- Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagents
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Abstract: In this research, two improved and scalable methods for the synthesis of midazolam and its analogues have been described. Midazolam has been synthesized using isocyanide reagents in satisfactory yield. In this methodology, imidazobenzodiazepine intermediates can be easily prepared via an improved process. One-pot condensation of benzodiazepines with mono-anion of tosylmethyl isocyanide or ethyl isocyanoacetate under mild condition led to formation of imidazobenzodiazepine. In the first method, tosylmethyl isocyanide (Tos-MIC) is used and the number of synthetic steps are decreased in comparison to previous report. In the second method, ethyl isocyanoacetate which is commonly used for the synthesis of some imidazobenzodiazepines, is consumed to generate midazolam. The latter, a relatively different method for the synthesis of midazolam analogues has been reported. Graphical abstract: [Figure not available: see fulltext.].
- Taghizadeh, Mohammad Javad,malakpouri, Gholam reza,Javidan, Abdollah
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p. 785 - 794
(2019/03/27)
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- Synthesis 4 H - imidazo [1, 5 - a] [1, 4] the benzene two nitrogen are outstanding, especially midazolam method
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The invention relates to a method for preparation of 4H-imidazo[1, 5-a][1, 4]benzodiazepine, especially midazolam through a selective decarboxylation reaction of formula (VII) with a DBU (1,8-diazabicyclo[5.4.0.]-undec-7-ene) novel catalyst in an NMP (N-methyl pyrrolidone) solvent. According to the invention, isomerization of 4H-imidazo[1, 5-a][1, 4]benzodiazepine is avoided, the midazolam synthesis yield is enhanced, and the post-treatment difficulty is reduced.
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Paragraph 0029; 0030; 0032; 0033
(2017/10/22)
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- Benzodiazepines method for the preparation of compound
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The invention relates to a method for preparing benzodiazepine compounds, and discloses a method for preparing 8-R2-6-(2-R1-phenyl)-1-methyl-3a,4-dihydro-3H-imidazo[1,5-a][1,4] benzodiazepine (midbody II) and 8-R2-6-(2-R1-phenyl)-1-methyl-4H-imidazo[1,5-a][1,4] benzodiazepine (product III), wherein R is hydrogen, fluorine, chlorine, bromine or iodine; R2 is fluorine, chlorine, bromine or iodine. The midbody II is prepared from 7-R2-5-(2-R1-phenyl)-2-aminomethyl-2,3-dihydro-1H-[1,4] benzodiazepine and triethyl orthoacetate as raw materials through ultrasonic reaction; the product III is prepared by performing enzyme dehydrogenation on the midbody II. By adopting the technical scheme of the invention, the dehydrogenation reaction selectivity is improved, and the reaction yield is improved.
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Paragraph 0057; 0058; 0059
(2016/10/08)
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- PROCESS FOR THE SYNTHESIS OF 4H-IMIDAZO [1,5-a] [1,4] BENZODIAZEPINES, IN PARTICULAR MIDAZOLAM AND SALTS THEREOF
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The present invention refers to a process for the preparation of 4H-imidazo[1,5-a][1,4]benzodiazepines, in particular Midazolam, through an efficient and selective decarboxylation reaction of the derivative compound of the 5-aminomethyl-1-phenyl-1H-imidazole-4-carboxylic acid of formula (II) avoiding the formation of the 6H-imidazo[1,5-a][1,4]benzodiazepines by-products and the ensuing process for the isomerisation of a 4H-imidazo[1,5-a][1,4]benzodiazepine product.
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Page/Page column 6
(2011/11/13)
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- Process for the synthesis of 4H-imidazo[1,5-a][1,4]benzodiazepines, in particular midazolam and salts thereof
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The present invention refers to a process for the preparation of 4H-imidazo[1,5-a] [1,4]benzodiazepines, in particular Midazolam, through an efficient and selective decarboxylation reaction of the derivative compound of the 5-aminomethyl-1-phenyl-1H-imidazole-4-carboxylic acid of formula (II) avoiding the formation of the 6H-imidazo[1,5-a][1,4]benzodiazepines by-products and the ensuing process for the isomerisation of a 4H-imidazo[1,5-a][1,4]benzodiazepine product.
