and no systemic effects. The observed changes are related to the irritant properties of sulfuric acid and are most likely due to the H+ ion. In a 28-day inhalation study in the rat exposed to sulfuric acid aerosol, minimal squamous metaplasia was observed in the laryngeal epithelium following exposure to the lowest concentration used (0.3 mg/cu m). This effect was fully reversible. Exposure to 1.38 mg/cu m caused more severe metaplasia accompanied by cell proliferation. Sulfuric acid has been shown to be without effect in the Ames test using various strains of S. typhimurium (pH 4 to 9) and E. coli (0.002 to 0.005%), both with and without metabolic activation. It has been shown to cause chromosomal aberrations in CHO cells (pH 3.5 to 7.4, both with and without metabolic activation), and in a non-standard assay in developing sea urchin embryos (pH 5 - without metabolic activation). No carcinogenic effect was observed in carcinogenicity studies conducted by inhalation with sulfuric acid aerosol using 3 different animal species. Small increases in tumor incidence were reported in rats and mice after chronic gastric intubation or intratracheal instillation of sulfuric acid solution, but no clear conclusion can be drawn from these studies. Because sulfuric acid is a direct-acting toxicant, and because it is unlikely to reach the reproductive organs, reproductive effects in mammals are not likely to occur following exposure to sulfuric acid by any route. In a developmental toxicity/teratogenicity study conducted by inhalation with sulfuric acid aerosol, the NOAEL for maternal toxicity appears to be 20 mg/cu m in mice and rabbits. No evidence of fetotoxicity or teratogenicity was seen in either species. ECOTOXICITY STUDIES: The toxicity of sulfuric acid to aquatic life is a function of the resulting pH. A pH of 4.0 gave pronounced gill irritation and 3.5 caused death of sunfish, bass, and carp. The concentration of hydrogen ion which caused 50% mortality of bluegill in 96 hr (96 hr LC50) was between 3.5 and 3.0. In fish the major causes of toxicity seem to be related to disruption of sodium balance and respiration.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

许多强酸通过蛋白质的变性和部分水解导致组织烧伤。大多数蛋白质在pH值小于3-4时会变性。蛋白质的大规模变性、脂质的脱酯化和随后组织的干燥会导致化学烧伤。症状包括瘙痒、皮肤或组织的漂白或变黑、起泡和烧灼感。更具体地说，硫酸通过酰胺水解和酯水解轻易分解蛋白质和脂质，接触活组织时。此外，它对碳水化合物表现出强烈的脱水性质，释放额外的热量并导致二次热烧伤。其强烈的氧化性质也可能扩大对组织的腐蚀性。由于这些原因，硫酸造成的损害可能比其他类似的强酸，如盐酸和硝酸造成的损害更为严重。

Many strong acids cause tissue burns through the denaturation of proteins and partial hydrolysis of proteins. Most proteins denature at pH values of less than 3-4. The large-scale denaturation of proteins, de-esterification of lipids and subsequent desiccation of tissues leads to chemical burns. Symptoms include itching, bleaching or darkening of skin or tissues, blistering and burning sensations. More specifically, sulfuric acid readily decomposes proteins and lipids through amide hydrolysis and ester hydrolysis upon contact with living tissues. In addition, it exhibits a strong dehydrating property on carbohydrates, liberating extra heat and causing secondary thermal burns. The strong oxidizing property may also extend its corrosiveness on the tissue. Because of such reasons, damage posed by sulfuric acid is potentially more severe than that caused by other comparable strong acids, such as hydrochloric acid and nitric acid.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌性证据

评估：有充分证据表明，职业接触含有硫酸的强无机酸雾具有致癌性。总体评估：职业接触强无机酸雾对人类具有致癌性（第1组）。

Evaluation: There is sufficient evidence that occupational exposure to strong-inorganic-acid mists containing sulfuric acid is carcinogenic. Overall evaluation: Occupational exposure to strong-inorganic-acid mists is carcinogenic to humans (Group 1).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

A2；疑似人类致癌物。（分类指的是含有强无机酸雾中的硫酸。）

A2; Suspected human carcinogen. /Classification refers to sulfuric acid contained in strong inorganic acid mists.)/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 致癌性证据

含有硫酸的强无机酸雾已知是人类致癌物，这一结论基于人类致癌性研究的充分证据。

Strong inorganic acid mists containing sulfuric acid are known to be human carcinogens based on sufficient evidence of carcinogenicity from studies in humans.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项实验研究中，研究者观察了不同物种通过血液清除放射性标记的硫酸酸雾的过程。研究发现，动物吸入硫酸酸雾后，硫酸中的硫磺迅速从肺部清除到血液中（从2到9分钟）。硫酸盐是血液的正常组成部分，是含硫氨基酸的正常代谢产物，过量的硫酸盐通过尿液排出。身体中这种阴离子的总量很大，因此职业性气溶胶暴露不太可能显著改变正常的身体负荷。

In an experiment studying the clearance via the blood of radiolabeled sulfuric acid aerosol in different species, the authors have observed that sulfur from sulfuric acid was rapidly cleared (from 2 to 9 minutes) from the lungs of animals into the blood following inhalation exposure. Sulfate is a normal constituent of the blood and is a normal metabolite of sulfur-containing amino acids, and excess sulfate is excreted in the urine. The body pool of this anion is large, and it is therefore unlikely that occupational aerosol exposures significantly modify the normal body load.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

