CN114671811A - Racemization recovery method of dexmedetomidine resolution byproduct - Google Patents
Racemization recovery method of dexmedetomidine resolution byproduct Download PDFInfo
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- CN114671811A CN114671811A CN202210391022.XA CN202210391022A CN114671811A CN 114671811 A CN114671811 A CN 114671811A CN 202210391022 A CN202210391022 A CN 202210391022A CN 114671811 A CN114671811 A CN 114671811A
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- dexmedetomidine
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- 238000000034 method Methods 0.000 title claims abstract description 32
- 229960004253 dexmedetomidine Drugs 0.000 title claims abstract description 21
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 title claims abstract description 21
- 238000011084 recovery Methods 0.000 title claims abstract description 19
- 230000006340 racemization Effects 0.000 title claims abstract description 17
- 239000006227 byproduct Substances 0.000 title claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 24
- 229960002746 dexmedetomidine hydrochloride Drugs 0.000 claims abstract description 23
- VPNGEIHDPSLNMU-MERQFXBCSA-N dexmedetomidine hydrochloride Chemical compound Cl.C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 VPNGEIHDPSLNMU-MERQFXBCSA-N 0.000 claims abstract description 23
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960002140 medetomidine Drugs 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000012670 alkaline solution Substances 0.000 claims abstract description 8
- 239000012452 mother liquor Substances 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- -1 alkali metal amide Chemical class 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000000047 product Substances 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000012044 organic layer Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 10
- CUHVIMMYOGQXCV-LLVKDONJSA-N levomedetomidine Chemical compound C1([C@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 CUHVIMMYOGQXCV-LLVKDONJSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010030 laminating Methods 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- NTOIKDYVJIWVSU-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(4-methylbenzoyl)butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)C(O)(C(O)=O)C(O)(C(O)=O)C(=O)C1=CC=C(C)C=C1 NTOIKDYVJIWVSU-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- MIOPJNTWMNEORI-ZDFGOMNRSA-N [2,2,3,3,4,5,5-heptadeuterio-7-methyl-6-oxo-7-(trideuteriomethyl)-1-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C12(C(=O)C(C(C(C1([2H])[2H])([2H])[2H])(C2(C([2H])([2H])[2H])C)[2H])([2H])[2H])CS(=O)(=O)O MIOPJNTWMNEORI-ZDFGOMNRSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 1
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005399 mechanical ventilation Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a racemization recovery method of a dexmedetomidine split byproduct, which comprises the following steps: 1) concentrating mother liquor obtained after the dexmedetomidine hydrochloride is subjected to chiral acid resolution in the production process of the dexmedetomidine hydrochloride under reduced pressure, dissociating the mother liquor by using an alkaline solution to obtain a recovered substance, 2) dissolving the recovered substance in an organic solvent, then using a strong alkaline reagent to remove hydrogen of alpha-chiral carbon to obtain an ionic recovered substance, and 3) adding acid water into the ionic recovered substance to destroy the ionic recovered substance, and then using an alkaline solution to neutralize the ionic recovered substance to obtain the racemate medetomidine. The method provided by the invention is reported for the first time, has the characteristics of readily available raw materials, low cost, less three wastes, simple method, mild conditions, convenience in operation, high product purity, greenness, environmental friendliness, suitability for industrial production and the like, can be applied to production of dexmedetomidine hydrochloride, and has great significance in controlling the production cost of raw material medicines of dexmedetomidine hydrochloride.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a racemization recovery method of a dexmedetomidine split byproduct.
Background
Dexmedetomidine hydrochloride injection is an alpha 2-adrenoceptor agonist developed by the cooperation of Orion Pharma (Finland) and Abott (USA) and is first marketed in the United states 3 months in 2000. The product is dextroisomer of alpha 2-adrenergic receptor stimulant medetomidine, and compared with medetomidine, the product has stronger selectivity on central alpha 2-adrenergic receptor stimulation, short half-life and small dosage. Sedation of surgical patients undergoing general anesthesia during endotracheal intubation and mechanical ventilation.
