阅读说明：本技术 光稳定化药物组合物及其制备方法和制药用途 (Light-stabilized pharmaceutical composition, preparation method and pharmaceutical application thereof ) 是由 王波 侯奇伟 冯建辉 于 2019-11-19 设计创作，主要内容包括：本发明涉及光稳定化药物组合物及其制备方法和制药用途。具体地,本发明提供的药物组合物包含劳拉西泮结晶,以及药用辅料；所述劳拉西泮结晶使用Cu-Kα辐射,在以2θ角度表示的粉末X-射线衍射图谱中,在约12.17°、约14.15°、约15.27°、约16.84°、约17.91°、约20.81°处有衍射峰；例如,该结晶在约7.93°、约9.04°、约12.17°、约14.15°、约15.27°、约16.84°、约17.91°、约20.81°、约21.44°、约26.38°处有衍射峰。本发明还提供了该药物组合物的制备方法。还提供了该药物组合物的制药用途。本发明方法制备得到的制备劳拉西泮的新晶型以及药物组合物呈现例如本发明说明书所述优良性能。(The invention relates to a photostabilized pharmaceutical composition, a preparation method and a pharmaceutical application thereof, in particular to a pharmaceutical composition which comprises lorazepam crystals and pharmaceutic adjuvants, wherein the lorazepam crystals are irradiated by Cu-K α, and diffraction peaks are shown at about 12.17 degrees, about 14.15 degrees, about 15.27 degrees, about 16.84 degrees, about 17.91 degrees and about 20.81 degrees in a powder X-ray diffraction pattern expressed by an angle of 2 theta, for example, the crystals have diffraction peaks at about 7.93 degrees, about 9.04 degrees, about 12.17 degrees, about 14.15 degrees, about 15.27 degrees, about 16.84 degrees, about 17.91 degrees, about 20.81 degrees, about 21.44 degrees and about 26.38 degrees.)

1. A pharmaceutical composition comprising lorazepam crystals and a pharmaceutical excipient, wherein the lorazepam crystals are irradiated with Cu-K α, and 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 terms of 2 θ.

2. A pharmaceutical composition according to claim 1, the lorazepam crystals are irradiated with Cu-K α,

in a powder X-ray diffraction pattern expressed by an angle of 2 theta, 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 a powder X-ray diffraction pattern expressed by a 2 theta angle, 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;

(ii) a powder X-ray diffraction pattern in degrees 2 Θ having 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 by an angle of 2 theta, diffraction peaks exist 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 and 26.38 +/-0.20 degrees; or

In a powder X-ray diffraction pattern expressed by an 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; and/or

Irradiated with Cu-K α, having the powder X-ray diffraction pattern shown in FIG. 1.

3. The pharmaceutical composition according to claim 1, wherein the lorazepam crystalline form is prepared using a process 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.

4. The pharmaceutical composition according to claim 1, the lorazepam crystals,

adding 250-350 ml of ethanol, 2-3 g of formic acid and 0.5-1% of medicinal carbon into every 20g of lorazepam crude product;

stirring for 30-45 minutes at 70-90 ℃ during treatment in ethanol; and/or, carrying out heat preservation and crystallization at the temperature of 5-10 ℃ for 2-4 hours;

adding 100-150 ml of ethyl acetate and 0.5-1% of medicinal carbon into every 10g of dried substances;

stirring for 20-30 minutes at 60-80 ℃ during treatment in ethyl acetate;

carrying out heat preservation and crystallization for 2-4 hours at the temperature of 5-10 ℃; and/or

It is carried out 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 hot, cooling the filtrate to 5-10 ℃ while stirring, performing heat preservation and crystallization for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; and (3) putting 10g of the dried product, 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 hot, cooling to 5-10 ℃ under stirring, carrying out heat preservation and crystallization for 2-4 hours, carrying out suction filtration, and carrying out vacuum drying for 5-7 hours at 60-70 ℃ to obtain the lorazepam crystal.

5. The pharmaceutical composition according to claim 1, which is in the form of a tablet; for example, each tablet of the lorazepam tablet comprises 0.5-5 mg of lorazepam, especially 0.5-2.5 mg of lorazepam.

6. The pharmaceutical composition according to claim 1, comprising: 1 part of lorazepam, 0.2-0.5 part of citric acid, 60-70 parts of sugar alcohol, 30-40 parts of water-insoluble filler and 0.5-1.5 parts of lubricant.

7. The pharmaceutical composition according to claim 1, wherein:

the sugar alcohol is selected from: lactose, mannitol, sucrose, xylitol;

the water insoluble filler is selected from: starch, microcrystalline cellulose, calcium phosphate;

the lubricant is selected from: magnesium stearate, stearic acid, calcium stearate, talcum powder and colloidal silicon dioxide.