对于吸入硫酸气溶胶的暴露，重要的问题在于气溶胶在呼吸道中的沉积位置以及暴露的持续时间。决定气溶胶在呼吸道沉积位置的因素包括环境条件，特别是相对湿度，它会影响气溶胶的大小，以及受试者的生理因素，包括呼吸频率和深度，以及呼吸方式，例如通过口、鼻或口鼻。气溶胶在呼吸道内沉积的吸湿增长效应已经在成人和儿童中进行了建模...儿童可能对硫酸气溶胶的呼吸道效应更为敏感，因为肺沉积量增加是由于较小的气道直径。

For inhalation exposure to sulfuric acid aerosols, the important issues are where in the respiratory tract the aerosols deposit and the duration of exposure. Factors that determine the site of deposition in the respiratory tract include environmental conditions, especially relative humidity which affects aerosol size, and physiological factors of the subject including breathing rate and depth, and method of breathing, e.g., mouth, nose, or oronasal. The effect of hygroscopic growth on deposition within the respiratory tract has been modeled in adults ... and children ... Children may be more sensitive to the respiratory tract effects of sulfuric acid aerosols because pulmonary deposition is increased as a result of smaller airway diameter.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

稀释硫酸，就像硫酸雾一样，通过粘膜吸收为硫酸盐和氢离子，最终进入血液。... 血浆池中的一些硫酸盐（6%至8%）在肝脏与酚、甲酚、吲哚和粪臭素等代谢物结合，并以“醚硫酸盐”的形式通过尿液排出。这种醚硫酸盐的尿液排出构成了解毒机制。有机硫酸盐（85%至90%）以硫酸与钠、钾、钙和氨的化合物形式排出。剩余的中性硫（4%至6%）以含硫氨基酸、硫代硫酸盐和硫氰酸盐等化合物形式排出。

Dilute sulfuric acid, as with sulfuric acid mist, is absorbed as sulfate and hydrogen ions through mucous membranes, ultimately into the bloodstream. ... Some sulfate (6 to 8%) from the plasma pool is conjugated in the liver with such metabolites as phenol, cresol, indole, and skatole and excreted in the urine as "ethereal sulfates". Such urinary excretion of the ethereal sulfates constitutes a detoxicating mechanism. The organic sulfate (85 to 90%) is excreted as compounds of sulfuric acid with sodium, potassium, calcium, and ammonia. The remainder, neutral sulfur (4 to 6%), is excreted in compounds such as sulfur-containing amino acids, thiosulfates, and thiocyanates.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

吸入的不溶性颗粒物会沉积在人类和其他哺乳动物正常健康的气管支气管气道中，并随着向喉部移动的粘液衬里被运输，在那里它们被吞咽。从最末端的纤毛气道的传输时间从0.1到1天不等，每个个体都有相对恒定、特征性的时间。清除的确切时间进程取决于颗粒沉积和气道中粘液速度的分布。目前对于实验动物的支气管内沉积和粘液纤毛传输率的数据太少，无法进行物种间的全面比较。然而，对于各种物种的相对肺大小和解剖差异的了解已经足够进行一些初步但重要的区分。与常用的实验动物相比，人类拥有更大的肺和更对称的上级支气管气道分支模式。此外，人类进行大量的口腔呼吸，从而绕过了鼻气道有效的空气清洁功能。这些差异导致人类上支气管气道中颗粒物的沉积量更大，以及气道分叉附近局部表面沉积的浓度更高。沉积在小型纤毛气道中的气态刺激物可能会显著改变粘液纤毛传输。这类物质包括香烟烟雾、亚微米级的硫酸雾、二氧化氮和臭氧。

Inhaled insoluble particles that deposit along normal healthy tracheobronchial airways of humans and other mammals are transported on the proximally moving mucous lining to the larynx, where they are swallowed. The transit time from the most distal ciliated airways varies from 0.1 to 1 days, with each individual having a relatively constant, characteristic time. The exact time course of clearance depends on the distributions of both particle deposition and mucus velocities along the airways. There are too few data on intrabronchial deposition and mucociliary transport rates for laboratory animals to permit a thorough intercomparison among species. However, enough is known about the relative lung sizes and anatomical differences among the various species to make some preliminary, but important, distinctions. As compared to commonly used experimental animals, humans have larger lungs and a more symmetric upper bronchial airway branching pattern. In addition, humans do considerable oral breathing, thus bypassing the effective air cleaning capability of the nasal airways. These differences contributed to a greater amount of upper bronchial airway particle deposition in humans, as well as to greater concentrations of deposition on localized surfaces near airway bifurcations. Airborne irritants that deposit in small ciliated airways may produce marked changes in mucociliary transport. Such materials include cigarette smoke, submicrometer sized sulfuric acid mist, nitrogen dioxide, and ozone. ...

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

制备方法

目前，国内生产蓄电池硫酸的方法主要有吹出法和蒸馏法。国外则采用从硫酸厂发烟硫酸中获取纯净三氧化硫，并通入特制的蒸馏水配制浓度为98%的吸收硫酸循环吸收塔来制得高质量的蓄电池硫酸。

• 吹出法：将具有一定压力的干净空气直接通入工业硫酸中，直至溶解在硫酸中的二氧化硫完全被吹出来。
• 蒸馏法：将工业硫酸加热蒸发，使液体变成蒸汽，通过冷凝器冷却后得到成品硫酸。

此外，硫酸的制备还可以通过精馏法或微孔滤膜过滤等方法进一步纯化。原料来源广泛，包括硫、硫化铁矿和石油精制产物，其中接触法制取最为普遍，分为三个阶段：黄铁矿的焙烧或硫的燃烧生成二氧化硫；在V2O5催化下将SO2氧化为三氧化硫；用98.3%的浓硫酸吸收SO3得到发烟硫酸。