Dexmedetomidine hydrochloride is used as an injection, the impurity content of the dexmedetomidine hydrochloride is strictly controlled, and deeper research is carried out, and especially, the research on unknown impurities has great significance on the safety and the effectiveness of the dexmedetomidine hydrochloride.
The structural formula of dexmedetomidine hydrochloride is as follows:
the mainstream synthesis method of dexmedetomidine hydrochloride reported in the literature and data at present needs to carry out resolution of racemate (medetomidine).
The chinese patent cn201310700021.x reports that (+) -di-p-toluoyl tartaric acid [ (+) -DDTA ] is used for chiral selective salt-forming resolution;
the chiral selective salifying resolution is carried out by using L- (-) camphorsulfonic acid reported in Chinese patent CN 201410332901.0;
the chiral selective salifying resolution is carried out by using L- (-) dibenzoyl tartaric acid reported in Chinese patent CN 201510650046.2;
in Chinese patent CN201510650046.2, a series of chiral acids (such as R-mandelic acid, S-mandelic acid, D-tartaric acid, L-tartaric acid, D-camphoric acid, D-10-camphorsulfonic acid, D-malic acid, (+) -di-p-toluoyl tartaric acid) are reported to be used for chiral selective salt formation resolution;
the synthetic route of dexmedetomidine hydrochloride disclosed in Chinese Journal of Pharmaceuticals 2008, 39(6) and equal wanghong steel illustrates that medetomidine synthesized by four synthetic methods in the text requires chiral selective salt-forming resolution of chiral acid (L-tartaric acid).
The defects of low utilization rate and low yield of specific raw materials of chiral resolution directly result in the current situation that the cost of the dexmedetomidine hydrochloride raw material medicine is high. The method is characterized in that the method comprises the steps of racemizing and recovering a waste mother solution (consisting of a large amount of optical isomers, namely, levomedetomidine and dexmedetomidine) after the salt forming and splitting of chiral acid, so as to prepare the medetomidine, and repeatedly utilizing and splitting again to improve the utilization rate of raw materials, so that the method is an effective means for reducing the cost.
Therefore, the racemization recovery method of the dexmedetomidine split by-product is explored, the aim of reducing the production cost of the dexmedetomidine hydrochloride raw material drug is achieved, the price of the dexmedetomidine hydrochloride related preparation drug is further reduced, and the significance is great in the reduction of the drug cost of common people and the drug supply interruption risk of drug production enterprises.
Disclosure of Invention
Based on the technical background, the invention provides a racemization recovery method of a dexmedetomidine hydrochloride splitting byproduct, which solves the problem of high production cost of dexmedetomidine hydrochloride raw material medicines and preparations.
According to the structure of dexmedetomidine hydrochloride, the chiral carbon is located at alpha positions of a benzene ring and an imidazole ring, the hydrogen activity of the chiral carbon at the positions is relatively highest due to conjugation, and strong alkaline substances can be used for removing and converting the chiral carbon into a positive ion form, so that the purpose of racemization is achieved.
The racemization recovery method of the dexmedetomidine hydrochloride split by-product provided by the invention is realized by the following steps:
1) in the production process of dexmedetomidine hydrochloride, mother liquor obtained by resolving medetomidine with chiral acid is decompressed and concentrated, and is dissociated with alkaline solution to obtain a recovered substance, wherein the recovered substance consists of a large amount of levomedetomidine and a small amount of dexmedetomidine;
2) dissolving the recovered substance in an organic solvent, and then using a strong alkaline reagent to remove hydrogen of alpha-chiral carbon to obtain an ionic recovered substance;
3) the recovered ionic form was destroyed by adding acid water and neutralized with an alkaline solution to obtain the racemic medetomidine.
The alkaline solvent in step 1 is selected from aqueous solutions of inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and preferably aqueous solutions of sodium hydroxide or potassium hydroxide are used.
The organic solvent of step 2 is selected from aprotic polar solvents, preferably tetrahydrofuran or N, N-dimethylformamide.
The strongly basic reagent of step 2 is selected from alkali metal amides or alkali metal hydrides or alkali metal alcoholates, preferably LDA or sodium hydride.