8. The pharmaceutical composition according to claim 1, characterized in that:

the tablet is in a tablet form and is prepared by adopting a wet granulation and tabletting process;

the tablet is in a tablet form and is prepared by adopting a wet granulation and tabletting process with water as a wetting agent; the citric acid is dissolved in water as a wetting agent and added; or

It is in the form of a tablet and is prepared by the following method: dissolving citric acid in an amount of water as a wetting agent; mixing lorazepam, sugar alcohol and water insoluble filler uniformly, making the mixture into soft material with wetting agent, granulating with 18 mesh sieve, drying until water content is less than 3%, adding lubricant, mixing uniformly, and pressing into tablet with die with proper size.

9. A process for preparing a pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of: dissolving citric acid in an amount of water as a wetting agent; mixing lorazepam, sugar alcohol and water insoluble filler uniformly, making the mixture into soft material with wetting agent, granulating with 18 mesh sieve, drying until water content is less than 3%, adding lubricant, mixing uniformly, and pressing into tablet with die with proper size.

10. Use of a pharmaceutical composition according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment or prevention of anxiety, depressive psychosis, convulsions and sedative hypnosis.

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 of lorazepam in preparing medicines with anxiolytic, antiepileptic, anticonvulsant and sedative and hypnotic effects. The lorazepam of the present invention exhibits a new crystal form. Further, the invention also relates to a photostabilized lorazepam pharmaceutical composition, a preparation method and pharmaceutical application thereof.

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, and lorazepam, belongs to the Benzodiazepine (BZD) class of 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 momentum. 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 higher than 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 huge market potential in China in terms of better curative effect and good selling form internationally (Liying, Chinese medicine introduction, 2000, 2(6): 30).

The synthesis of lorazepam was first described in s.c. bell BE621819 and US3296249(1963, 1967, am. homeprod.), melting point 166-168 ℃ (melting point 161 and 164 ℃ is also described). The Luxiali literature (Luxiali, et al, synthesis of lorazepam, proceedings of Huaihai institute of Industrial science (Nature science edition), 2005, 14(3):44) designs a synthesis route of lorazepam, and the main processes include condensation reaction (I), condensation reaction (II), cyclization reaction, ring expansion reaction, acylation rearrangement reaction and hydrolysis reaction, and the lorazepam synthesized by the method is qualitatively and puritly analyzed by using a high performance liquid chromatograph, and the purity is believed to 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 documents on the pharmacology, drug metabolism and clinical studies of lorazepam have been disclosed in g.owen et al, arzneim. -forsch.21, 1047-; toxicity studies of lorazepam were first disclosed in g.owen et al, arzneim. -forsch.21, 1047-one 1102(1971). 1065; for reviews of lorazepam, see j.g. rutgers, c.m. shearer, anal.profiles Drug subs.9, 397-; for a review of clinical pharmacology and therapeutic applications of lorazepam, see b.amoeer, d.j.greenblatt, Drugs 21, 161-200 (1981); the 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 multi-national 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 a crystal is 166-168 ℃, the crystal is unstable when exposed to light, the properties bring challenges to the preparation of a medicament preparation, for example, the problem of low oral bioavailability of the medicament is usually caused when the solubility is low, and the stability problem of a raw material medicament not only influences the preparation of the medicament 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.

In addition, lorazepam is known to be sensitive to light and readily decompose upon exposure to light, and therefore its bulk drugs and preparations such as tablets generally need to be stored protected from light. 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 is another object of the present invention to provide a method for photostabilizing a lorazepam pharmaceutical composition and the pharmaceutical composition provided thereby. 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 or compositions thereof. 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 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, using irradiation with Cu-K α.

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 °, 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 irradiation with Cu-K α.

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 irradiation with Cu-K α.

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 irradiation with Cu-K α.

The crystal according to any one of the embodiments of the first aspect of the present invention, which is irradiated with Cu-K α, has a powder X-ray diffraction pattern as 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 to every 20g of lorazepam crude product.

The crystal according to any one of the embodiments of the first aspect of the present invention, in the production process, the crystal is stirred at 70 to 90 ℃ for 30 to 45 minutes while being treated in ethanol; and/or, carrying out heat preservation and crystallization at the temperature of 5-10 ℃ for 2-4 hours.

The crystal according to any one of the embodiments of the first aspect of the present invention is prepared by adding 100 to 150ml of ethyl acetate and 0.5 to 1% of medicinal charcoal to 10g of dried product.

The crystal according to any one of the embodiments of the first aspect of the present invention, in the production method, the crystal is 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 is prepared by heat-insulating crystallization 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, performing heat preservation and crystallization for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; and (3) putting 10g of the dried product, 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 hot, cooling to 5-10 ℃ under stirring, carrying out heat preservation and crystallization for 2-4 hours, carrying out suction filtration, and carrying out vacuum drying for 5-7 hours at 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 to every 20g of lorazepam crude product.

