CN113493460A - Preparation method of oxycodone hydrochloride impurity B - Google Patents

Preparation method of oxycodone hydrochloride impurity B Download PDF

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CN113493460A
CN113493460A CN202010205114.5A CN202010205114A CN113493460A CN 113493460 A CN113493460 A CN 113493460A CN 202010205114 A CN202010205114 A CN 202010205114A CN 113493460 A CN113493460 A CN 113493460A
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sodium
potassium
hydroxide
impurity
oxycodone hydrochloride
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陈道鹏
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
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08—Oxygen atom

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Abstract

The invention belongs to the field of chemical industry, and particularly relates to a preparation method of oxycodone hydrochloride impurity B. The method takes 14-hydroxycodeinone as a raw material, and obtains the impurity B through Michael addition reaction under the alkaline condition.

Description

Preparation method of oxycodone hydrochloride impurity B
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 impurity B.
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.
The oxycodone hydrochloride impurity B is an oxycodone hydrochloride process impurity, and has the chemical name: 4,5 α -epoxy-8 β, 14-dihydroxy-3-methoxy-17-methylmorphinan-6-one, USP: 7, 8-dihydro-8 beta-14-dihydroxycodeinone.
The preparation process of oxycodone hydrochloride reported in the literature mainly uses thebaine as a starting material, and the thebaine is oxidized and converted into 14-hydroxycodeinone by formic acid, and the oxycodone is obtained by palladium catalytic hydrogenation reduction, and the oxycodone is salified in aqueous ethanol by hydrochloric acid to obtain the finished product of oxycodone hydrochloride. The process route is as follows:
Figure BDA0002418685880000011
during the oxidation of thebaine to 14-hydroxycodeinone, the impurity 8-hydroxyoxycodone may be formed, and 8-hydroxyoxycodone may have two stereo configurations, i.e., 8 α -hydroxyoxycodone and 8 β -hydroxyoxycodone (i.e., impurity B), and it is known from the prior art that 8 α -hydroxyoxycodone is unstable and can be easily converted to 14-hydroxycodeinone under acidic conditions (WO 2005/097801); under more severe reaction conditions, 8 β -hydroxyoxycodone can also be converted to 14-hydroxycodeinone (Weiss u., j. org. chem.22(1957), P)1505-1508)。
According to the process route, the cause of the generation of the impurity B is presumed as follows:
first, it is possible that thebaine is obtained by oxidation of the double bond at the 8,14 position to epoxy and ring opening in the oxidation with peroxyformic acid (Helvetica Chimica Acta; vol.60; nb.7; (1977); p.2135-2137), which is possibly generated as follows (Scheme 2):
Figure BDA0002418685880000021
secondly, the addition of 14-hydroxycodeinone under acidic conditions produces 8-hydroxy oxycodone (CN 104507947) by the following process (Scheme 3):
Figure BDA0002418685880000022
the main preparation method of impurity B reported in literature is that thebaine is used as raw material, acetic acid is used as solvent to prepare 8-acetoxyl-14-hydroxy dihydrothebaine, 8-acetoxyl-14-hydroxy dihydrothebaine is hydrolyzed under alkaline condition to obtain 8, 14-dihydroxy dihydrothebaine, 8, 14-dihydroxy dihydrothebaine is dehydrated under acidic condition to obtain impurity B (7, 8-dihydro-8 beta-14-dihydroxy codeinone). (Helvetica Chimica Acta; vol.60; nb.7; (1977); p.2135-2137; Chemische Berichte; vol.67; 1934); p.197-199.) the process has a long route, and the obtained 8-acetoxy-14-hydroxydihydrothebaine is not easy to purify and has a low yield. The synthetic route is shown in Scheme 4:
Figure BDA0002418685880000023
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.
The existing method for preparing oxycodone injection impurity B has the defects of difficulty in purification and low yield, 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:
the invention provides a preparation method of oxycodone impurity B, aiming at solving the problems in the prior art. The method takes 14-hydroxycodeinone as a raw material, and obtains the impurity B through Michael addition reaction under the alkaline condition.
