CN110776473B

CN110776473B - Process for preparing lorazepam

Info

Publication number: CN110776473B
Application number: CN201911136843.3A
Authority: CN
Inventors: 王波; 侯奇伟; 冯建辉
Original assignee: Hunan Dongting Pharmaceutical Co Ltd
Current assignee: Hunan Dongting Pharmaceutical Co Ltd
Priority date: 2019-11-19
Filing date: 2019-11-19
Publication date: 2023-09-15
Anticipated expiration: 2039-11-19
Also published as: CN110776473A

Abstract

The present invention relates to a process for the preparation of lorazepam comprising the steps of: reacting the ketone compound of the formula I, glacial acetic acid, potassium acetate, potassium persulfate and iodine under heating and stirring to obtain an acetoxyl compound of the formula II; dropwise adding a sodium hydroxide solution into a mixture of an acetoxy compound of the formula II and ethanol, stirring to complete the reaction, and reacting a filter cake obtained by filtering with ethyl acetate and a citric acid solution to obtain a coarse lorazepam product; the crude lorazepam product was crystallized using ethanol followed by ethyl acetate. The invention also relates to the pharmaceutical use of lorazepam prepared by the method of the invention, in particular for the treatment or prevention of anxiety, epilepsy, convulsions and sedation hypnosis. The method of the invention has excellent technical effects as described in the specification.

Description

Process for preparing lorazepam

Technical Field

The invention belongs to the technical field of medicines, and relates to a preparation method of a benzodiazepine drug lorazepam. Also relates to lorazepam prepared by the method and the application thereof in medicaments for resisting anxiety, epilepsy, convulsion and sedative hypnotic actions.

Background

Lorazepam (Loarzepam), molecular formula C15H10Cl2N2O2, molecular weight 321.16, chemical name: 7-chloro-5- (2-chlorophenyl) -1, 3-dihydro-3-hydroxy-2H-1, 4-benzodiazepine-2-one having the formula:

Lorazepam is a white or off-white crystalline powder; no odor; lorazepam is slightly soluble in ethanol and almost insoluble in water.

Lorazepam, also known as loratadine, clomazone and clomazone, belongs to the benzodiazepine class (BZD) of drugs. It acts on GABAa regulating part in nerve center, strengthens the inhibiting function of GABA, starts chloride ion channel, produces powerful anxiolytic effect, and has replaced various sedative medicines in history to become the mainstream medicine for treating anxiety. In addition, lorazepam also has good anti-epileptic, anticonvulsant and sedative hypnotic effects.

The current medicines for first-line antiepileptic state, such as diazepam, phenytoin sodium, phenobarbital and the like, have defects in clinical application. Diazepam has quick response time, but lacks persistence, often has repeated convulsion in a short time, has strong respiratory depression effect on children, and can also cause hypotension and phlebitis at injection sites; the phenytoin sodium has slow onset time, needs to be combined with diazepam, and needs to strictly grasp the intravenous injection speed, otherwise, hypotension can occur; phenobarbital is difficult to observe clinically, has slow onset of intramuscular injection and is easy to produce respiratory depression when used in combination with diazepam. The occurrence of lorazepam is a great progress in treating epileptic status, the onset time of the anti-epileptic status is basically consistent with that of the local American, the convulsion can be rapidly controlled by singly applying the lorazepam, the action time is more durable than that of the diazepam, the convulsion is less repeatedly, and the lorazepam is easy to take and observe clinically and is effective on various epileptic status. Respiratory and cardiovascular inhibition rarely occurs and other side effects are rare compared to diazepam, phenobarbital, etc. The drug has no side effect when being used in combination with other drugs, especially in combination with phenobarbital (most patients still need the drug to maintain the control of the attack), no respiratory depression phenomenon is observed, no active metabolite is generated in human body, and the tissue distribution is small. Therefore, the lorazepam basically has the characteristics of ideal anti-epileptic status medicaments and can be used as a first-line anti-epileptic status medicament in the future.

Lorazepam is widely used abroad and has good sales potential. This product was listed at 64 in the 1997 top hundred prescription drug rank in the united states. Lorazepam (Ativan) developed by us home products company subordinate sub-company Hui Shi alstet was estimated to sell 2.5 billion dollars in 2000 and listed as a worldwide mass-market drug in 2000. Currently, there are only three enterprises in China.

At present, antipyretic analgesics and anti-gout drugs, skeletal muscle relaxants and brain function improving drugs are main consumer varieties of nervous system drugs in China, and the proportion of antiepileptics, anticonvulsants, sedative hypnotics and anxiolytics (main indication drugs of lorazepam) is smaller, and the lorazepam is not listed in the main use varieties of the classes, which indicates that the use amount of the drugs is small. Expert analysis: on one hand, the promotion and propaganda of lorazepam are probably insufficient, and on the other hand, the lorazepam is also related to the physiological diseases of people in China and the light physiological diseases. As the medical model gradually shifts to the bio-psycho-social model, more and more people will seek medical attention for psychological diseases. The prevalence of psychological disorders is far higher than we imagine, as a survey by WHO in 15 centers (including Shanghai) shows that 24% of patients WHO are integrated with hospital visits are psychological disorders. Taking the psychological outpatient service of Zhongshan hospitals as an example, various anxiety diseases account for 30% of the total number of outpatients. A number of facts prove that psychological and physiological inseparables, not only can psychological and social stresses become causative factors for humans, but also the behavioral types of humans have been shown to be closely related to certain diseases, and that many patients with physical diseases also present with the need to treat depression and anxiety disorders. Investigation shows that 22% -33% of patients in internal medicine have anxiety and other psychological disorders, 20% -45% of cancer patients have major depression and anxiety, the anxiety of chronic renal failure dialysis patients is higher than 65.96%, anorexia nervosa patients also have anxiety, the incidence rate of the anxiety has a year-by-year rising trend at home and abroad, and potential anxiety patients are quite extensive. Therefore, with the continuous improvement of the living standard and the recognition level of people in China, the lorazepam has huge market potential in China (Li Ying, chinese medical journal, 2000,2 (6): 30) in terms of the better curative effect of the current lorazepam and the good international sales form of the lorazepam.

The synthesis of lorazepam was first described in BE621819 and US3296249 of S.C. Bell (1963, 1967,Am.Home Prod.), melting points 166-168 ℃ (melting points 161-164 ℃ also described). Lv Xiaoli (Lv Xiaoli, et al, lalazepam synthesis, national academy of sciences of the Huaihai industry, 2005, 14 (3): 44) designed a synthesis route for Lalazepam, the main processes being condensation reaction (one), condensation reaction (two), cyclization reaction, ring-expanding reaction, acylation rearrangement reaction and hydrolysis reaction, and the Lalazepam synthesized by the method was qualitatively and purity analyzed by high performance liquid chromatography, which is believed to be 98.6% pure, and the total reaction yield was 42.5%. The study of the structure-activity relationship of lorazepam was first disclosed in S.C.Bell, J.Med.Chem.11, 457 (1968); HPLC assays for lorazepam were disclosed earliest in I.Jane, A.McKinnon, J.Chromatogr.323, 191 (1985); several documents of pharmacological, drug metabolism and clinical studies of lorazepam have been published in g.owen et al, arzneim-forsch.21, 1047-1102 (1971); the toxicity study of lorazepam was originally disclosed in g.owen et al, arzneim-forsch.21, 1047-1102 (1971) 1065; for a review, lorazepam, see J.G.Rutgers, C.M.Shearer, anal.Profiles Drug subs.9, 397-426 (1980); for reviews of clinical pharmacological and therapeutic uses of lorazepam, see B.Ameer, D.J.Greenblatt, drugs 21, 161-200 (1981); clinical trials of lorazepam to prevent recurrent seizures of alcoholic epilepsy are described in g.d' Onofrio et al, n.engl.j.med.340, 915 (1999).

