CN110683994B - Novel crystal form of lorazepam, preparation method and pharmaceutical application thereof - Google Patents

Abstract

The invention relates to a novel crystal form for preparing lorazepam, a preparation method and a pharmaceutical application thereof. Specifically, the present invention provides lorazepam crystals that use Cu-ka radiation and have 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 2 Θ; for example, the crystal has 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 °. The invention also provides a preparation method of the lorazepam new crystal form. Also provides the pharmaceutical application of the new crystal form. The novel crystal form for preparing lorazepam, which is prepared by the method disclosed by the invention, has excellent performances such as described in the specification of the invention.

Description

Novel crystal form of lorazepam, preparation method and pharmaceutical application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a preparation method of lorazepam, a benzodiazepine medicine. Also relates to lorazepam prepared by the method and application thereof in medicines with anxiolytic, antiepileptic, anticonvulsant and sedative and hypnotic effects. The invention also relates to a new crystal form of lorazepam prepared by the method, and pharmaceutical application of the new crystal form.

Background

Lorazepam (lorazepam), 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 chemical structure:

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

Lorazepam, also known as lorazepam, chlordiazepam, and chlordiazepam, belongs to Benzodiazepine (BZD) drugs. It acts on the GABAa regulating part in nerve center, strengthens the GABA inhibiting function, starts chloride ion channel, produces strong anxiolytic effect, and has replaced various historical sedative drugs to become the main drug for treating anxiety. In addition, lorazepam also has good antiepileptic, anticonvulsant and sedative hypnotic effects.

At present, medicines for first-line anti-epileptic state, such as diazepam, phenytoin sodium, phenobarbital and the like, have defects in clinical application. Diazepam has quick response time but lacks persistence, convulsion is repeated frequently in a short time, the diazepam has strong respiratory inhibition effect on children, and hypotension and phlebitis at injection parts can also be caused; phenytoin sodium has slow response time, needs to be combined with diazepam, and the speed of intravenous injection needs to be strictly controlled, otherwise hypotension can occur; the phenobarbital is difficult to observe clinically, the intramuscular injection has slow effect time, and the combined application with the diazepam is easy to cause respiratory depression. The lorazepam is an important progress for treating the status epilepticus, has the effect time of resisting the status epilepticus basically consistent with that of the diazepam, can quickly control convulsion when being used independently, but has more lasting effect time than the diazepam, has less convulsion repetition, is easy to take and observe clinically, and is effective to various status epilepticus. Respiratory and cardiovascular depression is less frequent and other side effects are less frequent than with diazepam, phenobarbital, etc. When the composition is used in combination with other medicines, side effects are not increased, particularly when the composition is used in combination with phenobarbital (most patients still need to use the composition to maintain control over attacks), the phenomenon of respiratory depression is not observed, active metabolites are not generated in a human body, and the tissue distribution is low. Therefore, lorazepam basically has the characteristics of an ideal anti-epileptic persistent state medicament, and can be used as a first-line anti-epileptic persistent state medicament in the future.

Lorazepam is widely used abroad, and has a good sales trend. This product was named in the first hundred prescription drug ranks 64 th in the United states in 1997. Lorazepam (Ativan), developed by heysk alt, a subordinate subsidiary of the american household products company, was predicted to sell for $ 2.5 billion in 2000 and was listed as a world-wide drug in 2000. At present, only three enterprises are produced in China.

Currently, antipyretic analgesics, anti-gout drugs, skeletal muscle relaxants and brain function improving drugs are main consumer varieties of Chinese nervous system drugs, while antiepileptics, anticonvulsants, sedative hypnotics and anxiolytics (main evidence drugs of lorazepam) account for a smaller proportion, and lorazepam is not listed in the main use varieties of the categories, which indicates that the usage amount of the drugs is very small. And (3) related expert analysis: on one hand, the popularization and publicity of lorazepam are not enough, and on the other hand, the lorazepam is related to the serious physiological diseases and the mild psychological diseases of people in China. As the medical model gradually shifts to the bio-psycho-social model, more and more people seek medical attention for psychological diseases. The prevalence of psychological disease is far higher than we imagine, as the WHO surveys it in 15 centers (including shanghai) shows that 24% of patients seeking hospital-integrated diagnosis are psychological disorders. In the case of the psychological outpatient service of Zhongshan hospital, various anxiety diseases account for 30% of the total outpatient service. It is well documented that not only psychological and physiological stress can be a causative factor in humans, but also the types of human behavior are well correlated with certain diseases, and many patients with physical disorders also develop a need for treatment of depression and anxiety disorders. The survey 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 as high as 65.96%, anorexia nervosa patients are also accompanied with anxiety, the incidence rate of the disease tends to rise year by year at home and abroad, and the potential anxiety patients are quite extensive. Therefore, with the continuous improvement of the living standard and the cognitive level of people in China, the lorazepam has very great market potential in China in terms of better curative effect and good selling form internationally (Li Ying, chinese medicine guide, 2000,2 (6): 30).

The synthesis of lorazepam was first described in s.c. bell BE621819 and US3296249 (1963, 1967, am. Home Prod.), and has a melting point of 166-168 ℃ (also described as melting point 161-164 ℃). 3238 Zxft 3238 (3262 Zxft 3262, et al, synthesis of lorazepam, proceedings of the Huaihai academy of Industrial science (Nature science edition), 2005, 14 (3): 44) designs a synthetic route of lorazepam, and the main processes include a condensation reaction (I), a condensation reaction (II), a cyclization reaction, a ring expansion reaction, an acylation rearrangement reaction and a hydrolysis reaction, and the lorazepam synthesized by the method is analyzed by using a high performance liquid chromatograph, so that the qualitative purity of the lorazepam can reach 98.6%, and the total reaction yield is 42.5%. The structure-activity relationship studies of lorazepam were first disclosed in s.c. bell, j.med. chem.11, 457 (1968); HPLC assays for lorazepam were first disclosed in i.jane, a.mckinnon, j.chromanogr.323, 191 (1985); some literature on the pharmacology, drug metabolism and clinical studies of lorazepam has been disclosed in g.owen et al, arzneim. -forsch.21, 1047-1102 (1971); toxicity studies of lorazepam were first disclosed in g.owen et al, arzneim. -forsch.21, 1047-1102 (1971). 1065; for reviews of lorazepam see j.g. rutgers, c.m. shearer, anal. Profiles Drug subs.9, 397-426 (1980); for a review of clinical pharmacology and therapeutic applications of lorazepam, see b.amoeer, d.j.greenblatt, drugs 21, 161-200 (1981); clinical trials of lorazepam to prevent recurrent seizures of alcoholic epilepsy are described in g.d' onoflorio et al, n.engl.j.med.340, 915 (1999).

