CN110804023A - Lorazepam purification method - Google Patents
Lorazepam purification method Download PDFInfo
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- CN110804023A CN110804023A CN201911253630.9A CN201911253630A CN110804023A CN 110804023 A CN110804023 A CN 110804023A CN 201911253630 A CN201911253630 A CN 201911253630A CN 110804023 A CN110804023 A CN 110804023A
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- lorazepam
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a purification method of lorazepam, which specifically comprises the following steps: heating and refluxing a benign solvent, cooling under the protection of inert gas, adding a lorazepam crude product, stirring and dissolving, adding activated carbon for decolorization, filtering, adding the inert solvent into filtrate, cooling and crystallizing, and filtering to obtain a lorazepam product, wherein the purity of the lorazepam product is not lower than 99.85%, and the content of an impurity 6-chloro-4- (2-chlorophenyl) quinazoline-2-formaldehyde in the lorazepam product is not higher than 0.05%. The method has the advantages of simple operation, controllable quality and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a purification method of lorazepam.
Background
Lorazepam (Lorazepam) belongs to benzodiazepine sedative hypnotics, is a benzodiazepine psychotropic drug developed by Wyeth company in the United states, has the effects of tranquilizing central nerves, hypnosis, antianxiety, antiepileptic and the like, can be used as a first-line first-choice drug for resisting the status epilepticus, and is a national basic drug. Lorazepam raw material medicines are collected in Chinese pharmacopoeia, United states pharmacopoeia, British pharmacopoeia, European pharmacopoeia and Japanese pharmacopoeia, wherein 2 known impurities I (namely USP impurity B) and impurities II (namely USP impurity C) are collected in CHP 2015. The structural formulas of the impurity I and the impurity II in Chinese pharmacopoeia are as follows:
the lorazepam impurity II collected and carried by lorazepam collected and carried in Chinese pharmacopoeia is the main process impurity and degradation impurity. In the literature, "research on key quality attributes of lorazepam tablets" (drug evaluation research, 2018, 41(9), 1630-: lorazepam impurity ii is the most neurotoxic. The limit of impurities II in the lorazepam raw material in the Chinese pharmacopoeia is 0.5 percent, and the limit of impurities C (namely CHP impurities II) in the United states pharmacopoeia is 0.3 percent. Neither british pharmacopoeia 2017 nor european pharmacopoeia 9.0 contain this impurity, but the limit of unknown impurities is specified to be 0.1%. With the gradual expansion of the market of the imitation pharmaceuticals and the evaluation of the consistency of the imitation pharmaceuticals in China, the requirement of pharmaceutical enterprises on the limit of impurities under related substance items is far higher than the national standard, and the limit of lorazepam impurity II is tightened to 0.1% by a plurality of enterprises.
The literature "Synthesis of lorazepam" (proceedings of the Huaihai institute of Industrial science (Nature science edition), 2005,14(3),44-46) and
the 2-amino-2 ', 5-dichlorobenzophenone is prepared by six steps of ketoxime, cyclization, ring expansion, acylation rearrangement, hydrolysis, refining and the like by taking 2-amino-2', 5-dichlorobenzophenone as an initial raw material, and the lorazepam is obtained by twice recrystallization in the refining and purifying step by respectively adopting 95% ethanol and dichloromethane as solvents. The process route is as follows:
the lorazepam bulk drug obtained in the existing lorazepam preparation technology contains about 0.2% of impurity II, and the impurity is also the largest single impurity under the relevant substance examination item of the lorazepam bulk drug. The existence of the lorazepam impurity II ensures that the quality of the raw material medicine product meets the requirements of Chinese pharmacopoeia and United states pharmacopoeia, but hardly reaches the quality standard specified in British pharmacopoeia 2017 and European pharmacopoeia 9.0. In the preparation process of lorazepam, the existing purification method is difficult to control the impurity II within 0.1 percent and the total impurity within 0.2 percent. Therefore, a new technical scheme is necessary for purifying lorazepam.
Disclosure of Invention
The invention provides a purification method of lorazepam, which aims to solve the problems in the background technology. The purification method can effectively reduce the content of lorazepam impurity II (6-chloro-4- (2-chlorophenyl) quinazoline-2-formaldehyde), so that lorazepam reaches a stricter quality standard. The technical scheme of the invention can obtain high-purity lorazepam, and the used solvent raw materials are easy to obtain, the operation is simple and convenient, the yield is high, and the method is suitable for industrial production.
The invention provides a purification method of lorazepam, which specifically comprises the following steps:
heating and refluxing a benign solvent, cooling under the protection of inert gas, adding a lorazepam crude product, stirring and dissolving, adding activated carbon for decolorization, filtering, adding the inert solvent into filtrate, cooling and crystallizing, and filtering to obtain a lorazepam product, wherein the purity of the lorazepam product is not lower than 99.85%, and the content of an impurity 6-chloro-4- (2-chlorophenyl) quinazoline-2-formaldehyde in the lorazepam product is not higher than 0.05%.