Lorazepam has been loaded in multinational pharmacopoeias including chinese pharmacopoeia, united states pharmacopoeia, european pharmacopoeia, japanese pharmacopoeia, korean pharmacopoeia, etc. As known, lorazepam has a melting point which is almost insoluble in water, the solubility in water is reported to be only 0.08mg/ml, the melting point of crystals is 166-168 ℃, and the crystals are unstable in light, and the properties bring challenges to preparation of a drug, for example, problems of low oral bioavailability and the like of the drug are usually caused when the solubility is low, and the stability of raw materials not only can influence preparation of the drug, but also can influence long-term storage and transportation of the drug. Thus, there is provided a process for the preparation of lorazepam and which exhibits one or more of the benefits that would be highly desirable to one skilled in the art.

Disclosure of Invention

The present invention aims to provide a novel process for the preparation of lorazepam which is expected to exhibit the technical effects of one or more aspects of the present invention. It has surprisingly been found that one or more technical effects can be obtained by preparing lorazepam using the process of the invention. The present invention has been completed based on this finding.

To this end, a first aspect of the present invention provides a process for the preparation of lorazepam comprising the steps of:

Step 1: reacting ketone compound of formula I, glacial acetic acid, potassium acetate, potassium persulfate and iodine under heating and stirring, and distilling under reduced pressure to remove acid liquor; then adding ethyl acetate and sodium thiosulfate solution, and layering after stirring; collecting an organic layer, adding saturated sodium chloride solution into the organic layer, separating the organic layer, decolorizing with medicinal carbon, concentrating the filtrate under reduced pressure, crystallizing, and drying the crystals to obtain an acetoxy compound of formula II;

step 2: dropwise adding sodium hydroxide solution into a mixture of an acetoxy compound of a formula II and ethanol, stirring to complete the reaction, filtering to obtain a filter cake, reacting with ethyl acetate and citric acid solution, and layering; adding saturated sodium chloride solution into the collected organic layer, separating the organic layer, adding medicinal carbon for decoloring, filtering the obtained filtrate, distilling under reduced pressure, crystallizing, and drying the filtered crystal to obtain a coarse lorazepam product;

step 3: heating and dissolving the lorazepam crude product, ethanol, formic acid and medicinal carbon, filtering to remove carbon, cooling filtrate for crystallization, and vacuum drying the filtered crystals; heating and dissolving the dried substance, ethyl acetate and medicinal carbon, filtering to remove carbon, cooling filtrate for crystallization, and vacuum drying the filtered crystals to obtain the lorazepam refined product. In the invention, unless otherwise specified, the crude lorazepam product is dissolved in materials such as ethanol and the dry lorazepam is heated and stirred in materials such as ethyl acetate, and the operation is the conventional operation of the refining process.

The process according to any of the embodiments of the first aspect of the invention, wherein in step 1, the reaction is carried out with a feed ratio of 1mol (305 g) of the ketone compound of formula I, 12 to 15mol of glacial acetic acid, 2 to 3mol of potassium acetate, 1.5 to 2mol of potassium persulfate, 2 to 3mol of iodine.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 1, the reaction is carried out for 6 to 8 hours with stirring at 70 to 90 ℃.

The method according to any one of the first aspect of the present invention, wherein in step 1, ethyl acetate 3 to 5 times the amount of the ketone compound and sodium thiosulfate 5 to 7 times the amount of the ketone compound are added to the reaction solution after the completion of the reaction. In the present invention, the term "3 to 5 times the amount of ketone compound to be fed" or the like means a weight-fold unless otherwise specified. In the present invention, the term "5 to 7 times the amount of ketone compound fed" or the like referring to sodium thiosulfate refers to the multiple of sodium thiosulfate rather than the multiple in terms of its solution, unless otherwise specified.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 1, the sodium thiosulfate solution is an aqueous solution having a concentration of 5%.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 1, the decolorizing of the medicinal charcoal, the distillation under reduced pressure, and the vacuum drying are each independently performed at a temperature of 60 to 70 ℃.

The method according to any one of the embodiments of the first aspect of the present invention, wherein step 1 is performed as follows: adding 1mol (305 g) of ketone compound of the formula I, 12-15 mol of glacial acetic acid, 2-3 mol of potassium acetate, 1.5-2 mol of potassium persulfate and 2-3 mol of iodine into a reaction bottle, stirring at 70-90 ℃ to react for 6-8 hours, and then distilling at 60-70 ℃ under reduced pressure to remove acid liquor; then adding ethyl acetate (3-5 times of the feeding amount of ketone) and 5% sodium thiosulfate solution (5-7 times of the feeding amount of ketone) into a reaction bottle, stirring for 20-30 minutes, and standing for layering; collecting an organic layer, extracting a water layer with ethyl acetate for 2 times, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution into the organic layers, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding medicinal carbon (0.5-1%) into the organic layer, stirring at 60-70 ℃ for decoloration for 20-30 minutes, filtering, decompressing and evaporating the filtrate at 60-70 ℃ until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2-3 hours, filtering, and vacuum drying at 60-70 ℃ for 5-6 hours to obtain the acetoxy compound of the formula II.

The process according to any of the embodiments of the first aspect of the invention, wherein in step 2, 2.5 to 3.5L of ethanol are added per 1mol of acetoxy of formula II.

The process according to any of the embodiments of the first aspect of the invention, wherein in step 2, 3 to 5mol of sodium hydroxide are added per 1mol of acetoxy of formula II.

The method according to any one of the embodiments of the first aspect of the invention, wherein in step 2 the concentration of sodium hydroxide solution is between 5 and 8%.

In the method according to any one of the first aspect of the present invention, in the step 2, the temperature of the reaction solution is controlled to be 2-8 ℃ during the dropwise addition of sodium hydroxide and the subsequent reaction.

The process according to any one of the embodiments of the first aspect of the invention, wherein in step 2 the obtained filter cake is reacted with 3.5 to 4.5L of ethyl acetate and 8 to 10mol of citric acid.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 2, the decolorizing of the medicinal charcoal, the distillation under reduced pressure, and the vacuum drying are each independently performed at a temperature of 60 to 70 ℃ or 60 to 80 ℃.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in the step 2, the crystallization is performed by heat-preserving crystallization at 5 to 10 ℃ for 3 to 4 hours.

The method according to any one of the embodiments of the first aspect of the present invention, wherein step 2 is performed according to the following operations: adding 1mol (363 g) of acetoxy of the formula II and ethanol (2.5-3.5L) into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 5-8% sodium hydroxide solution (3-5 mol of sodium hydroxide), and controlling the dropwise acceleration to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 12-15 hours after the dripping is finished to ensure that the reaction is complete, and filtering to obtain a filter cake; adding a filter cake, ethyl acetate (3.5-4.5L) and a 10% citric acid solution (citric acid 8-10 mol) into a reaction bottle, stirring for 1-2 hours, standing for layering, and collecting an organic layer; extracting the water layer with ethyl acetate twice, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding medicinal carbon (0.5-1%) into the organic layer, stirring at 60-70 ℃ for decoloring for 1-2 hours, filtering, distilling the filtrate at 60-80 ℃ under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction liquid to 5-10 ℃, preserving heat for crystallization for 3-4 hours, filtering, and vacuum drying at 60-70 ℃ for 3-8 hours to obtain a lorazepam crude product.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 3, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal charcoal are added per 20g of crude lorazepam.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 3, the mixture is stirred at 70 to 90 ℃ for 30 to 45 minutes during the treatment in ethanol; and/or, preserving heat and crystallizing for 2-4 hours at the temperature of 5-10 ℃.