Lorazepam has been collected in multinational pharmacopoeias including chinese pharmacopoeia, united states pharmacopoeia, european pharmacopoeia, japanese pharmacopoeia, korean pharmacopoeia, and the like. The melting point of lorazepam is known to be almost insoluble in water, the solubility in water is only 0.08mg/ml, the melting point of crystal is 166-168 ℃, the crystal is unstable when exposed to light, the properties bring challenges to the preparation of the medicine, for example, the problem of low oral bioavailability of the medicine is usually caused when the solubility is low, and the stability problem of the raw material medicine not only influences the preparation of the medicine preparation, but also influences the long-term storage and transportation of the preparation. Accordingly, it would be highly desirable to those skilled in the art to provide a process for preparing lorazepam that exhibits one or more beneficial effects.

Disclosure of Invention

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

To this end, the present invention provides, in a first aspect, a lorazepam crystal that exhibits diffraction peaks at about 12.17 °, about 14.15 °, about 15.27 °, about 16.84 °, about 17.91 °, and about 20.81 ° in a powder X-ray diffraction pattern expressed in degrees 2 θ using Cu-ka radiation.

The crystal according to any one of the embodiments of the first aspect of the present invention, which has diffraction peaks 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 ° in a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu — K α radiation.

The crystal according to any one of the embodiments of the first aspect of the present invention, which has diffraction peaks at 12.17 ± 0.10 °, 14.15 ± 0.10 °, 15.27 ± 0.10 °, 16.84 ± 0.10 °, 17.91 ± 0.10 °, and 20.81 ± 0.10 ° in a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu — K α radiation.

The crystal according to any one of the embodiments of the first aspect of the present invention, which has 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 a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu-ka radiation.

The crystal according to any one of the embodiments of the first aspect of the present invention, which has diffraction peaks 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 a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu — K α radiation.

The crystal according to any one of the embodiments of the first aspect of the present invention, which has diffraction peaks 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 a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu — K α radiation.

The crystal according to any one of the embodiments of the first aspect of the present invention, which uses Cu — ka radiation, has a powder X-ray diffraction pattern shown in fig. 1.

The crystal according to any one of the embodiments of the first aspect of the present invention, which is produced by a method comprising the steps of:

heating and dissolving the lorazepam crude product, ethanol, formic acid and medicinal carbon, filtering to remove the carbon, cooling the filtrate for crystallization, and vacuum-drying the filtered crystal; heating and dissolving the dried substance with ethyl acetate and medicinal carbon, filtering to remove carbon, cooling the filtrate for crystallization, and vacuum drying the filtered crystal to obtain the lorazepam crystal.

According to the crystallization of any embodiment of the first aspect of the invention, in the preparation method, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon are added into each 20g of lorazepam crude product.

The crystal according to any one of the embodiments of the first aspect of the present invention, which is produced by a method in which the crystal is stirred at 70 to 90 ℃ for 30 to 45 minutes while being treated in ethanol; and/or, heat-preserving and crystallizing for 2-4 hours at the temperature of 5-10 ℃.

The crystal according to any one of the embodiments of the first aspect of the present invention, wherein 100 to 150ml of ethyl acetate and 0.5 to 1% of medicinal charcoal are added to 10g of the dried product.

The crystals according to any one of the embodiments of the first aspect of the present invention can be produced by a method in which the crystals are stirred at 60 to 80 ℃ for 20 to 30 minutes while being treated in ethyl acetate.

The crystal according to any one of the embodiments of the first aspect of the present invention, which is prepared by the method, is crystallized at 5 to 10 ℃ for 2 to 4 hours.

The crystallization according to any one of the embodiments of the first aspect of the present invention, said production method is carried out by 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 hot, cooling the filtrate to 5-10 ℃ while stirring, preserving heat, crystallizing for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; 10g of the dried substance, 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon are taken and placed in a reaction bottle, stirred for 20-30 minutes at the temperature of 60-80 ℃, filtered when the solution is hot, cooled to 5-10 ℃ under stirring, filtered after heat preservation and crystallization for 2-4 hours, and vacuum-dried for 5-7 hours at the temperature of 60-70 ℃ to obtain the lorazepam crystal.

Further, the second process of the invention provides a process for the preparation of a lorazepam crystal, for example a crystal according to any of the embodiments of the first aspect of the invention, comprising the steps of:

heating and dissolving the lorazepam crude product, ethanol, formic acid and medicinal carbon, filtering to remove the carbon, cooling the filtrate for crystallization, and vacuum-drying the filtered crystal; heating and dissolving the dried substance with ethyl acetate and medicinal carbon, filtering to remove carbon, cooling the filtrate for crystallization, and vacuum drying the filtered crystal to obtain the lorazepam crystal.

According to the method of any embodiment of the second aspect of the invention, 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon are added into each 20g of lorazepam crude product.

According to the method of any one of the embodiments of the second aspect of the present invention, the ethanol is stirred at 70 to 90 ℃ for 30 to 45 minutes during the treatment; and/or, heat-preserving and crystallizing for 2-4 hours at the temperature of 5-10 ℃.

According to the method of any one of the embodiments of the second aspect of the present invention, 100 to 150ml of ethyl acetate and 0.5 to 1% of medicinal charcoal are added per 10g of the dried product.

According to the process of any one of the embodiments of the second aspect of the present invention, the stirring is carried out for 20 to 30 minutes at 60 to 80 ℃ while treating in ethyl acetate.

According to the method of any embodiment of the second aspect of the present invention, the crystallization is carried out at 5 to 10 ℃ for 2 to 4 hours.

The process according to any of the embodiments of the second aspect of the present invention, which is carried out as follows: 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 hot, cooling the filtrate to 5-10 ℃ while stirring, preserving heat, crystallizing for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; 10g of the dried product, 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon are taken and placed in a reaction bottle, stirred for 20-30 minutes at the temperature of 60-80 ℃, filtered while hot, cooled to 5-10 ℃ under stirring, filtered after heat preservation and crystallization for 2-4 hours, and then filtered, and dried in vacuum for 5-7 hours at the temperature of 60-70 ℃ to obtain lorazepam crystals.

