CN110724155A - Preparation method of oxycodone aldol dimer - Google Patents
Preparation method of oxycodone aldol dimer Download PDFInfo
- Publication number
- CN110724155A CN110724155A CN201911095840.XA CN201911095840A CN110724155A CN 110724155 A CN110724155 A CN 110724155A CN 201911095840 A CN201911095840 A CN 201911095840A CN 110724155 A CN110724155 A CN 110724155A
- Authority
- CN
- China
- Prior art keywords
- oxycodone
- aldol dimer
- group
- reaction
- enolate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of oxycodone aldol dimer, which is characterized by comprising the following steps: (1) reacting oxycodone with a protective reagent under the action of alkali and an optionally added catalyst to obtain oxycodone enolate 1; (2) reacting the oxycodone enolate 1 with oxycodone under the catalysis of Lewis acid to obtain an oxycodone aldol dimer 2; the reaction route is as follows:wherein PG group in oxycodone enolate 1 is a protective group. The preparation method of the invention can produce the aldol dimer with high yield and high selectivity.
Description
Technical Field
The invention relates to a preparation method of an organic compound, in particular to a preparation method of an oxycodone aldol dimer.
Background
Oxycodone, also known as oxycodone, has the structure:
oxycodone is a semi-synthetic opioid extracted from thebaine (alkaloid), has a history of being used clinically for many years as a potent analgesic, and is widely applied clinically due to high bioavailability and multiple administration routes of oxycodone. The pharmacopoeia and registration standards of various countries disclose that degradation impurities exist in oxycodone hydrochloride injection, the impurities are aldol dimers of oxycodone, and the structures of the impurities are as follows:the degradation impurity is a reference substance necessary for the reporting process of oxycodone hydrochloride injection, so that the method for producing the aldol dimer of oxycodone has commercial value andthe utility value is high.
Patent US2006/167258a1 reports the reduction of hydrocodone to hydrocortisone, followed by polymerization to hydrocodone aldehyde dimer under the action of benzophenone and potassium tert-butoxide. However, in this reaction, hydrocodone dimer is only a by-product, the reaction yield is 10% or less, the reaction conditions also need to be carried out under high-temperature reflux conditions, and this reaction yield is extremely low, and the selectivity is poor, so that there is almost no industrial value.
In addition, there is a literature (Journal of the Chemical Society-Perkin Transactions 1, v.no.17, pp.2943 Date:1998) that reports the direct polymerization of hydrocodone under the action of potassium tert-butoxide and diisopropyltriphenylphosphine iodide to produce hydrocodone aldehyde dimer, but the reaction yield is only below 10%.
However, no synthesis method of aldol dimer of oxycodone has been reported in the prior patents and documents, and the synthesis method of the similar compounds does not consider the influence of active substituent groups on the reaction, for example, when hydroxyl exists in the compound, the hydroxyl can preferentially participate in the reaction, so that side reactions are more, the yield is low, and even the preparation fails. When the oxycodone aldol dimer is prepared by the existing method, a dimer product cannot be obtained.
Therefore, in order to solve the above problems, there is an urgent need in the art to provide a method that can be used for producing oxycodone aldol dimer.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the technical problems, the invention provides the method for preparing the oxycodone aldol dimer, which has the advantages of high reaction yield, good reaction selectivity and mild reaction conditions and is suitable for industrial production.
Means for solving the problems
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a method for preparing an oxycodone aldol dimer, comprising the steps of:
(1) reacting oxycodone with a protective reagent under the action of alkali and an optionally added catalyst to obtain oxycodone enolate 1;
(2) reacting the oxycodone enolate 1 with oxycodone under the catalysis of Lewis acid to obtain an oxycodone aldol dimer 2;
the reaction route is as follows:
wherein PG group in oxycodone enolate 1 is a protective group.
Preferably, the protecting agent in step (1) is an organosilicon agent.
Preferably, the protective agent in the step (1) is trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, butyldimethylsilane, triethylsilane, tert-butyldimethylsilane, triisopropylsilane, phenyl-substituted silane or bridge-type silane, and the molar ratio of the protective agent to oxycodone is 1-5: 1.
