三唑巴坦

三唑巴坦用途

【用途一】
青霉烷砜类β-内酰胺酶抑制剂，对I～Ⅵ型3-内酰胺酶均有效，特别是对I型酶更为有效。其毒性低，稳定性好，抑酶活性强。临床用于治疗多种细菌包括需氧菌和厌氧菌引起的感染，包括下呼吸道感染、皮肤和腹部感染等。
【用途二】
β-内酰胺酶抑制剂，第三代抗菌强增效剂，与哌拉西林或头孢哌酮合用可增强二者的药效及延长作用时间。他唑巴坦钠与哌拉西林钠联合使用时，产生明显的协同作用，广泛用于治疗严重全身性和局部感染、腹腔感染、下呼吸道感染、软组织感染、败血症等，比已使用的其它抗菌复合剂具有更广泛的抗菌谱及适应症，克服耐药性显示了巨大优势。

三唑巴坦名称

[ CAS 号 ]:
89786-04-9

[ 中文名 ]:
他唑巴坦

[ 英文名 ]:
Tazobactam

[中文别名 ]:

[英文别名 ]:

MFCD00867002
YTR 830H
Tazobactam
UNII-SE10G96M8W
TAZOBACTANACID
YTR-830H
Tazobactan acid

三唑巴坦生物活性

[ 描述 ]:

Tazobactam是一种β-内酰胺酶抑制剂, 具有抗菌活性。

[ 相关类别 ]:

信号通路 >> 抗感染 >> 细菌

研究领域 >> 感染

[相关活性小分子]

三唑巴坦物理化学性质

[ 密度 ]:
1.9±0.1 g/cm3

[ 沸点 ]:
707.1±70.0 °C at 760 mmHg

[ 熔点 ]:
172 °C(dec.)

[ 分子式 ]:
C₁₀H₁₂N₄O₅S

[ 分子量 ]:
300.291

[ 闪点 ]:
381.4±35.7 °C

[ 精确质量 ]:
300.052826

[ PSA ]:
130.84000

[ LogP ]:
-1.70

[ 外观性状 ]:
白色或灰白色粉末

[ 蒸汽压 ]:
0.0±2.4 mmHg at 25°C

[ 折射率 ]:
1.818

[ 储存条件 ]:
Store at?0-5°C

[ 水溶解性 ]:
水溶性：实际上不溶；可溶于：二甲基甲酰胺；极微溶：乙醇,甲醇

三唑巴坦毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: XI0191400

CHEMICAL NAME :: 4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3-methyl-7-oxo-3-(1H-1,2,3-triazol-1- ylmethyl)-, 4,4-dioxide, (2S-(2-alpha,3-beta,5-alpha))-

CAS REGISTRY NUMBER :: 89786-04-9

LAST UPDATED :: 199612

DATA ITEMS CITED :: 12

MOLECULAR FORMULA :: C10-H12-N4-O5-S

MOLECULAR WEIGHT :: 300.32

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Sense Organs and Special Senses (Olfaction) - effect, not otherwise specified Gastrointestinal - hypermotility, diarrhea

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression Gastrointestinal - hypermotility, diarrhea

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Sense Organs and Special Senses (Eye) - ptosis Behavioral - somnolence (general depressed activity) Skin and Appendages - dermatitis, other (after systemic exposure)

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Sense Organs and Special Senses (Eye) - ptosis Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity)

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Sense Organs and Special Senses (Eye) - ptosis Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Skin and Appendages - dermatitis, other (after systemic exposure)

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression Nutritional and Gross Metabolic - body temperature decrease

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Lungs, Thorax, or Respiration - dyspnea Gastrointestinal - hypermotility, diarrhea Kidney, Ureter, Bladder - hematuria

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),145,1994 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 14560 mg/kg/26W-I

TOXIC EFFECTS :: Liver - changes in liver weight Blood - pigmented or nucleated red blood cells Blood - changes in erythrocyte (RBC) count

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),155,1994

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 29120 mg/kg/26W-I

TOXIC EFFECTS :: Biochemical - Metabolism (Intermediary) - other proteins Related to Chronic Data - changes in ovarian weight Related to Chronic Data - changes in uterine weight

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),177,1994 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intraperitoneal

DOSE :: 33288 mg/kg

SEX/DURATION :: female 17-21 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Effects on Newborn - stillbirth

REFERENCE :: JTSCDR Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- Volume(issue)/page/year: 19(Suppl 2),233,1994

三唑巴坦安全信息

[ 危害码 (欧洲) ]:
Xi: Irritant;

[ 风险声明 (欧洲) ]:
R36/37/38

[ 安全声明 (欧洲) ]:
S26-S36/37/39-S45

[ 危险品运输编码 ]:
UN 1770 8/PG 2

[ WGK德国 ]:
3

[ 包装等级 ]:
II

[ 危险类别 ]:
8

[ 海关编码 ]:
29036990

三唑巴坦合成路线

详细合成路线

三唑巴坦上下游产品

三唑巴坦上游产品

三唑巴坦下游产品

三唑巴坦制备

方法1：以舒巴克坦为原料，经酯化保护羧基，再和叠氮钠反应，在3位的一个甲基上引入叠氮基。和乙酸乙烯酯反应，形成三唑化合物，最后氢解脱去保护基，得到三唑巴坦。

方法2：以6-APA为原料，经重氮化、溴化，在6位引入溴。过氧乙酸氧化，再酯化后，在锌的作用下脱去溴。然后和三甲基硅基三唑化合物反应，引入三唑化合物，高锰酸钾氧化，最后水解得三唑巴坦钠。

