CN103664967B - [ 2h 3the synthetic method of]-morphine - Google Patents
[ 2h 3the synthetic method of]-morphine Download PDFInfo
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- CN103664967B CN103664967B CN201210341843.9A CN201210341843A CN103664967B CN 103664967 B CN103664967 B CN 103664967B CN 201210341843 A CN201210341843 A CN 201210341843A CN 103664967 B CN103664967 B CN 103664967B
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- morphine
- deuterated
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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:
- C07D489/02—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 oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
Abstract
The invention provides one [
2h
3the synthetic method of]-morphine, present method is starting raw material with morphine, comprise with chloro-formic ester carry out demethylation generation [
2h
3the precursor of]-morphine, then by this precursor with deuterated go back original reagent such as deuterated Lithium aluminum hydride reduction obtain [
2h
3]-morphine.The present invention has simple to operate, and raw material is easy to get, and the reaction times is short, reaction yield high.
Description
Technical field
The present invention relates to one [
2h
3the synthetic method of]-morphine.
Background technology
Drug problem is worldwide on the rise in recent years, and strengthening is one of important measures of the prohibition of drug to the detection of drugs particularly drug addict.The identification of taking drugs needs the biomaterial of drug abuse suspect as urine, blood, saliva, sweat and hair carry out the detection of drugs and metabolite thereof.
Heroine abuses one of the widest drugs in the world, after heroine enters blood, is decomposed into rapidly 6-monoacetylmorphine, and then is hydrolyzed to morphine.
Carry out in the method for qualitative and quantitative analysis accurately to heroine (morphine), gas chromatographymass spectrum can be accepted by court and can carry out the final method assert to detected result, and [
2h
3]-morphine is the best internal standard substance of the method.
But, [
2h
3]-morphine is also not easy to obtain.Domesticly to there is no [
2h
3the batch production of]-morphine and sale, and external import [
2h
3]-morphine is expensive, up to several thousand yuans every milligram.Therefore, a kind of synthesis of research [
2h
3the simple and easy method of]-morphine is of great significance.
For [
2h
3the synthesis of]-morphine, at J.Med.Chem., 1963, report two kinds of methods in 6 (3), 237-246.One be with demethylation morphine be starting raw material carry out [
2h
3the synthesis of]-morphine.The morphine the method using demethylation is starting raw material, and this starting raw material does not have naturally occurring, needs by carrying out demethylation to morphine, and then on nitrogen and 3-position oxygen, reaction generates N, O again
3the morphine replaced, operates consuming time loaded down with trivial details; Meanwhile, on nitrogen and 3-position oxygen, reaction generates N, O
3use tubing products Vinyl chloroformate during the morphine replaced, this raw material is not easy to obtain and is deadly poisonous compound, higher to experiment operator skill set requirements; Moreover this reaction times is longer, it is also uneconomic that energy consumption aspect is considered.
Another kind is method is carry out deuterated methylating with deuterated methyl iodide to demethyl morphine monomethyl ether, the methyl then removed above the oxygen of 3-position obtains [
2h
3]-morphine, first, demethyl morphine monomethyl ether also needs to be synthesized from morphine monomethyl ether by chemical synthesis process, operates relatively loaded down with trivial details, and the method needs practical deuterated methyl iodide human body to strong carcinogenesis, and yield only has 33%.
Therefore, still there are a kind of needs in the prior art, it is desirable to obtain easy, efficient synthesis preparation [
2h
3the method of]-morphine.Instant invention overcomes the deficiencies in the prior art, a kind of simple, stable, safe method is provided, prepare efficiently [
2h
3]-morphine.
Summary of the invention
There is provided herein one prepare [
2h
3the method of]-morphine, comprises the following steps
I () is by morphine and chloro-formic ester:
Wherein
R is selected from following:
wherein represented by dotted arrows link position,
Be obtained by reacting the first intermediate:
First intermediate;
(ii) this first intermediate and deuterated reduction reagent react are obtained [
2h
3]-morphine.
According to hereinbefore method, wherein step (i) is carried out under the alkaline condition of pH7-12; Wherein alkaline condition can by adding acid binding agent and producing in a solvent.Be such as mineral alkali for acid binding agent herein, comprise sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, cesium carbonate; Or organic bases, comprise triethylamine, DIPEA, diazabicylo (DBU), pyridine.