The method according to any one of the embodiments of the first aspect of the present invention, wherein in step 3, 100 to 150ml of ethyl acetate and 0.5 to 1% of medicinal charcoal are added per 10g of dry matter. In the present invention, the percentage of the medicinal carbon is described as weight/volume percentage unless otherwise specified.

The process according to any one of the embodiments of the first aspect of the present invention, wherein in step 3, the mixture is stirred at 60 to 80 ℃ for 20 to 30 minutes while being treated in ethyl acetate; and/or, preserving heat and crystallizing for 2-4 hours at the temperature of 5-10 ℃.

The method according to any one of the embodiments of the first aspect of the present invention, wherein step 3 is performed according to the following operations: adding 20g of lorazepam crude product, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon into a reaction bottle, stirring at 70-90 ℃ for 30-45 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat and crystallizing for 2-4 hours, filtering, and vacuum drying at 50-60 ℃ for 3-5 hours; 10g of dried substance, 100-150 ml of ethyl acetate and medicinal carbon (0.5-1%) are put into a reaction bottle, stirred for 20-30 minutes at 60-80 ℃, filtered while hot, cooled to 5-10 ℃ under stirring, subjected to heat preservation and crystallization for 2-4 hours, filtered by suction, and dried in vacuum at 60-70 ℃ for 5-7 hours to obtain the lorazepam refined product.

The method according to any one of the embodiments of the first aspect of the invention is performed according to the following operations:

step 1, acetoxylation reaction to prepare acetoxylation compound of formula II

Adding 1mol (305 g) of ketone compound of the formula I, 12-15 mol of glacial acetic acid, 2-3 mol of potassium acetate, 1.5-2 mol of potassium persulfate and 2-3 mol of iodine into a reaction bottle, stirring at 70-90 ℃ to react for 6-8 hours, and then distilling at 60-70 ℃ under reduced pressure to remove acid liquor; then adding ethyl acetate (3-5 times of the feeding amount of ketone) and 5% sodium thiosulfate solution (5-7 times of the feeding amount of ketone) into a reaction bottle, stirring for 20-30 minutes, and standing for layering; collecting an organic layer, extracting a water layer with ethyl acetate for 2 times, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution into the organic layers, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding medicinal carbon (0.5-1%) into the organic layer, stirring at 60-70 ℃ for decoloration for 20-30 minutes, filtering, decompressing and evaporating the filtrate at 60-70 ℃ until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2-3 hours, filtering, and vacuum drying at 60-70 ℃ for 5-6 hours to obtain the acetoxy compound of the formula II;

step 2, preparing lorazepam by hydrolysis

Adding 1mol (363 g) of acetoxy of the formula II and ethanol (2.5-3.5L) into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 5-8% sodium hydroxide solution (3-5 mol of sodium hydroxide), and controlling the dropwise acceleration to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 12-15 hours after the dripping is finished to ensure that the reaction is complete, and filtering to obtain a filter cake; adding a filter cake, ethyl acetate (3.5-4.5L) and a 10% citric acid solution (citric acid 8-10 mol) into a reaction bottle, stirring for 1-2 hours, standing for layering, and collecting an organic layer; extracting the water layer with ethyl acetate twice, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding medicinal carbon (0.5-1%) into the organic layer, stirring at 60-70 ℃ for decoloring for 1-2 hours, filtering, distilling the filtrate at 60-80 ℃ under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction liquid to 5-10 ℃, preserving heat for crystallization for 3-4 hours, filtering, and vacuum drying at 60-70 ℃ for 3-8 hours to obtain a lorazepam crude product;

step 3, refining

Adding 20g of lorazepam crude product, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon into a reaction bottle, stirring at 70-90 ℃ for 30-45 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat and crystallizing for 2-4 hours, filtering, and vacuum drying at 50-60 ℃ for 3-5 hours; 10g of dried substance, 100-150 ml of ethyl acetate and medicinal carbon (0.5-1%) are put into a reaction bottle, stirred for 20-30 minutes at 60-80 ℃, filtered while hot, cooled to 5-10 ℃ under stirring, subjected to heat preservation and crystallization for 2-4 hours, filtered by suction, and dried in vacuum at 60-70 ℃ for 5-7 hours to obtain the lorazepam refined product.

The process according to any of the embodiments of the first aspect of the present invention, which produces lorazepam concentrate using Cu-ka radiation, having diffraction peaks at about 12.17 °, about 14.15 °, about 15.27 °, about 16.84 °, about 17.91 °, about 20.81 ° in a powder X-ray diffraction pattern expressed in degrees 2θ; alternatively, in a powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 12.17±0.20°, 14.15±0.20°, 15.27±0.20°, 16.84±0.20°, 17.91±0.20°, and 20.81±0.20°; or, diffraction peaks at 12.17+ -0.10 °, 14.15+ -0.10 °, 15.27+ -0.10 °, 16.84+ -0.10 °, 17.91+ -0.10 °, 20.81+ -0.10 °; alternatively, diffraction peaks at about 7.93 °, about 9.04 °, about 12.17 °, about 14.15 °, about 15.27 °, about 16.84 °, about 17.91 °, about 20.81 °, about 21.44 °, about 26.38 °; alternatively, in a powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 7.93±0.20°, 9.04±0.20°, 12.17±0.20°, 14.15±0.20°, 15.27±0.20°, 16.84±0.20°, 17.91±0.20°, 20.81±0.20°, 21.44 ±0.20°, 26.38 ±0.20°; alternatively, in a powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 7.93±0.10°, 9.04±0.10°, 12.17±0.10°, 14.15±0.10°, 15.27±0.10°, 16.84±0.10°, 17.91±0.10°, 20.81±0.10°, 21.44 ±0.10°, 26.38 ±0.10°; alternatively, it has a powder X-ray diffraction pattern as shown in FIG. 1.

Further, the second aspect of the present invention provides a crystal of lorazepam prepared by the method according to any one of the embodiments of the first aspect of the present invention.

Further, a third aspect of the invention relates to the use of lorazepam prepared by a process according to any one of the embodiments of the first aspect of the invention or a crystal according to the second aspect of the invention in the manufacture of a medicament for the treatment or prevention of anxiety, depressive pain, convulsions and sedative hypnotic.

Among the steps of the above-described preparation method of the present invention, although the specific steps described therein are distinguished in some details or language description from the steps described in the preparation examples of the following detailed description, the above-described method steps can be fully summarized by one skilled in the art based on the detailed disclosure of the present invention as a whole.

Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict. The present invention is further described below.

All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this invention. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present invention.

