沙林 | 107-44-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 中文名称: 沙林
• 中文别名: 甲氟膦酸异丙酯
• 英文名称: O-isopropyl methylphosphonofluoridate
• 英文别名: sarin；2-[fluoro(methyl)phosphoryl]oxypropane
• CAS: 107-44-8
• 化学式: C₄H₁₀FO₂P
• 分子量: 140.094
• InChiKey: DYAHQFWOVKZOOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  8
• 可旋转键数：
  2
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

东京地铁的超过20,000名乘客因战争有毒化学品而中毒。大多数接受检查的患者有明显的小瞳和血清胆碱酯酶活性降低。接触后3天血清CK活性短暂升高是另一个迹象。作者对4名患者的尿液代谢物进行了深入分析。以下分析结果表明接触了沙林以及污染的化合物，如二异丙基甲基膦酸盐（DIMP）、乙基甲基膦酸盐氟化物（EMPF，或乙基沙林）、二乙基甲基膦酸盐（DEMP）和乙基异丙基甲基膦酸盐（EIMP）。(1) 尿液样本中检测到大量异丙醇（IPA）和乙醇（EtOH），认为来源于沙林及其对应物，乙基甲基膦酸盐氟化物、二异丙基甲基膦酸盐、二乙基甲基膦酸盐和乙基异丙基甲基膦酸盐。(2) 单烷基甲基膦酸（异丙基甲基膦酸（IMPA）和乙基甲基膦酸（EMPA））也大量排出，排出模式与异丙醇和EtOH相似。(3) 仅来源于沙林和乙基沙林的代谢物是F阴离子，其尿液中的总排出量低于等摩尔水平的排出量（异丙基甲基膦酸+乙基甲基膦酸+异丙醇+乙醇）。(4) 其他确凿的发现是低致命性：在治疗的超过5,510名患者中，有11人急性死亡。(5) 9名接触的男性姐妹染色单体交换（SCE）率（5.00 + 或 - 1.48/细胞）高于对照组（3.81 + 或 - 0.697/细胞），因为二烷基甲基膦酸盐似乎具有烷基化活性并能产生DNA加合物。淋巴细胞在体外接触二烷基甲基膦酸盐后，姐妹染色单体交换率也增加。

More than 20,000 passengers of Tokyo underground trains were intoxicated with warfare toxic chemicals. Most of the patients examined had marked miosis and decreased serum cholinesterase activity. Transient increase of serum CPK activity after 3 days of the exposure was the another sign. /The authors/ intensively analyzed the metabolites in the urine of 4 patients. The following analytic results indicated the exposure to sarin as well as contaminated compounds such as diisopropyl methylphosphonate (DIMP), ethyl methylphosphonate fluoridate (EMPF, or ethylsarin), diethyl methylphosphonate (DEMP), and ethyl isopropyl methylphosphonate (EIMP). (1) Isopropanol (IPA) and ethanol (EtOH) were detected of large quantities in the urine samples, and were thought to be derived from sarin and the sarin counterpart, ethyl methylphosphonate fluoridate, diisopropyl methylphosphonate, diethyl methylphosphonate and ethyl isopropyl methylphosphonate. (2) Monoalkyl methylphosphonic acids (isopropyl methylphosphonic acid (IMPA) and ethyl methylphosphonic acid (EMPA) also were excreted in large amounts with taking the similar excretion pattern of isopropanol and EtOH. (3) The metabolite only derived from sarin and ethylsarin is F anions whose integral output in the urine was less than the equimolar level of the excreted (isopropyl methylphosphonic acid + ethyl methylphosphonic acid + isopropanol + ethanol). (4) Other corroborative findings were low lethality: of more than 5,510 patients treated, 11 were acutely dead. (5) Nine exposed males had higher sister chromatid exchange (SCE) rate (5.00 + or - 1.48/cell) than the control (3.81 + or - 0.697/cell), because dialkyl methylphosphonates seemed to have alkylating activity and producing DNA adducts. The sister chromatid exchange rate also increased after the in vitro exposure of lymphocytes to dialkyl methylphosphonates.