Further, the third process of the present invention provides a process for the preparation of lorazepam crystals, such as the crystals according to any of the embodiments of the first aspect of the present invention, comprising the steps of:

step 1: reacting ketone base material 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 stirring to separate layers; collecting organic layer, adding saturated sodium chloride solution, separating organic layer, decolorizing with medicinal carbon, concentrating filtrate under reduced pressure, crystallizing, and drying to obtain acetoxyl compound of formula II;

step 2: dropwise adding a sodium hydroxide solution into a mixture of an acetoxyl substance shown in the formula II and ethanol, stirring to ensure that the reaction is complete, filtering to obtain a filter cake, reacting the filter cake with ethyl acetate and a citric acid solution, and layering; adding a saturated sodium chloride solution into the collected organic layer, separating the organic layer, adding medical carbon for decolorization, filtering the obtained filtrate, carrying out reduced pressure distillation and crystallization, and drying the filtered crystals to obtain a lorazepam crude product;

and step 3: heating and dissolving the lorazepam crude product, ethanol, formic acid and medicinal carbon, filtering to remove the carbon, cooling the filtrate for crystallization, and vacuum-drying the filtered crystal; heating and dissolving the dried substance with ethyl acetate and medicinal carbon, filtering to remove carbon, cooling the filtrate for crystallization, and vacuum drying the filtered crystal to obtain the lorazepam crystal. In the invention, if not specifically stated, the lorazepam crude product is dissolved in materials such as ethanol, and the lorazepam dry product is dissolved in materials such as ethyl acetate after being heated and stirred, and the operation is the conventional operation of the refining process.

According to the third aspect of the invention of any embodiment of the method, in step 1, the formula I ketone compound 1mol (305 g), glacial acetic acid 12 ~15 mol, potassium acetate 2~ 3mol, potassium persulfate 1.5 ~ 2mol, iodine 2~ 3mol feeding ratio reaction.

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

In the process according to any one of the embodiments of the third aspect of the present invention, in step 1, ethyl acetate in an amount of 3 to 5 times the charged amount of the ketone-based material and sodium thiosulfate in an amount of 5 to 7 times the charged amount of the ketone-based material are added to the reaction mixture after the completion of the reaction. In the present invention, the term "3 to 5 times the amount of a ketone charged" or the like means a weight-fold unless otherwise specified. In the present invention, the term "5 to 7 times the charged amount of ketone material" or the like in relation to sodium thiosulfate, as it is not otherwise specified, refers to a multiple of sodium thiosulfate rather than a multiple of its solution.

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

The process according to any one of the embodiments of the third aspect of the present invention, wherein step 1 is carried out as follows: adding 1mol (305 g) 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 ℃ for reacting for 6-8 hours, and then distilling under reduced pressure at 60-70 ℃ to remove acid liquor; then adding ethyl acetate (3-5 times of the feeding amount of the ketone) and 5% sodium thiosulfate solution (5-7 times of the feeding amount of the ketone) into the reaction bottle, stirring for 20-30 minutes, and standing for layering; collecting organic layers, extracting a water layer for 2 times by using ethyl acetate, combining the organic layers, adding a saturated sodium chloride solution with the volume of 1-1.5 times of that of 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 and decolorizing for 20-30 min at 60-70 ℃, filtering, evaporating the filtrate at 60-70 ℃ under reduced pressure to remove the solvent until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing for 2-3 h at 0-5 ℃, filtering, and drying in vacuum for 5-6 h at 60-70 ℃ to obtain the acetoxyl substance of the formula II.

The process according to any one of the embodiments of the third aspect of the present invention, wherein in step 2, 2.5 to 3.5L of ethanol is added per 1mol of the acetoxy compound of formula II.

The process according to any one of the embodiments of the third aspect of the present invention, wherein in step 2, 3 to 5mol of sodium hydroxide is added per 1mol of the acetoxy compound of formula II.

The process according to any one of the embodiments of the third aspect of the present invention, wherein the concentration of the sodium hydroxide solution in the step 2 is 5 to 8%.

The method according to any one of the embodiments of the third aspect of the present invention, wherein in the step 2, the sodium hydroxide is added dropwise and the temperature of the reaction solution is controlled to be 2 to 8 ℃ during the subsequent reaction.

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

The method according to any embodiment of the third aspect of the present invention, wherein step 2 is performed as follows: adding 1mol (363 g) of acetoxyl compound of formula II and 2.5-3.5L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 5-8% sodium hydroxide solution (3-5 mol) and controlling the dropwise adding speed to keep the temperature of the reaction solution at 2-8 ℃; after the dropwise addition is finished, the mixture is kept at the temperature and is continuously stirred for 12 to 15 hours to ensure that the reaction is complete, and the mixture is filtered to obtain a filter cake; adding the filter cake, ethyl acetate (3.5-4.5L) and 10% citric acid solution (8-10 mol of citric acid) into a reaction bottle, stirring for 1-2 hours, standing for layering, and collecting an organic layer; extracting the water layer twice with ethyl acetate, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution, stirring for 20-30 min, standing for layering, and separating the organic layers; adding medicinal carbon (0.5-1%) into the organic layer, stirring and decoloring at 60-70 ℃ 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 ℃, 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 the lorazepam crude product.

According to the third aspect of the invention in any embodiment of the method, in step 3, every 20g of lorazepam crude product is added with 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal charcoal.

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

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

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

The method according to any one of the embodiments of the third aspect of the present invention, wherein step 3 is performed by: 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 hot, cooling the filtrate to 5-10 ℃ while stirring, preserving heat, crystallizing for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; 10g of the dried product, 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon are taken and placed in a reaction bottle, stirred for 20-30 minutes at the temperature of 60-80 ℃, filtered while hot, cooled to 5-10 ℃ under stirring, filtered after heat preservation and crystallization for 2-4 hours, and then filtered, and dried in vacuum for 5-7 hours at the temperature of 60-70 ℃ to obtain the lorazepam refined product.