The invention provides a preparation method of oxycodone impurity B, which is characterized in that 14-hydroxycodeinone is added in a solvent under an alkaline condition, and the impurity B has the following structure:
Figure BDA0002418685880000031
in the above method for preparing impurity B of oxycodone hydrochloride, the base used in the alkaline condition is an inorganic base or an organic base; further, the inorganic base 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 or sodium hydride; the organic base is selected from one or more of butyllithium, (hexahydro) pyridine, quinoline, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium tert-butoxide, diethylamine, triethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, tetrabutylammonium chloride and tetrabutylammonium bromide.
Preferably, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the organic base is selected from one or more of 4-dimethylamino pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, diethylamine, triethylamine, tetrabutylammonium bromide or tetrabutylammonium bromide.
In the above method for preparing impurity B of oxycodone hydrochloride, the solvent is one or more of water, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol, N-pentanol, isopentanol, ethylene glycol, propylene glycol glycerol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, acetone, butanone and the like. Preferably, the solvent is selected from one or more of water, methanol, ethanol, N-propanol, isopropanol, N-butanol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane and N-methylpyrrolidone.
In the above-mentioned method for producing oxycodone hydrochloride impurity B, the reaction time of the production method is 1 hour to 12 hours, preferably 2 hours to 8 hours.
In the preparation method of the oxycodone hydrochloride impurity B, the reaction temperature of the preparation method is 0-150 ℃, and preferably 20-100 ℃.
The invention has the beneficial technical effects that:
the method takes 14-hydroxycodeinone as a raw material, and obtains the impurity B through Michael addition reaction under the alkaline condition.
Example (b):
thebaine is purchased from Gansu province pharmaceutical alkali factory
General reaction scheme for oxycodone impurity B:
14-hydroxycodeinone is used as a raw material, and an impurity B is obtained through Michael addition reaction under the alkaline condition.
Figure BDA0002418685880000041
Example 1: preparation of 14-hydroxycodeinone
Adding 30.00g thebaine, 41.64g water and 26.22g formic acid into a reaction bottle, stirring, dropwise adding 12.30g hydrogen peroxide, heating to 48-60 ℃ after adding, keeping the temperature for reaction, monitoring by TLC until the reaction is complete, cooling the reaction liquid to 6 ℃ by using ice water, dropwise adding ammonia water below 20 ℃ to ensure that the pH is 9-10, extracting the water phase by using dichloromethane three times (200 ml/time), combining the organic phases, washing by using 200ml water once, drying the organic phase by using anhydrous magnesium sulfate, filtering, and evaporating the solvent from the filtrate under reduced pressure to obtain 29.11g yellow solid.
Adding 260ml of dichloromethane into the mixture for refluxing and complete dissolution, dropwise adding 400ml of absolute ethyl alcohol, stirring the mixture at room temperature for 18 hours, separating out a solid, performing suction filtration, and performing vacuum drying on a filter cake at 50 +/-1 ℃ for 6 hours to obtain 25.82g of off-white solid with the yield of 86.1%.
Example 2: preparation of oxycodone impurity B
5.00g of 14-hydroxycodeinone, 150ml of 10% potassium hydroxide aqueous solution and 150ml of absolute ethyl alcohol are added into a 500ml reaction bottle, heated to 70-75 ℃ with stirring and kept for reaction, and the reaction is monitored by TLC until the reaction is complete.
After completion of the reaction, the mixture was stirred at room temperature, 150ml of water and 250ml of dichloromethane were added to the reaction solution, followed by liquid separation, extraction of the aqueous phase with dichloromethane twice (250 ml/time), combination of the organic phases, washing with water once (250 ml/time), drying of the organic phase with anhydrous magnesium sulfate, suction filtration, and evaporation of the solvent from the filtrate under reduced pressure to give 5.89g of a yellow oil.