制备途径

• 精馏法：以工业硫酸为原料，经精馏、冷凝和分离后获得无色透明的BV1级硫酸。
• 蒸馏法：同样以工业硫酸为原料，通过蒸馏纯化去除杂质，并使用微孔滤膜过滤除去尘埃颗粒，最终制得MOS级和低尘高纯级硫酸。

另一种方法是利用硫磺或硫铁矿。首先将硫磺转化为二氧化硫气体并催化氧化生成三氧化硫；或者直接以硫铁矿为原料，经过焙烧、净化、氧化成三氧化硫后用稀硫酸吸收得到成品。

用途简介

硫酸广泛应用于化学肥料的生产，并在化工、医药、塑料、染料及石油提炼等多个行业中都有重要应用。其特性使它成为多种工业过程中的理想化学品。

详细用途

1. 实验室使用：常用于分析和实验中，如钡、锶和铅的沉淀物，有机物分析与合成中的水分吸收，磺化作用，缩合作用以及与硝酸混合进行硝化。
2. 工业应用：可用作硬水软化剂、离子交换再生剂、pH值调节剂、氧化剂和洗涤剂等。此外在化肥、农药、染料、颜料、塑料、化纤、炸药及各种硫酸盐的制造中也十分常见，广泛用于石油炼制、有色金属冶炼、钢铁酸洗处理、制革过程以及国防军工等领域。
3. 合成与加工：作为强无机酸使用的同时还用作脱水剂、氧化剂、助硝化剂、酸洗剂和磺化剂等。例如，在集成电路制造中用于硅片清洗，同时也是高熔点聚酰胺的溶剂，用于纺丝原液的制备。
4. 特殊用途：与双氧水配合使用作为强酸性清洗腐蚀剂；在含醇饮料、干酪加工及淀粉水解制葡萄糖等过程中有重要应用。此外还用于去除柑橘果皮制作罐头和精炼食用油时除去有机物并水洗去杂质，甚至在啤酒生产中防止二氧化碳损失。
5. 化学肥料：再次提及其广泛应用于化工、医药、塑料及石油提炼等多个领域。

参考文献

[22]

反应信息

• 作为反应物：
  描述：

  硫酸 在 aluminium oxide 作用下， 生成 二氧化硫
  参考文献：
  名称：

  Study of the Stability of Catalysts for Decomposition of Spent Sulfuric Acid

  摘要：

  分析了各种因素对用于分解废硫酸的异质催化剂操作稳定性的影响。

  DOI：

  10.1007/s11167-005-0419-4
• 作为产物：
  描述：

  硒脲酸 在 硫化氢 作用下， 以 水 为溶剂， 生成 硫酸
  参考文献：
  名称：

  Jakubowitsch, W. W., 1934, # 2, p. 148 - 154

  摘要：

  DOI：
• 作为试剂：
  描述：

  邻苯二甲醚 在 盐酸 、 磷酸 、 硫酸 、 硝酸 、 铁粉 、 溶剂黄146 、 potassium hydroxide 、 三氯氧磷 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成 5-(2,6-dimethoxyphenoxy)-6-methoxy-4-methyl-8-nitroquinoline
  参考文献：
  名称：

  探索未开发的化学空间：合理鉴定具有抗疟特性的新型他非诺喹类似物

  摘要：

  专利倾向于定义由马库什结构的组合性质描述的巨大化学空间。然而，新主要活性成分的优化通常是由简单的 Free Wilson 方法驱动的。这一过程导致对命中化合物附近的化学空间进行高度集中的研究，留下许多可能存在高度生物活性储层的未探索区域。这项研究旨在证明，这种公开的化学空间可以隐藏具有值得研究的有趣潜在生物活性的化合物。这强调了拓宽传统策略之外的方法的价值和必要性。因此，我们主张采用一种在早期药物发现阶段可能更有效的替代方法。我们选择2018年FDA批准的单剂量根治疟疾药物他非诺喹的案例来说明这一过程。通过对他非诺喹化学空间的深入探索，合理鉴定并合成了七种具有潜在抗疟活性的化合物。这一小组代表了迄今为止报道的 58 种类似物尚未探索的化学多样性。经过生物学评估，结果证明我们的合理设计方法已被证明是一种非常有效的探索性方法，适合早期药物发现阶段。

  DOI：

  10.1016/j.bioorg.2024.107472

文献信息

• Stereospecific production of 6- or 7-carbon-substituted-.beta.-lactams
  申请人：Schering Corporation