The process according to any of the embodiments of the third aspect of the present invention, which is carried out as follows:

step 1, acetoxylation reaction to prepare acetoxyl substance of formula II

Adding 1mol (305 g) 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 ℃ for reacting for 6-8 hours, and then distilling under reduced pressure at 60-70 ℃ to remove acid liquor; then adding ethyl acetate (3-5 times of the feeding amount of the ketone) and 5% sodium thiosulfate solution (5-7 times of the feeding amount of the ketone) into the reaction bottle, stirring for 20-30 minutes, and standing for layering; collecting organic layers, extracting a water layer for 2 times by using ethyl acetate, combining the organic layers, adding a saturated sodium chloride solution with the volume of 1-1.5 times of that of 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 and decoloring at 60-70 ℃ for 20-30 minutes, filtering, evaporating the filtrate at 60-70 ℃ under reduced pressure to remove the solvent until a large amount of crystals are separated out, stopping concentration, cooling, crystallizing at 0-5 ℃ for 2-3 hours, filtering, and drying in vacuum at 60-70 ℃ for 5-6 hours to obtain the acetoxyl substance of the formula II;

step 2, hydrolyzing to prepare lorazepam

Adding 1mol (363 g) of acetoxyl compound of formula II and 2.5-3.5L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 5-8% sodium hydroxide solution (3-5 mol) and controlling the dropwise adding speed to keep the temperature of the reaction solution at 2-8 ℃; after the dropwise addition is finished, the mixture is kept at the temperature and is continuously stirred for 12 to 15 hours to ensure that the reaction is complete, and the mixture is filtered to obtain a filter cake; adding the filter cake, ethyl acetate (3.5-4.5L) and 10% citric acid solution (8-10 mol of citric acid) into a reaction bottle, stirring for 1-2 hours, standing for layering, and collecting an organic layer; extracting the water layer twice with ethyl acetate, combining the organic layers, adding 1-1.5 times of saturated sodium chloride solution, stirring for 20-30 min, standing for layering, and separating the organic layers; adding medicinal carbon (0.5-1%) into the organic layer, stirring and decoloring for 1-2 hours at the temperature of 60-70 ℃, filtering, distilling the filtrate at the temperature of 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 ℃, carrying out heat preservation and crystallization for 3-4 hours, filtering, and carrying out vacuum drying for 3-8 hours at the temperature of 60-70 ℃ 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 hot, cooling the filtrate to 5-10 ℃ while stirring, preserving heat, crystallizing for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; 10g of the dried product, 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon are taken and placed in a reaction bottle, stirred for 20-30 minutes at the temperature of 60-80 ℃, filtered while hot, cooled to 5-10 ℃ under stirring, filtered after heat preservation and crystallization for 2-4 hours, and then filtered, and dried in vacuum for 5-7 hours at the temperature of 60-70 ℃ to obtain lorazepam crystals.

According to the process of any embodiment of the third aspect of the present invention, lorazepam crystals are produced that have diffraction peaks at about 12.17 °, about 14.15 °, about 15.27 °, about 16.84 °, about 17.91 °, and about 20.81 ° in a powder X-ray diffraction pattern, expressed in degrees 2 θ, using Cu-ka radiation.

According to the process of any embodiment of the third aspect of the present invention, the lorazepam crystals produced therefrom have diffraction peaks 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 ° in a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu-ka radiation.

According to the method of any embodiment of the third aspect of the present invention, the lorazepam crystals prepared therefrom have diffraction peaks at 12.17 ± 0.10 °, 14.15 ± 0.10 °, 15.27 ± 0.10 °, 16.84 ± 0.10 °, 17.91 ± 0.10 °, and 20.81 ± 0.10 ° in a powder X-ray diffraction pattern expressed in terms of 2 θ using Cu-ka radiation.

According to the process of any embodiment of the third aspect of the invention, the lorazepam crystals produced using Cu-ka radiation have 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 the powder X-ray diffraction pattern expressed in degrees 2 Θ.

According to the process of any embodiment of the third aspect of the present invention, lorazepam crystals prepared using Cu-Ka radiation have diffraction peaks 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 a powder X-ray diffraction pattern expressed in degrees 2 θ.

According to the method of any embodiment of the third aspect of the present invention, the lorazepam crystals prepared therefrom have diffraction peaks 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 a powder X-ray diffraction pattern expressed in 2 θ using Cu-ka radiation.

The process according to any embodiment of the third aspect of the invention, which produces lorazepam crystals using Cu-ka radiation, has a powder X-ray diffraction pattern as shown in figure 1.

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

In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.

All documents cited herein are incorporated herein by reference in their entirety and to the extent they do not conform to the teachings of the present invention, the statements made therein shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

Anxiety disorder is also known as anxiety neurosis, and is one of the most common diseases in the general category of neurosis. The anxiety emotional experience is mainly characterized by two forms of generalized anxiety and panic attack. The main performance is as follows: there is no clear and objective object such as tension, restlessness, palpitation, trembling hands, sweating, frequent micturition and restlessness, which seriously affect the physical and mental health of the patient. In the category of anxiolytic drugs, lorazepam (Lorazepam) is a better therapeutic drug and is deeply trusted by patients. Lorazepam is a benzodiazepine anxiolytic, named 7-chloro-5- (2-chlorobenzene) -1,3-dihydro-3-hydroxy-2H-1,4-Benzodiazem-2-one, is a benzodiazepine psychotropic drug synthesized by Wyeth corporation, USA, and developed by Wyeth corporation, japan.

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

Drawings

FIG. 1: the powder X-ray diffraction pattern of the lorazepam refined product is disclosed.

Detailed Description

The following examples are provided for illustrative purposes only and are not intended to, nor should they be construed as limiting the invention in any way. Those skilled in the art will recognize that conventional variations and modifications can be made to the following embodiments without departing from the spirit or scope of the invention.

The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.