According to hereinbefore method, wherein step (i) and (ii) react all in organic solvent.The organic solvent that can use in this article is selected from, such as acetonitrile, chloroform, tetrahydrofuran (THF) etc.
The deuterated original reagent of going back used in step (ii) is herein such as deuterated lithium aluminium hydride.
Herein, the mol ratio of morphine and chloro-formic ester is 1: (3-10); The mol ratio of morphine and acid binding agent is 1: (6-16); Morphine volumetric molar concentration is in organic solvent 0.01-0.3mol/L; The deuterated mol ratio of original reagent and the first intermediate of going back is for (3-9): 1.
Embodiment
There is provided herein one prepare [
2h
3the method of]-morphine.In preparation method as herein described, with morphine be starting raw material preparation [
2h
3]-morphine, comprises the following steps:
I morphine and chloro-formic ester are obtained by reacting the first intermediate by ():
First intermediate
Wherein
R is selected from following:
wherein represented by dotted arrows link position,
(ii) this first intermediate and deuterated reduction reagent react are obtained [
2h
3]-morphine
In step (i), use chloro-formic ester demethylation is carried out to morphine and use generate amido formate as generation [
2h
3the precursor of]-morphine is the first intermediate.Chloro-formic ester used herein is such as phenyl chloroformate, chloroformic acid benzyl ester.The mol ratio of morphine and chloro-formic ester is 1: (3-10), preferably 1: (4-8); More preferably 1: (5-7).
The reaction of this step (i) is carried out under neutrality to alkaline condition, preferably carries out under the condition of pH value 7-12, and more preferably pH value is carried out under the condition being greater than 8 to 10.In order to obtain this pH value, acid binding agent can be added in step (i).Can use acid binding agent known in the art, comprise, such as, mineral alkali, comprises sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, cesium carbonate; Or organic bases, comprise triethylamine, DIPEA, diazabicylo (DBU), pyridine.Herein, the mol ratio of morphine and acid binding agent can be 1: (6-16), preferably 1: (8-15), more preferably 1: (10-12).
Step (i) is carried out in organic solvent, and selectable solvent comprises acetonitrile, chloroform, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, N, N-dimethyl methyl (second) acid amides, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone etc., preferred acetonitrile, chloroform.
Particularly, the reaction times of step (i) is generally 3-18 hour.After obtaining the first intermediate, can simple aftertreatment be carried out, such as, ethyl acetate be added cooled reaction solution, clean with salt solution, collect organic phase, carry out drying, obtain the first intermediate of the first step, next step reaction can be directly used in, simple to operate, poison little to human body.
In step (ii), the first intermediate that step (i) is obtained and deuterated reduction reagent react, obtain [
2h
3]-morphine.Deuterated original reagent of going back can use and known in the artly deuteratedly goes back original reagent, such as deuterated lithium aluminium hydride.The deuterated mol ratio of original reagent and the first intermediate of going back is for (3-9): 1, is preferably (4-8): 1, more preferably (5-7): 1.Advantageously this step (ii) is carried out in organic solvent.Those of ordinary skill in the art can select the organic solvent that can use as required.Such as, can be such as with organic solvent in this article: tetrahydrofuran (THF), ether.Preferred tetrahydrofuran (THF), morphine volumetric molar concentration is in organic solvent 0.01-0.3mol/L.
After reaction terminates, post processing mode aftertreatment known to persons of ordinary skill in the art can be used to obtain [
2h
3]-morphine.
In the application's preferred embodiment, aftertreatment by with hydrochloric acid and sodium-potassium tartrate or trisodium citrate cancellation, with the extraction of chloroform-isopropanol system, can obtain thus purity be greater than 90% [
2h
3]-morphine.
Present method simplifies original synthetic method, and raw material is easy to get, simple to operate, safety, and the reaction times is short, and yield is high.
Following examples only for illustration of object, be not used in restriction the present invention.Unless stated otherwise, following shown numerical value is weight or weight percent.