The acid water of step 3 is selected from aqueous solutions of organic or inorganic acids, preferably dilute hydrochloric acid solutions.
The alkaline solution in step 3 is selected from aqueous solution of inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., and preferably aqueous solution of sodium hydroxide or potassium hydroxide is used.
The invention has the following beneficial effects:
the waste materials generated by splitting in the dexmedetomidine hydrochloride production process are recycled, the utilization rate of raw materials is improved, the production cost is obviously reduced, the effects of reducing the cost and the selling price of dexmedetomidine hydrochloride raw material medicines and preparation products thereof can be achieved, and the medication cost and the risk are reduced. Mild reaction conditions, simple operation, obvious reduction of energy consumption, no high-risk process and high-pollution process, and suitability for industrial production.
Detailed Description
The invention is described in further detail below with reference to specific examples, which are provided only for the purpose of further illustrating the invention, but are not to be construed as limiting the invention in any way.
Example 1: racemization recovery method
Concentrating the dexmedetomidine resolution mother liquor (20L) under reduced pressure until the dexmedetomidine resolution mother liquor is dried, adding dichloromethane (20L), water (10L) and a sodium hydroxide aqueous solution (10 percent), adjusting the pH value to 10-11, separating the liquid, and concentrating the organic layer under reduced pressure until the organic layer is dried to obtain a recovered substance.
Dissolving the recovered substance (10 g) in tetrahydrofuran (100 mL), cooling to-10-0 ℃, adding LDA/THF solution (2.0M, 30 mL), keeping the temperature and stirring for reaction for 3 hours, slowly dropping dilute hydrochloric acid solution (1M) until the pH value is 3-4, stirring for 0.5 hour, adding dichloromethane (100 mL) and sodium hydroxide solution (10%) and adjusting the pH value to 10-11, separating, extracting the aqueous phase twice with dichloromethane, laminating the organic layers, concentrating under reduced pressure until the organic layers are dried to obtain medetomidine, and detecting the content of the dexmedetomidine and the content of the levomedetomidine in the sample by an HPLC isomer method to be 48.3% and 49.0%.
Example 2: racemization recovery method
Dissolving the recovered substance (10 g) obtained in example 1 in tetrahydrofuran (100 mL), cooling to-10-0 ℃, adding sodium hydride (1.8 g), keeping the temperature and stirring for reaction for 8 hours, slowly dropping a dilute hydrochloric acid solution (1M) until the pH value is 3-4, stirring for 0.5 hour, adding dichloromethane (100 mL) and a sodium hydroxide solution (10%), adjusting the pH value to 10-11, separating, extracting the aqueous phase twice with dichloromethane, laminating the organic layer, and concentrating under reduced pressure until the organic layer is dried to obtain medetomidine, wherein the content of dexmedetomidine and the content of levomedetomidine in the sample are detected by an HPLC isomer method to be 48.7% and 48.5%.
Example 3: racemization recovery method
Dissolving the recovered substance (10 g) obtained in example 1 in toluene (100 mL), cooling to-5-0 ℃, adding LDA/THF solution (2.0M, 30 mL), keeping the temperature, stirring for reaction for 4h, slowly dropping dilute hydrochloric acid solution (1M) until the pH value is 3-4, stirring for 0.5h, adding dichloromethane (100 mL) and sodium hydroxide solution (10%) and adjusting the pH value to 10-11, separating, extracting the aqueous phase twice with dichloromethane, laminating the organic layer, concentrating under reduced pressure until the organic layer is dry to obtain medetomidine, and detecting the content of the dexmedetomidine and the content of the levomedetomidine in the sample by an HPLC isomer method to be 41.0% and 56.9%.