Anxiety disorder, also known as anxiety neurosis, is one of the most common of the major classes of disorders of the neurosis. The anxiety emotion experience is mainly characterized and can be divided into two forms of generalized anxiety and panic attacks. The main manifestations are: the physical and mental health of the patient is seriously affected without the tension worry, restlessness, palpitation, hand tremble, sweating, frequent urination, and restlessness of the specific and objective objects. In the line of anxiolytic drugs, lorazepam (Lorazepam) is used as a drug with better curative effect and is deeply trusted by patients. Lorazepam is a benzodiazepine anxiolytic, which is fully named 7-chloro-5- (2-chlorobenzene) -1, 3-dihydro-3-hydroxy-2H-1, 4-benzodiazepine-2-one, a benzodiazepine-type psychotropic synthesized by Wyeth corporation in the United states, and developed by Wyeth corporation in Japan.

The present invention surprisingly found that the process of the present invention has one or more of the following advantageous properties, such as simple process, high product yield, low impurities, etc.

Drawings

Fig. 1: powder X-ray diffraction pattern of lorazepam concentrate of the present invention.

Detailed Description

The following examples are provided for illustrative purposes only and are not intended to be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications may be made to the following embodiments without departing from the spirit or scope of the invention.

The present invention generally and/or specifically describes the materials used in the test as well as the test methods. Although many materials and methods of operation are known in the art for accomplishing the objectives of the present invention, the present invention will be described in as much detail herein. It will be clear to those skilled in the art that hereinafter, unless otherwise indicated, the materials and methods of operation used in the present invention are well known in the art.

Detection method example 1: high performance liquid chromatography for determining lorazepam content or purity

The following HPLC condition methods can be used to determine the chromatographic purity of lorazepam or related substances:

Taking a to-be-detected product, precisely weighing, adding acetonitrile for dissolving and quantitatively diluting to prepare a solution containing 1mg of each 1ml of the to-be-detected product as a to-be-detected product solution; in addition, 2-amino-2', 5-dichlorobenzophenone (impurity I) reference substance is precisely weighed, acetonitrile is added for dissolution and quantitative dilution are carried out to prepare a solution containing 10ug per 1ml, and the solution is used as reference substance solution; precisely measuring 1ml of each of the sample solution and the reference solution, placing into a 100ml measuring flask, diluting with acetonitrile to scale, and shaking to obtain reference solution. According to chromatographic condition test under the content measurement item, precisely measuring 20ul of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram till 3 times of the retention time of the main component peak. The specific impurity calculation method comprises the following steps: the chromatogram of the sample solution has chromatographic peaks with the retention time consistent with that of the impurity I in the control solution, and the content of the impurity I is calculated according to an external standard method by using the peak area; if there is a chromatographic peak with the retention time consistent with that of 6-chloro-4- (2-chlorophenyl) quinazoline-2-formaldehyde (impurity II), comparing the peak area with the peak area of lorazepam in the control solution to calculate the percentage content; comparing the peak areas of other single impurities with the peak areas of lorazepam in the control solution to calculate the percentage content; the sum of the peak areas of the impurities is compared with the peak area of lorazepam in the control solution to calculate the percentage content (total impurity content). The chromatographic purity (minus the solvent peak), i.e. HPLC purity, was calculated by area normalization.

The HPLC method described above can also be used to determine the HPLC purity of the acetoxy compound of formula II.

Detection method example 2: determination of crystalline powder X-ray diffraction patterns

The diffraction pattern of the crystals was determined using the following powder X-ray diffraction analysis method: rigaku Dmax/2400 powder X diffractometer; cuK alpha radiation, a graphite monochromator, 40KV,100MA,2 theta scanning range of 0.0-40 DEG, scanning speed of 3 DEG/min and step length of 0.01 DEG; the scanning mode is continuous scanning; slit arrangement, exit slit DS:1/2 ° anti-scatter slit: SS 1/2 °; RS is 0.3mm.

The crystalline powder X-ray diffraction pattern of the lorazepam refined product obtained in example 1 of the present invention is shown in fig. 1 (the X-ray diffraction patterns of the lorazepam refined products in examples 2 to 4 are basically the same as fig. 1, and 10 characteristic peaks are shown as the same as fig. 1), and specific data of diffraction peak positions (2θ, °, ±0.2) of fig. 1 are shown in the following table:

typically, lorazepam obtained in example 1 of the present invention has diffraction peaks at about 12.17 °, about 14.15 °, about 15.27 °, about 16.84 °, about 17.91 °, about 20.81 ° in a powder X-ray diffraction pattern expressed in terms of 2θ degrees; in particular, in a powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 12.17±0.20°, 14.15±0.20°, 15.27±0.20°, 16.84±0.20°, 17.91±0.20°, 20.81±0.20°; in particular, in a powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 12.17±0.10°, 14.15±0.10°, 15.27±0.10°, 16.84±0.10°, 17.91±0.10°, 20.81±0.10°; in particular, in a powder X-ray diffraction pattern expressed in terms of 2θ, there are diffraction peaks at about 7.93 °, about 9.04 °, about 12.17 °, about 14.15 °, about 15.27 °, about 16.84 °, about 17.91 °, about 20.81 °, about 21.44 °, about 26.38 °; in particular, in a powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 7.93±0.20°, 9.04±0.20°, 12.17±0.20°, 14.15±0.20°, 15.27±0.20°, 16.84±0.20°, 17.91±0.20°, 20.81±0.20°, 21.44 ±0.20°, 26.38 ±0.20°; in particular, in the powder X-ray diffraction pattern expressed in terms of 2θ, diffraction peaks are present at 7.93±0.10°, 9.04±0.10°, 12.17±0.10°, 14.15±0.10°, 15.27±0.10°, 16.84±0.10°, 17.91±0.10°, 20.81±0.10°, 21.44 ±0.10°, 26.38 ±0.10°; in particular, it has a powder X-ray diffraction pattern as shown in FIG. 1. The lorazepam concentrate obtained in step 3 of examples 1-4 of the present invention is in the typical crystalline form described above, which may be referred to herein as form L.

The present invention uses as starting material the ketone of formula I, which is available directly from the commercial source, and which (or analogues thereof) has also been described for example in US3296429 published 1967. When lorazepam is prepared in the following specific examples of example 1 and the like, the reaction is mainly performed in three stages, and the reaction scheme is as follows:

(1) Acetoxylation reaction

(2) Hydrolysis

Example 1: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxylation compound of formula II

1mol (305 g) of ketone compound of formula I, 14mol of glacial acetic acid, 2.5mol of potassium acetate, 1.8mol of potassium persulfate and 2.5mol of iodine are added into a reaction bottle, stirred at 80 ℃ to react for 7 hours, and then the acid liquor is distilled off under reduced pressure at 65 ℃; then adding ethyl acetate (4 times of the feeding amount of ketone) and 5% sodium thiosulfate solution (6 times of the feeding amount of ketone) into a reaction bottle, stirring for 25 minutes, and standing for layering; the organic layer was collected, the aqueous layer was extracted 2 times with ethyl acetate, the organic layers were combined, 1.25 times the volume of saturated sodium chloride solution was added thereto, stirred for 25 minutes, left to stand to separate the layers, and the organic layer was separated; adding medicinal charcoal (0.75%) into the organic layer, stirring at 65deg.C for decolorizing for 25 min, filtering, evaporating the filtrate at 65deg.C under reduced pressure until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5deg.C for 2.5 hr, filtering, and vacuum drying at 65deg.C for 5.5 hr to obtain acetoxy of formula II (yield 78.4%, HPLC purity 92.3%).