Embodiment 1
114 milligrams of morphines and 640 milligrams of saleratus are joined 10 milliliters of chloroforms by the first step, when stirring, add wherein by 502 milligrams of phenyl chloroformates, displacement argon shield, and 70 DEG C are stirred 6 hours.Cool to room temperature.Add 50 milliliters of ethyl acetate, respectively 2-3 time is washed with water and salt solution (each 10 milliliters), organic phase anhydrous sodium sulfate drying, revolves steaming removing ethyl acetate with Rotary Evaporators and namely obtains 360 milligram of first intermediate (crude product LCMS purity 90%).ESI512(M+H)
+，534(M+Na)
+。
Second step, under ice bath cooling, 118 milligrams of deuterated lithium aluminium hydride are added in there-necked flask, displacement argon shield, 8 milliliters of tetrahydrofuran (THF) needle tubings are squeezed into there-necked flask, then 360 milligram of first intermediate is dissolved in 2 milliliters of tetrahydrofuran (THF)s, slowly reaction solution is squeezed into needle tubing, remove ice bath, reaction solution is refluxed 4 hours, reaction solution ice-water bath is cooled, carefully add 5 milliliters of 4N hydrochloric acid and 5 grams of trisodium citrates by its cancellation, then reaction solution stirs 2 hours at 100 DEG C, cool to room temperature, by extracted with diethyl ether three times (each 5 milliliters), aqueous phase 12N aqueous sodium hydroxide solution adjusts pH to 8.5, then chloroform-isopropanol (volume ratio 3: 1) mixed solvent is used to extract 5 times (each 10 milliliters), organic phase has anhydrous sodium sulfate drying, be spin-dried for obtain 72 milligrams [
2h
3]-morphine, two step total recoverys 62%.Fusing point is 254-256 DEG C.
1HNMR(400MHz，MeOD)δ6.65(d，J＝8.0Hz，1H)，6.57(d，J＝8.0Hz，1H)，5.78-5.72(m，1H)，5.37-5.31(m，1H)，4.92(dd，J＝6.3，1.1Hz，1H)，4.26(dt，J＝5.9，2.6Hz，1H)，4.07(dd，J＝6.6，3.1Hz，1H)，3.30-3.19(m，2H)，3.09-2.99(m，2H)，2.83(dd，J＝19.7，6.8Hz，1H)，2.39(td，J＝13.6，4.9Hz，1H)，2.08-2.01(m，1H)；ESI289(M+H)
+；GC-MS288。
Embodiment 2
114 milligrams of morphines and 640 milligrams of saleratus are joined 10 milliliters of acetonitriles by the first step, when stirring, add wherein by 502 milligrams of phenyl chloroformates, displacement argon shield, and 60 DEG C are stirred 6 hours.Cool to room temperature.Revolve solvent, add 20 milliliters of ethyl acetate, respectively wash 2-3 time, organic phase anhydrous sodium sulfate drying with water and salt solution (each 10 milliliters), revolve ethyl acetate and namely obtain 377 milligram of first intermediate (crude product).
Second step, under ice bath cooling, 118 milligrams of deuterated lithium aluminium hydride are added in there-necked flask, displacement argon shield, 5 milliliters of tetrahydrofuran (THF) needle tubings are squeezed into there-necked flask, then 377 milligram of first intermediate is dissolved in 2 milliliters of tetrahydrofuran (THF)s, slowly reaction solution is squeezed into needle tubing, remove ice bath, reaction solution is refluxed 4 hours, reaction solution ice-water bath is cooled, carefully add 5 milliliters of 4N hydrochloric acid and 5 grams of trisodium citrates by its cancellation, then reaction solution stirs 2 hours at 100 DEG C, cool to room temperature, by extracted with diethyl ether three times (each 5 milliliters), aqueous phase 12N aqueous sodium hydroxide solution adjusts pH to 8.5, then chloroform-isopropanol (volume ratio 3: 1) mixed solvent is used to extract 5 times (each 10 milliliters), organic phase anhydrous sodium sulfate drying, be spin-dried for obtain 76 milligrams [
2h
3]-morphine, two step total recoverys 66%.Fusing point is 254-256 DEG C.
Embodiment 3
114 milligrams of morphines and 552 milligrams of salt of wormwood are joined 10 milliliters of acetonitriles by the first step, when stirring, add wherein by 502 milligrams of phenyl chloroformates, displacement argon shield, and 55 DEG C are stirred 6 hours.Cool to room temperature.Revolve solvent, add 50 milliliters of ethyl acetate, respectively wash 2-3 time, organic phase anhydrous sodium sulfate drying with water and salt solution (each 10 milliliters), revolve ethyl acetate and namely obtain 377 milligram of first intermediate (crude product).