  公开号：US04237051A1

  公开（公告）日：1980-12-02

  Reaction of 6- or 7-diazo-.beta.-lactams with allylic halides in the presence of a catalytic amount of metallic copper or a copper salt affords 6- or 7-carbon-substituted-.beta.-lactams with the desired stereochemical configuration at the 6- or 7-position. Subsequent reduction with a trialkyl stannane affords useful intermediates for further syntheses affording 6- or 7-carbon-substituted-.beta.-lactams. The present invention relates to a process for the production of 6- or 7-carbon-substituted-.beta.-lactams having the desired stereochemical configuration at the 6- or 7-position. More particularly, this invention provides a process for the preparation of a .beta.-lactam of the formula ##STR1## wherein R.sub.1 is cyano or COOR.sub.2 wherein R.sub.2 is a readily removable ester-forming moiety, hydrogen or an alkali-metal cation; R.sub.3 and R.sub.4 are independently hydrogen, lower alkyl, aryl or aralkyl; Z is a group of the formula ##STR2## wherein R.sub.5 is hydrogen, lower alkyl or aralkyl; and the dotted line indicates the optional presence of a double bond; which comprises (1) reacting a diazo-.beta.-lactam of the formula ##STR3## wherein Y is a sulfur or an oxygenated sulfur atom and Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinbefore defined; with an allyl halide of the formula ##STR4## wherein R.sub.3 and R.sub.4 are as hereinbefore defined and X is bromo or iodo; in the presence of a catalytic amount of metallic copper or a copper salt; and where Y is an oxygenated sulfur atom, followed by transformation of the resultant oxygenated sulfur intermediate to a compound wherein Y is a sulfur atom; and (2) subjecting the resultant intermediate of the formula ##STR5## wherein X, Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinabove defined, to reduction with a trialkyl stannane to afford the compound of formula I. The lower alkyl groups referred to contain 1 to 6 carbon atoms and are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl and the corresponding branched-chain isomers thereof. The lower alkoxy groups referred to above likewise contain 1 to 6 carbon atoms and are exemplified by methoxy, ethoxy, propoxy, and the like. The term "aryl" as used herein refers to phenyl substituted by one or more substituent groups selected from among chloro, bromo, fluoro, lower alkyl, hydroxy, nitro, amino, aminomethyl, lower monoalkylamino, lower dialkylamino, lower alkoxy and carboxy. Such aryl groups represented by R.sub.1 can be, for example, 4-hydroxyphenyl, 3,4-dichlorophenyl, 2,6-dimethoxyphenyl, 4-methylphenyl, 2-fluorophenyl, 4-carboxyphenyl, 3-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 4-dimethylaminophenyl, 4-aminomethylphenyl and 4-ethoxyphenyl. The term "aralkyl" encompasses aryl-substituted lower alkyl groups such as benzyl, phenethyl, p-fluorobenzyl, o-tolylethyl and m-hydroxy-phenethyl. The process of this invention initially involves the reaction of a diazo-.beta.-lactam of formula II and the allyl halide of formula III in the presence of a catalytic amount of metallic copper or a copper salt to induce the decomposition of the diazo-.beta.-lactam at temperatures of about 0.degree.-50.degree. C. to provide the intermediate of formula IV. The diazo-.beta.-lactam utilizable in this step of the invention may be any type of readily removable ester-blocked acid, i.e., the compound of formula II wherein R.sub.1 is COOR.sub.2 or a nitrile, i.e., the compound of formula II wherein R.sub.1 is cyano. Preferably, benzyl or benzhydryl esters are employed in the reaction wherein R.sub.1 is COOR.sub.2. The starting materials of formula II wherein Y is oxygenated sulfur are preferred due to the stability of the starting compound. However, the reaction using the equivalent sulfide also proceeds with good yields and avoids the need for a subsequent deoxygenation step. The allyl halides of formula III utilizable in the present invention are those wherein the halogen is iodine or bromine with iodine being most particularly preferred. The allyl halide of formula III may be substituted by lower alkyl, aryl or aralkyl groups. Those compounds wherein R.sub.3 and R.sub.4 are methyl or phenyl are preferred. The copper compound utilizable as a catalyst for this step of the instant invention may be almost any copper salt or finely divided elemental copper. Preferably, 1-10 mole percent of the copper or copper salt is utilized. The most preferred catalysts are cuprous chloride and copper (II)-2,4-pentanedioate. In order to maximize the yield for this step of the instant invention, it is preferable to use a large excess of the allyl halide of formula III. Most preferably, allyl bromide or allyl iodide is used as the reaction medium. Substituted allyl halides of formula III are preferably diluted with a non-polar co-solvent such as methylene chloride. Polar solvents may also be used, e.g., dimethylformamide, dimethylsulfoxide or acetonitrile, but these provide poorer yields. The reaction is preferably carried out at room temperature; however, depending on the nature of the starting materials, the reaction temperatures may range from about 0.degree. to 50.degree. C. Occasionally, warming to about 40.degree. C. is utilized to initiate the reaction which is then continued without further heating. The stereochemistry at C-6 or C-7 of the intermediate of formula IV is generally a mixture of alpha and beta compounds. Generally, use of the bromides gives a higher ratio of beta to alpha compounds, i.e., 5 to 6:1. Use of the iodides gives more approximately equal amounts of the alpha and beta isomers. The reduction of step 2 to afford the cis product of formula I is accomplished using trialkyl stannane (trialkyl tin hydride). Preferably, tri-n-butyl stannane is utilized. The intermediate of formula IV is heated at about 60.degree.-100.degree. C. with 1-2 equivalents of the tin hydride in an inert solvent. Preferred solvents are tetrahydrofuran, benzene and toluene. Typically, the product is separated by chromatography in yields of greater than 80%. The compounds of formula II wherein Y is an oxygenated sulfur atom may be obtained from the corresponding compounds wherein Y is sulfur by any of the conventional oxidation procedures, e.g., ozone, iodobenzene dichloride in aqueous pyridine, etc. An oxygenated sulfur penicillin compound, i.e., wherein Z is ##STR6## may then be converted to the corresponding cephalosporin, i.e., wherein Y is S and Z is ##STR7## by various literature methods. See, for instance, Flynn, "Cephalosporins and Penicillins", Academic Press, pp. 193-199 and 670-673 (1972). By such methods benzyl 6.beta.-allyl-6.alpha.-bromopenicillanate-1.beta.-oxide may be converted to benzyl 7.beta.-allyl-6.alpha.