Step 2, preparing lorazepam by hydrolysis

Adding 1mol (363 g) of acetoxy of the formula II and ethanol (3L) into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 6 sodium hydroxide solution (4 mol of sodium hydroxide), and controlling the dropwise adding speed to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 14 hours after the dripping is finished to complete the reaction, and filtering to obtain a filter cake; adding the filter cake, ethyl acetate (4L) and 10% citric acid solution (citric acid 9 mol) into a reaction bottle, stirring for 1.5 hours, standing to separate layers, and collecting an organic layer; extracting the water layer with ethyl acetate twice, mixing the organic layers, adding 1.25 times of saturated sodium chloride solution, stirring for 25 min, standing for layering, and separating the organic layers; adding medicinal charcoal (0.75%) into the organic layer, stirring at 65deg.C for decolorizing for 1.5 hr, filtering, distilling the filtrate at 70deg.C under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction solution to 5-10deg.C, maintaining the temperature for crystallization for 3.5 hr, filtering, and vacuum drying at 65deg.C for 6 hr to obtain lorazepam crude product (yield 64.3% and HPLC purity 95.7%).

Step 3, refining

Adding 20g of lorazepam crude product, 300ml of ethanol, 2.5g of formic acid and medicinal carbon (0.75%) into a reaction bottle, stirring at 80 ℃ for 40 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat, crystallizing for 3 hours, filtering, and vacuum drying at 55 ℃ for 4 hours; 10g of dried substance, 120ml of ethyl acetate and medicinal carbon (0.75%) are placed in a reaction bottle, stirred at 70 ℃ for 25 minutes, filtered while the mixture is hot, cooled to 5 to 10 ℃ under stirring, subjected to heat preservation and crystallization for 3 hours, filtered by suction, and dried in vacuum at 65 ℃ for 6 hours to obtain a lorazepam refined product (yield 78.8 percent and HPLC purity 99.4 percent). In the present invention, unless otherwise indicated, the "lorazepam concentrate" may also be referred to as "lorazepam", "lorazepam crystals", "crystals" and the like.

Example 2: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxylation compound of formula II

1mol (305 g) of ketone compound of the formula I, 15mol of glacial acetic acid, 2mol of potassium acetate, 2mol of potassium persulfate and 2mol of iodine are added into a reaction bottle, stirred at 70 ℃ for reaction for 8 hours, and then acid liquor is removed by reduced pressure distillation at 70 ℃; then adding ethyl acetate (3 times of the feeding amount of ketone) and 5% sodium thiosulfate solution (7 times of the feeding amount of ketone) into a reaction bottle, stirring for 20 minutes, and standing for layering; the organic layer was collected, the aqueous layer was extracted 2 times with ethyl acetate, the organic layers were combined, 1-fold volume of saturated sodium chloride solution was added thereto, stirred for 20 minutes, left to stand for delamination, and the organic layer was separated; adding medicinal charcoal (0.5%) into the organic layer, stirring at 70deg.C for decolorizing for 20 min, filtering, evaporating the filtrate at 60deg.C under reduced pressure until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5deg.C for 2 hr, filtering, and vacuum drying at 70deg.C for 5 hr to obtain acetoxy of formula II (yield 78.6%, HPLC purity 92.6%).

Step 2, preparing lorazepam by hydrolysis

Adding 1mol (363 g) of acetoxy of the formula II and ethanol (2.5L) into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 8% sodium hydroxide solution (3 mol of sodium hydroxide), and controlling the dropwise adding speed to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 12 hours after the dripping is finished to complete the reaction, and filtering to obtain a filter cake; adding the filter cake, ethyl acetate (4.5L) and 10% citric acid solution (10 mol of citric acid) into a reaction bottle, stirring for 1 hour, standing to separate layers, and collecting an organic layer; extracting the water layer with ethyl acetate twice, mixing the organic layers, adding 1.5 times of saturated sodium chloride solution, stirring for 20 min, standing for layering, and separating the organic layers; adding medicinal charcoal (0.5%) into the organic layer, stirring at 70deg.C for decolorizing for 2 hr, filtering, distilling the filtrate at 80deg.C under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction solution to 5-10deg.C, maintaining the temperature for crystallization for 4 hr, filtering, and vacuum drying at 70deg.C for 3 hr to obtain Laurazepam crude product (yield 64.3%, HPLC purity 95.7%).

Step 3, refining

Adding 20g of lorazepam crude product, 250ml of ethanol, 3g of formic acid and medicinal carbon (1%) into a reaction bottle, stirring at 90 ℃ for 30 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat, crystallizing for 4 hours, filtering, and drying at 50 ℃ in vacuum for 5 hours; 10g of dried substance, 100ml of ethyl acetate and medicinal carbon (1%) are put into a reaction bottle, stirred for 30 minutes at 60 ℃, filtered while the mixture is hot, cooled to 5 to 10 ℃ under stirring, subjected to heat preservation and crystallization for 4 hours, filtered by suction, and dried in vacuum at 60 ℃ for 7 hours to obtain the lorazepam refined product (yield 79.6% and HPLC purity 99.6%).

Example 3: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxylation compound of formula II

1mol (305 g) of ketone compound of the formula I, 12mol of glacial acetic acid, 3mol of potassium acetate, 1.5mol of potassium persulfate and 3mol of iodine are added into a reaction bottle, stirred at 90 ℃ to react for 6 hours, and then acid liquor is removed by reduced pressure distillation at 60 ℃; then adding ethyl acetate (5 times of the feeding amount of ketone) and 5% sodium thiosulfate solution (5 times of the feeding amount of ketone) into a reaction bottle, stirring for 30 minutes, and standing for layering; the organic layer was collected, the aqueous layer was extracted 2 times with ethyl acetate, the organic layers were combined, 1.5 times the volume of a saturated sodium chloride solution was added thereto, stirred for 30 minutes, left to stand to separate the layers, and the organic layer was separated; adding medicinal charcoal (1%) into the organic layer, stirring at 60deg.C for decolorizing for 30 min, filtering, evaporating the filtrate at 70deg.C under reduced pressure until a large amount of crystals are precipitated, stopping concentrating, cooling, crystallizing at 0-5deg.C for 3 hr, filtering, and vacuum drying at 60deg.C for 6 hr to obtain acetoxy of formula II (yield 77.8%, HPLC purity 91.8%).

Step 2, preparing lorazepam by hydrolysis

Adding 1mol (363 g) of acetoxy of the formula II and ethanol (3.5L) into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 5% sodium hydroxide solution (5 mol of sodium hydroxide), and controlling the dropwise adding speed to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 15 hours after the dripping is finished to complete the reaction, and filtering to obtain a filter cake; adding the filter cake, ethyl acetate (3.5L) and 10% citric acid solution (citric acid 8 mol) into a reaction bottle, stirring for 2 hours, standing to separate layers, and collecting an organic layer; extracting the water layer with ethyl acetate twice, mixing the organic layers, adding 1 time volume of saturated sodium chloride solution, stirring for 30 min, standing for layering, and separating the organic layers; adding medicinal charcoal (1%) into the organic layer, stirring at 60deg.C for decolorizing for 2 hr, filtering, distilling the filtrate at 60deg.C under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction solution to 5-10deg.C, standing for crystallization for 3 hr, filtering, and vacuum drying at 60deg.C for 8 hr to obtain Laobazepam crude product (yield 64.3%, HPLC purity 95.7%).