Second step, under ice bath cooling, 118 milligrams of deuterated lithium aluminium hydride are added in there-necked flask, displacement argon shield, 5 milliliters of tetrahydrofuran (THF) needle tubings are squeezed into there-necked flask, then 377 milligram of first intermediate is dissolved in 2 milliliters of tetrahydrofuran (THF)s, slowly reaction solution is squeezed into needle tubing, remove ice bath, reaction solution is refluxed 2 hours, reaction solution ice-water bath is cooled, carefully add 5 milliliters of 4N hydrochloric acid and 5 grams of lemon sodium-potassium tartrates by its cancellation, then reaction solution stirs 0.5 hour at 85 DEG C, cool to room temperature, by extracted with diethyl ether three times (each 5 milliliters), aqueous phase 12N aqueous sodium hydroxide solution adjusts pH to 8.5, then chloroform-isopropanol (volume ratio 3: 1) mixed solvent is used to extract 5 times (each 10 milliliters), organic phase anhydrous sodium sulfate drying, be spin-dried for obtain 77 milligrams [
2h
3]-morphine, two step total recoverys 67%.Fusing point is 254-256 DEG C.
Embodiment 4
570 milligrams of morphines and 2.76 grams of salt of wormwood are joined 50 milliliters of acetonitriles by the first step, when stirring, add wherein by 1.57 grams of phenyl chloroformates, displacement argon shield, and 55 DEG C are stirred 18 hours.Cool to room temperature.Revolve solvent, add 200 milliliters of ethyl acetate, respectively wash 2-3 time, organic phase anhydrous sodium sulfate drying with water and salt solution (each 20 milliliters), revolve ethyl acetate and namely obtain 1.97 gram of first intermediate (crude product).
Second step, under ice bath cooling, 420 milligrams of deuterated lithium aluminium hydride are added in there-necked flask, displacement argon shield, 8 milliliters of tetrahydrofuran (THF) needle tubings are squeezed into there-necked flask, then 1.97 gram of first intermediate is dissolved in 5 milliliters of tetrahydrofuran (THF)s, slowly reaction solution is squeezed into needle tubing, remove ice bath, reaction solution is refluxed 2 hours, reaction solution ice-water bath is cooled, carefully add 25 milliliters of 4N hydrochloric acid and 10 grams of sodium-potassium tartrates by its cancellation, then reaction solution stirs 0.5 hour at 85 DEG C, cool to room temperature, by extracted with diethyl ether three times (each 25 milliliters), aqueous phase 12N aqueous sodium hydroxide solution adjusts pH to 8.5, then chloroform-isopropanol (volume ratio 3: 1) mixed solvent is used to extract 5 times (each 30 milliliters), organic phase has anhydrous sodium sulfate drying, be spin-dried for obtain 403 milligrams [
2h
3]-morphine, two step total recoverys 70%.Fusing point is 254-256 DEG C.
Embodiment 5
1.14 grams of morphines and 5.52 grams of salt of wormwood are joined 80 milliliters of acetonitriles by the first step, when stirring, add wherein by 3.14 grams of phenyl chloroformates, displacement argon shield, and 60 DEG C are stirred 6 hours.Cool to room temperature.Revolve solvent, add 200 milliliters of ethyl acetate, respectively wash 2-3 time, organic phase anhydrous sodium sulfate drying with water and salt solution (each 30 milliliters), revolve ethyl acetate and namely obtain 4.12 gram of first intermediate (crude product).
Second step, under ice bath cooling, 900 milligrams of deuterated lithium aluminium hydride are added in there-necked flask, displacement argon shield, 5 milliliters of tetrahydrofuran (THF) needle tubings are squeezed into there-necked flask, then 4.12 gram of first intermediate is dissolved in 10 milliliters of tetrahydrofuran (THF)s, slowly reaction solution is squeezed into needle tubing, remove ice bath, reaction solution is refluxed 2 hours, reaction solution ice-water bath is cooled, carefully add 25 milliliters of 4N hydrochloric acid and 15 grams of sodium-potassium tartrates by its cancellation, then reaction solution stirs 0.5 hour at 85 DEG C, cool to room temperature, by extracted with diethyl ether three times (each 25 milliliters), aqueous phase 12N aqueous sodium hydroxide solution adjusts pH to 8.5, then chloroform-isopropanol (volume ratio 3: 1) mixed solvent is used to extract 8 times (each 30 milliliters), organic phase anhydrous sodium sulfate drying, be spin-dried for obtain 795 milligrams [
2h
3]-morphine, two step total recoverys 69%.Fusing point is 254-256 DEG C.
