CN113493470A - Preparation method of oxycodone hydrochloride injection impurity A - Google Patents

Preparation method of oxycodone hydrochloride injection impurity A Download PDF

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CN113493470A
CN113493470A CN202010199445.2A CN202010199445A CN113493470A CN 113493470 A CN113493470 A CN 113493470A CN 202010199445 A CN202010199445 A CN 202010199445A CN 113493470 A CN113493470 A CN 113493470A
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acid
sodium
oxycodone hydrochloride
hydrochloride injection
potassium
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陈道鹏
庄涛
张乐
杨相平
陈亮
许向阳
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Nhwa Pharmaceutical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention belongs to the field of chemical industry, and particularly relates to a preparation method of oxycodone hydrochloride injection impurity A. Under the acidic or alkaline condition, oxycodone is subjected to Aldol condensation reaction to generate a beta hydroxyketone compound, and then the impurity A is obtained. The synthesis process disclosed by the invention has the advantages of easiness in obtaining required reagents, mild reaction conditions, easiness in control, simplicity and convenience in operation, easiness in purification of obtained impurities and high liquid phase purity, and can be used for quality research of oxycodone hydrochloride injection after nuclear magnetism and mass spectrum confirmation of the structure.

Description

Preparation method of oxycodone hydrochloride injection impurity A
The technical field is as follows:
the invention belongs to the field of chemical industry, and particularly relates to a preparation method of oxycodone hydrochloride injection impurity A.
Background art:
oxycodone (oxycodone) is an opioid receptor pure agonist, an opioid central nerve analgesic synthesized from the alkaloid thebaine (thebaine) extract. It has affinity for opioid receptors in brain and spinal cord, and oxycodone acts like morphine. The medicine has the characteristics of high bioavailability, good analgesic effect, small adverse reaction and the like, and the single and compound preparations thereof are widely used for treating moderate to severe pain in clinic.
Oxycodone hydrochloride injection can generate a larger impurity with the time during the acceleration test and the long-term stability test. Through the presumption of Q-TOF LC/MS primary mass spectrum and secondary mass spectrum, the impurity is oxycodone aldol hydrochloride dimer, namely impurity A.
The impurities have important significance in the aspect of quality control of the medicine, the preparation of the high-purity impurity reference substance becomes the key for establishing an impurity detection method, and the high-purity impurities have important significance in effectively controlling the quality of the bulk drugs and the preparations thereof.
At present, the preparation method of oxycodone injection impurity A is not reported in related documents, and a synthetic method with a simple synthetic route and high purity of prepared samples is urgently needed to be developed.
The invention content is as follows:
in order to solve the problems in the prior art, experiments show that oxycodone is subjected to self-condensation (Aldol condensation reaction) under an acidic or alkaline condition to generate a beta hydroxyketone compound, namely impurity A.
The invention provides a preparation method of oxycodone hydrochloride injection impurity A, which comprises the step of carrying out Aldol reaction on oxycodone under acidic or alkaline conditions.
Figure BDA0002418646750000011
In the above method for preparing oxycodone hydrochloride injection impurity A, Aldol reaction is carried out under acidic conditions, and the acid is selected from one or more of protonic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, p-toluenesulfonic acid, benzenesulfonic acid, cation exchange resin, acetic acid, trifluoroacetic acid, L-proline, boron trifluoride, trimethylaluminum, titanium tetrachloride, tin trifluoromethanesulfonate, aluminum chloride, nickel chloride and the like, and Lewis acid.
Further, in the above method for preparing oxycodone hydrochloride injection impurity A, the acid is preferably p-toluenesulfonic acid and titanium tetrachloride, and more preferably titanium tetrachloride.
In the above method for preparing oxycodone hydrochloride injection impurity A, the pH value under acidic condition is 1-4.
In the above method for preparing oxycodone hydrochloride injection impurity A, the reaction temperature under the acid condition is 0-30 ℃, preferably 0-10 ℃;
