制备方法

以对氯苯胺为原料,经邻氟苯甲酰氯酮化。氯乙酰氯酰化,然后与乌洛托品环合,再感情盐酸二乙氨基氯乙烷缩合成盐制得氟安定盐酸盐。1.酮化将对氯苯胺51g,氯化锌70g,邻氟苯甲酰氯140g投入反应瓶中,缓缓加热至200℃,反应2h,用硫酸水解40min,缓缓加热反应物倾入冰水中,经处理得2-氨基-5-氯-2'氟二苯甲酮(C13H9CIFNO)。熔点℃收率50%。2.氯乙酰化将酮化产物50g,冰醋酸150ml投入反应瓶内,加热至50℃,缓缓加入氯乙酰氯34g,反应2h。冷却过滤,得2-氯乙酰氨基-5-氯2'-氟二苯甲酮,熔点138-141℃,收率80%。3.环合将氯乙酰化产物16.3g,无水乙醇150ml,乌洛托品15.9g,氯化铵13.4g加入反应瓶内,回流反应10h,蒸去乙醇,得7-氯-5-(2-氟苯基)-1,3-二氢-1,4-苯并二氮杂-2-酮,熔点202-206℃,收率70-75%。4.缩合,成盐将环合产物43.3g,二氯乙烷300ml,氢氧化钟21g和二乙氨基氯乙烷盐酸盐31g加入反应瓶中,回流反应2h,减压浓缩,将残余物溶于甲醇-氯晶,即为氟安定盐酸盐,熔点194-210℃(分解),收率50-55%。

合成制备方法

以对氯苯胺为原料，经邻氟苯甲酰氯酮化。氯乙酰氯酰化，然后与乌洛托品环合，再感情盐酸二乙氨基氯乙烷缩合成盐制得氟安定盐酸盐。1.酮化将对氯苯胺51g，氯化锌70g，邻氟苯甲酰氯140g投入反应瓶中，缓缓加热至200℃，反应2h，用硫酸水解40min，缓缓加热反应物倾入冰水中，经处理得2-氨基-5-氯-2'氟二苯甲酮（C13H9CIFNO）。熔点℃收率50%。2.氯乙酰化将酮化产物50g，冰醋酸150ml投入反应瓶内，加热至50℃，缓缓加入氯乙酰氯34g，反应2h。冷却过滤，得2-氯乙酰氨基-5-氯2'-氟二苯甲酮，熔点138-141℃，收率80%。3.环合将氯乙酰化产物16.3g，无水乙醇150ml，乌洛托品15.9g，氯化铵13.4g加入反应瓶内，回流反应10h，蒸去乙醇，得7-氯-5-（2-氟苯基）-1，3-二氢-1，4-苯并二氮杂-2-酮，熔点202-206℃，收率70-75%。4.缩合，成盐将环合产物43.3g，二氯乙烷300ml，氢氧化钟21g和二乙氨基氯乙烷盐酸盐31g加入反应瓶中，回流反应2h，减压浓缩，将残余物溶于甲醇-氯晶，即为氟安定盐酸盐，熔点194-210℃（分解），收率50-55%。

用途简介

该品为非巴比妥类催眠镇压静药,基肌肉松驰作用和抗惊作用与利眠宁相似,催眠作用比利眠宁,安定强,对短期或长期失眠症疗效显著,毒性较小,成瘾性较小。雄小鼠口服LD50为1450mg/kg,雌小鼠口服LD50为1300mg/kg。

用途

该品为非巴比妥类催眠镇压静药，基肌肉松驰作用和抗惊作用与利眠宁相似，催眠作用比利眠宁，安定强，对短期或长期失眠症疗效显著，毒性较小，成瘾性较小。雄小鼠口服LD50为1450mg/kg，雌小鼠口服LD50为1300mg/kg。

包装等级：

III

风险类别：

6.1(b)

危险类别码：

22-33

安全标志：

S22:不要吸入粉尘。
S36:穿戴合适的防护服装。
S1/2:保持密封，保存在远离儿童的地点。

危险标志：

Xn: Harmful;

CHEMICAL IDENTIFICATION

RTECS NUMBER :

DF2368050

CHEMICAL NAME :

2H-1,4-Benzodiazepin-2-one, 1,3-dihydro-7-chloro-1-(2-(diethylamino)ethyl)-5-(o- fluorophenyl)-

CAS REGISTRY NUMBER :

17617-23-1

BEILSTEIN REFERENCE NO. :

0767925

LAST UPDATED :

199612

DATA ITEMS CITED :

13

MOLECULAR FORMULA :

C21-H23-Cl-F-N3-O

MOLECULAR WEIGHT :

387.92

WISWESSER LINE NOTATION :

T67 GNV JN IHJ CG G2N2&2 KR BF

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human

DOSE/DURATION :

380 ug/kg

TOXIC EFFECTS :

Lungs, Thorax, or Respiration - dyspnea Lungs, Thorax, or Respiration - other changes

REFERENCE :

AJMEAZ American Journal of Medicine. (Technical Pub., 875 Third Ave., New York, NY 10022) V.1- 1946- Volume(issue)/page/year: 73,239,1982

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

980 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 14,637,1977

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

600 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 14,637,1977

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>3844 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 14,637,1977

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

38700 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 6,530,1975

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

500 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

THERAP Therapie. (Doin, Editeurs, 8, Place de l'Odeon, F-75006 Paris, France) V.1- 1946- Volume(issue)/page/year: 26,439,1971

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

540 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 14,637,1977

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

3844 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 14,637,1977

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

59100 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 6,530,1975

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - cat

DOSE/DURATION :

250 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

DRFUD4 Drugs of the Future. (J.R. Prous, S.A., Apartado de Correos 540, 08080 Barcelona, Spain) V.1- 1975/76- Volume(issue)/page/year: 9,152,1984 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

12 gm/kg/30D-C

TOXIC EFFECTS :

Liver - changes in liver weight Kidney, Ureter, Bladder - changes in bladder weight Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :

OYYAA2 Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- Volume(issue)/page/year: 14,637,1977 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

504 mg/kg

SEX/DURATION :

female 1-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - behavioral

REFERENCE :

PLRCAT Pharmacological Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1969- Volume(issue)/page/year: 9,325,1977 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X6124 No. of Facilities: 25 (estimated) No. of Industries: 1 No. of Occupations: 2 No. of Employees: 3703 (estimated) No. of Female Employees: 3592 (estimated)

毒理学数据：

急性毒性：大鼠口经LD50： 980 mg/kg；大鼠腹腔LD50： 600 mg/kg；大鼠静脉LD50： 38700 ug/kg；小鼠口经LD50： 500 mg/kg；小鼠腹腔LD50： 540 mg/kg；小鼠静脉LD50： 59100 ug/kg

分子结构数据

1、   摩尔折射率：107.60

2、   摩尔体积（m³/mol）：319.0

3、   等张比容（90.2K）：808.4

4、   表面张力（dyne/cm）：41.2

5、   极化率（10^-24cm³）：42.65

计算化学数据

1.疏水参数计算参考值（XlogP）:无

2.氢键供体数量:0

3.氢键受体数量:4

4.可旋转化学键数量:6

5.互变异构体数量:2

6.拓扑分子极性表面积35.9

7.重原子数量:27

8.表面电荷:0

9.复杂度:540

10.同位素原子数量:0

11.确定原子立构中心数量:0

12.不确定原子立构中心数量:0

13.确定化学键立构中心数量:0

14.不确定化学键立构中心数量:0

15.共价键单元数量:1