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

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 to 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 invention, the crystallization is carried out at the temperature of 5-10 ℃ for 2-4 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, performing heat preservation and crystallization for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; and (3) putting 10g of the dried product, 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 hot, cooling to 5-10 ℃ under stirring, carrying out heat preservation and crystallization for 2-4 hours, carrying out suction filtration, and carrying out vacuum drying for 5-7 hours at 60-70 ℃ to obtain the lorazepam crystal.

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 medicinal carbon for decolorization, filtering to obtain filtrate, distilling under reduced pressure and crystallizing, and drying the filtered crystal 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, in step 1, the reaction is carried out with the feeding ratio of 1mol (305g) 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.

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

In the method according to any one of the embodiments of the third aspect of the present invention, in the step 1, after the completion of the reaction, ethyl acetate in an amount 3 to 5 times the charged amount of the ketone-based material and sodium thiosulfate in an amount 5 to 7 times the charged amount of the ketone-based material are added to the reaction solution. In the present invention, the term "3 to 5 times the amount of ketone material charged" or the like, unless otherwise specified, refers to the weight. In the present invention, the term "5 to 7 times the amount of a ketone material charged" or the like in relation to sodium thiosulfate, unless otherwise stated, 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 in the step 1, the decolorization of the medicinal charcoal, the distillation under reduced pressure, and the vacuum drying are 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 (305g) 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; adding ethyl acetate (3-5 times of the feeding amount of the ketone) and a 5% sodium thiosulfate solution (5-7 times of the feeding amount of the ketone) into a reaction bottle, stirring for 20-30 minutes, and standing to stratify; 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 concentrating, 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 shown in the formula II.

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

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

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

According to the third 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 method according to any embodiment of the third aspect of the present invention, wherein in the 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, the distillation under reduced pressure and the vacuum drying are respectively and 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 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 (363g) 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 of sodium hydroxide), 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 12-15 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 by using ethyl acetate, combining the organic layers, adding a saturated sodium chloride solution with the volume of 1-1.5 times 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 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 a lorazepam crude product.

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

The method 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, carrying out heat preservation and crystallization at the temperature of 5-10 ℃ for 2-4 hours.

The method 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 to 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, carrying out heat preservation and crystallization at the temperature of 5-10 ℃ for 2-4 hours.

The method according to any embodiment of the third aspect of the present invention, wherein step 3 is performed 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, performing heat preservation and crystallization for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; and (3) putting 10g of the dried product, 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 hot, cooling to 5-10 ℃ under stirring, preserving heat, crystallizing for 2-4 hours, then carrying out suction filtration, and carrying out vacuum drying for 5-7 hours at 60-70 ℃ to obtain a 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 (305g) 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; adding ethyl acetate (3-5 times of the feeding amount of the ketone) and a 5% sodium thiosulfate solution (5-7 times of the feeding amount of the ketone) into a reaction bottle, stirring for 20-30 minutes, and standing to stratify; 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 concentrating, 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 shown in the formula II;

step 2, hydrolyzing to prepare lorazepam

Adding 1mol (363g) 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 of sodium hydroxide), 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 12-15 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 by using ethyl acetate, combining the organic layers, adding a saturated sodium chloride solution with the volume of 1-1.5 times 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 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 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, performing heat preservation and crystallization for 2-4 hours, performing suction filtration, and performing vacuum drying at 50-60 ℃ for 3-5 hours; and (3) putting 10g of the dried product, 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 hot, cooling to 5-10 ℃ under stirring, carrying out heat preservation and crystallization for 2-4 hours, carrying out suction filtration, and carrying out vacuum drying for 5-7 hours at 60-70 ℃ to obtain the lorazepam crystal.

According to the process of any embodiment of the third aspect of the present invention, the lorazepam crystals produced therefrom 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 irradiation with Cu-K α.

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 ± 0.20 °, 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 irradiation with Cu-K α.

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 irradiation with Cu-K α.

According to the process of any of the embodiments of the third aspect of the present invention, lorazepam crystals prepared therefrom 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 °, and about 26.38 ° in a powder X-ray diffraction pattern expressed in degrees 2 θ using irradiation with Cu-K α.

According to the process of any embodiment of the third aspect of the present invention, lorazepam crystals prepared therefrom 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 terms of 2 θ using irradiation with Cu-K α.

According to the process of any embodiment of the third aspect of the present invention, 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 terms of 2 θ using irradiation with Cu-K α.