in the preparation method of the oxycodone hydrochloride injection impurity A, Aldol reaction is carried out under alkaline condition, the alkali is selected from one or more of metal oxides, hydroxides, organic amine compounds and anion exchange resins, such as sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride, butyllithium, (hexahydro) pyridine, quinoline, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, aluminum t-butoxide, magnesium t-butoxide bromide, triethylamine, lutidine and the like, hydroxides, organic amine compounds and anion exchange resins; further, the base is preferably sodium ethoxide and t-butoxymagnesium bromide, more preferably t-butoxymagnesium bromide.
In the above method for preparing oxycodone hydrochloride injection impurity A, the pH value under alkaline condition is 8-14; the reaction temperature under the alkali condition is 0-80 ℃.
The invention has the beneficial technical effects that:
the synthesis process disclosed by the invention has the advantages of easiness in obtaining required reagents, mild reaction conditions, easiness in control, simplicity and convenience in operation, easiness in purification of obtained impurities and high liquid phase purity, and can be used for quality research of oxycodone hydrochloride injection after nuclear magnetism and mass spectrum confirmation of the structure.
Description of the drawings:
FIG. 1: detection of impurity a for oxycodone preparative examples:
oxycodone hydrochloride purchased from Beijing Huasu pharmaceutical Co., Ltd
Examples
Oxycodone is subjected to self-condensation (Aldol condensation reaction) under alkaline or acidic conditions to generate a beta hydroxyketone compound, namely an impurity A, wherein the reaction formula is as follows:
Figure BDA0002418646750000031
example 1
Adding 5.00g of oxycodone hydrochloride and 40ml of water into a reaction bottle, stirring and dissolving, dropwise adding ammonia water to adjust the pH value to 9-10, extracting with dichloromethane for three times (20 ml/time), combining organic phases, washing with 20ml of water once, drying the organic phases with anhydrous magnesium sulfate, filtering, decompressing the filtrate, and distilling off the solvent to obtain 4.38g of off-white solid.
Adding 0.71g of magnesium chips and 15ml of tetrahydrofuran into a reaction bottle, firstly dropwise adding 3ml of a solution of 2.73g of bromoethane dissolved in 15ml of tetrahydrofuran under stirring until the reaction is initiated, continuously dropwise adding, refluxing for 30 minutes after the dropwise adding is finished, cooling the reaction liquid to 0 ℃, dropwise adding 1.85g of tert-butyl alcohol, and stirring for 1 hour at the temperature of 0-5 ℃ after the dropwise adding is finished.
After the timing is finished, 4.38g of oxycodone base solution dissolved in 25ml of tetrahydrofuran is dripped at the temperature of 0-5 ℃, and the solution is stirred for 6 hours at the temperature of 0-5 ℃ and then stirred for 16 hours at room temperature.
Cooling the reaction liquid to 0-5 ℃, dropwise adding 100ml of water, stirring for 30 minutes, extracting with dichloromethane for three times (50 ml/time), combining organic phases, washing with 50ml of water once, drying the organic phase with anhydrous magnesium sulfate, performing suction filtration, evaporating the filtrate under reduced pressure to remove the solvent to obtain 3.72g of yellow solid, adding 100ml of anhydrous ethanol, heating and dissolving, stirring for 4 hours at room temperature, performing suction filtration, and performing vacuum drying on the filter cake for 16 hours at 30-35 ℃ to obtain 1.93g of light yellow solid, and performing HPLC: 97.6 percent.
1H NMR(500MHz,DMSO-d6+CF3COOD)δ:6.88(d,1H),6.81(d,1H),6.79(d,1H),6.680(d,1H),5.19(s,1H),4.63(s,1H),3.88(s,3H),3.84(s,3H),3.76(d,1H),3.53(d,1H),3.50(d,1H),3.42(d,1H),3.34(d,1H),3.20(m,1H),3.10(m,1H),3.05(d,1H),2.98(d,1H),2.913(s,3H),2.842(s,3H),2.722(d,1H),2.55(m,2H),2.46(d,1H),2.38(d,1H),2.13(d,1H),1.58(d,1H),1.53(d,1H),1.462(d,1H),1.39(m,2H),1.21(m,1H).
13C-NMR(125MHz,DMSO-d6+CF3COOD)δ:207.75,146.70,145.04,143.26,142.21,130.69,128.23,122.98,122.06,120.60,118.79,116.08,115.17,91.03,89.79,71.95,70.12,70.07,67.15,66.41,56.73,56.58,49.85,49.69,47.64,47.27,44.58,41.40,41.29,31.73,29.31,27.56,25.33,24.87,23.64,23.54.
Q-TOF LC-MS(m/z):631.3007[M+H]+.
Example 2
Adding 5.00g of oxycodone hydrochloride and 40ml of water into a reaction bottle, stirring and dissolving, dropwise adding ammonia water to adjust the pH value to 9-10, extracting with dichloromethane for three times (20 ml/time), combining organic phases, washing with 20ml of water once, drying the organic phases with anhydrous magnesium sulfate, performing suction filtration, and evaporating the filtrate under reduced pressure to remove the solvent to obtain 4.45g of off-white solid.