来源:Hazardous Substances Data Bank (HSDB)

代谢

沙林在人体内的分布、代谢和排泄似乎与在动物身上的发现相似。... 在东京地铁系统恐怖袭击后，人类的尿液中发现了沙林代谢物异丙基甲基膦酸（IMPA）...。/尿液中IMPA或甲基膦酸的峰值水平出现在暴露后10到18小时...。尿液中IMPA的水平与临床症状的程度相关。/也有...证据表明，在12名死于暴露的人中有4人的大脑中分布了沙林。从东京袭击受害者的福尔马林固定的小脑组织中溶解的沙林结合AChE含有沙林水解产物甲基膦酸（MPA）的衍生物。估计的MPA量从0.32到1.13 nmol/g组织不等。尽管没有发现IMPA，但假设IMPA在福尔马林溶液中储存2年后已水解为MPA。

Distribution, metabolism, and elimination of sarin in humans appear to resemble findings in animals. ... The sarin metabolite isopropyl methylphosphonic acid (IMPA) was found in urine of humans after the terrorist attack on the Tokyo subway system... . /There were/ peak levels of IMPA or methylphosphonic acid in urine 10 to 18 hours after exposure ... . The levels of IMPA in urine correlated with the degree of clinical symptoms. /There was/ also ... evidence of distribution of sarin to the human brain in 4 of the 12 people who died after exposure. Solubilized sarin-bound AChE from formalin-fixed cerebellar tissue of victims of the Tokyo attack contained a derivative of the sarin hydrolysis product methylphosphonic acid (MPA). The estimated amounts of MPA ranged from 0.32 to 1.13 nmol/g tissue. Although no IMPA was found, it was assumed that IMPA had hydrolyzed to MPA in the formalin solution over 2 years of storage.

来源:Hazardous Substances Data Bank (HSDB)

代谢

老鼠被注射了75微克/公斤剂量的沙林，并测量了水解代谢物，包括异丙基甲基膦酸和其他甲基膦酸的排泄。尿液排出速度相当快；沙林代谢物在尿液中的终末消除半衰期为3.7±0.1小时。在两天内，几乎所有的沙林剂量都以代谢物的形式从尿液中回收。

... rats /were injected/ sc with a single dose of 75 ug/kg of sarin /and/ excretion of the hydrolyzed metabolites, the alkylmethylphosphonic acids, which include isopropyl methylphosphonic acid and other methylphosphonic acids /was measured/. Urinary elimination was found to be quite rapid; the terminal elimination half-life of sarin metabolites in urine was 3.7 +/- 0.1 hours. Nearly all of the administered dose of sarin was retrieved from the urine in metabolite form after 2 days.

来源:Hazardous Substances Data Bank (HSDB)

代谢

有机磷抗胆碱酯酶剂在体内通过两种酶家族的水解，这两种酶家族被称为羧酸酯酶和过氧化物酶（A-酯酶）。这些酶存在于血浆和肝脏中，通过切断磷酯键、酐键、PF或PCN键，清除或水解大量有机磷化合物。/抗胆碱酯酶剂/

The organophosphorus anti-ChE agents are hydrolyzed in the body by two families of enzymes known as the carboxylesterases and the paraoxonases (A-esterases). The enzymes are found in plasma and liver and scavenge or hydrolyze a large number of organophosphorus compounds by cleaving the phosphoester, anhydride, PF, or PCN bonds. /Anticholinesterase agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

神经毒剂用于恐怖主义目的对民用和军事人口的威胁日益增加，这要求有效的治疗准备。目前，建议使用阿托品和一种肟类化合物，尽管在临床试验中这种治疗的有效性尚未得到证实。在此，监测有机磷(OP)农药的中毒情况可能有所帮助，因为它们的行动与神经毒剂紧密相关，中毒和治疗遵循相同的原则。为此，研究了需要人工通气的患者的临床病程和解毒治疗的有效性，这些患者正在接受阿托品和欧比多辛治疗。然而，OP农药中毒表现出极其异质性的胆碱能危象，常伴有临床并发症。为了获得治疗神经毒剂中毒的有价值信息，必须提取出与神经毒剂中毒情况相似的病例：(a)中毒，形成可重新激活的OP-AChE复合物，OP在体内的持久性短暂，类似于吸入沙林中毒；(b)中毒，迅速形成老化的OP-AChE复合物，类似于吸入梭曼中毒；(c)中毒，形成可重新激活的AChE-OP复合物，OP在体内的持久性延长，类似于经皮的VX中毒。从这些病例中得出结论，如果毒物负荷不是太高，且有效肟类化合物早期且适当持续给药，应该有可能充分重新激活被神经毒剂抑制的非老化AChE.../神经毒剂/