According to the process of any embodiment of the third aspect of the present invention, lorazepam crystals produced by the process are irradiated with Cu-K α and have the powder X-ray diffraction pattern shown in fig. 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.

Further, a fifth aspect of the present invention relates to a pharmaceutical composition comprising the lorazepam crystal according to any of the embodiments of the first to fourth aspects of the present invention or the lorazepam crystal prepared by the method, and a pharmaceutically acceptable excipient.

The pharmaceutical composition according to any embodiment of the fifth aspect of the invention, which is in the form of a tablet.

A pharmaceutical composition according to any embodiment of the fifth aspect of the invention, comprising: 1 part of lorazepam, 0.2-0.5 part of citric acid, 60-70 parts of sugar alcohol, 30-40 parts of water-insoluble filler and 0.5-1.5 parts of lubricant.

The pharmaceutical composition according to any embodiment of the fifth aspect of the invention, wherein the sugar alcohol is selected from the group consisting of: lactose, mannitol, sucrose, xylitol, and the like.

The pharmaceutical composition according to any embodiment of the fifth aspect of the invention, wherein the water insoluble filler is selected from the group consisting of: starch, microcrystalline cellulose, calcium phosphate, and the like.

The pharmaceutical composition according to any embodiment of the fifth aspect of the invention, wherein the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, calcium stearate, talc, colloidal silicon dioxide, and the like.

The pharmaceutical composition according to any embodiment of the fifth aspect of the invention, which is in the form of a tablet and is prepared by a wet granulation tableting process.

The pharmaceutical composition according to any one of the embodiments of the fifth aspect of the present invention, which is in the form of a tablet and is prepared by a wet granulation tableting process using water as a wetting agent; the citric acid is dissolved in water as a wetting agent.

The pharmaceutical composition according to any embodiment of the fifth aspect of the present invention, which is in the form of a tablet, and is prepared by the following method: dissolving citric acid in an amount of water as a wetting agent; mixing lorazepam, sugar alcohol and water insoluble filler uniformly, making the mixture into soft material with wetting agent, granulating with 18 mesh sieve, drying until water content is less than 3%, adding lubricant, mixing uniformly, and pressing into tablet with die with proper size.

The pharmaceutical composition according to any of the embodiments of the fifth aspect of the present invention is in the form of tablets comprising lorazepam 0.5-5 mg, especially 0.5-2.5 mg per tablet.

Further, a sixth aspect of the present invention provides a process for preparing the pharmaceutical composition according to any of the embodiments of the fifth aspect of the present invention, wherein the pharmaceutical composition is in the form of a tablet and is prepared by a wet granulation tableting process using water as a wetting agent; the citric acid is dissolved in water as a wetting agent.

The method according to any of the embodiments of the sixth aspect of the present invention, comprising the steps of: dissolving citric acid in an amount of water as a wetting agent; mixing lorazepam, sugar alcohol and water insoluble filler uniformly, making the mixture into soft material with wetting agent, granulating with 18 mesh sieve, drying until water content is less than 3%, adding lubricant, mixing uniformly, and pressing into tablet with die with proper size.

Further, according to a seventh aspect of the present invention, there is provided a use of the pharmaceutical composition according to any one of the embodiments of the fifth aspect of the present invention for the manufacture of a medicament for treating or preventing anxiety, depressive psychosis, convulsion and sedation 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 by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention 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 drug, named 7-chloro-5- (2-chlorobenzene) -1, 3-dihydro-3-hydroxy-2H-1, 4-benzodiazepine-2-one, which is a benzodiazepine psychotropic drug synthesized by Wyeth corporation, usa, and developed by Wyeth corporation, japan.

The present invention has 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 crystal was measured by using the following powder X-ray diffraction analysis method, namely a Rigaku Dmax/2400 type powder X-ray diffractometer, CuK α radiation, a graphite monochromator, 40KV 100MA, a 2 theta scanning range of 0.0-40 degrees, a scanning speed of 3 degrees/minute, a step size of 0.01 degrees, a scanning mode of continuous scanning, a slit arrangement of an exit slit DS: 1/2 degrees anti-scatter slit SS 1/2 degrees and RS:0.3 mm. the X-ray diffraction pattern of the crystal powder of the lorazepam refined product obtained in example 1 of the present invention is shown in FIG. 1 (the X-ray diffraction pattern of the lorazepam refined products in examples 2-4 is substantially the same as FIG. 1, 10 characteristic peaks shown are the same as in FIG. 1), and the specific data of the diffraction peak positions (2 theta, °, ± 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 the powder X-ray diffraction pattern expressed by the angle of 2 theta, 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 exist 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 and 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 crystal form as described above, and they may be referred to as L crystal 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 analogues 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 stages, and the reaction scheme is as follows:

(1) acetoxylation reaction

(2) Hydrolysis