- A synthetic method of a diazepam drug intermediate 2-chloroacetamido-5-chlorobenzophenone
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A synthetic method of a diazepam drug intermediate that is 2-chloroacetamido-5-chlorobenzophenone is disclosed. The method includes (i) a step of adding 0.09 mol of 2-amino-5-chlorobenzophenone (2) and 300-350 mL of an ethyl acetate solution into a reactor provided with a stirrer, a thermometer, a reflux condenser and a dropping funnel, controlling the stirring speed to be 120-160 rpm and the temperature of the solution to be 27-30 DEG C, adding dropwise 0.11 mol of chloroacetanilide, slowly heating after the addition of the chloroacetanilide is finished, maintaining the temperature of the solution to be 80-85 DEG C, reacting for 4-4.5 h, cooling the solution until the temperature of the solution is 5-8 DEG C, precipitating a yellow crystal, performing suction filtration, washing with ethylenediamine, washing with a salt solution and dehydrating with a dehydrating agent to obtain the 2-chloroacetamido-5-chlorobenzophenone. The mass percentage of the ethyl acetate solution in the step (i) is 80-85%.
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Paragraph 0014; 0015
(2016/11/21)
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- An alprazolam intermediate benzodiazepine preparation process of thione
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The invention relates to a preparation method of benzodiazothioketone serving as an intermediate of alprazolam. The preparation method comprises the following steps: performing a typical acylation reaction, a cyclization reaction and a vulcanization reaction on 2-amino-5-chloro-benzophenone (M2) serving as a raw material to obtain a benzodiazothioketone crude product (the HPLC (High Performance Liquid Chromatography) content is about 94 percent); and recrystallizing the crude product in a mixed solvent at the normal temperature to obtain a fine product of which the HPLC content is over 98.5 percent, wherein the melting point of the fine product is 238-242 DEG C (the melting range is below 3 DEG C). The preparation method has the advantages of small number of synthesis steps, mild process condition, easiness in controlling a refining method, high yield, high fine product content, controllable low production cost, reduction in environmental pollution, and contribution to industrialization.
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Paragraph 0019; 0021; 0022
(2016/10/10)
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- Design, synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential central nervous system antitumor agent
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A series of novel substituted aminobenzophenone derivatives containing nitrogen mustard moiety (5a-f) were synthesized and characterized on the basis of their IR, 1H NMR, 13C NMR, CHN, and mass spectral data. All the compounds when evaluated for chemical 4-(4-nitrobenzyl) pyridine alkylating activity proved to be active alkylating agents. All the synthesized compounds were subjected to physicochemical parameters determination required for central nervous system (CNS) activity through computational, online software, and QikProp 3.2. The log P values and other in silico ADME physicochemical descriptors analyzed lay between the ranges those are required for good BBB penetration. The in vitro antiproliferative activity against human cancer cell lines viz. A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) was investigated. Most of the test compounds showed potent antitumor activity, especially compound (5f) which displayed the highest activity against CNS cancer cell line comparable to that of chlorambucil and docetaxel. The preliminary structure-activity relationship (SAR) revealed that 5-chloroaminobenzophenone-mustard series (5a-c) exhibited better antitumor activity than 5-nitroaminobenzophenone-mustard series (5d-f).
- Singh, Rajesh K.,Prasad,Bhardwaj
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p. 5901 - 5911
(2013/11/06)
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- Synthesis, alkylation activity and physico-chemical evaluation of benzodiazepine linked nitrogen mustard agent to penetrate the blood-brain barrier
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The design of drugs for the chemotherapy of tumours of the central nervous system contains numerous challenges. Most of clinical alkylating anticancer agent, such as nitrogen mustard (mustine) is too polar to cross blood-brain barrier. So it is aimed to link nitrogen mustard to CNS active 1,4-benzodiazepine carrier to obtain CNS active benzodiazepine derivative of nitrogen mustard. The benzodiazepinemustard agent was oily at room temperature and stable when stored at less than 0 °C. Structures of all the synthesized compounds were confirmed by UV, IR and 1H NMR spectroscopy. The in vitro chemical alkylation activity studies (NBP) of benzodiazepine-mustard was comparable to that of N,N-bis-(2-chloroethyl)amino moiety as standard alkylating agent. The log P value of benzo-mustard determined experimentally is significantly higher than nordiazepam. Value of polar surface area for the benzo-mustard agent (35.9 A2) predicts that > 90 % of any amount present in the intestinal tract will be absorbed. The study of some physico-chemical properties calculated by online software such as lipophilicity, log BB (0.295), no. of violation of Lipinski's rule of five (0), number of NH or OH hydrogen bond donors (0) and nON value (4) also indicates that it can be a potential candidate for targeted delivery of nitrogen mustard to the brain for the treatment of brain tumour.
- Singh, Rajesh K.,Prasad, D. N.,Bhardwaj, T. R.