The solid was dissolved in 180ml of absolute ethanol, 4.00g of 20% sodium ethoxide was added, and the mixture was refluxed until the reaction was completed. After the reaction, the solvent was distilled off under reduced pressure at an external temperature of 30 to 35 ℃, 100ml of dichloromethane was added, 50ml of water was added dropwise with stirring, the mixture was separated, the organic phase was washed three times with water (50 ml/time), the organic phase was dried over anhydrous magnesium sulfate, suction filtration was performed, and the solvent was distilled off under reduced pressure from the filtrate to obtain 3.12g of a yellow solid. Adding 90ml of absolute ethyl alcohol, heating to dissolve, stirring at room temperature for 4 hours, performing suction filtration, and performing vacuum drying on a filter cake at 30-35 ℃ for 16 hours to obtain 1.73g of light yellow solid, and performing HPLC: 97.3 percent.
Example 3
Adding 5.00g of oxycodone hydrochloride and 40ml of water into a reaction bottle, stirring and dissolving, dropwise adding ammonia water to adjust the pH value to 9-10, extracting with dichloromethane for three times (20 ml/time), combining organic phases, washing with 20ml of water once, drying the organic phases with anhydrous magnesium sulfate, performing suction filtration, and evaporating the filtrate under reduced pressure to remove the solvent to obtain 4.36g of off-white solid.
Under the protection of nitrogen, the solid and 200ml dichloromethane are added into a 500ml reaction bottle, cooled in ice-water bath, added with 1.60g triethylamine and 4.12g titanium tetrachloride at 0-5 ℃, and stirred for 3 hours at 0-5 ℃.
After the end of the time measurement, 300ml of dichloromethane and 200ml of water are sequentially dropped at 0-5 ℃, stirred, ammonia water is dropped to adjust the pH value to 8-9, liquid separation is carried out, the water phase is extracted twice (100 ml/time) by dichloromethane, the organic phase is combined, washed twice (100 ml/time) by water, the organic phase is dried by anhydrous magnesium sulfate, suction filtration is carried out, the filtrate is decompressed and evaporated to remove the solvent, and 4.52g of yellow foamy solid is obtained.
Column chromatography: and (2) loading the column by a 100-plus 200-mesh silica gel wet method, dissolving 4.50g of a sample by 10ml of dichloromethane for wet loading, carrying out gradient elution by using methanol/dichloromethane as an eluent on a mobile phase, collecting a target product, and evaporating the solvent under reduced pressure to obtain 1.82g of off-white solid, wherein HPLC: 98.8 percent.
Example 4
Adding 5.00g of oxycodone hydrochloride and 40ml of water into a reaction bottle, stirring and dissolving, dropwise adding ammonia water to adjust the pH value to 9-10, extracting with dichloromethane for three times (20 ml/time), combining organic phases, washing with 20ml of water once, drying the organic phases with anhydrous magnesium sulfate, performing suction filtration, and evaporating the filtrate under reduced pressure to remove the solvent to obtain 4.46g of off-white solid.
Adding the solid and 200ml dichloromethane into a 250ml reaction bottle, cooling in ice-water bath, adding 2.70g p-toluenesulfonic acid at 0-5 ℃, keeping the temperature and stirring for 3 hours at 0-5 ℃ after the addition.
After the end of the time measurement, ammonia was added dropwise at 0-5 ℃ to adjust the pH to 8-9, the solution was separated, the aqueous phase was extracted twice (100 ml/time) with dichloromethane, the organic phases were combined, washed twice (100 ml/time) with water, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give 4.12g of a yellow foamy solid.
Adding 120ml of absolute ethyl alcohol, heating to dissolve, stirring at room temperature for 4 hours, performing suction filtration, and performing vacuum drying on a filter cake at 30-35 ℃ for 16 hours to obtain 2.13g of light yellow solid, and performing HPLC: 98.1 percent.
Example 5: impurity A for oxycodone detection
High performance liquid chromatography (China pharmacopoeia 2015 edition four-part general rules 0512) test with octyl silane bonded silica gel as filler (InertSustain)TMC8, 4.6mm x 250mm, 5 μm or equivalent performance columns); gradient elution was performed using 0.11% sodium heptanesulfonate monohydrate solution (pH adjusted to 1.8 with phosphoric acid) -methanol-acetonitrile (85:10:5) as mobile phase A and 0.13% sodium heptanesulfonate monohydrate solution (pH adjusted to 1.8 with phosphoric acid) -methanol-acetonitrile (60:5:35) as mobile phase B according to the following table; flow rate was 1.5ml per minute; the detection wavelength is 206 nm; the column temperature was 40 ℃.
Figure BDA0002418646750000051
Accurately weighing an appropriate amount of impurity A, placing into a measuring flask, dissolving with acetic acid solution, and diluting to obtain 1mg per 1ml solution for use. Precisely measuring 20ul, injecting into liquid chromatograph, and calculating content by peak area normalization method, wherein detailed information is shown in FIG. 1. The high-purity impurity A can be well used for the quality control of oxycodone injection.