The increasing threat of nerve agent use for terrorist purposes against civilian and military population calls for effective therapeutic preparedness. At present, administration of atropine and an oxime are recommended, although effectiveness of this treatment is not proved in clinical trials. Here, monitoring of intoxications with organophosphorus (OP) pesticides may be of help, as their actions are closely related to those of nerve agents and intoxication and therapy follow the same principles. To this end, the clinical course of poisoning and the effectiveness of antidotal therapy were investigated in patients requiring artificial ventilation being treated with atropine and obidoxime. However, poisoning with OP pesticides shows extremely heterogeneous pictures of cholinergic crisis frequently associated with clinical complications. To achieve valuable information for the therapy of nerve agent poisoning, cases resembling situations in nerve agent poisoning had to be extracted: (a) intoxication with OPs forming reactivatable OP-AChE-complexes with short persistence of the OP in the body resembling inhalational sarin intoxication; (b) intoxication with OPs resulting rapidly in an aged OP-AChE-complex resembling inhalational soman intoxication; (c) intoxications with OPs forming a reactivatable AChE-OP complex with prolonged persistence of the OP in the body resembling percutaneous VX intoxication. From these cases it was concluded that sufficient reactivation of nerve agent inhibited non-aged AChE should be possible, if the poison load was not too high and the effective oximes were administered early and with an appropriate duration.../Nerve agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 副作用

其他毒物 - 有机磷

Other Poison - Organophosphate

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 毒性数据

大鼠LC50 = 150毫克/立方米/10分钟

LC50 (rat) = 150 mg/m3/10min

来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases

毒理性

• 相互作用

进行了一项时间过程研究，以测量暴露于不同剂量沙林和毒扁豆碱的大鼠大脑中乙酰胆碱酯酶（AChE）基因的表达。短期效应研究采用急性单次皮下剂量（s.c.）80微克/千克（0.5 x LD50）沙林。在大脑皮层和小脑中，AChE mRNA表达在2.5小时、24小时和72小时显著下降。生化研究显示，血浆丁酰胆碱酯酶（BChE）和大脑AChE活性在2.5小时显著降低，在两种情况下都在24小时恢复到接近对照组的值。对于长期慢性研究，三组雌性大鼠分别每天肌肉注射（i.m.）毒扁豆碱（0.1毫克/千克/天），皮下注射（s.c.）沙林（15微克/千克/天）独立给药，以及联合剂量毒扁豆碱（i.m.）（0.1毫克/千克/天）随后是沙林（s.c.）（15微克/千克/天），连续给药30天。在大鼠大脑皮层和小脑中观察到30天后的差异AChE mRNA水平，以及在没有进一步给药的另一个30天的滞后期后。在30天的生化研究中，血浆（BChE）和大脑（AChE）显示出不规则的抑制轮廓，在60天后恢复到控制水平。无论是短期还是长期的慢性研究，急性单次皮下给药沙林的实验表明，AChE抑制本身并不导致AChE基因mRNA表达的变化。这些观察结果进一步表明，给药途径以及剂量暴露方案也参与了AChE mRNA表达的调节。

A time-course study was carried out to measure the acetylcholinesterase (AChE) gene expression in the brain of female rats exposed to different doses of sarin and physostigmine. Short-term effects were studied with an acute single subcutaneous dose (s.c.) of 80 ug kg(-1) (0.5 x LD50) sarin. Cortex and cerebellum showed a significant decline in AChE mRNA expression at 2.5, 24 and 72 hr. Biochemical studies showed that plasma butrylcholinesterase (BChE) and brain AChE activities were significantly decreased at 2.5 hr, which came back to near control values by 24 hr in both cases. For long-term chronic studies, three groups of female rats received daily doses of physostigmine (0.1 mg kg(-1) day(-1)) intramuscularly (i.m.), sarin (15 ug kg(-1) day(-1)) s.c. independently and a combined dose of physostigmine (i.m.) (0.1 mg kg(-1) day(-1)) followed by sarin (s.c.) (15 ug kg(-1) day(-1)) continuously for 30 days. Differential AChE mRNA levels in cortex and cerebellum of rat brain were observed after 30 days and after a lag period of another 30 days with no further administration. Plasma (BChE) and brain (AChE) showed irregular inhibition profile in biochemical studies at 30 days and returned to control levels after 60 days. The acute single subcutaneous administration of sarin for short-term as well as chronic long-term studies showed that AChE inhibition alone does not lead to observed changes in mRNA expression of AChE gene. These observations further suggest that route of administration as well as dose exposure regimen also contributes to the regulation of AChE mRNA expression.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