Preferably, the benign solvent is tetrahydrofuran.
Preferably, the inert gas is nitrogen or argon.
Preferably, the temperature for cooling the benign solvent and the temperature for stirring and dissolving the lorazepam crude product under the protection of inert gas are 50-60 ℃.
Preferably, the inert solvent is petroleum ether or n-hexane, preferably n-hexane.
Preferably, the volume ratio of the benign solvent to the inert solvent is 1:1 to 5, preferably 1:2 to 3.
Preferably, the cooling process after the inert solvent is added is that the temperature is firstly reduced to 40-45 ℃ and kept for 1 hour; then cooling to 20-25 ℃ and keeping for 1 hour; and continuously cooling to-5-10 ℃ for crystallization, and crystallizing for 2 hours.
Preferably, the crystallization temperature is 0-5 ℃.
The purification method of lorazepam provided by the invention has the beneficial effects that: the purity of the lorazepam product obtained by the purification method is not lower than 99.85%, and the content of 6-chloro-4- (2-chlorphenyl) quinazoline-2-formaldehyde in the product is not higher than 0.05%. Before the lorazepam crude product is dissolved, a benign solvent is subjected to reflux degassing treatment and inert gas protection is adopted in the cooling process, and impurities are prevented from being introduced through oxidation reaction in the purification process; the content of the impurity 6-chloro-4- (2-chlorphenyl) quinazoline-2-formaldehyde can be effectively reduced by adopting a mixed solvent for purification. The method has the advantages of simple operation, controllable quality and suitability for industrial production.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
The invention provides a purification method of lorazepam, which comprises the following steps:
100ml of tetrahydrofuran was added to the reaction flask, warmed to reflux and degassed for 30 minutes while maintaining reflux. Under the protection of nitrogen, cooling to 55-60 ℃, adding 20g of lorazepam crude product while stirring, preserving heat for 2 hours at 55-60 ℃ after the feeding is finished, and adding 1g of active carbon and preserving heat for 1 hour at 55-60 ℃. Filtering while the solution is hot, heating the filtrate to 55-60 ℃, adding 300ml of petroleum ether, controlling the adding speed of the petroleum ether, keeping the system temperature at 50-60 ℃ in the process of adding the petroleum ether, keeping the temperature at 55-60 ℃ after the addition is finished, stirring for 30 minutes, then cooling to 40-45 ℃ and keeping for 1 hour; then cooling to 20-25 ℃ and keeping for 1 hour; and continuously cooling to-5-0 ℃ for crystallization, performing crystallization for 2 hours, filtering and drying to obtain 16.3g of lorazepam product, wherein the HPLC purity is 99.89%, and the impurity 6-chloro-4- (2-chlorphenyl) quinazoline-2-formaldehyde is 0.02%.
Example 2
The invention provides a purification method of lorazepam, which comprises the following steps:
120ml of tetrahydrofuran was added to the reaction flask, warmed to reflux and degassed while maintaining reflux for 30 minutes. Under the protection of argon, the temperature is reduced to 50-55 ℃, 20g of lorazepam crude product is added with stirring, the temperature is kept for 2 hours at 50-55 ℃ after the feeding is finished, and 1g of active carbon is added to keep the temperature for 1 hour at 50-55 ℃. Filtering while the solution is hot, heating the filtrate to 55-60 ℃, adding 360ml of normal hexane, controlling the adding speed of the normal hexane, keeping the system temperature at 50-60 ℃ in the normal hexane adding process, keeping the temperature at 55-60 ℃ after the addition is finished, stirring for 30 minutes, then cooling to 40-45 ℃ and keeping the temperature for 1 hour; then cooling to 20-25 ℃ and keeping for 1 hour; and continuously cooling to-5-0 ℃ for crystallization, performing crystallization for 2 hours, filtering and drying to obtain 15.7g of lorazepam product, wherein the HPLC purity is 99.91 percent, and the impurity 6-chloro-4- (2-chlorphenyl) quinazoline-2-formaldehyde is 0.01 percent.
Example 3
The invention provides a purification method of lorazepam, which comprises the following steps:
100ml of tetrahydrofuran was added to the reaction flask, warmed to reflux and degassed for 30 minutes while maintaining reflux. Under the protection of argon, the temperature is reduced to 55-60 ℃, 20g of lorazepam crude product is added with stirring, the temperature is kept for 2 hours at 55-60 ℃ after the feeding is finished, and 1g of active carbon is added to keep the temperature for 1 hour at 55-60 ℃. Filtering while hot, heating the filtrate to 55-60 ℃, adding 250ml of normal hexane, controlling the adding speed of the normal hexane, keeping the system temperature at 50-60 ℃ in the normal hexane adding process, keeping the temperature at 55-60 ℃ after the addition is finished, stirring for 30 minutes, then cooling to 40-45 ℃ and keeping for 1 hour; then cooling to 20-25 ℃ and keeping for 1 hour; and continuously cooling to 5-10 ℃ for crystallization, carrying out crystallization for 2 hours, filtering and drying to obtain 15g of lorazepam product, wherein the HPLC purity is 99.93%, and the impurity 6-chloro-4- (2-chlorphenyl) quinazoline-2-formaldehyde is not detected.