-bromo-3-methyl-3-cephem-4-carboxylate. The sulfoxide compound is also particularly useful wherein it is desired to convert a mixture of 2- and 3-cephem compounds to a pure 3-cephem compound. The 6- or 7-diazo starting materials of formula II are preparable via a variety of literature methods or variations thereof. A preferred method involves degradation of the penicillin or cephalosporin side chain via the N-nitroso derivative as described by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967); and Sheehan, J. Org. Chem., 39, 1444 (1974). This process involves treatment of the penicillin or cephalosporin, e.g., benzylpenicillin benzyl ester or benzhydryl ester, to form the N-nitroso derivative, followed by decomposition of the nitroso amide side chain with methylene chloride-pyridine or methylene chloride at about 40.degree. C. to afford the diazo compound. An improvement of this process, omitting the pyridine and allowing the reaction to proceed at room temperature in a polar solvent, e.g., dimethylsulfoxide or dimethylformamide, affords a cleaner reaction and better conversion, i.e., >90%. This reaction sequence may be represented by the following scheme: ##STR8## wherein Y, Z and R.sub.1 are as hereinbefore defined. Preferable by this route are the following: benzyl 6-diazopenicillanate; benzhydryl 6-diazopenicillanate; 6-diazopenicillanonitrile; and benzyl 7-diazo-3-methylcephalosporanate. Another modification of the decomposition step in the preparation of the starting materials of formula II is to utilize triphenylphosphine and water in place of the methylene chloride and pyridine according to the method of Sheehan, J. Org. Chem., 42, 1012 ( 1977) to afford the hydrazone of the formula: ##STR9## Oxidation of this hydrazone by the method of U.S. Pat. No. 3,880,837 affords the desired diazo compound. This route is particularly preferred for the cephalosporin starting materials of this invention. Preparable by this route are the following: benzhydryl 7-diazo-3-methylcephalosporinate; benzhydryl 7-diazo-3-acetoxymethylcephalosporinate; and benzhydryl 6-diazopenicillanate. An additional method for preparing the 6- or 7-diazo compounds of formula II involves diazotisation of the corresponding amino compounds using nitrous acid according to the procedure originally carried out by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967) and further delineated in J. Amer. Chem. Soc., 94, 1408 (1972) and J. Org. Chem., 41, 1578 (1976). Once prepared, the compounds of formula I are utilizable to prepare various 6- or 7-substituted-.beta.-lactams having useful antimicrobial activity, many of which are known in the art. For instance, ozonolysis of 6.beta.-(allyl)penicillanonitrile, benzyl 6.beta.-(allyl)penicillanate or benzhydryl 6.beta.-allylpenicillanate affords 6.beta.-(formylmethyl)-penicillanonitrile, benzyl 6.beta.-(formylmethyl)penicillanate and benzhydryl 6.beta.-(formylmethyl)penicillanate, respectively. This ozonolysis is carried out according to standard methodology. The aldehyde obtained by the ozonolysis described in the preceding paragraph may then be subjected to reduction utilizing a mild reducing agent such as sodium borohydride to afford the corresponding alcohol. For instance, obtainable by this reaction is 6.beta.-(2-hydroxyethyl)penicillanonitrile, benzyl 6.beta.-(2-hydroxyethyl)penicillanate and benzhydryl 6.beta.-(2-hydroxyethyl)penicillanate. The ester group of the preceding two compounds may, of course, be removed utilizing standard hydrogenolysis typically with a palladium catalyst to afford the resulting free acids. Workup with a weak base, e.g., potassium carbonate or sodium carbonate, will afford the potassium or sodium salts, e.g., potassium 6.beta.-(2-hydroxyethyl)penicillanate or sodium 6.beta.-(2-hydroxyethyl)penicillanate. Oxidation of the aldehydes obtainable by the ozonolysis procedure affords the corresponding carboxylic acids. For instance, benzhydryl 6.beta.-(formylmethyl)penicillanate treated with chromic acid in acetone and water affords benzhydryl 6.beta.-(carboxymethyl)penicillanate. Reaction of the foregoing carboxylic acids with suitable azides provides various homo-penicillanates. For instance, benzhydryl 6.beta.-(carboxymethyl)penicillanate treated with diphenylphosphoryl azide and triethylamine at a reaction temperature of about 80.degree. C. according to the method of Ninomiya, et. al., Chem. Pharm. Bull. Japan, 22, 1398 (1974), affords benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate which is typically not isolated. Treatment of this intermediate with the desired acid or alcohol provides homopenicillanates which then may be optionally deblocked. Obtainable in this method are potassium 6.beta.-(phenylacetamidomethyl)penicillanate and potassium 6.beta.-(ethoxycarbonylaminomethyl)penicillanate. Treatment of benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate with trichloroethanol followed by a zinc/acetic acid reduction affords benzhydryl 6.beta.-(aminomethyl)penicillanate. Conventional deblocking of this compound then affords 6.beta.-(aminomethyl)penicillanic acid. Several of the foregoing compounds are described by Sheehan, et. al. as having useful and interesting antimicrobial activity in German Pat. Nos. 2,416,492 and 2,643,085. However, 6.beta.-(aminomethyl)penicillanic acid has not heretofore been described in any publication and is therefore a novel compound. The 6.beta.-(aminomethyl)penicillanic acid produced by the process of this invention possesses antibacterial activity. Additionally, it is a penicillinase inhibitor which may be used concomitantly with other penicillin-type antibiotics in infection therapy. Thus, when tested in standardized microbiological assays, this compound exhibits activity vis-a-vis such organisms as Staphylococcus aureus, Klebsiella, Bacillus subtilis, and Pseudomonas aeruginosa at test levels of 0.1 to 100 .mu.cg/ml. Thus, as antibacterial agents this compound is conventionally formulated for oral, intramuscular, intravenous or topical therapy. Thus, the present invention includes within its scope pharmaceutical compositions comprising an antibacterially effective amount of the novel 6.beta.-(aminomethyl)penicillanic acid with a compatible pharmaceutical carrier therefor, and a method of using such compositions for the treatment of microbial infections. The dosage administered of this compound is dependent upon the age and weight of the animal species being treated, the mode of administration, and the type and severity of bacterial infection being prevented or reduced. Typically, the dosage administered per day will be in the range of 100-5000 mg with 500-1000 mg being preferred. For oral administration, this compound may be formulated in the form of tablets, capsules, elixirs or the like. For parenteral administration it may be formulated into solutions or suspensions for intramuscular injection. Topical formulations include creams, ointments, gels and the like.

