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Method for preparing lorazepam

The technology of lorazepam and crystallization is applied in the field of preparation of benzodiazepine drugs lorazepam, and can solve the problems of affecting the long-term storage and transportation of preparations, being unstable when exposed to light, and being low in oral bioavailability of the drug.

Pending Publication Date: 2020-02-11
HUNAN DONGTING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is known that the melting point of lorazepam is almost insoluble in water. It is reported that the solubility in water is only 0.08 mg / ml, and the melting point of the crystals is 166-168 ° C. It is unstable when exposed to light. These properties bring challenges to the formulation of drugs, such as Low solubility usually leads to problems such as low oral bioavailability of the drug, and the stability of the API will not only affect the preparation of pharmaceutical preparations, but also affect the long-term storage and transportation of the preparations

Method used

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  • Method for preparing lorazepam
  • Method for preparing lorazepam
  • Method for preparing lorazepam

Examples

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Embodiment 1

[0069] Embodiment 1: Preparation of lorazepam

[0070] Step 1, acetoxylation reaction prepares the acetoxy compound of formula II

[0071] Add 1 mol (305 g) of the ketone base of formula I, 14 mol of glacial acetic acid, 2.5 mol of potassium acetate, 1.8 mol of potassium persulfate, and 2.5 mol of iodine into the reaction flask, stir at 80°C to react for 7 hours, then distill under reduced pressure at 65°C Remove the acid solution; then add ethyl acetate (4 times the amount of the ketone base), 5% sodium thiosulfate solution (6 times the amount of the ketone base) in the reaction flask, stir for 25 minutes, let stand layer; collect the organic layer, extract the aqueous layer twice with ethyl acetate, combine the organic layers, add 1.25 times the volume of saturated sodium chloride solution therein, stir for 25 minutes, let stand to separate the layers, and separate the organic layer; the organic layer Add medicinal charcoal (0.75%), stir and decolorize at 65°C for 25 minu...

Embodiment 2

[0076] Embodiment 2: Preparation of lorazepam

[0077]Step 1, acetoxylation reaction prepares the acetoxy compound of formula II

[0078] Add 1 mol (305 g) of ketones of formula I, 15 mol of glacial acetic acid, 2 mol of potassium acetate, 2 mol of potassium persulfate, and 2 mol of iodine into the reaction flask, stir at 70°C to react for 8 hours, then distill off the acid solution at 70°C under reduced pressure Then add ethyl acetate (3 times of the ketone-based charging capacity), 5% sodium thiosulfate solution (7 times of the ketone-based charging capacity) in the reaction flask, stir for 20 minutes, leave standstill and make layering; collect Extract the organic layer and the aqueous layer twice with ethyl acetate, combine the organic layers, add 1 times the volume of saturated sodium chloride solution to it, stir for 20 minutes, let stand to separate the layers, and separate the organic layer; the organic layer is used for medicinal purposes Charcoal (0.5%), stirred a...

Embodiment 3

[0083] Embodiment 3: Preparation of lorazepam

[0084] Step 1, acetoxylation reaction prepares the acetoxy compound of formula II

[0085] Add 1 mol (305 g) of ketones of formula I to the reaction flask, 12 mol of glacial acetic acid, 3 mol of potassium acetate, 1.5 mol of potassium persulfate, and 3 mol of iodine, stir at 90°C to react for 6 hours, then distill off the acid at 60°C under reduced pressure solution; then add ethyl acetate (5 times of the ketone-based feeding amount), 5% sodium thiosulfate solution (5 times of the ketone-based feeding amount) in the reaction flask, stir for 30 minutes, and let stand to make stratification; Collect the organic layer, extract the aqueous layer twice with ethyl acetate, combine the organic layers, add 1.5 times the volume of saturated sodium chloride solution to it, stir for 30 minutes, let stand to separate the layers, and separate the organic layer; add medicine to the organic layer Use charcoal (1%), stir and decolorize at 60...

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Abstract

The invention relates to a method for preparing lorazepam. The method comprises the following steps: subjecting a ketone substrate as shown in a formula I, glacial acetic acid, potassium acetate, potassium persulfate and iodine to a reaction under heating and stirring conditions to obtain an acetoxy substrate as shown in a formula II; dropwise adding a sodium hydroxide solution into a mixture of ethanol and the acetoxy substance as shown in the formula II, carrying out stirring to realize a complete reaction, performing filtering to obtain a filter cake, and reacting the filter cake with ethylacetate and a citric acid solution to obtain a crude lorazepam product; and crystallizing the crude lorazepam product by using ethanol and ethyl acetate in sequence. The invention further relates tothe pharmaceutical application of larazepam prepared by using the method. The larazepam is particularly used for treating or preventing anxiety, epilepsy, convulsion, sedation and hypnosis. The methoddisclosed by the invention has excellent technical effects as described in the specification.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of benzodiazepine drug lorazepam. It also relates to lorazepam prepared by the method, and its use in drugs with anxiolytic, antiepileptic, anticonvulsant and sedative hypnotic effects. Background technique [0002] Loarzepam, molecular formula C15H10Cl2N2O2, molecular weight 321.16, chemical name: 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzo Diazepin-2-one, its chemical structural formula is: [0003] [0004] Lorazepam is white or off-white crystalline powder; odorless; lorazepam is slightly soluble in ethanol and almost insoluble in water. [0005] Lorazepam, also known as lorazepam, lorazepam and lorazepam, belongs to benzodiazepine (BZD) drugs. It acts on the GABAa regulatory site in the nerve center, strengthens the inhibitory function of GABA, activates chloride ion channels, and produces a powerful anti-anxiety effect. It has re...

Claims

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Application Information

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IPC IPC(8): C07D243/26A61P25/22A61P25/08A61P25/20
CPCC07D243/26A61P25/22A61P25/08A61P25/20C07B2200/13
Inventor 王波侯奇伟冯建辉
Owner HUNAN DONGTING PHARMA
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