Claims (9)

1. A preparation method of oxycodone hydrochloride injection impurity A is characterized by comprising the following steps of carrying out Aldol reaction on oxycodone under acidic or alkaline conditions,
Figure FDA0002418646740000011
2. the method for preparing oxycodone hydrochloride injection impurity A according to claim 1, wherein the acid used for the acidity is selected from one or more of protonic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, p-toluenesulfonic acid, benzenesulfonic acid, cation exchange resins, acetic acid, trifluoroacetic acid, L-proline, boron trifluoride, trimethylaluminum, titanium tetrachloride, tin trifluoromethanesulfonate, aluminum chloride and nickel chloride, and Lewis acids.
3. The method for preparing oxycodone hydrochloride injection impurity A according to claim 2, wherein the acid is preferably p-toluenesulfonic acid and titanium tetrachloride.
4. The method for preparing oxycodone hydrochloride injection impurity A according to claim 1, wherein the reaction temperature under the acid condition is 0-30 ℃.
5. The method for preparing oxycodone hydrochloride injection impurity A according to claim 4, wherein the reaction temperature under the acid condition is 1-10 ℃.
6. The method for preparing oxycodone hydrochloride injection impurity A according to claim 1, wherein the alkali used for the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, cesium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydride, butyllithium, pyridine, quinoline, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, aluminum t-butoxide, magnesium t-butoxide, triethylamine and lutidine.
7. The method for preparing oxycodone hydrochloride injection impurity A according to claim 6, wherein the base is sodium ethoxide and tert-butoxymagnesium bromide.
8. The method of claim 7, wherein the base is tert-butoxymagnesium bromide.
9. The method for preparing oxycodone hydrochloride injection impurity A according to claim 1, wherein the reaction temperature under the alkaline condition is 0-80 ℃.
CN202010199445.2A 2020-03-20 2020-03-20 Preparation method of oxycodone hydrochloride injection impurity A Pending CN113493470A (en)

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Publication number Priority date Publication date Assignee Title
CN110724155A (en) * 2019-11-11 2020-01-24 北京华素制药股份有限公司 Preparation method of oxycodone aldol dimer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110724155A (en) * 2019-11-11 2020-01-24 北京华素制药股份有限公司 Preparation method of oxycodone aldol dimer

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