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:

accurately weighing a to-be-detected product, adding acetonitrile to dissolve the to-be-detected product, and quantitatively diluting the to-be-detected product to prepare a solution containing 1mg of acetonitrile in each 1ml of the to-be-detected product as a test solution; accurately weighing a proper amount of 2-amino-2', 5-dichlorobenzophenone (impurity I) reference substance, adding acetonitrile to dissolve, and quantitatively diluting to obtain a solution containing 10ug of the reference substance per 1 ml; precisely measuring 1ml of each of the test solution and the reference solution, placing the test solution and the reference solution in the same 100ml measuring flask, diluting the solutions to the scale with acetonitrile, and shaking up to obtain the reference solution. According to the chromatographic condition test under the content determination item, 20ul of each of the test solution and the control solution is precisely measured, the measured solution and the control solution are respectively injected into a liquid chromatograph, and the retention time of the chromatogram to the main component peak is recorded to be 3 times. Specific impurity calculation method: if a chromatographic peak with the retention time consistent with that of the impurity I in the reference solution exists in the chromatogram of the test solution, calculating the content of the impurity I by the peak area according to an external standard method; if a chromatographic peak which is consistent with the retention time of the 6-chloro-4- (2-chlorophenyl) quinazoline-2-formaldehyde (impurity II) exists, the percentage content of the chromatographic peak is calculated by comparing the peak area of the chromatographic peak with the peak area of lorazepam in a control solution; comparing the peak areas of other single impurities with the peak areas of lorazepam in the control solution to calculate the percentage content of the impurities; the sum of the peak areas of the impurities is compared with the area of the peak of the lorazepam in the control solution to calculate the percentage content (total impurity content). The chromatographic purity (minus the solvent peak), i.e. the HPLC purity, was calculated by area normalization.

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

Detection method example 2: determination of powder X-ray diffraction Pattern of Crystal

The diffraction pattern of the crystals was determined using the following powder X-ray diffraction analysis method: rigaku Dmax/2400 type powder X-ray diffractometer; cuKa radiation, graphite monochromator, 40KV,100MA,2 theta scanning range is 0.0-40 degrees, scanning speed is 3 degrees/minute, step length is 0.01 degrees; the scanning mode is continuous scanning; and the slit is arranged as follows: 1/2 degree anti-scatter slit: SS 1/2 °; RS is 0.3mm.

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

No.	position (2 theta, degree)	Relative abundance (%)
			1	7.93	34.37
2	9.04	48.93
			3	12.17	100.00
4	14.15	52.41
			5	15.27	59.36
6	16.84	64.12
			7	17.91	77.24
8	20.81	61.13
			9	21.44	48.42
10	26.38	48.91

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 °, and about 20.81 ° in a powder X-ray diffraction pattern expressed in degrees 2 Θ; in particular, in a powder X-ray diffraction pattern expressed by 2 theta angles, diffraction peaks exist at 12.17 +/-0.20 degrees, 14.15 +/-0.20 degrees, 15.27 +/-0.20 degrees, 16.84 +/-0.20 degrees, 17.91 +/-0.20 degrees and 20.81 +/-0.20 degrees; in particular, in the powder X-ray diffraction pattern expressed by the angle of 2 theta, diffraction peaks exist at 12.17 +/-0.10 degrees, 14.15 +/-0.10 degrees, 15.27 +/-0.10 degrees, 16.84 +/-0.10 degrees, 17.91 +/-0.10 degrees and 20.81 +/-0.10 degrees; in particular, in the powder X-ray diffraction pattern expressed in degrees 2 Θ, 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 the powder X-ray diffraction pattern expressed by the angle of 2 theta, diffraction peaks are found at 7.93 +/-0.20 degrees, 9.04 +/-0.20 degrees, 12.17 +/-0.20 degrees, 14.15 +/-0.20 degrees, 15.27 +/-0.20 degrees, 16.84 +/-0.20 degrees, 17.91 +/-0.20 degrees, 20.81 +/-0.20 degrees, 21.44 +/-0.20 degrees, 26.38 +/-0.20 degrees; in particular, in the powder X-ray diffraction pattern expressed by the angle of 2 theta, diffraction peaks exist at 7.93 +/-0.10 degrees, 9.04 +/-0.10 degrees, 12.17 +/-0.10 degrees, 14.15 +/-0.10 degrees, 15.27 +/-0.10 degrees, 16.84 +/-0.10 degrees, 17.91 +/-0.10 degrees, 20.81 +/-0.10 degrees, 21.44 +/-0.10 degrees and 26.38 +/-0.10 degrees; in particular, the powder X-ray diffraction pattern shown in FIG. 1. The lorazepam refined products obtained in step 3 of examples 1-4 of the present invention are in the typical crystalline forms as described above, and they may be referred to as L-form in the present invention.

The present invention uses as starting material a keto compound of formula I, which is directly obtainable from commercial sources, which (or analogs thereof) has also been described for example in US3296429, published in 1967. In the following specific examples, such as example 1, lorazepam is prepared in three main stages, and the reaction scheme is as follows:

(1) Acetoxylation reaction

(2) Hydrolysis

Example 1: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxyl substance 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 ℃ and reacted for 7 hours, and then acid liquor is distilled off under reduced pressure at 65 ℃; then adding ethyl acetate (4 times of the feeding amount of the ketone) and a 5% sodium thiosulfate solution (6 times of the feeding amount of the ketone) into the reaction bottle, stirring for 25 minutes, and standing for layering; collecting organic layer, extracting water layer with ethyl acetate for 2 times, mixing organic layers, adding 1.25 times volume of saturated sodium chloride solution, stirring for 25 min, standing for layering, and collecting organic layer; adding medicinal carbon (0.75%) into the organic layer, stirring and decoloring at 65 ℃ for 25 minutes, filtering, evaporating the filtrate at 65 ℃ under reduced pressure to remove the solvent until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2.5 hours, filtering, and drying at 65 ℃ in vacuum for 5.5 hours to obtain the acetoxyl compound of the formula II (the yield is 78.4%, and the HPLC purity is 92.3%).

Step 2, hydrolyzing to prepare lorazepam

Adding 1mol (363 g) of acetoxyl compound of formula II and 3L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 6 mol of sodium hydroxide solution (4 mol of sodium hydroxide), and controlling the dropwise adding speed to keep the temperature of the reaction solution at 2-8 ℃; after the dropwise addition, the temperature is maintained and the stirring is continued for 14 hours to ensure that the reaction is complete, and the filtration is carried out 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 for layering, 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 layer; adding medicinal carbon (0.75%) into the organic layer, stirring and decoloring at 65 ℃ for 1.5 hours, filtering, distilling the filtrate at 70 ℃ 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 and crystallizing for 3.5 hours, filtering, and drying in vacuum at 65 ℃ for 6 hours to obtain a lorazepam crude product (the yield is 64.3%, and the HPLC purity is 95.7%).