Column chromatography: and (3) loading the column by a 100-plus-200-mesh silica gel wet method, dissolving 5.80g of a sample by 10ml of dichloromethane, loading the sample by the wet method, carrying out gradient elution on a mobile phase by using methanol/dichloromethane as an eluent, collecting a target product, and evaporating the solvent under reduced pressure to obtain 3.82g of an off-white solid with the yield of 72.2%.
1H NMR(500MHz,DMSO-d6)δ：8.194(s,1H),6.74(d,1H),6.68(d,1H),4.78(s,1H),3.78(s,3H),3.26-3.22(m,2H),3.14(d,1H),3.06(d,1H),2.58-2.52(m,2H),2.46-2.4(m,1H),2.40(s,3H),2.19(d,1H),2.07(d,1H),1.33(d,1H).
13C NMR(126MHz,DMSO-d6)δ：206.64,163.50,144.24,142.04,128.91,125.80,119.36,114.74,89.59,72.30,67.29,60.10,56.31,47.10,45.70,44.92,42.27,29.59,21.24.
Q-TOF LC-MS(m/z):332.1485[M+H]+.
EXAMPLE 3 preparation of oxycodone impurity B
5.00g of 14-hydroxycodeinone prepared in example 1, 200ml of 10% potassium carbonate aqueous solution and 150ml of absolute ethanol were added to a 500ml reaction flask, heated to 70-75 ℃ with stirring and kept for reaction, and the reaction was monitored to be complete by TLC.
After completion of the reaction, the mixture was stirred at room temperature, 150ml of water and 250ml of dichloromethane were added to the reaction solution, followed by liquid separation, extraction of the aqueous phase with dichloromethane twice (250 ml/time), combination of the organic phases, washing with water once (250 ml/time), drying of the organic phase with anhydrous magnesium sulfate, suction filtration, and evaporation of the solvent from the filtrate under reduced pressure to give 5.61g of a yellow oil.
Column chromatography: and (3) loading the column by a 100-plus 200-mesh silica gel wet method, dissolving 5.60g of a sample by 10ml of dichloromethane for wet loading, performing gradient elution on a mobile phase by using methanol/dichloromethane as an eluent, collecting a target product, and evaporating the solvent under reduced pressure to obtain 3.66g of an off-white solid with the yield of 69.2%.
EXAMPLE 4 preparation of oxycodone impurity B
5.00g of 14-hydroxycodeinone prepared in example 1, 1.95g of 4-dimethylaminopyridine, 0.50g of water and 150ml of isopropanol were added to a 250ml reaction flask, heated to 75 to 80 ℃ with stirring and kept for reaction, and the reaction was monitored by TLC until completion.
After completion of the reaction, the mixture was stirred at room temperature, 150ml of water and 250ml of dichloromethane were added to the reaction solution, followed by liquid separation, extraction of the aqueous phase with dichloromethane twice (250 ml/time), combination of the organic phases, washing with water once (250 ml/time), drying of the organic phase with anhydrous magnesium sulfate, suction filtration, and evaporation of the solvent from the filtrate under reduced pressure to give 5.45g of a yellow oil.
Column chromatography: and (3) loading the column by a 100-plus 200-mesh silica gel wet method, dissolving 5.40g of a sample by 10ml of dichloromethane for wet loading, performing 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 3.92g of an off-white solid with the yield of 74.1%.
EXAMPLE 5 preparation of oxycodone impurity B
5.00g of 14-hydroxycodeinone prepared in example 1, 5.00g of tetrabutylammonium chloride, 5ml of water and 250ml of acetonitrile were added to a 500ml reaction flask, heated to 75 to 80 ℃ with stirring and the reaction was maintained, and the reaction was monitored by TLC until completion.
After the reaction, the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, 150ml of water and 250ml of dichloromethane were added to the reaction mixture, the mixture was separated, the aqueous phase was extracted twice with dichloromethane (250 ml/time), the organic phases were combined, washed once with water (250 ml/time), the organic phase was dried over anhydrous magnesium sulfate, suction filtration was carried out, and the solvent was distilled off under reduced pressure from the filtrate to obtain 5.68g of a yellow oil.
Column chromatography: and (3) loading the column by a 100-plus-200-mesh silica gel wet method, dissolving 5.60g of a sample by 10ml of dichloromethane, loading the sample by the wet method, carrying out gradient elution on a mobile phase by using methanol/dichloromethane as an eluent, collecting a target product, and evaporating the solvent under reduced pressure to obtain 4.12g of an off-white solid with the yield of 77.9%.