  在微量金属铜或铜盐的催化下，6-或7-重氮-.beta.-内酰胺与烯丙基卤化物的反应，可得到在6-或7位具有所需立体化学配置的6-或7-碳取代-.beta.-内酰胺。随后使用三烷基锡烷进行还原，可得到适用于进一步合成6-或7-碳取代-.beta.-内酰胺的有用中间体。本发明涉及一种生产在6-或7位具有所需立体化学配置的6-或7-碳取代-.beta.-内酰胺的方法。更具体地，本发明提供了一种制备具有以下公式的.beta.-内酰胺的方法： ##STR1## 其中R1是氰基或COOR2，其中R2是易于移除的酯形成基团、氢或碱金属阳离子；R3和R4独立地为氢、低级烷基、芳基或芳烷基；Z是具有以下公式的基团： ##STR2## 其中R5是氢、低级烷基或芳烷基；虚线表示双键的可选存在；该方法包括：(1)将具有以下公式的重氮-.beta.-内酰胺： ##STR3## 其中Y是硫或氧化的硫原子，Z、R1、R3和R4如前所述；与具有以下公式的烯丙基卤化物反应： ##STR4## 其中R3和R4如前所述，X是溴或碘；在微量金属铜或铜盐的存在下；当Y是氧化的硫原子时，随后将所得的氧化的硫中间体转化为Y为硫原子的化合物；以及(2)将具有以下公式的所得中间体： ##STR5## 其中X、Z、R1、R3和R4如前所述，进行还原，使用三烷基锡烷得到公式I的化合物。所提及的低级烷基含有1至6个碳原子，例如甲基、乙基、丙基、丁基、戊基、己基及其相应的支链异构体。所提及的低级烷氧基同样含有1至6个碳原子，例如甲氧基、乙氧基、丙氧基等。术语“芳基”如本文所用，指的是被一个或多个选自氯、溴、氟、低级烷基、羟基、硝基、氨基、氨基甲基、低级单烷基氨基、低级二烷基氨基、低级烷氧基和羧基的取代基团取代的苯基。代表R1的此类芳基可以是例如4-羟基苯基、3,4-二氯苯基、2,6-二甲氧基苯基、4-甲基苯基、2-氟苯基、4-羧基苯基、3-硝基苯基、4-氨基苯基、3-氨基苯基、4-二甲基氨基苯基、4-氨基甲基苯基和4-乙氧基苯基。术语“芳烷基”包括被芳基取代的低级烷基基团，如苄基、苯乙基、对氟苄基、邻甲苯乙基和间羟基苯乙基。本发明的过程首先涉及在微量金属铜或铜盐的存在下，将公式II的重氮-.beta.-内酰胺与公式III的烯丙基卤化物反应，以在约0°至50°C的温度下诱导重氮-.beta.-内酰胺的分解，提供公式IV的中间体。在本发明这一步骤中可用的重氮-.beta.-内酰胺可以是任何类型的易于移除的酯阻断酸，即公式II的化合物，其中R1是COOR2或腈，即公式II的化合物，其中R1是氰基。优选地，在R1是COOR2的反应中使用苄基或二苄基酯。由于起始化合物的稳定性，公式II的起始材料，其中Y是氧化的硫，是优选的。然而，使用等效硫化物的反应也以良好的产率进行，并避免了随后的脱氧步骤的需要。在本发明中可用的公式III的烯丙基卤化物是那些卤素为碘或溴的，其中碘是最特别优选的。公式III的烯丙基卤化物可以被低级烷基、芳基或芳烷基基团取代。那些R3和R4为甲基或苯基的化合物是优选的。在本发明这一步骤中可用的铜化合物可以是几乎任何铜盐或细分的金属铜。优选地，使用1-10摩尔百分比的铜或铜盐。最优选的催化剂是氯化亚铜和铜(II)-2,4-戊二酸酯。为了最大化本发明这一步骤的产率，优选使用大量过量的公式III的烯丙基卤化物。最优选地，作为反应介质使用烯丙基溴或烯丙基碘。公式III的取代烯丙基卤化物优选地用非极性共溶剂如二氯甲烷稀释。也可以使用极性溶剂，例如二甲基甲酰胺、二甲基亚砜或乙腈，但这些提供较差的产率。反应优选在室温下进行；然而，根据起始材料的性质，反应温度可以从约0°到50°C。偶尔，加热到约40°C以启动反应，然后在没有进一步加热的情况下继续进行。公式IV的中间体在C-6或C-7的立体化学通常是α和β化合物的混合物。一般来说，使用溴化物给出β到α化合物的更高比例，即5到6:1。使用碘化物给出α和β异构体更接近相等的量。步骤2的还原以得到公式I的顺式产物是通过使用三烷基锡烷（三烷基锡烷氢化物）完成的。优选地，使用三正丁基锡烷。将公式IV的中间体在约60°至100°C下与1-2当量的锡烷在惰性溶剂中加热。优选的溶剂是四氢呋喃、苯和甲苯。通常，产品通过色谱法分离，产率超过80%。公式II的化合物，其中Y是氧化的硫原子，可以通过任何常规氧化程序从相应的Y为硫的化合物获得，例如臭氧、碘苯二氯化物在水性吡啶中等。氧化的硫青霉素化合物，即Z为： ##STR6## 可以然后通过各种文献方法转换为相应的头孢菌素，即Y为S且Z为： ##STR7## 例如，参见Flynn，“头孢菌素和青霉素”，学术出版社，第193-199页和670-673页（1972）。通过这些方法，苄基6.β.-烯丙基-6.α.-溴青霉烷酸-1.β.-氧化物可以转换为苄基7.β.-烯丙基-6.α.-溴-3-甲基-3-头孢-4-羧酸酯。当希望将2-和3-头孢化合物混合物转换为纯3-头孢化合物时，亚砜化合物也特别有用。公式II的6-或7-重氮起始材料可以通过各种文献方法或其变体制备。优选的方法涉及通过N-亚硝基衍生物描述的青霉素或头孢菌素侧链的降解，如Hausler和Sigg，Helv. Chim. Acta.,1327（1967）；以及Sheehan，J. Org. Chem.,39,1444（1974）。