Step 3, refining

Adding 20g of lorazepam crude product, 350ml of ethanol, 2g of formic acid and medicinal carbon (0.5%) into a reaction bottle, stirring at 70 ℃ for 45 minutes, filtering while the mixture is hot, cooling the filtrate to 5 ℃ under stirring, preserving heat, crystallizing for 2 hours, filtering, and vacuum drying at 60 ℃ for 3 hours; 10g of dried substance, 150ml of ethyl acetate and medicinal carbon (0.5%) are placed in a reaction bottle, stirred at 80 ℃ for 20 minutes, filtered while the mixture is hot, cooled to 5-10 ℃ under stirring, subjected to heat preservation and crystallization for 2 hours, filtered by suction, and dried in vacuum at 70 ℃ for 5 hours to obtain a lorazepam refined product (yield 78.1% and HPLC purity 99.5%).

Example 4: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxylation compound of formula II

1mol (305 g) of ketone compound of formula I, 12mol of glacial acetic acid, 2.2mol of potassium acetate, 1.7mol of potassium persulfate and 2.7mol of iodine are added into a reaction bottle, stirred at 80 ℃ to react for 7 hours, and then the acid liquor is distilled off under reduced pressure at 67 ℃; then adding ethyl acetate (3.8 times of the feeding amount of ketone) and 5% sodium thiosulfate solution (6.5 times of the feeding amount of ketone) into a reaction bottle, stirring for 27 minutes, and standing to separate layers; the organic layer was collected, the aqueous layer was extracted 2 times with ethyl acetate, the organic layers were combined, 1.3 times the volume of a saturated sodium chloride solution was added thereto, stirred for 23 minutes, left to stand to separate the layers, and the organic layer was separated; adding medicinal charcoal (0.8%) into the organic layer, stirring at 63deg.C for decolorizing for 28 min, filtering, evaporating the filtrate at 65deg.C under reduced pressure until a large amount of crystals are precipitated, stopping concentrating, cooling, crystallizing at 0-5deg.C for 2.7 hr, filtering, and vacuum drying at 67 deg.C for 5.3 hr to obtain acetoxy of formula II (yield 79.1%, HPLC purity 92.3%).

Step 2, preparing lorazepam by hydrolysis

Adding 1mol (363 g) of acetoxy of the formula II and ethanol (2.9L) into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 7% sodium hydroxide solution (3.8 mol of sodium hydroxide), and controlling the dropwise adding speed to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 14 hours after the dripping is finished to complete the reaction, and filtering to obtain a filter cake; adding the filter cake, ethyl acetate (4.2L) and 10% citric acid solution (citric acid 9 mol) into a reaction bottle, stirring for 1.4 hours, standing for layering, and collecting an organic layer; extracting the water layer with ethyl acetate twice, mixing the organic layers, adding 1.2 times of saturated sodium chloride solution, stirring for 28 min, standing for layering, and separating the organic layers; adding medicinal charcoal (0.85%) into the organic layer, stirring at 68deg.C for decolorizing for 1 hr, filtering, distilling the filtrate at 68deg.C under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction solution to 5-10deg.C, maintaining the temperature for crystallization for 3.3 hr, filtering, and vacuum drying at 68deg.C for 4 hr to obtain Laobazepam crude product (yield 65.7%, HPLC purity 94.5%).

Step 3, refining

Adding 20g of lorazepam crude product, 290ml of ethanol, 2.7g of formic acid and medicinal carbon (0.88%) into a reaction bottle, stirring at 83 ℃ for 36 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat and crystallizing for 3.6 hours, filtering, and vacuum drying at 54 ℃ for 4.5 hours; 10g of dried substance, 130ml of ethyl acetate and medicinal carbon (0.68%) are placed in a reaction bottle, stirred for 28 minutes at 73 ℃, filtered while the mixture is hot, cooled to 5 to 10 ℃ under stirring, subjected to heat preservation and crystallization for 2.4 hours, then subjected to suction filtration, and dried in vacuum at 68 ℃ for 6.7 hours to obtain the lorazepam refined product (yield 79.5% and HPLC purity 99.5%).

Example 11: preparation of lorazepam

With reference to the methods of examples 1 to 4, respectively, the difference is that formic acid was not added during the purification of step 3, and four batches of lorazepam concentrates were obtained, each having a purification step yield in the range of 78 to 80% and an HPLC purity in the range of 98.2 to 98.6%, for example, the lorazepam concentrate obtained with reference to example 1 had a purification step yield in the range of 78.7% and an HPLC purity of 98.4%. This result shows that the yield was substantially unchanged without adding formic acid during the purification process, but the HPLC purity was slightly lowered.

The melting points of the lorazepam refined products obtained in the examples 1-4 are all within the range of 187-191 ℃ through measurement, for example, the melting point of the lorazepam refined products obtained in the example 1 is 188.6-190.4 ℃; the melting points of the four batches of lorazepam concentrate obtained in example 11 were determined to be in the range 165-169 ℃, for example 167.3-168.1 ℃ for the lorazepam concentrate obtained in reference example 1. From the difference in melting points, it can be assumed that: the lorazepam concentrate obtained in examples 1-4 may have a different crystal form than the four lorazepam concentrates obtained in example 11.

The four batches of lorazepam concentrate obtained in example 11 were tested for their powder X-ray diffraction patterns and showed that none of these four substances had diffraction peaks or relative abundances of less than 5% at 7.93 °, 9.04 °, 12.17 °, 17.91 ° typical of 2θ, while the strongest diffraction peak occurred at 14.86 °. As can be seen, the powder X-ray diffraction patterns further demonstrate that the lorazepam concentrate obtained in examples 1-4 has a different crystal form than the four batches of lorazepam concentrate obtained in example 11.

Although the difference in crystallization process between examples 1 to 4 and example 11 was merely reflected in the addition or non-addition of formic acid, the resultant products exhibited significantly different physical property differences. It is expected that the differences between the physical properties of the products, such as melting point, powder X-ray diffraction patterns, among others, may be more unpredictable if the crystallization process is larger than the above-mentioned differences.

Detection method example 3: solubility determination

Adding proper amount (supersaturated amount) of lorazepam refined product into double distilled water which is boiled and cooled to 25 ℃ at room temperature of 25 ℃, stirring for 12 hours, centrifuging, and then filtering the supernatant with a 0.22um microporous filter membrane; the subsequent filtrate was taken in an appropriate amount, diluted with a mobile phase if necessary, and the concentration of lorazepam in the subsequent filtrate was determined and the solubility calculated according to the HPLC method of detection method example 1. Results: the solubility of the four batches of lorazepam concentrate of examples 1-4 is in the range of 0.89-0.96 mg/ml, e.g., the solubility of the lorazepam concentrate of example 1 is 0.915mg/ml; whereas the solubility of the four lorazepam concentrates of example 11 was in the range of 0.064-0.071 mg/ml, for example the lorazepam concentrate of example 11 obtained by the method of reference example 1 had a solubility of 0.068mg/ml, and it was seen that the solubility of the lorazepam concentrates of examples 1-4 was significantly higher.

Detection method example 3: dissolution of the prepared tablets

The second part of the pharmacopoeia of 2015 edition receives lorazepam and tablets, wherein the requirement of the dissolution rate specified in the lorazepam tablets is that the limit of the dissolution rate under the specified condition should be 70% of the marked amount, and the limit is relatively low in the field of preparation due to the low solubility of the bulk drugs.

Lorazepam tablets were prepared with the following typical recipe/process:

prescription (per tablet): 1mg of lorazepam, 35mg of lactose, 45mg of microcrystalline cellulose, 3mg of low-substituted hydroxypropyl cellulose, 5mg of PVP-K30 and 0.7mg of magnesium stearate;

the preparation method comprises the following steps: pulverizing lorazepam to pass through a 200-mesh sieve, and pulverizing the rest materials to pass through a 120-mesh sieve; five materials except magnesium stearate are uniformly mixed, prepared into granules which are sized by a 20-mesh sieve by adopting a dry granulation process (extrusion/crushing), then mixed with the magnesium stearate, pressed into tablets by using a die with proper size, and the pressures of the tablets in different batches are controlled to be basically consistent.