两只豚鼠模型被用来研究地西泮、咪达唑仑和东莨菪碱对由神经毒剂塔崩、沙林、梭曼、环沙林、O-乙基S-(2-(二异丙氨基)乙基)甲基硫代磷酰氧酸盐（VX）和O-异丁基S-(2-二乙氨基)乙基)-甲基磷酰硫代酸盐（VR）诱导的惊厥的抗惊厥效力。在电生理记录的动物在挑战前30分钟预先接受吡啶斯的明溴化物（0.026 mg/kg 肌注）。在模型A中，硫酸阿托品（2.0 mg/kg 肌注）和2-吡啶醛肟甲基氯化物（2-PAM；25.0 mg/kg 肌注）在神经毒剂挑战后1分钟给予，测试的抗惊厥药物在惊厥发作后5分钟给予（肌注）。在模型B中，在神经毒剂挑战后1分钟给予较低剂量的硫酸阿托品（0.1 mg/kg 肌注）和2-PAM，抗惊厥药物在惊厥发作时给予。使用较低剂量的阿托品，所有毒剂的惊厥发生率几乎增加到100%；沙林、环沙林和VX的惊厥发作时间缩短；神经毒剂中毒的症状更严重；并且经常出现由环沙林引起的昏迷。东莨菪碱或地西泮的抗惊厥ED50剂量通常在两个模型之间没有差异，而咪达唑仑的抗惊厥ED50值随着较低阿托品剂量的增加而增加了3到17倍。惊厥终止时间并未系统地受到不同剂量阿托品的影响。在每个模型内，抗惊厥有效性的顺序是东莨菪碱≥咪达唑仑>地西泮。这些发现表明，作为解毒疗法的阿托品剂量可以显著影响神经毒剂毒性和对抗惊厥治疗的反应性。

Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl)methylphosphonothioate (VX), and O-isobutyl S-(2-diethylamino)ethyl)-methyl phosphonothioate (VR). Animals instrumented for electroencephalogram recording were pretreated with pyridostigmine bromide (0.026 mg/kg im) 30 min before challenge with 2 x LD50 (s.c.) of a nerve agent. In model A, atropine sulfate (2.0 mg/kg im) and pyridine-2-aldoxime methylchloride (2-PAM; 25.0 mg/kg im) were given 1 min after nerve agent challenge, and the tested anticonvulsant was given (im) 5 min after seizure onset. In model B, a lower dose of atropine sulfate (0.1 mg/kg im) was given along with 2-PAM 1 min after nerve agent challenge, and the anticonvulsant was given at seizure onset. With the lower dose of atropine, seizure occurrence increased to virtually 100% for all agents; the time to seizure onset decreased for sarin, cyclosarin, and VX; the signs of nerve agent intoxication were more severe; and coma resulted frequently with cyclosarin. The anticonvulsant ED50 doses for scopolamine or diazepam were, in general, not different between the two models, whereas the anticonvulsant ED50 values of midazolam increased 3- to 17-fold with the lower atropine dose. Seizure termination times were not systematically affected by the different doses of atropine. The order of anticonvulsant effectiveness within each model was scopolamine > or = midazolam > diazepam. The findings indicate that the dose of atropine given as antidotal therapy can significantly influence measures of nerve agent toxicity and responsiveness to anticonvulsant therapy.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

血液中沙林的命运是决定沙林有多少能够到达中枢神经系统和其他系统性毒性部位的主要因素。在血液中，沙林首先与几种酯酶相互作用...其中一些酯酶，如对氧磷酶，将沙林水解为无活性的代谢物。另外两种血液酯酶 - 乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BuChE) - 不可逆地与沙林结合。红细胞(RBC)表面的AChE虽然在化学上与神经系统中的AChE无法区分，但其生理功能尚不清楚。这些血液中的酯酶通常被称为“假目标”——通过不可逆地与沙林结合，AChE和BuChE在血液中隔离沙林，从而阻止部分或全部沙林到达中枢神经系统。然而，血液中的酯酶可能被高剂量的沙林所压倒。当红细胞AChE被抑制75到80%时，会发生急性胆碱能综合症。

The fate of sarin in the blood is a major determinant of how much sarin reaches the central nervous system and other sites of systemic toxicity. In the blood, sarin first interacts with several esterases... Some of the esterases, such as paraoxonase, hydrolyze sarin to inactive metabolites. Two other blood esterases - AChE and butyrylcholinesterase (BuChE) - irreversibly bind to sarin. AChE found on the surface of red blood cells (RBCs), although chemically indistinguishable from AChE in the nervous system, has unknown physiological functions. These esterases in the blood are often described as "false targets" - by binding irreversibly to sarin, AChE and BuChE sequester sarin in the blood, thereby preventing some or all from reaching the CNS. However, esterases in the blood can be overwhelmed by high doses of sarin. The acute cholinergic syndrome occurs when RBC AChE is inhibited by 75 to 80 percent