Example 4
The invention provides a purification method of lorazepam, which comprises the following steps:
100ml of tetrahydrofuran was added to the reaction flask, warmed to reflux and degassed for 30 minutes while maintaining reflux. Under the protection of nitrogen, cooling to 55-60 ℃, adding 20g of lorazepam crude product while stirring, preserving heat for 2 hours at 55-60 ℃ after the feeding is finished, and adding 1g of active carbon and preserving heat for 1 hour at 55-60 ℃. Filtering while hot, heating the filtrate to 55-60 ℃, adding 300ml of normal hexane, controlling the adding speed of the normal hexane, keeping the system temperature at 50-60 ℃ in the normal hexane adding process, keeping the temperature at 55-60 ℃ after the addition is finished, stirring for 30 minutes, then cooling to 40-45 ℃ and keeping for 1 hour; then cooling to 20-25 ℃ and keeping for 1 hour; and continuously cooling to 0-5 ℃ for crystallization, carrying out crystallization for 2 hours, filtering and drying to obtain 16.1g of lorazepam product, wherein the HPLC purity is 99.93%, and the impurity 6-chloro-4- (2-chlorphenyl) quinazoline-2-formaldehyde is not detected.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A purification method of lorazepam is characterized by comprising the following steps:
heating and refluxing a benign solvent, cooling under the protection of inert gas, adding a lorazepam crude product, stirring and dissolving, adding activated carbon for decolorization, filtering, adding the inert solvent into filtrate, cooling and crystallizing, and filtering to obtain a lorazepam product, wherein the purity of the lorazepam product is not lower than 99.85%, and the content of an impurity 6-chloro-4- (2-chlorophenyl) quinazoline-2-formaldehyde in the lorazepam product is not higher than 0.05%.
2. The purification method of lorazepam according to claim 1, wherein: the benign solvent is tetrahydrofuran.
3. The purification method of lorazepam according to claim 1, wherein: the inert gas is nitrogen or argon.
4. The purification method of lorazepam according to claim 1, wherein: the temperature of the benign solvent and the temperature of the lorazepam crude product dissolved by stirring under the protection of inert gas are 50-60 ℃.
5. The purification method of lorazepam according to claim 1, wherein: the inert solvent is petroleum ether or n-hexane.
6. The purification method of lorazepam according to claim 5, wherein: the inert solvent is n-hexane.
7. The purification method of lorazepam according to claim 1, wherein: the volume ratio of the benign solvent to the inert solvent is 1: 1-5.
8. The purification method of lorazepam according to claim 7, wherein: the volume ratio of the benign solvent to the inert solvent is 1: 2-3.
9. The purification method of lorazepam according to claim 1, wherein: the cooling process after the inert solvent is added is that the temperature is firstly reduced to 40-45 ℃ and kept for 1 hour; then cooling to 20-25 ℃ and keeping for 1 hour; and continuously cooling to-5-10 ℃ for crystallization, and crystallizing for 2 hours.
10. The purification method of lorazepam according to claim 9, wherein: the crystallization temperature is 0-5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201911253630.9A CN110804023A (en) | 2019-12-09 | 2019-12-09 | Lorazepam purification method |
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| CN201911253630.9A CN110804023A (en) | 2019-12-09 | 2019-12-09 | Lorazepam purification method |
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| CN110804023A true CN110804023A (en) | 2020-02-18 |
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| CN201911253630.9A Pending CN110804023A (en) | 2019-12-09 | 2019-12-09 | Lorazepam purification method |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001066062A2 (en) * | 2000-03-06 | 2001-09-13 | Teva Pharmaqceutical Industries Ltd. | Process for preparing pure crystalline lorazepam |
| WO2005054211A1 (en) * | 2003-12-03 | 2005-06-16 | Zentiva, A.S. | A method of purification of lorazepam |
-
2019
- 2019-12-09 CN CN201911253630.9A patent/CN110804023A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001066062A2 (en) * | 2000-03-06 | 2001-09-13 | Teva Pharmaqceutical Industries Ltd. | Process for preparing pure crystalline lorazepam |
| WO2005054211A1 (en) * | 2003-12-03 | 2005-06-16 | Zentiva, A.S. | A method of purification of lorazepam |
Non-Patent Citations (3)
| Title |
|---|
| 吕小丽 等: "劳拉西泮的合成", 《淮海工学院学报（自然科学版）》 * |
| 王伟 等: "氯甲西泮的合成工艺研究", 《药学研究》 * |
| 王慧 等: "劳拉西泮中杂质6 － 氯－ 4 － （2 － 氯苯基）－ 2 － 喹唑啉甲醛的定位鉴别研究", 《药物分析杂志》 * |
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Application publication date: 20200218 |
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