The lorazepam bulk drug adopts four batches of lorazepam refined products in examples 1-4 and four batches of lorazepam refined products in example 11 respectively to prepare 8 batches of tablets.

The dissolution rates of 8 batches of tablets were measured according to the pharmacopoeia method described above, respectively, and the results were: the dissolution rates of 4 batches of tablets obtained by taking four batches of lorazepam refined products of the examples 1-4 as raw materials are all in the range of 81-86%, for example, the dissolution rate of the tablets obtained by taking the lorazepam refined products of the example 1 as raw materials is 82.7%; example 11 four refined lorazepam batches were used as starting materials, and the dissolution rates of the 4 tablets obtained from each batch were in the range of 57 to 62%, for example, the dissolution rates of the tablets obtained from the refined lorazepam batches obtained in example 11 by the method of reference example 1 were 60.3%. Although one can improve the dissolution of the tablets by improving the formulation recipe/process so that the dissolution of the tablets meets the pharmacopoeia requirements, the formulation performance of the lorazepam concentrate of examples 1-4 is significantly better than that of the lorazepam concentrate of example 11 from the above-described tablet dissolution results.

Commercial lorazepam bulk drug (national drug standard H20031064): melting point 167.6-168.4 ℃, solubility 0.074mg/ml, no diffraction peak at 7.93 degrees, 9.04 degrees, 12.17 degrees and 17.91 degrees typical of 2 theta in a powder X-ray diffraction pattern or relative abundance less than 5 percent, and dissolution rate 66.4 percent of the tablet according to the detection method example 3; these data indicate that the physical and chemical properties of the commercial lorazepam are less excellent than the finished products of examples 1-4 of the present invention.

Lorazepam was prepared according to Lv Xiaoli (Lv Xiaoli, et al, synthesis of lorazepam, national academy of sciences, 2005, 11 (3): 44), which document lorazepam: melting point 163.7-165.1 ℃, solubility 0.067mg/ml, no diffraction peak at 7.93 degrees, 9.04 degrees, 12.17 degrees and 17.91 degrees typical of 2 theta in a powder X-ray diffraction pattern or relative abundance less than 5 percent, and dissolution rate of the tablet according to detection method example 3 of 63.6 percent; these data indicate that the physical and chemical properties of lorazepam of this document are less excellent than the refined products of examples 1-4 of the present invention.

Lorazepam tablets (7-chloro-5- (O-chlorophenyl) -3-hydroxy-1, 3-dihydro-2H-1, 4-benzodiazepine-2-one) have been used clinically for decades and commercially available formats typically include: 0.5mg, 1.0mg, 2.0mg. Lorazepam tablets are useful in the treatment of anxiety disorders or short-term treatment for relief of anxiety symptoms and anxiety associated with depressive symptoms; anxiety or stress associated with stress in daily life is generally not required for treatment with anxiolytic drugs. The long-term application effect of lorazepam, namely the effect of more than 4 months of application, is not evaluated by clinical study of the system; the physician should periodically re-evaluate the effectiveness of the drug for the individual patient.

The dosage, frequency and treatment period of lorazepam tablets should be individually adjusted according to the response of patients. During the convenience period, there were 0.5mg,1.0mg and 2.0mg tablet alternatives. The conventional dosage range is 2 to 6mg per day, the administration is divided into several times, the maximum dosage is given before sleeping, and the daily dosage can be adjusted by changing from 1 to 10 mg. For anxiety symptoms, the initial dose for most patients is 2 to 3mg daily, twice or three times daily. Insomnia patients due to anxiety or temporary mood stress are given a single oral dose of 2 to 4mg daily, usually scheduled to be administered prior to falling asleep. For elderly patients or infirm patients, the recommended initial dose is 1-2 mg/day, and the administration dose can be adjusted according to the needs and the tolerance of the patients. The dosage of lorazepam should be gradually increased as necessary without abrupt adjustment to avoid adverse effects. When an increase in the dosage of lorazepam is required, the dosage of medication at night should be increased first before the daytime dosage is increased. Patients are advised to consult physicians before increasing doses or stopping suddenly.

Clinical studies have shown that healthy volunteers take high doses of lorazepam a single time, have central sedation, and have no effect on respiratory and cardiovascular systems. Reproduction toxicity: reproduction toxicity tests were performed in mice, rats and rabbits, in which various abnormal manifestations (tarsal bones, reduction of bones in tibia, poor rotation of limbs, abdominal fissures, cranial deformities, small eyeballs, etc.) were occasionally observed but without dose dependency. When the dosage is higher than 40mg/kg, absorption of the young fetus occurs, and the loss rate of the young fetus increases. The clinical significance found above is not clear, but there are several studies suggesting that the use of sedative hypnotics (chlordiazepoxide, diazepam, and chlordiazepoxide) in the early stages of pregnancy may increase the risk of congenital malformations. Since such drugs are not normally used in emergency situations, the use of lorazepam should be avoided during the initial stages of pregnancy. Carcinogenesis: no carcinogenesis was seen in the trial conducted in rats for 18 months of the dosing cycle.

The oral administration of lorazepam is rapid in absorption and has an absolute bioavailability of 90%. The peak plasma concentration occurs approximately 2 hours after administration. The peak plasma drug concentration after oral administration of 2mg lorazepam was about 20ng/ml. The average elimination half-life of free lorazepam in human plasma is about 12 hours and the main metabolite glucuronic acid lorazepam is about 18 hours. At clinically relevant blood concentration levels, the plasma protein binding rate of lorazepam was approximately 85%. Lorazepam rapidly associates with glucuronic acid at the 3-hydroxy position to form glucuronate which is then excreted in urine. Glucuronic acid lorazepam showed no significant central nervous system activity in animals. The plasma drug levels of lorazepam are proportional to the dose administered. There is no evidence that excessive accumulation can occur up to 6 months of administration. Results of comparative studies performed on young and old subjects showed that: the age increase did not have a significant effect on the pharmacokinetics of lorazepam. However, in one study with single doses of 1.5-3mg of lorazepam injection, it was found that the average total clearance of lorazepam in 15 cases of age groups of 60 to 84 years was reduced by 20% compared to 15 cases of age groups of 19 to 38 years.

The spirit of the present invention has been described in detail by the preferred embodiments of the present invention. It will be appreciated by those skilled in the art that any modifications, equivalent variations and modifications made to the above embodiments according to the technical substance of the present invention fall within the scope of the present invention.