方法3:(1) 6a-溴青霉烷-3a-羧酸(012-1)的制备

在反应瓶中加2.5mol/L硫酸500ml,,搅拌下冷却到约10ºC,加入6-氨基青霉烷酸(6-APA)43.2g(0.2mol)和溴化钾120.2g,然后再加入95%乙醇400ml,将混合物冷却到6-8ºC,滴加亚硝酸钠21.2g溶于水100ml的溶液,在1h内滴加完#保持混合物温度在6-8ºC搅拌3.5h反应毕,用氯仿(2*250ml,4*100ml,3*50ml)提取,合并氯仿层,用50%冷盐水(2*250ml)洗,无水硫酸钠干燥,过滤,滤液浓缩,得到012-1黏稠泡沫状物49.96g,收率89%.
(2)6a-溴青霉烷-3a-羧酸二苯甲酯-1B-氧化物(012-2)的制备

在反应瓶中加入012-1 22.4g(0.08mol)、二苯腙17.5g(0.09mol）和氯仿200ml,搅拌溶解,再加入
80%甲酸3.90g(0.072mol)和30%双氧水10.6g(0.094mol),冷却到5ºC加入90%多聚磷酸(H6P4O13)3.75g(0.01mol),搅拌4h,TLC监控012-1基本消失.反应液用2.8%碳酸氢钠和1.7%亚硫酸氢钠溶液(3*40ml)洗,水洗(2*40ml)至中性,无水硫酸钠干燥,过滤,滤液减压下蒸除溶剂,加入环己烷/乙酸乙酯(8:1)150ml,白色固体过滤抽干,干燥,得012-2 30.33g收率80%,mp148~150ºC.

(3)青霉烷-3a-羧酸二苯甲酯-1B-氧化物(012-3)的制备
在反应瓶中加入(012-2)33.58g(0.0726mol)和
THF180ml,搅拌溶解,再加入乙酸铵溶液(22.78g溶于水182ml),分批加入锌粉15(0.237mol),室温搅拌反应1h后,TLC监控012-2消失,减压蒸除THF,加入乙酸乙酯200ml提取,提取液用饱和氯化钠溶液100ml洗至中性,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,加入环己烷-乙酸乙酯(8:1)150ml,析出白色固体,过滤,干燥,得012-3 22.3g,收率80.1%,mp149~151ºC.

(4)2a-甲基-2B-(1,2,3-三唑-1-基)甲基青霉烷-3a-羧酸二苯甲酯(012-4)的制备

在微型压热釜中加入012-3 19.2g(0.05mol)、2-三甲基硅-1，2，3-三唑7.2（0.051mol）和甲苯180ml,搅拌(或振摇)下通入氮气排去釜内空气,充氮密闭,加热至116~120 ºC反应4h.冷却,取出反应液蒸除甲苯(减压下),剩余物用乙酸乙酯250ml提取，水（8ml）洗,氯化钠溶液(80ml)洗,无水硫酸钠干燥,过滤,滤液减压蒸除溶剂,剩余物用乙醇重结晶,得012-4白色固体12.1g,收率55.7%,mp140~142 ºC

2-三甲基硅-1,2,3-三唑按文献[8]法制得,该化合物为无色油状物,经溶剂结晶mp147~148 ºC

(5).2a-甲基-2B-(1,2,3-三唑-1-基)甲基青霉烷-3a-羧酸二苯甲酯1,1-二氧化物(012-5)的制备

在反应瓶中加入012-4 10.86g(0.025mol)和丙酮10ml,搅拌,加水23ml和冰醋酸32ml,冷却至0~5 ºC ,再加入高锰酸钾7.9g(0.05mol),室温搅拌反应3h.滴加30%双氧水至反应液无色,过滤析出固体,甲醇重结晶,得白色固体10.5g(012-5),收率90%.mp205~207 ºC

(6).他唑巴坦(012)的合成

在反应瓶中加入012-5 10.5g(0.0225mol)与间甲基苯酚85ml,拌均匀,加热到80 ºC 保持反应3h反应毕,冷却至室温,用甲基异丁基酮80ml溶解,用20%碳酸氢钠水溶液洗,分出水层,冷却至0~5 ºC ,用6mol/L盐酸调PH至1.8，析出固体过滤收集，水洗（冰水），丙酮洗抽干，干燥，得白色粉末结晶012 5.6g,mp136~138 ºC .收率82.3%.

将他唑巴坦(012)溶于乙酸乙酯,加入异辛酸钠的乙酸乙酯溶液,搅拌#过滤,乙酸乙酯洗,干燥,得他唑巴坦钠,收率85.7%,mp167~169 ºC (分解).含量98.6%.

三唑巴坦海关

[ 海关编码 ]: 29036990