Preferably, the base in step (1) is selected from one or more of butyllithium, lithium diisopropylamide, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
Preferably, the reaction temperature of the step (1) is-80 ℃ to 30 ℃, and the reaction solvent is one or more selected from dichloromethane, tetrahydrofuran, cyclohexane, benzene and toluene.
Preferably, the catalyst in step (1) is an organic or inorganic base, preferably sodium hydroxide, potassium hydroxide, sodium hydrogen, 2, 6-lutidine, pyridine, piperidine, morpholine, pyrrolidine, diisopropylamine, N-diisopropylethylamine, triethylamine, diethylamine or dimethylamine.
Preferably, the lewis acid in the step (2) is aluminum trichloride, titanium tetrachloride, boron tribromide or boron trifluoride.
Preferably, the reaction temperature in the step (2) is-70 ℃ to 50 ℃.
Preferably, the reaction solvent in step (2) is an aprotic solvent.
Preferably, the solvent is a mixture of one or more selected from the group consisting of diethyl ether, dichloromethane, chloroform, tetrahydrofuran, benzene and toluene.
ADVANTAGEOUS EFFECTS OF INVENTION
The oxycodone carbonyl alpha hydrogen is inactive and not unique and can be polymerized in multiple positions, and the invention adopts an organic silicon reagent to protect the hydroxyl in the enol to form an enol compound 1, and then the enol compound reacts with another molecule of oxycodone, thereby greatly avoiding the occurrence of side reactions. Meanwhile, the structure of oxycodone contains hydroxyl groups, and the properties of the oxycodone are easier to react than carbonyl alpha hydrogen, so that a plurality of byproducts are generated. In addition, the method has mild reaction conditions and simple post-treatment, and is suitable for industrial production.
Drawings
FIG. 1 hydrogen spectrum of oxycodone aldol dimer 2;
FIG. 2 carbon spectrum of oxycodone aldol dimer 2;
Detailed Description
The invention provides a preparation method of oxycodone aldol dimer, which comprises the following steps:
(1) reacting oxycodone with a protective reagent under the action of alkali and an optionally added catalyst to obtain oxycodone enolate 1;
(2) reacting the oxycodone enolate 1 with oxycodone optionally added under the catalysis of Lewis acid to obtain an oxycodone aldol dimer 2;
the reaction route is as follows:
wherein PG group in oxycodone enolate 1 is a protective group. The PG group is a protective group corresponding to the reaction of oxycodone and a protective reagent.
The basic principle of the invention is as follows: reacting oxycodone under the action of a nucleophilic reagent to obtain an enolic compound of oxycodone; then, the obtained enol compound is condensed with another molecule of oxycodone under the action of a catalyst to obtain an aldol dimer. The following reaction scheme is specifically shown:
in a preferred embodiment, the base in step (1) is a strong base, preferably one or more selected from the group consisting of butyllithium, lithium diisopropylamide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide, more preferably one or more selected from the group consisting of butyllithium and lithium diisopropylamide. The base is used in excess relative to oxycodone.
In a preferred embodiment, the protecting agent in the step (1) is an organosilicon agent, the organosilicon agent is trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, butyldimethylsilane, triethylsilane, tert-butyldimethylsilane, triisopropylsilane, phenyl-substituted silane or bridged silane, and the molar ratio of the protecting agent to oxycodone is 1-5: 1, preferably 1.1-4: 1.
The protection of the hydroxyl group by the organosilicon reagent is intended to stabilize the hydroxyl group and eliminate or reduce side reactions caused by the hydroxyl group. The smaller the steric hindrance of the group connected with the silicon atom in the protecting group is, the larger the reactivity of the protecting group is, the poorer the stability of the generated corresponding silyl ether is, and the silyl ether can be removed under the condition of weak acid or weak base; the larger the group to which the silicon atom is bonded, the smaller the reactivity of the protecting group, and the more difficult the silylizing reaction to occur, it is necessary to conduct the reaction by means of a catalyst. Therefore, the optionally added catalyst means that the catalyst may or may not be added in the step (1), and when the catalyst is added, the catalyst is an organic base or an inorganic base, and is preferably sodium hydroxide, potassium hydroxide, sodium hydrogen (also called sodium hydride), 2, 6-lutidine, pyridine, piperidine, morpholine, tetrahydropyrrole, diisopropylamine, N-diisopropylethylamine, triethylamine, diethylamine or dimethylamine, and the like.