该过程涉及处理青霉素或头孢菌素，例如苄基青霉素苄基酯或二苄基酯，形成N-亚硝基衍生物，然后在大约40°C的甲基氯仿-吡啶或甲基氯仿中分解亚硝基酰胺侧链，得到重氮化合物。对该过程的改进，省略了吡啶并允许反应在极性溶剂如二甲基亚砜或二甲基甲酰胺中在室温下进行，提供了更清洁的反应和更好的转换，即>90%。该反应序列可以由以下方案表示： ##STR8## 其中Y、Z和R1如前所述。通过这条路线优选的是以下：苄基6-重氮青霉烷酸酯；二苄基6-重氮青霉烷酸酯；6-重氮青霉烷腈；和苄基7-重氮-3-甲基头孢菌酸酯。在制备公式II的起始材料的分解步骤的另一种修改是使用三苯基膦和水代替甲基氯仿和吡啶，根据Sheehan的方法，J. Org. Chem.,42,1012（1977），得到具有以下公式的肼： ##STR9## 根据美国专利第3,880,837号方法氧化此踪可得到所需的重氮化合物。此路线特别适用于本发明中的头孢菌素起始原料。通过此路线可制备以下物质：苯并二氢吡喃-7-重氮-3-甲基头孢菌酸酯；苯并二氢吡喃-7-重氮-3-乙酰氧甲基头孢菌酸酯；以及苯并二氢吡喃-6-重氮青霉烷酸酯。制备公式II中6-或7-重氮化合物的另一种方法涉及使用亚硝酸对相应氨基化合物进行重氮化，该方法最初由Hausler和Sigg在Helv. Chim. Acta.,1327 (1967)中描述，并在J. Amer. Chem. Soc.,94,1408 (1972)和J. Org. Chem.,41,1578 (1976)中进一步详细说明。一旦制备完成，公式I中的化合物可用于制备各种6-或7-取代的β-内酰胺，这些化合物具有有用的抗微生物活性，其中许多已为业界所知。例如，6.β.-(烯丙基)青霉烷腈、苄基6.β.-(烯丙基)青霉烷酸酯或苯并二氢吡喃-6.β.-烯丙基青霉烷酸酯的臭氧化反应分别产生6.β.-(甲酰甲基)青霉烷腈、苄基6.β.-(甲酰甲基)青霉烷酸酯和苯并二氢吡喃-6.β.-(甲酰甲基)青霉烷酸酯。此臭氧化反应按照标准方法进行。前述段落中描述的臭氧化反应得到的醛可以通过使用如硼氢化钠等温和还原剂还原，得到相应的醇。例如，通过此反应可得到6.β.-(2-羟乙基)青霉烷腈、苄基6.β.-(2-羟乙基)青霉烷酸酯和苯并二氢吡喃-6.β.-(2-羟乙基)青霉烷酸酯。前述两种化合物中的酯基当然可以通过标准氢解（通常使用钯催化剂）去除，得到相应的自由酸。使用弱碱（如碳酸钾或碳酸钠）处理，将得到钾盐或钠盐，例如钾6.β.-(2-羟乙基)青霉烷酸酯或钠6.β.-(2-羟乙基)青霉烷酸酯。通过臭氧化反应得到的醛的氧化可以得到相应的羧酸。例如，苯并二氢吡喃-6.β.-(甲酰甲基)青霉烷酸酯在丙酮和水中用铬酸处理，得到苯并二氢吡喃-6.β.-(羧甲基)青霉烷酸酯。上述羧酸与适当的叠氮化物反应可以提供各种同型青霉烷酸酯。例如，苯并二氢吡喃-6.β.-(羧甲基)青霉烷酸酯在约80°C的反应温度下，按照Ninomiya等人（Chem. Pharm. Bull. Japan,22,1398 (1974)）的方法，与二苯基磷酰叠氮和三乙胺反应，得到苯并二氢吡喃-6.β.-(羰基氨基甲基)青霉烷酸酯，该中间体通常不进行分离。将此中间体与所需的酸或醇反应，得到同型青霉烷酸酯，然后可以进行选择性脱保护。通过此方法可得到钾6.β.-(苯乙酰氨基甲基)青霉烷酸酯和钾6.β.-(乙氧羰基氨基甲基)青霉烷酸酯。苯并二氢吡喃-6.β.-(羰基氨基甲基)青霉烷酸酯与三氯乙醇反应后，通过锌/乙酸还原，得到苯并二氢吡喃-6.β.-(氨基甲基)青霉烷酸酯。对此化合物进行常规脱保护，得到6.β.-(氨基甲基)青霉烷酸。Sheehan等人描述了上述几种化合物在德国专利第2,416,492号和第2,643,085号中具有有用和有趣的抗微生物活性。然而，6.β.-(氨基甲基)青霉烷酸在此前未在任何出版物中描述过，因此是一种新化合物。本发明过程中产生的6.β.-(氨基甲基)青霉烷酸具有抗菌活性。此外，它是一种青霉素酶抑制剂，可与其他青霉素类抗生素联合用于感染治疗。因此，在标准微生物学测定中测试时，该化合物对金黄色葡萄球菌、克雷伯菌、枯草杆菌和铜绿假单胞菌等微生物在0.1至100微克/毫升的测试水平上显示出活性。因此，作为抗菌剂，该化合物通常被配制成口服、肌肉注射、静脉注射或局部治疗的形式。因此，本发明包括其范围内的药物组合物，该组合物包含有效量的新6.β.-(氨基甲基)青霉烷酸和兼容的药物载体，以及使用这些组合物治疗微生物感染的方法。该化合物的给药剂量取决于被治疗动物的年龄和体重、给药方式以及预防或减少的细菌感染的类型和严重程度。通常，每日给药剂量将在100-5000毫克范围内，其中500-1000毫克为首选。对于口服给药，该化合物可以制备成片剂、胶囊、糖浆等形式。对于肠胃外给药，它可以制备成用于肌肉注射的溶液或悬浮液。局部制剂包括乳膏、软膏、凝胶等。
• Darstellung einiger substituierter Triphthaloyl-benzole als Ausgangsmaterialien für grüne Küpenfarbstoffe
  作者：H. E. Fierz-David、L. Blangey、W. Von Krannichfeldt