Embodiment 6
2.28 grams of morphines and 12 grams of salt of wormwood are joined 150 milliliters of acetonitriles by the first step, when stirring, add wherein by 6.5 grams of phenyl chloroformates, displacement argon shield, and 60 DEG C are stirred 8 hours.Cool to room temperature.Revolve solvent, add 300 milliliters of ethyl acetate, respectively wash 2-3 time, organic phase anhydrous sodium sulfate drying with water and salt solution (each 30 milliliters), revolve ethyl acetate and namely obtain 9.1 gram of first intermediate (crude product).
Second step, under ice bath cooling, 2.3 grams of deuterated lithium aluminium hydride are added in there-necked flask, displacement argon shield, 30 milliliters of tetrahydrofuran (THF) needle tubings are squeezed into there-necked flask, then 9.1 gram of first intermediate is dissolved in 20 milliliters of tetrahydrofuran (THF)s, slowly reaction solution is squeezed into needle tubing, remove ice bath, reaction solution is refluxed 2 hours, reaction solution ice-water bath is cooled, carefully add 75 milliliters of 4N hydrochloric acid and 25 grams of sodium-potassium tartrates by its cancellation, then reaction solution stirs 0.5 hour at 85 DEG C, cool to room temperature, by extracted with diethyl ether three times (each 25 milliliters), aqueous phase 12N aqueous sodium hydroxide solution adjusts pH to 8.5, then chloroform-isopropanol (volume ratio 3: 1) mixed solvent is used to extract 10 times (each 30 milliliters), organic phase anhydrous sodium sulfate drying, be spin-dried for obtain 1.56 grams [
2h
3]-morphine, two step total recoverys 68%.Fusing point is 254-256 DEG C.
According to above embodiment, can know and find out, by method as herein described, morphine can be used for starting raw material, and the reaction times is short, can simply, convenient, safety, obtain efficiently [
2h
3]-morphine.Should [
2h
3]-morphine is through further preparing purifying, and purity can reach more than 99%, can detect in heroine as internal standard substance in employing gas chromatography mass spectrometry method completely.
Claims (11)
1. one kind prepare [
2h
3the method of]-morphine, comprises the following steps:
I () is by morphine and chloro-formic ester:
Wherein
R is selected from following:
wherein represented by dotted arrows link position;
Be obtained by reacting the first intermediate:
(ii) this first intermediate and deuterated reduction reagent react are obtained have following structural formula [
2h
3]-morphine, wherein said deuterated original reagent of going back is selected from deuterated lithium aluminium hydride,
2. method according to claim 1, wherein step (i) is reacted under the condition of pH7-12.
3. method according to claim 1, wherein step (i) and step (ii) are reacted under protection of inert gas.
4. method according to claim 1, wherein said step (i) and (ii) carry out in the presence of an organic.
5. method according to claim 4, wherein said organic solvent is selected from: acetonitrile, chloroform or tetrahydrofuran (THF).
6. method according to claim 2, wherein adds acid binding agent to obtain described pH value in step (i).
7. method according to claim 6, wherein said acid binding agent is selected from mineral alkali, and it is sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus and/or cesium carbonate; Or organic bases, it is triethylamine, DIPEA, diazabicylo (DBU), and/or pyridine.
8. method according to claim 1, wherein said step (i) is reacted the temperature of 50-80 DEG C.
9. method according to claim 1, wherein the mol ratio of morphine and chloro-formic ester is 1:(3-10).
10., according to the method for claims 1, wherein step (i) morphine volumetric molar concentration is in organic solvent 0.01-0.3mol/L.
11. according to the method for claims 1, and wherein the mol ratio of deuterated reagent and the first intermediate is (3-9): 1.
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