In a preferred embodiment, the reaction temperature of step (1) is from-80 ℃ to 30 ℃, preferably from-40 ℃ to room temperature; the reaction solvent is an aprotic solvent, and comprises dichloromethane, tetrahydrofuran, cyclohexane, benzene, toluene and the like.
In a preferred embodiment, the lewis acid in step (2) of the preparation method is a lewis acid catalyst commonly used in the art, including aluminum trichloride, titanium tetrachloride, boron tribromide, boron trifluoride and the like, the boron trifluoride is boron trifluoride or boron trifluoride diethyl ether, and the lewis acid is preferably titanium tetrachloride or boron trifluoride diethyl ether.
In a preferred embodiment, the reaction temperature in step (2) is from-70 ℃ to 50 ℃, preferably from-30 ℃ to room temperature.
In a preferred embodiment, the reaction solvent in step (2) is an aprotic solvent, including diethyl ether, dichloromethane, chloroform, tetrahydrofuran, benzene, toluene, and the like.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Example 1
Preparation of the silyl enol ether compound: adding 250ml of tetrahydrofuran and 5g of oxycodone into a reaction bottle, cooling to-30 ℃, adding 14ml of lithium diisopropylamide, stirring for 1 hour, dropwise adding 5.8g of trimethylchlorosilane (M108,53.7 mu M), stirring for 2 hours after the addition, raising the temperature to room temperature, continuing stirring for 2.5 hours, adding 100ml of saturated ammonium chloride water, stirring for 10 minutes, separating liquid, drying an organic phase with anhydrous magnesium sulfate, filtering, and concentrating a filtrate to be dry to obtain 6.1g of oily matter.
Preparation of aldol dimer: adding oxycodone 1.0g, dichloromethane 50ml and enol silyl ether compound 4.0g into a reaction flask, cooling to-30 deg.C (external temperature), adding boron trifluoride diethyl etherate 2ml, stirring for 5 hrAdding 200ml of water, stirring for 30 minutes, standing for liquid separation, discarding an organic phase, adding 50ml of saturated potassium bicarbonate aqueous solution into an aqueous phase, stirring for 20 minutes, adding 200ml of dichloromethane, stirring for 10 minutes, standing for liquid separation, washing the organic phase with water for 2 times, drying, filtering, and concentrating to obtain a light yellow solid. The obtained product was dissolved in chloroform, purified by silica gel, and eluted with chloroform-anhydrous ethanol solution to give 1.3g of a white solid.1H-NMR(400MHz,DMSO-d6):δ6.73(d,1H),6.66(d,1H),6.63(d,1H),6.52(d,1H),5.17(s,1H),4.96(s,1H),4.74(s,1H),4.40(s,1H),3.81(s,3H),3.74(s,3H),3.32(d,1H),3.09(m,3H),2.86(t,1H),2.68(t,1H),2.43(m,3H),2.34(s,3H),2.29(s,3H),2.06(m,6H),1.44(t,1H),1.26(m,4H),1.11(m,2H).13C-NMR(100MHz,DMSO-d6):δ208.69,146.02,144.39,142.01,140.93,131.89,129.53,125.37,124.60,119.07,117.38,114.78,114.19,91.22,90.48,79.15,71.94,69.83,69.52,64.33,63.75,56.58,56.33,56.22,51.24,50.83,45.37,45.30,44.96,42.21,32.55,31.37,29.65,25.78,25.71,21.52.MS(ESI):m/z 631.3[M+H]+。
Example 2
Preparation of the silyl enol ether compound: adding 40ml of tetrahydrofuran into a reaction bottle, cooling to-30 ℃, adding 19ml of butyl lithium, stirring for ten minutes, dropwise adding 5.8g of trimethylchlorosilane, and stirring for 10 minutes after the addition. Adding oxycodone solution (7.0g oxycodone dissolved in 210ml tetrahydrofuran), stirring for 2 hr, adding 100ml water, stirring for 10 min, adding 100ml saturated ammonium chloride water, stirring for 10 min, separating, drying organic phase with anhydrous magnesium sulfate, filtering, and concentrating the filtrate to dryness to obtain 8.3g oily substance