Step 3, refining

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

Example 2: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxyl substance of formula II

Adding 1mol (305 g) of ketone compound of formula I, 15mol of glacial acetic acid, 2mol of potassium acetate, 2mol of potassium persulfate and 2mol of iodine into a reaction bottle, stirring at 70 ℃ for reaction for 8 hours, and then distilling under reduced pressure at 70 ℃ to remove acid liquor; then adding ethyl acetate (3 times of the feeding amount of the ketone) and a 5% sodium thiosulfate solution (7 times of the feeding amount of the ketone) into the reaction bottle, stirring for 20 minutes, and standing to separate layers; collecting organic layer, extracting water layer with ethyl acetate for 2 times, mixing organic layers, adding 1 volume times of saturated sodium chloride solution, stirring for 20 min, standing for layering, and collecting organic layer; adding medicinal carbon (0.5%) into the organic layer, stirring and decoloring at 70 ℃ for 20 minutes, filtering, evaporating the filtrate at 60 ℃ under reduced pressure to remove the solvent until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2 hours, filtering, and drying at 70 ℃ in vacuum for 5 hours to obtain the acetoxyl compound of the formula II (the yield is 78.6%, and the HPLC purity is 92.6%).

Step 2, hydrolyzing to prepare lorazepam

Adding 1mol (363 g) of acetoxyl compound of formula II and 2.5L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 8% sodium hydroxide solution (3 mol) and controlling the dropwise adding speed to keep the temperature of the reaction solution at 2-8 ℃; after the dropwise addition, the mixture is kept at the temperature and is continuously stirred for 12 hours to ensure that the reaction is complete, and the mixture is filtered to obtain a filter cake; adding the filter cake, ethyl acetate (4.5L) and 10% citric acid solution (citric acid 10 mol) into a reaction bottle, stirring for 1 hour, standing for layering, and collecting an organic layer; extracting the water layer with ethyl acetate twice, mixing the organic layers, adding 1.5 times volume of saturated sodium chloride solution, stirring for 20 min, standing for layering, and separating the organic layer; adding medicinal carbon (0.5%) into the organic layer, stirring and decoloring at 70 ℃ for 2 hours, filtering, distilling the filtrate at 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 and crystallizing for 4 hours, filtering, and vacuum drying at 70 ℃ for 3 hours to obtain a lorazepam crude product (the yield is 64.3%, and the HPLC purity is 95.7%).

Step 3, refining

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

Example 3: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxyl substance of formula II

1mol (305 g) of ketone compound of 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 ℃ for reaction for 6 hours, and then decompressed and distilled at 60 ℃ to remove acid liquor; then adding ethyl acetate (5 times of the feeding amount of the ketone) and a 5% sodium thiosulfate solution (5 times of the feeding amount of the ketone) into the reaction bottle, stirring for 30 minutes, and standing to separate layers; collecting organic layer, extracting water layer with ethyl acetate for 2 times, mixing organic layers, adding 1.5 times volume of saturated sodium chloride solution, stirring for 30 min, standing for layering, and collecting organic layer; adding medicinal carbon (1%) into the organic layer, stirring and decoloring at 60 ℃ for 30 minutes, filtering, evaporating the filtrate at 70 ℃ under reduced pressure to remove the solvent until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 3 hours, filtering, and vacuum-drying at 60 ℃ for 6 hours to obtain the acetoxyl compound of the formula II (the yield is 77.8%, and the HPLC purity is 91.8%).

Step 2, hydrolyzing to prepare lorazepam

Adding 1mol (363 g) of acetoxyl compound of formula II and 3.5L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 5% sodium hydroxide solution (5 mol) and controlling the dropwise adding speed to keep the temperature of the reaction solution at 2-8 ℃; after the dropwise addition, the temperature is maintained and the stirring is continued for 15 hours to ensure that the reaction is complete, and the filtration is carried out to obtain a filter cake; adding the filter cake, ethyl acetate (3.5L) and 10% citric acid solution (8 mol of citric acid) into a reaction bottle, stirring for 2 hours, standing for layering, and collecting an organic layer; extracting the water layer twice with ethyl acetate, combining the organic layers, adding 1 volume of saturated sodium chloride solution, stirring for 30 min, standing for layering, and separating the organic layer; adding medicinal carbon (1%) into the organic layer, stirring and decoloring for 2 hours at 60 ℃, filtering, distilling the filtrate at 60 ℃ 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 and crystallizing for 3 hours, filtering, and drying in vacuum for 8 hours at 60 ℃ to obtain a lorazepam crude product (the yield is 64.3%, and the HPLC purity is 95.7%).

Step 3, refining

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

Example 4: preparation of lorazepam

Step 1, acetoxylation reaction to prepare acetoxyl substance 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 flask, stirred at 80 ℃ and reacted for 7 hours, and then the acid solution is distilled off under reduced pressure at 67 ℃; then adding ethyl acetate (3.8 times of the feeding amount of the ketone) and a 5% sodium thiosulfate solution (6.5 times of the feeding amount of the ketone) into the reaction bottle, stirring for 27 minutes, and standing to separate layers; collecting organic layer, extracting water layer with ethyl acetate for 2 times, mixing organic layers, adding 1.3 times volume of saturated sodium chloride solution, stirring for 23 min, standing for layering, and collecting organic layer; adding medicinal carbon (0.8%) into the organic layer, stirring and decoloring at 63 ℃ for 28 minutes, filtering, evaporating the filtrate at 64 ℃ under reduced pressure to remove the solvent until a large amount of crystals are separated out, stopping concentrating, cooling, crystallizing at 0-5 ℃ for 2.7 hours, filtering, and drying in vacuum at 67 ℃ for 5.3 hours to obtain the acetoxy compound of formula II (yield 79.1% and HPLC purity 92.3%).