Example 4: racemization recovery method
Dissolving the recovered substance (10 g) obtained in example 1 in N, N-dimethylformamide (50 mL), cooling to-5-0 ℃, adding LDA/THF solution (2.0M, 30 mL), keeping the temperature, stirring for reaction for 4h, slowly dropping dilute hydrochloric acid solution (1M) until the pH value is 3-4, stirring for 0.5h, adding dichloromethane (100 mL) and sodium hydroxide solution (10%) and adjusting the pH value to 10-11, separating, extracting the aqueous phase twice with dichloromethane, laminating the organic layers, concentrating under reduced pressure until the organic layers are dried to obtain medetomidine, and detecting 47.6% of the content of dexmedetomidine and 47.4% of the content of levomedetomidine in the sample by an HPLC isomer method.
Example 5: racemization recovery method
Dissolving the recovered substance (10 g) obtained in example 1 in N, N-dimethylformamide (50 mL), adding potassium tert-butoxide (14 g), heating to 70-80 ℃ for reaction for 4h, cooling to room temperature, slowly dropping a dilute hydrochloric acid solution (1M) until the pH value is 3-4, stirring for 0.5h, adding dichloromethane (100 mL) and a sodium hydroxide solution (10%) and adjusting the pH value to 10-11, separating, extracting the aqueous phase twice with dichloromethane, laminating the organic layers, concentrating under reduced pressure until the organic layers are dried to obtain medetomidine, and detecting the content of dexmedetomidine and the content of levomedetomidine in the sample by an HPLC isomer method to be 48.3% and 47.1%.
Example 6: racemization recovery method
Dissolving the recovered substance (10 g) obtained in example 1 in N, N-dimethylformamide (50 mL), adding sodium methoxide (6.7 g), heating to 70-80 ℃ for reaction for 4h, cooling to room temperature, slowly dropping dilute hydrochloric acid solution (1M) until the pH value is 3-4, stirring for 0.5h, adding dichloromethane (100 mL) and sodium hydroxide solution (10%) and adjusting the pH value to 10-11, separating, extracting the aqueous phase twice with dichloromethane, laminating the organic layers, concentrating under reduced pressure until the organic layers are dried to obtain medetomidine, and detecting the content of the dexmedetomidine and the content of the levomedetomidine in the sample by an HPLC isomer method to be 45.7% and 50.6% respectively.
Claims (6)
1. A racemization recovery method of dexmedetomidine resolution byproduct is characterized by comprising the following steps: 1) concentrating mother liquor obtained after the dexmedetomidine hydrochloride is subjected to chiral acid resolution in the production process of the dexmedetomidine hydrochloride under reduced pressure, dissociating the mother liquor by using an alkaline solution to obtain a recovered substance, 2) dissolving the recovered substance in an organic solvent, then using a strong alkaline reagent to remove hydrogen of alpha-chiral carbon to obtain an ionic recovered substance, and 3) adding acid water into the ionic recovered substance to destroy the ionic recovered substance, and then using an alkaline solution to neutralize the ionic recovered substance to obtain the racemate medetomidine.
2. The racemization recovery method of dexmedetomidine resolution byproduct according to claim 1, characterized in that the alkaline solvent of step 1 is selected from the group consisting of aqueous solution of inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., preferably sodium hydroxide or potassium hydroxide aqueous solution is used.
3. Process for the racemisation recovery of dexmedetomidine resolution by-product according to claim 1 characterized in that the organic solvent of step 2 is selected from aprotic polar solvents, preferably tetrahydrofuran or N, N-dimethylformamide.
4. Process for the racemisation recovery of dexmedetomidine resolution by-product according to claim 1 characterized in that the strongly basic reagent of step 2 is selected from alkali metal amide or alkali metal hydride or alkali metal alcoholate, preferably LDA or sodium hydride.
5. Process for the racemisation recovery of the dexmedetomidine resolution by-product according to claim 1, characterized in that the acid water of step 3 is selected from aqueous solutions of organic or inorganic acids, preferably dilute hydrochloric acid solutions.
6. The racemization recovery method of dexmedetomidine resolution byproduct as claimed in claim 1, characterized in that the alkaline solution of step 3 is selected from the group consisting of aqueous solution of inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc., preferably sodium hydroxide or potassium hydroxide aqueous solution is used.
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Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2101114A (en) * | 1981-07-10 | 1983-01-12 | Farmos Group Ltd | Substituted imidazole derivatives and their preparation and use |
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