Preparation of aldol dimer: adding 1.0g of oxycodone, 50ml of dichloromethane and 2.0g of enolsilyl ether compound into a reaction bottle, cooling to-30 ℃ (external temperature), dropwise adding 2ml of titanium tetrachloride dichloromethane solution, stirring for 1 hour, stirring for not less than 8 hours at room temperature, adding 200ml of water, stirring for 30 minutes, standing for liquid separation, removing an organic phase, adding 50ml of saturated ammonium chloride aqueous solution into an aqueous phase, stirring for 20 minutes, adding 200ml of dichloromethane, stirring for 10 minutes, standing for liquid separation, washing the organic phase with water for 2 times, removing the organic phase, alkalifying the aqueous phase with saturated sodium bicarbonate solution, filtering and drying. The obtained product was dissolved in chloroform, purified by silica gel, and eluted with chloroform-anhydrous ethanol solution to give 0.7g of a white solid.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Claims (10)
1. A method for preparing oxycodone aldol dimer, comprising the steps of:
(1) reacting oxycodone with a protective reagent under the action of alkali and an optionally added catalyst to obtain oxycodone enolate 1;
(2) reacting the oxycodone enolate 1 with oxycodone under the catalysis of Lewis acid to obtain an oxycodone aldol dimer 2;
the reaction route is as follows:
wherein PG group in oxycodone enolate 1 is a protective group.
2. The method of claim 1, wherein the protecting agent in step (1) is an organosilicon reagent.
3. The method for preparing oxycodone aldol dimer according to claim 1, wherein the protective reagent in step (1) is trimethylchlorosilane, trimethylsilyl trifluoromethanesulfonate, butyldimethylsilane, triethylsilane, tert-butyldimethylsilane, triisopropylsilane, phenyl-substituted silane or bridged silane, and the molar ratio of the protective reagent to oxycodone is 1-5: 1.
4. The method according to claim 1, wherein the base in step (1) is one or more selected from the group consisting of butyllithium, lithium diisopropylamide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
5. The method for preparing oxycodone aldol dimer according to claim 1, wherein the reaction temperature in step (1) is-80 ℃ to 30 ℃, and the reaction solvent is one or more selected from dichloromethane, tetrahydrofuran, cyclohexane, benzene and toluene.
6. The method according to claim 1, wherein the catalyst in step (1) is an organic or inorganic base, preferably sodium hydroxide, potassium hydroxide, sodium hydrogen, 2, 6-lutidine, pyridine, piperidine, morpholine, tetrahydropyrrole, diisopropylamine, N-diisopropylethylamine, triethylamine, diethylamine or dimethylamine.
7. The method for preparing oxycodone aldol dimer according to claim 1, wherein the lewis acid in step (2) is aluminum trichloride, titanium tetrachloride, boron tribromide or boron trifluoride.
8. The method for preparing oxycodone aldol dimer according to claim 1, wherein the reaction temperature in step (2) is-70 ℃ to 50 ℃.