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p. 5605 - 5608,4
(2020/09/15)
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- Synthesis and in vitro anti-hepatitis B virus activities of 4-aryl-6-chloro-quinolin-2-one and 5-aryl-7-chloro-1,4-benzodiazepine derivatives
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A series of 4-aryl-6-chloro-quinolin-2-ones and 5-aryl-7-chloro-1,4-benzodiazepine were synthesized and assayed for their in vitro anti-hepatitis B virus activities and cytotoxicities for the first time. Some of the tested compounds were active against HBsAg and HBeAg secretion in Hep G2.2.15 cells. Compound 5c showed IC50 of 0.074 and 0.449 mM on HBsAg and HBeAg secretions, respectively, which were 10 times higher than that of its analog 4c and led to better selective index (SI) values (SI = 23.2 and 3.4, respectively).
- Cheng, Pi,Zhang, Quan,Ma, Yun-Bao,Jiang, Zhi-Yong,Zhang, Xue-Mei,Zhang, Feng-Xue,Chen, Ji-Jun
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supporting information; experimental part
p. 3787 - 3789
(2009/04/06)
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- Efficient synthesis of 3-hydroxy-1,4-benzodiazepines oxazepam and lorazepam by new acetoxylation reaction of 3-position of 1,4-benzodiazepine ring
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Simple, efficient, and scalable syntheses of 3-hydroxy-1,4-benzodiazepines, oxazepam (1), and lorazepam (2) were developed. The syntheses are based on the new acetoxylation reaction of the 3-position of the 1,4-benzodiazepine ring. The reaction involves iodine (20-50 mol %)-catalyzed acetoxylation in the presence of potassium acetate (2 equiv) and potassium peroxydisulfate (1-2 equiv) as a stoichiontetric oxidant affording the corresponding 3-acetoxy-1,4- benzodiazepines in good-to-high yields. The latter were converted by selective saponification to 3-hydroxy-1,4-benzodiazepines of very high purity (>99.8%) in an overall yield of 83% (oxazepam) and 64% (lorazepam).
- Cepanec, Ivica,Litvic, Mladen,Pogorelic, Ivan
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p. 1192 - 1198
(2012/12/23)
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- NOVEL 3-SUBSTITUTED-1,4-BENZODIAZEPINES
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The present invention relates to compounds of formula (I). The invention also relates to methods for preparing the compounds and their uses as CCK receptor ligands and CCK antagonists.
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- New syntheses of 2-alkylthio-4-oxo-3,4-dihydroquinazolines, 2-alkylthioquinazolines, as well as their hetero analogues
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N-Chloroacetylanthranilic acid ethyl ester reacts with potassium thiocyanate in the presence of alcohol to give the (4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)acetic acid ester (3a). In the presence of water or amines the acetic acid derivative (3b) or the acetamide derivatives (3c,d) are obtained. 2-Amino-4-oxo-3,4-dihydroquinazolines (4) arise if vigorous reaction conditions are employed. Analogously, N-chloroacetyl derivatives of 5-membered heterocycles with enaminocarbonyl structure (5, 7, 9, 11, 13, 20, 23) react with potassium thiocyanate to yield thieno[2,3-d]-, thieno[3,2-d]-, imidazo[4,5-d]-, pyrrolo[3,2-d]-, and thiazolo[4,5-d]pyrimidines (6, 8, 10, 12, 14, 21, 24). Quinazolines (18, 19) are formed from the reaction of 2-chloroacetylaminoacetophenone (16a) and 2-chloroacetylaminobenzophenone (16b) with potassium thiocyanate and subsequent treatment of the intermediates with amines.
- Gruner, Margit,Rehwald, Matthias,Eckert, Katrin,Gewald, Karl
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p. 2363 - 2377
(2007/10/03)
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- 3-amino-2(1H)-quinolones by cyclization of N-acylated anthranilic acid derivatives
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Reaction of secondary amines with the N-(iodoacetyl)anthranilic acid derivatives, 2-(iodoacetylamino)acetophenone and 2-(iodoacetylamino)benzophenone yields 3-amino-2(1H)-quinolones in two steps. Analogously heterocondensed 5-amino-6(7H)-pyrazolo[5,4-b]pyridoues were prepared. Hydroxyquinolines were subjected to Cl/OH exchange to give chloroquinolines, which are convenient for consecutive reactions.
- Rehwald, Matthias,Gewald, Karl,Lankau, Hans-Joachim,Unverferth, Klaus
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p. 483 - 492
(2007/10/03)
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- Process for preparing 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide and intermediates therefor
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A process is described for the preparation of 6-chloro-2-chloromethyl-4-phenylquinazoline-3-oxide, a key intermediate in the synthesis of the known useful psychotherapeutic agents: chlorodiazepoxide and diazepam. This intermediate is prepared by the cyclization of 2-(1'-chloroimino-2'-chloromethyl)-5-chlorobenzophenone, itself a new compound. This compound in turn is prepared by the chloroacetylation of 2-amino-5-chlorobenzophenone to 2-chloroacetamido-5-chlorobenzophenone, another novel compound, and subsequent iminochloride formation.
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