Step 2, hydrolyzing to prepare lorazepam

Adding 1mol (363 g) of acetoxyl compound of formula II and 2.9L of ethanol into a reaction bottle, stirring at room temperature, cooling to 2-8 ℃, slowly dropwise adding 7% sodium hydroxide solution (3.8 mol) and controlling the dropwise adding speed to keep the temperature of the reaction solution at 2-8 ℃; after the dropwise addition, the temperature is maintained and the stirring is continued for 14 hours to ensure that the reaction is complete, and the filtration is carried out 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 twice with ethyl acetate, combining the organic layers, adding 1.2 times volume of saturated sodium chloride solution, stirring for 28 min, standing for layering, and separating the organic layer; adding medicinal carbon (0.85%) into the organic layer, stirring and decoloring at 68 ℃ for 1 hour, filtering, distilling the filtrate at 64 ℃ under reduced pressure to remove most of ethyl acetate until the filtrate becomes turbid or crystals are separated out, cooling the reaction solution to 5-10 ℃, preserving heat and crystallizing for 3.3 hours, filtering, and drying in vacuum at 68 ℃ for 4 hours to obtain a lorazepam crude product (the yield is 65.7%, and the HPLC purity is 94.5%).

Step 3, refining

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

Example 11: preparation of lorazepam

Referring to the methods of examples 1 to 4, respectively, except that formic acid was not added in the purification process of step 3, four batches of the lorazepam purified products were obtained, and the yields of the lorazepam purified products in the purification steps were all in the range of 78 to 80% and the HPLC purities thereof were all in the range of 98.2 to 98.6%, for example, the yield of the lorazepam purified product obtained in example 1 in the purification step was in the range of 78.7% and the HPLC purities thereof were 98.4%. This result shows that the yield is almost unchanged without adding formic acid during the purification process, but the HPLC purity is slightly decreased.

The melting points of the lorazepam refined products obtained in the examples 1 to 4 are measured to be in the range of 187 to 191 ℃, for example, the melting point of the lorazepam refined product obtained in the example 1 is 188.6 to 190.4 ℃; the melting points of the four batches of lorazepam refined products obtained in example 11 were determined to be within the range of 165-169 ℃, for example, the melting point of the lorazepam refined product obtained in reference example 1 was 167.3-168.1 ℃. It can be presumed from the difference in melting point that: the lorazepam refined products obtained in examples 1-4 and the four lorazepam refined products obtained in example 11 may have different crystal forms.

The four batches of lorazepam purifications obtained in example 11 were subjected to powder X-ray diffraction pattern analysis, and showed that these four substances had no diffraction peak or relative abundance of less than 5% at typical 2 θ angles of 7.93 °, 9.04 °, 12.17 ° and 17.91 °, and the strongest diffraction peak appeared at 14.86 °. It can be seen that the powder X-ray diffraction pattern further demonstrates that the lorazepam refined products obtained in examples 1-4 have different crystal forms from the four lorazepam refined products obtained in example 11.

Although the difference in crystallization process between examples 1 to 4 and example 11 is only reflected in the presence or absence of formic acid addition, the resulting products exhibit significantly different physical property differences. It is expected that physical properties between products, such as, inter alia, melting point, differences between powder X-ray diffraction patterns, may be more unpredictable if the crystallization process is larger than the above-mentioned differences.

Detection method example 3: solubility determination

Adding a 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 filtering supernate by using a 0.22um microporous filter membrane; an appropriate amount of the subsequent filtrate was taken, diluted with a mobile phase as necessary, and the concentration of lorazepam in the subsequent filtrate was measured and the solubility was calculated according to the HPLC method of detection method example 1. As a result: examples 1-4 the solubility of four batches of refined lorazepam products were all in the range of 0.89-0.96 mg/ml, for example, the solubility of the refined lorazepam product of example 1 was 0.915mg/ml; in example 11, the solubility of four batches of lorazepam refined products is in the range of 0.064-0.071 mg/ml, for example, the solubility of lorazepam refined product obtained by referring to example 1 of example 11 is 0.068mg/ml, and the solubility of lorazepam refined products of examples 1-4 is obviously higher.

Detection method example 3: dissolution rate of the prepared tablet

Lorazepam and tablets are recorded in the second part of the chinese pharmacopoeia of 2015 edition, wherein the requirement of the dissolution rate in the lorazepam tablet requires that the limit of the dissolution rate under the specified conditions should be 70% of the labeled amount, and the limitation is lower in the field of the preparation because of the lower solubility of the raw material medicines.

Lorazepam tablets were prepared with a typical formulation/process as follows:

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: crushing lorazepam to a size which can pass through a 200-mesh sieve, and crushing the rest materials to a size which can pass through a 120-mesh sieve; mixing the five materials except magnesium stearate uniformly, preparing into granules through 20-mesh sieve by adopting a dry granulation process (extrusion/crushing), mixing with magnesium stearate, and pressing into tablets by using a die with a proper size, wherein the pressure of different batches of tablets is controlled to be basically consistent.

The lorazepam raw material medicines adopt 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 rate of 8 batches of tablets is measured according to the pharmacopoeia method, and the result is that: examples 1-4 four batches of lorazepam refined products were used as raw materials and the dissolution rates of the 4 batches of tablets were all in the range of 81-86%, for example, the dissolution rate of the tablet obtained by using the lorazepam refined product of example 1 as raw material was 82.7%; example 11 dissolution rates of 4 batches of tablets obtained by using four batches of lorazepam refined products as raw materials were all in the range of 57-62%, for example, dissolution rate of 60.3% of tablets obtained by using lorazepam refined products obtained by referring to the method of example 1 of example 11 as raw materials. Although one can improve the dissolution rate of the tablet by improving the formula/process of the preparation, so that the dissolution rate of the tablet meets the requirements of pharmacopoeia, from the dissolution rate results of the tablet, the preparation performances of the lorazepam refined products of the examples 1-4 are obviously better than those of the lorazepam refined product of the example 11.

The Lorazepam bulk drug sold in the market (national drug standard H20031064): the melting point is 167.6-168.4 ℃, the solubility is 0.074mg/ml, no diffraction peak exists at the typical positions of 7.93 degrees, 9.04 degrees, 12.17 degrees and 17.91 degrees of 2 theta in a powder X-ray diffraction pattern or the relative abundance is less than 5 percent, and the dissolution rate of the tablet in the detection method example 3 is 66.4 percent; these data indicate that the physical and chemical properties of the commercially available lorazepam are not as good as the refined products of examples 1-4 of the present invention.