9. The method of claim 1, wherein the reaction solvent in step (2) is an aprotic solvent.
10. The method according to claim 9, wherein the solvent is a mixture of one or more selected from the group consisting of diethyl ether, dichloromethane, chloroform, tetrahydrofuran, benzene and toluene.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911095840.XA CN110724155A (en) | 2019-11-11 | 2019-11-11 | Preparation method of oxycodone aldol dimer |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911095840.XA CN110724155A (en) | 2019-11-11 | 2019-11-11 | Preparation method of oxycodone aldol dimer |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110724155A true CN110724155A (en) | 2020-01-24 |
Family
ID=69225268
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911095840.XA Pending CN110724155A (en) | 2019-11-11 | 2019-11-11 | Preparation method of oxycodone aldol dimer |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110724155A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113237988A (en) * | 2021-04-30 | 2021-08-10 | 北京济圣康泰国际医药科技有限公司 | Method for detecting content of degraded impurity aldol dimer in oxycodone liquid preparation |
CN113493470A (en) * | 2020-03-20 | 2021-10-12 | 江苏恩华药业股份有限公司 | Preparation method of oxycodone hydrochloride injection impurity A |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101511342A (en) * | 2006-09-08 | 2009-08-19 | 惠氏公司 | Dry powder compound formulations and uses thereof |
CN101868462A (en) * | 2007-11-09 | 2010-10-20 | 赛诺菲-安万特 | Method for the preparation of morphine compounds |
WO2012153162A1 (en) * | 2011-05-12 | 2012-11-15 | Lupin Limited | Novel method for preparation of atovaquone |
-
2019
- 2019-11-11 CN CN201911095840.XA patent/CN110724155A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101511342A (en) * | 2006-09-08 | 2009-08-19 | 惠氏公司 | Dry powder compound formulations and uses thereof |
CN101868462A (en) * | 2007-11-09 | 2010-10-20 | 赛诺菲-安万特 | Method for the preparation of morphine compounds |
WO2012153162A1 (en) * | 2011-05-12 | 2012-11-15 | Lupin Limited | Novel method for preparation of atovaquone |
Non-Patent Citations (3)
Title |
---|
BHAIRAB N ROY ET AL.: "A novel process for synthesis of atovaquone", 《INDIAN JOURNAL OF CHEMISTRY》 * |
COLUMBUS,OHIO,US,: "REGISTRY[online]", 《STN检索报告 US REGISTRY》 * |
陈飞等: "羟考酮及其代谢物的定性及定量分析方法研究", 《中国药物依赖性杂质》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113493470A (en) * | 2020-03-20 | 2021-10-12 | 江苏恩华药业股份有限公司 | Preparation method of oxycodone hydrochloride injection impurity A |
CN113237988A (en) * | 2021-04-30 | 2021-08-10 | 北京济圣康泰国际医药科技有限公司 | Method for detecting content of degraded impurity aldol dimer in oxycodone liquid preparation |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105728046B (en) | A kind of ruthenium metal olefin metathesis catalyst and its methods for making and using same | |
CN110724155A (en) | Preparation method of oxycodone aldol dimer | |
CN103224473B (en) | Preparation method of triazine ring | |
WO2014077321A1 (en) | Aluminum catalyst | |
WO2021195751A1 (en) | Catalytic cannabigerol processes and precursors | |
CN111646964B (en) | Novel method for synthesizing 2H-pyran-2-one derivative by base catalysis | |
CN110937985B (en) | Synthesis method of paradol | |
CN105175346A (en) | Method for synthesis of rosuvastatin calcium intermediate | |
CN114853658B (en) | Synthesis method of 9- (4-bromophenyl) carbazole | |
JP4994772B2 (en) | Method for producing piperidin-4-one derivative using bisaminol ether compound | |
CN106432318A (en) | Design and synthesis of aryne precursor and application of aryne precursor in synthesis of multi-substituted arene | |
EP3885341A1 (en) | Preparation method for efinaconazole | |
CN111072450A (en) | Synthesis method of allyl alcohol derivative | |
EP1506958A1 (en) | Process for producing shogaol and intermediates for the synthesis thereof | |
CN112047815A (en) | Preparation method of cannabidiol compound | |
JPWO2010119890A1 (en) | Method for producing tetrahydropyran compound and intermediate thereof | |
CN103145787A (en) | Novel preparation method of ulipristal acetate key intermediate | |
US7745649B2 (en) | Processes for preparing tetrahydropyran-4-one and pyran-4-one | |
CN113429333B (en) | Synthesis method of gatifloxacin intermediate | |
JP7168161B2 (en) | Method for producing heterol multimer | |
JP2013540736A (en) | New process | |
EP3650452B1 (en) | Method for producing iodine-containing silicon compound | |
CN111777581B (en) | Method for synthesizing multi-connected benzofuran and derivative thereof | |
CN104961722B (en) | Method for preparing eprosartan intermediate by using reaction auxiliary agent | |
CN105218343A (en) | A kind of synthetic method of 3-bromine hexamethylene-2-alkene-1-ketone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200124 |
|
RJ01 | Rejection of invention patent application after publication |