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

一小量（3.21毫克）的液体沙林被涂抹在六个受试者的皮肤上，其中大约98%在空气中回收。在后来的一项更广泛的研究中，注意到了沙林倾向于蒸发而不是渗透皮肤。

A small amount (3.21 mg) of liquid sarin was applied to the skin of six subjects, and about 98% of it was recovered in the air. The tendency of sarin to evaporate rather than to penetrate skin was noted in a later, more extensive study.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

其他人研究了兔、猴和人吸收沙林蒸汽的情况。在兔和猴的鼻腔和喉部，保留率分别为98%和93%，到达终末气道的吸收量很少。在用鼻子呼吸时，人能保留吸入沙林的96%。

Others studied the absorption of sarin vapor in rabbits, monkeys and humans. Retention in the nasal tract and trachea was 98% in rabbits and 93% in monkeys, leaving little to be absorbed in the terminal airways. During nasal breathing humans retained 96% of inhaled sarin.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

最近在豚鼠的研究表明……。肾脏是沙林及其代谢物的主要排泄途径。沙林的尿液排泄速度很快（终末消除半衰期，3.7 +/- 0.1小时）。

A recent study in guinea pigs indicated that ... .The kidneys are the major route of elimination of sarin and its metabolites. Urinary elimination of sarin is rapid (terminal elimination half-life, 3.7 +/- 0.1 hr).

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 储存条件：
  库房应保持低温、通风和干燥，并与食品原料分开存放。

反应信息

• 作为反应物：
  描述：

  沙林 以 异辛烷 、 十二烷 为溶剂， 生成 三聚丙烯
  参考文献：
  名称：

  Measurement of gas phase reactions using automated headspace gaschromatography

  摘要：

  DOI：

  10.1007/bf00811273
• 作为产物：
  描述：

  甲基膦酰氟 生成 沙林
  参考文献：
  名称：

  Lorquet; Vassart, Bulletin des Societes Chimiques Belges, 1959, vol. 68, p. 336,338,341.

  摘要：

  DOI：
• 作为试剂：
  描述：

  (E)-pyrene-1-carbaldehyde O-tert-butyldimethylsilyl oxime 在 四丁基氟化铵 、 沙林 作用下， 以 乙腈 为溶剂， 反应 0.18h， 以99%的产率得到1-芘甲腈
  参考文献：
  名称：

  Detection of Chemical Warfare Nerve Agents via a Beckmann Fragmentation of Aldoxime

  摘要：

  A new (E)-pyrene-1-carbaldehyde O-tert-butyldimethylsilyl oxime 3 was synthesized for the detection of chemical warfare nerve agents, O-isopropyl methylphosphonofluoridate (GB) and O-pinacolyl methylphosphonofluoridate (GD). H-1 NMR spectrum showed that the tert-butyldimethylsilyl (TBDMS) group was deprotected using TBAF and the oximate supernucleophile was made. Upon addition of chemical warfare agents (GB and GD) (50 mol%), the reaction was completely finished within 5 min and also the color change of reaction mixture was observed under a hand-held UV lamp with the naked eye.

  DOI：

  10.1080/10426507.2011.636110

文献信息

• Hydrolysis of toxic organophosphorus compounds by o-iodosobenzoic acid and its derivatives
  作者：Philip S. Hammond、Jeffry S. Forster、Claire N. Lieske、H. Dupont Durst

  DOI：10.1021/ja00202a029

  日期：1989.9

  Hydrolyse des esters trimethyl-1,2,2 propyle et isopropyle de l'acide methyl phosphonofluoridique (soman et sarin respectivement), du N,N-dimethyl phosphoramidocyanidate d'ethyle (tabum) et du (diethyl nitro-4 phenyl) phosphate dans des solutions aqueuses micellaires de chlorure de (palmityl trimethyl) ammonium, en presence d'acide iodosyl-«2» benzoique

  水解酯三甲基-1,2,2 丙基和异丙基甲基磷酰氟（soman 和 sarin 相关），du N,N-二甲基磷酰胺氰化物 d'ethyle (tabum) et du (diethyl nitro-4 phenyl) 磷酸 dans dessolutions aqueuses micelliaires de chlorure de (palmityl trimethyl) 铵, en d'acide iodosyl-«2»benzoique