Lorazepam was prepared according to the Lv Xiaoli reference (Lv Xiaoli, et al, synthesis of lorazepam, proceedings of the Huaihai academy of industry (Nature sciences edition), 2005, 11 (3): 44), which is: melting point 163.7-165.1 ℃, solubility 0.067mg/ml, no diffraction peak or relative abundance less than 5% at typical positions of 7.93 degrees, 9.04 degrees, 12.17 degrees and 17.91 degrees of 2 theta in a powder X-ray diffraction pattern, and dissolution rate of the tablet according to detection method example 3 is 63.6%; these data indicate that the physical and chemical properties of lorazepam in this document are not as good as 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, with commercial specifications typically including: 0.5mg,1.0mg, 2.0mg. Lorazepam tablets are useful in the treatment of anxiety disorders or for the short-term treatment of relief of anxiety symptoms and anxiety associated with depressive symptoms; anxiety or stress associated with stress of daily living, often without the need for anxiolytic treatment. The effect of lorazepam in long-term application, i.e., the effect of lorazepam in more than 4 months, has not been evaluated by systematic clinical studies; the physician should periodically reevaluate the effectiveness of the drug for the individual patient.

The dosage, frequency and treatment period of lorazepam tablet administration should be individually adjusted according to the response of patients. Conveniently, there are 0.5mg,1.0mg and 2.0mg tablet alternatives. The usual dosage range is 2 to 6mg per day, administered in divided doses, the maximum dose being administered before sleep, and the daily dosage being variably adjusted between 1 and 10 mg. For anxiety symptoms, the initial dose for most patients is 2 to 3mg per day, twice or three times daily. Insomnia patients who suffer from anxiety or temporary emotional stress, are administered a single oral dose of 2 to 4mg daily, usually scheduled to be administered before going to sleep. For elderly patients or infirm patients, the recommended initial dose is 1-2 mg/day, and the dosage can be adjusted according to the need and tolerance of the patients. The dosage of lorazepam should be gradually increased as necessary without sudden adjustments to avoid adverse reactions. When the dosage of lorazepam needs to be increased, the dosage of lorazepam should be increased first in the evening before the daytime dosage is increased. Patients are advised to consult a physician before increasing the dosage or stopping the drug abruptly.

Clinical studies show that healthy volunteers take lorazepam with high dose once, have central calming effect and have no influence on respiratory and cardiovascular systems. Reproductive toxicity: reproductive toxicity tests were performed in mice, rats and rabbits, in which various abnormal manifestations (tarsal bones, tibia midbone shrinkage, poor limb rotation, abdominal fissure, cranial deformity, small eyeball, etc.) were occasionally observed but dose-dependently. When the dosage is higher than 40mg/kg, absorption of the litter occurs, and the loss rate of the litter is increased. The clinical significance of the above findings is unknown, but several studies suggest that the use of sedative hypnotic agents (chlordiazepoxide, diazepam, meprobamate) in the early pregnancy may increase the risk of congenital malformations. Since such drugs are not usually used in emergency situations, lorazepam should be avoided in the early stages of pregnancy. Carcinogenesis: no carcinogenesis was observed in the 18 month administration period test in rats.

After the lorazepam is orally taken, the lorazepam is quickly absorbed, and the absolute bioavailability is 90%. The peak plasma concentration occurs approximately 2 hours after dosing. The peak plasma drug concentration after oral administration of 2mg lorazepam was about 20ng/ml. The mean elimination half-life of free lorazepam in human plasma is about 12 hours, and the major metabolite glucuronic acid lorazepam is about 18 hours. At clinically relevant plasma concentration levels, the plasma protein binding rate of lorazepam was about 85%. Lorazepam rapidly binds glucuronic acid at the 3-hydroxyl position to form glucuronate, which is then excreted in the urine. The glucuronic acid lorazepam did not show significant central nervous system activity in animals. Plasma drug levels of lorazepam are proportional to the administered dose. There is no evidence of excessive accumulation up to 6 months of administration. Results of comparative studies performed on young and old subjects showed that: the increase in age had no significant effect on the pharmacokinetics of lorazepam. However, in a study involving a single dose of intravenous lorazepam injection of 1.5-3mg, it was found that the mean total clearance of lorazepam in humans was reduced by 20% in 15 examples of the aged age group aged 60-84 years compared to 15 examples of the aged age group aged 19-38 years.

The spirit of the present invention is described in detail by the preferred embodiments of the present invention. It will be understood by those skilled in the art that any modification, equivalent change and modification made to the above embodiments in accordance with the technical spirit of the present invention fall within the scope of the present invention.

Claims (7)

1. A lorazepam crystal that uses Cu-ka radiation and has 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 2 Θ angles.

2. The crystal according to claim 1, which has a diffraction peak 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 a powder X-ray diffraction pattern expressed in terms of 2 Θ angle using Cu — K α radiation.

3. A lorazepam crystal having diffraction peaks at 12.17 + -0.10 °, 14.15 + -0.10 °, 15.27 + -0.10 °, 16.84 + -0.10 °, 17.91 + -0.10 °, and 20.81 + -0.10 ° in a powder X-ray diffraction pattern expressed by an angle of 2 θ using Cu-Kalpha radiation.

4. The crystal according to claim 3, which has a diffraction peak 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 a powder X-ray diffraction pattern expressed in terms of 2 Θ angle using Cu-Ka radiation.

5. A lorazepam crystal, using Cu-ka radiation, having a powder X-ray diffraction pattern as shown in figure 1.

6. A process for preparing the lorazepam crystals of any of claims 1-5, comprising the steps of: adding 20g of lorazepam crude product, 250-350ml of ethanol, 2-3g of formic acid and 0.5-1% of medicinal carbon into a reaction bottle, stirring at 70-90 ℃ for 30-45 minutes, filtering while hot, cooling the filtrate to 5-10 ℃ while stirring, carrying out heat preservation and crystallization for 2~4 hours, carrying out suction filtration, and carrying out vacuum drying at 50-60 ℃ for 3~5 hours; and (3) putting 10g of the dried product, 100-150ml of ethyl acetate and 0.5-1% of medicinal carbon into a reaction bottle, stirring at 60-80 ℃ for 20-30 minutes, filtering while hot, cooling to 5-10 ℃ while stirring, performing heat preservation crystallization for 2~4 hours, performing suction filtration, and performing vacuum drying at 60-70 ℃ for 5~7 hours to obtain the lorazepam crystal.

7. Use of the lorazepam crystalline form of any of claims 1-5 for the manufacture of a medicament for the treatment or prevention of anxiety, depressive psychosis, convulsions and sedative hypnosis.

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