Claims

1. A method of preparing lorazepam having diffraction peaks at 12.17±0.20 °, 14.15±0.20 °, 15.27±0.20 °, 16.84±0.20 °, 17.91±0.20°, 20.81±0.20° in a powder X-ray diffraction pattern expressed in terms of 2θ using Cu-ka radiation; the method comprises the following steps:

step 1: reacting a ketone compound of the formula I, glacial acetic acid, potassium acetate, potassium persulfate and iodine for 6-8 hours under heating and stirring at 70-90 ℃, and distilling under reduced pressure to remove acid liquor; then adding ethyl acetate with the feeding amount of ketone groups being 3-5 times and sodium thiosulfate solution with the feeding amount of ketone groups being 5-7 times, and layering after stirring; collecting an organic layer, adding saturated sodium chloride solution into the organic layer, separating the organic layer, decolorizing with medicinal carbon, concentrating the filtrate under reduced pressure, crystallizing, and drying the crystals to obtain an acetoxy compound of formula II; the sodium thiosulfate solution is an aqueous solution with the concentration of 5%; the medical carbon decolorization, the reduced pressure concentration and the drying are respectively and independently carried out at the temperature of 60-70 ℃;

Step 2: dropwise adding 5-8% sodium hydroxide solution into a mixture of an acetoxy compound and ethanol in a formula II, stirring at 2-8 ℃ to complete the reaction, filtering to obtain a filter cake, reacting with ethyl acetate and citric acid solution, and layering; adding saturated sodium chloride solution into the collected organic layer, separating the organic layer, adding medicinal carbon for decoloring, filtering the obtained filtrate, distilling under reduced pressure, preserving heat at 5-10 ℃ for crystallization for 3-4 hours, and drying the crystal obtained by filtering to obtain a coarse lorazepam product;

step 3: adding 20g of lorazepam crude product, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon into a reaction bottle, stirring at 70-90 ℃ for 30-45 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat and crystallizing for 2-4 hours, filtering, and drying at 50-60 ℃ in vacuum for 3-5 hours; and (3) placing 10g of dried substance, 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon into a reaction bottle, stirring for 20-30 minutes at 60-80 ℃, filtering while the mixture is hot, cooling to 5-10 ℃ under stirring, preserving heat, crystallizing for 2-4 hours, filtering, and vacuum drying at 60-70 ℃ for 5-7 hours to obtain lorazepam.

2. The method according to claim 1, wherein in the step 1, the reaction is carried out according to the feeding proportion of 1mol of ketone compound in the formula I, 12-15 mol of glacial acetic acid, 2-3 mol of potassium acetate, 1.5-2 mol of potassium persulfate and 2-3 mol of iodine.

3. The method according to claim 1, wherein step 1 is performed as follows: adding 1mol of ketone compound of formula I, 12-15 mol of glacial acetic acid, 2-3 mol of potassium acetate, 1.5-2 mol of potassium persulfate and 2-3 mol of iodine into a reaction bottle, stirring at 70-90 ℃ to react for 6-8 hours, and then distilling at 60-70 ℃ under reduced pressure to remove acid liquor; then adding ethyl acetate with the ketone group dosage of 3-5 times and 5% sodium thiosulfate solution with the ketone group dosage of 5-7 times into a reaction bottle, stirring for 20-30 minutes, and standing for layering; collecting an organic layer, extracting a water layer with ethyl acetate for 2 times, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution into the organic layers, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding 0.5-1% of medicinal carbon into the organic layer, stirring at 60-70 ℃ for decoloration for 20-30 minutes, filtering, decompressing and evaporating the filtrate at 60-70 ℃ until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2-3 hours, filtering, and vacuum drying at 60-70 ℃ for 5-6 hours to obtain the acetoxy compound of the formula II.

4. The method according to claim 1, wherein in step 2, 2.5 to 3.5L of ethanol is added per 1mol of the acetoxy compound of formula II.

5. The process according to claim 1, wherein in step 2, 3 to 5mol of sodium hydroxide are added per 1mol of the acetoxy compound of formula II.

6. The method according to claim 1, wherein in step 2, the obtained filter cake is reacted with 3.5-4.5L of ethyl acetate and 8-10 mol of citric acid.

7. The method according to claim 1, wherein step 2 is performed as follows: adding 1mol of acetoxy of a formula II and 2.5-3.5L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 3-5 mol of 5-8% sodium hydroxide solution, and controlling the dropwise adding speed to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 12-15 hours after the dripping is finished to ensure that the reaction is complete, and filtering to obtain a filter cake; adding a filter cake, 3.5-4.5L of ethyl acetate and 8-10 mol of 10% citric acid solution into a reaction bottle, stirring for 1-2 hours, standing for layering, and collecting an organic layer; extracting the water layer with ethyl acetate twice, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding 0.5-1% of medicinal carbon into the organic layer, stirring and decoloring for 1-2 hours at 60-70 ℃, filtering, carrying out reduced pressure distillation on the filtrate at 60-80 ℃ to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction liquid to 5-10 ℃, carrying out heat preservation and crystallization for 3-4 hours, filtering, and carrying out vacuum drying at 60-70 ℃ for 3-8 hours to obtain a lorazepam crude product.

8. The method according to claim 1, which is performed as follows:

step 1, acetoxylation reaction to prepare acetoxylation compound of formula II

Adding 1mol of ketone compound of formula I, 12-15 mol of glacial acetic acid, 2-3 mol of potassium acetate, 1.5-2 mol of potassium persulfate and 2-3 mol of iodine into a reaction bottle, stirring at 70-90 ℃ to react for 6-8 hours, and then distilling at 60-70 ℃ under reduced pressure to remove acid liquor; then adding ethyl acetate with the ketone group dosage of 3-5 times and 5% sodium thiosulfate solution with the ketone group dosage of 5-7 times into a reaction bottle, stirring for 20-30 minutes, and standing for layering; collecting an organic layer, extracting a water layer with ethyl acetate for 2 times, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution into the organic layers, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding 0.5-1% of medicinal carbon into the organic layer, stirring at 60-70 ℃ for decoloration for 20-30 minutes, filtering, decompressing and evaporating the filtrate at 60-70 ℃ to remove the solvent until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2-3 hours, filtering, and vacuum drying at 60-70 ℃ for 5-6 hours to obtain an acetoxy compound of the formula II;

step 2, preparing lorazepam by hydrolysis

Adding 1mol of acetoxy of a formula II and ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 3-5 mol of 5-8% sodium hydroxide solution, and controlling the dropwise adding speed to maintain the temperature of the reaction solution at 2-8 ℃; continuously stirring at the temperature for 12-15 hours after the dripping is finished to ensure that the reaction is complete, and filtering to obtain a filter cake; adding a filter cake, 3.5-4.5L of ethyl acetate and 8-10 mol of 10% citric acid solution into a reaction bottle, stirring for 1-2 hours, standing for layering, and collecting an organic layer; extracting the water layer with ethyl acetate twice, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution, stirring for 20-30 minutes, standing for layering, and separating the organic layers; adding 0.5-1% of medicinal carbon into the organic layer, stirring and decoloring for 1-2 hours at 60-70 ℃, filtering, carrying out reduced pressure distillation on the filtrate at 60-80 ℃ to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction liquid to 5-10 ℃, preserving heat and crystallizing for 3-4 hours, filtering, and carrying out vacuum drying at 60-70 ℃ for 3-8 hours to obtain a lorazepam crude product;

Step 3, refining

Adding 20g of lorazepam crude product, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon into a reaction bottle, stirring at 70-90 ℃ for 30-45 minutes, filtering while the mixture is hot, cooling the filtrate to 5-10 ℃ under stirring, preserving heat and crystallizing for 2-4 hours, filtering, and drying at 50-60 ℃ in vacuum for 3-5 hours; and (3) placing 10g of dried substance, 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon into a reaction bottle, stirring for 20-30 minutes at 60-80 ℃, filtering while the mixture is hot, cooling to 5-10 ℃ under stirring, preserving heat, crystallizing for 2-4 hours, filtering, and vacuum drying at 60-70 ℃ for 5-7 hours to obtain lorazepam.