  DOI：10.1002/hlca.19470300317

  日期：1947.4.30

  Durch Kondensation entsprechend substituierter 1,4-Naphtho-chinone mittels Pyridin wurden das α-Trichlor-, α, α′-Hexachlor-, α- und β-Triacetamino- sowie das β-Trimethoxy-triphthaloyl-benzol neu hergestellt.

  通过将适当取代的1，4-萘醌与吡啶缩合，新制备了α-三氯-，α，α'-六氯-，α-和β-三乙酰氨基和β-三甲氧基-三邻苯二甲酰苯。
• Matrix metalloprotease inhibitors
  申请人：Syntex (U.S.A.), Inc.

  公开号：US06013792A1

  公开（公告）日：2000-01-11

  Compounds of formula (I): ##STR1## as single stereoisomers or mixtures thereof and their pharmaceutically acceptable salts inhibit matrix metalloproteases, such as interstitial collagenases, and are useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteases, for example arthritic diseases or bone resorption disease, such as osteoporosis.

  公式（I）的化合物：##STR1##，作为单一立体异构体或其混合物及其药学上可接受的盐，抑制基质金属蛋白酶，如间质胶原酶，并且在治疗通过抑制这种基质金属蛋白酶而缓解的哺乳动物疾病状态中有用，例如关节炎性疾病或骨吸收疾病，如骨质疏松症。
• A European Perspective on Depression in the Community: The DEPRES Study
  作者：Saena Arbabzadeh-Bouchez、Andre Tylee、Jean-Pierre Lépine

  DOI：10.1017/s1092852900017430

  日期：2002.2

  Depression is one of the most prevalent disorders in the general population, causing personal and social disability and impairment. Major studies assessing the diagnosis and management of depression have shown that it is often underdiagnosed and undertreated. A pan-European study aimed at assessing the extent and consequences of depression in six different countries is reported in this article. Different types of depressive profiles are analyzed and their respective management has been compared. The importance of improving diagnosis and treatment of depression is underlined. Appropriate management of depression depends on the recognition of depressive symptoms by patients, their possibility of seeking care, and the ability of the primary care physician to recognize the disorder and prescribe the appropriate medicines. Improvement in all of these fields is necessary.

  摘要抑郁症是普通人群中最常见的疾病之一，会造成个人和社会的残疾和损伤。对抑郁症的诊断和管理进行评估的主要研究表明，抑郁症往往诊断不足、治疗不力。本文报告了一项泛欧研究，旨在评估六个不同国家抑郁症的程度和后果。研究分析了不同类型的抑郁症，并对其各自的治疗方法进行了比较。文章强调了改进抑郁症诊断和治疗的重要性。抑郁症的适当治疗取决于患者对抑郁症状的认识、他们寻求治疗的可能性以及初级保健医生识别疾病和开具适当药物的能力。所有这些领域都需要改进。
• Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
  申请人：D'Sidocky Neil R.

  公开号：US20080242694A1

  公开（公告）日：2008-10-02

  Provided herein are Heterocyclic Compounds having the following structure: wherein R 1 , R 2 , X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.

  本文提供具有以下结构的杂环化合物： 其中R1、R2、X、Y和Z如本文所定义，包含有效量杂环化合物的组合物，以及治疗或预防癌症、炎症性疾病、免疫疾病、代谢性疾病以及通过给予患者需要的有效量杂环化合物来抑制激酶途径治疗或预防的疾病的方法。

表征谱图