Claims (10)

1. The preparation method of oxycodone hydrochloride impurity B is characterized in that 14-hydroxycodeinone is added under alkaline conditions, and the impurity B has the following structure:
Figure FDA0002418685870000011
2. the method of claim 1, wherein the base used in the alkaline condition is selected from an inorganic base and an organic base.
3. The method for preparing oxycodone hydrochloride impurity B according to claim 2, wherein the inorganic base is one or more selected from 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 and sodium hydride; the organic base is selected from one or more of butyllithium, (hexahydro) pyridine, quinoline, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium tert-butoxide, diethylamine, triethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, tetrabutylammonium bromide and tetrabutylammonium bromide.
4. The method for preparing oxycodone hydrochloride impurity B according to claim 2, wherein the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the organic base is preferably one or more of 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, diethylamine, triethylamine, tetrabutylammonium chloride or tetrabutylammonium bromide.
5. The method according to claim 1, wherein the solvent is one or more selected from water, methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, t-butanol, N-pentanol, isopentanol, ethylene glycol, propylene glycol glycerol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dioxane, N-methylpyrrolidone, dichloromethane, chloroform, acetone, butanone, etc.
6. The method according to claim 5, wherein the solvent is one or more selected from water, methanol, ethanol, N-propanol, isopropanol, N-butanol, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, and N-methylpyrrolidone.
7. The method of claim 1, wherein the reaction time of the method is 1-12 hours.
8. The method of claim 7, wherein the reaction time is 2 hours to 8 hours.
9. The method for preparing oxycodone hydrochloride impurity B according to claim 1, wherein the reaction temperature of the preparation method is 0-150 ℃.
10. The method for preparing oxycodone hydrochloride impurity B according to claim 1, wherein the reaction temperature of the preparation method is 20-100 ℃.
CN202010205114.5A 2020-03-20 2020-03-20 Preparation method of oxycodone hydrochloride impurity B Pending CN113493460A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101652370A (en) * 2006-12-04 2010-02-17 诺拉姆科有限公司 The method of the oxycodone that preparation 14-hydroxycodeine ketone level reduces
US20120259118A1 (en) * 2010-07-02 2012-10-11 Johnson Matthey Public Limited Company Low abuk oxycodone, its salts and methods of making same
CN104470928A (en) * 2012-07-16 2015-03-25 罗德科技公司 Process For Improved Opioid Synthesis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101652370A (en) * 2006-12-04 2010-02-17 诺拉姆科有限公司 The method of the oxycodone that preparation 14-hydroxycodeine ketone level reduces
US20120259118A1 (en) * 2010-07-02 2012-10-11 Johnson Matthey Public Limited Company Low abuk oxycodone, its salts and methods of making same
CN104470928A (en) * 2012-07-16 2015-03-25 罗德科技公司 Process For Improved Opioid Synthesis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GABRIEL G. LLANOS等: "Structure-based design, synthesis, and biological evaluation of withaferin A-analogues as potent apoptotic inducers", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *
IIJIMA, IKUO等: "The oxidation of thebaine with m-chloroperbenzoic acid. Studies in the (±)-morphinan series. III", 《HELVETICA CHIMICA ACTA》 *

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Application publication date: 20211012