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Page/Page column 11
(2012/01/06)
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- PROCESS FOR PRODUCING HIGHLY PURE MIDAZOLAM AND SALTS THEREOF
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Provided is a process for producing highly pure midazolam and salts thereof, and a pharmaceutical composition containing the highly pure midazolam and/or a salt thereof.
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Page/Page column 5-6
(2009/04/24)
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- Reactions of 1,4-benzodiazepinic N-nitrosoamidines with tosylmethyl isocyanide: A novel synthesis of midazolam
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Reaction of 1,4-benzodiazepinic N-nitrosoamidines, used as synthetic equivalents of imidoyl chlorides, with the monoanion of tosylmethyl isocyanide is described. The process gives entry to 3-(4-tosyl)imidazo[1,5-a][1,4] benzodiazepines, compounds which have not been described yet in the literature. These systems can be derivatized to the corresponding trisubstituted 1,4-benzodiazepines by alkylation or acylation of the imidazole ring. These new heterocyclic derivatives are potentially useful in the field of medicinal chemistry. In addition, midazolam 3, the anesthetic properties of which are well established, can be easily prepared in one step by desulfonylation of compound 7a.
- Del Pozo, Carlos,Macias, Alberto,Alonso, Eduardo,Gonzalez, Javier
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p. 2697 - 2703
(2007/10/03)
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- Cyclodextrin complexes of benzodiazepines
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Methods for enhancing the complexation efficiency of a drug with cyclodextrin and for enhancing the availability of a drug following administration of a cyclodextrin-drug complex.
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Page/Page column 17-18
(2008/06/13)
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- Process for the preparation of Midazolam
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The present invention provides a process for the synthesis of Midazolam I from a compound of formula II, using thermodynamic, basic workup conditions. Additional steps to isolate the pure bulk product follow.
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- Process for the preparation of midazolam
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The present invention provides a process for the synthesis of compounds of formula (II) or pharmaceutically acceptable salts thereof.
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- Process to produce midazolam
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The present invention discloses new processes in the preparation of midazolam (VII), STR1 a commercially important pharmaceutical, as well a new intermediates in those processes from a known benzophenone (I) starting material.
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- Quinazolines and 1,4-benzodiazepines. XCIII. (1). Synthesis of imidazo[1,5-a][1,4]benzodiazepines from nitrooximes
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The displacement of the nitro group in nitrooximes by other nucleophiles was used to prepare various 2-(hydroxyimino)methyl- and 2-(methoxyimino)methyl-1,4-benzodiazepines. These compounds were converted to imidazo[1,5-α][1,4]benzodiazepines bearing a tertiary amine, methoxy or thiomethyl group in the 3-position.
- Walser,Ian Fryer
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p. 551 - 558
(2007/10/02)
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- Imidazodiazepines and processes therefor
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Novel Imidazobenzodiazepines and their analogs are useful as anticonvulsants, muscle relaxant, anxiolytic and sedative agents. Preferred compounds of this class belong to the imidazo[1,5-a][1,4]diazepine series which may have a very wide variety of organic substituents. An especially preferred genus included within the purview of the invention encompasses a compound of the formula STR1 wherein R1 is hydrogen and lower alkyl preferably methyl; R3 and R5 are hydrogen; R4 is hydrogen, nitro and halogen, most preferably, chlorine, and in a most preferred embodiment when positioned on the fused benzo portion of the imidazobenzodiazepine is in the 8-position thereof, R6 is phenyl or halo, nitro, or lower alkyl-substituted phenyl, preferably, halo, with fluorine being the preferred halogen, the substituted fluoro being positioned in the 2-position of the phenyl moiety and R2 is hydrogen and lower alkyl.
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- 2-[[2-Methyl-1-[2-benzoyl(or benzyl)phenyl]-1H-imidazol-5-yl]methyl]-1H-isoindole-1,3(2H)-diones
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A multistep process is presented for the preparation of imidazobenzodiazepines of the formula STR1 wherein X and Y are selected from the group consisting of hydrogen, halogen and trifluoromethyl. Also presented are novel intermediates utilized in the process. The end products are useful as sedatives, anxiolytics, muscle relaxants and anticonvulsants. The end products are especially useful in intravenous compositions for use in preoperative anesthesia.
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