CN104693210A - Preparation process of standard products of morphine base and heroin base - Google Patents
Preparation process of standard products of morphine base and heroin base Download PDFInfo
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- CN104693210A CN104693210A CN201410839078.2A CN201410839078A CN104693210A CN 104693210 A CN104693210 A CN 104693210A CN 201410839078 A CN201410839078 A CN 201410839078A CN 104693210 A CN104693210 A CN 104693210A
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- morphine
- base
- heroine
- heroin
- standard substance
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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 discloses a preparation process of standard products of morphine base and heroin base. The preparation process comprises the following steps: (1) carrying out methanol extraction and acid hydrolysis on a heroin sample obtained during drug control, so as to obtain a morphine crude product; (2) purifying by virtue of silica gel chromatography preparation column; (3) carrying out methanol recrystallization to obtain a morphine standard product; (4) carrying out acetylation on morphine, so as to obtain a heroin sample; and (5) recrystallizing concentrated liquid obtained in the step (4), so as to obtain a heroin base standard product, wherein the detection result of gas chromatography mass spectrometry shows that the purity of morphine base is more than or equal to 97.8% and the purity of heroin is more than or equal to 98.4%. According to a project design, all technique processes are carried out at normal temperature and normal pressure, the operation is simple, safe and environmentally friendly, and the preparation cost is low.
Description
Technical field
The present invention relates to a kind of technique preparing heroinbase, morphine base standard substance.The technical problem to be solved in the present invention is to provide a kind of reaction conditions gentleness, yield is high, cost is low, the method preparing heroinbase, morphine base standard substance of green safety.
Background technology
At morphine alkaloids drugs, derive from natural product opium poppy (formal name used at school:
papaver somniferum L.); morphine, morphine monomethyl ether can be extracted from opium poppy; the monoacylated morphine of its acetylate 3-, the monoacylated morphine of 6-, 3 can be obtained through chemical conversion; 6-diacetylation morphine (heroine), acetylize morphine monomethyl ether; morphine and morphine monomethyl ether molecular structure similar; on molecule, 3-OH is morphine, 3-OCH on molecule
3be morphine monomethyl ether, on morphine monomethyl ether molecule, 6-OH acetylize is acetylize morphine monomethyl ether, as shown in Figure 1.Capture in drugs and be difficult to have single pure chemicals independently to exist, derive from the alkaloid of drugs not only containing more similar of natural matter opium, with the existence often containing additives such as caffeine and production auxiliary agent lactose, N.F,USP MANNITOL and sucrose.Suitable technological line purification drugs Alkaloid standard substance are selected to be the key core that judicial poison examines in research of technique.Obtain highly purified standard substance and can be scientific research, technical progress, the anti-Chinese mugwort of the prohibition of drug, the stable guarantee that provides material base of social safety.
Acetylize (English: Acetylation; IUPAC names: ethanoylation) also known as acetylating or acetylizing, refers to a chemical reaction acetyl functional group joined in an organic compound.Otherwise the reaction removed by ethanoyl is called deacetylation or deacetylation (English: Deacetylation).
Acetylization reaction is one of modal reaction in organic synthesis, and ethanoyl is also the conventional protecting group in complicated building-up reactions.According to bibliographical information; the acetylize protection of hydroxyl in alcohols and phenolic compound molecule; normal employing Acetyl Chloride 98Min. or diacetyl oxide carry out under acid or base catalysis; base catalysis is carried out as under alkaline reagents at tertiary amine or aromatic amine, and wherein pyridine, 4-Dimethylamino pyridine (DMAP) and 4-pyrroles's pyridine (PPY) etc. are all the basic catalysts of excellent property.In addition, an acidic catalyst such as protonic acid (as tosic acid), Lewis acid (as transition metal halide, fluoroform sulphonate, perchlorate) and solid acid (as molecular sieve etc.) also can the reaction of catalysis acetylating hydroxyl groups.Although above-described catalyzer is applied in laboratory scale even suitability for industrialized production, still there is the expensive and defects such as poisonous and harmful of such as long reaction time, severe reaction conditions, required reagent.
Drug molecule can utilize acetylization reaction, closes the hydroxyl of parent, its lipotropy is strengthened, owing to changing Determination of oil-water partition coefficient, is conducive to intestinal absorption, can improve curative effect.Also effect is larger usually, as acetylsalicylic acid (acetylsalicylic acid), diacetylmorphine (heroine) for acetylizad medicine.
Phenolic hydroxyl group on aromatic ring discharges by deacetylation, increases macromolecular polarity, and the alkaloid especially for indissoluble can significantly improve its dissolving power, increases polarity, is conducive to the compound separation with structural similitude.
The domestic shortage of heroine standard substance, the drug smuggling drug trafficking case parts such as some regional heroine of China are more, and drug abuse situation also has the gesture spread, and the situation is tense for the anti-Chinese mugwort of the whole nation prohibition of drug.For solve in judicial poison inspection qualification to the standard substance such as heroine to need be the task of top priority, Kunming public security science and technology institute and Yunnan University's experimental center joint study are once at the column chromatography method nineties in last century, the content of the heroine standard substance of purifying is 87.3%, slightly above standard specimen (87.2 the %) (Zhang Xuecheng joined at that time and state provides, Li Yulong, Huang Dongsen, Su Ren, Wen Yunbo, Li Cong, Ma Heng, Chen Shanna, the preparation of heroine standard substance, criminal technique, 1993, (3), 25-27.), preparation process is numerous and diverse, quantity is difficult to meet quantitative analysis testing requirement.Wei Yun etc. are with preparative RPLC combine with technique anti-solvent salting-out crystallization process, the heroine hydrochloride of 156.15 mg is contained from 180 mg() capture drugs the heroine standard substance 110.7 mg(Zhen Guo obtaining high purity (99.52%), Hui Zheng, Yanzhen Lu, Yun Wei, Isolation and purification of heroin from heroin street samples by preparative high performance liquid chromatography, Forensic Science International, 2012(221), (120 – 124).The method require high price equipment investment and a large amount of high purity reagents, consumptive material consumption.
The combination process of technique employing deacetylate of the present invention reaction, column chromatography purification, phenolic hydroxyl group acetylize, recrystallization technology realizes the preparation technology of morphine base, heroinbase standard substance, as shown in Figure 2.Deacetylate reaction makes heroine be converted into morphine; molecular polarity increases; increase dissolving power; be conducive to making it be separated with analog; in this technique, chloroform elutriant can be separated morphine monomethyl ether separately, with recrystallizing methanol purifying morphine, reduces purifying difficulty; overcome RPLC technology need high purity reagent, reagent consumption large, consume the shortcomings such as reversed material, there is reaction conditions gentleness, yield be high, cost is low, the feature such as green safety.
Summary of the invention
The present invention also proposes a kind of preparation method of heroine diacetyl compound; comprise the following steps: the morphine obtained by purifying mixes with the acetic anhydride of 3 ~ 5 times amount; 50 ~ 100 DEG C of heated and stirred, react 3 ~ 4 hours, reaction product 3 times amount 15% sodium acetate solutions dissolve.Solution sodium carbonate alkalizes pH ~ 9, and precipitation filters and uses distilled water wash 2 ~ 3 times, dry product recrystallizing methanol, obtains morphine diacetylation product (heroine).
First the present invention sets out with capturing drugs, and through the methanol extraction removal of impurity, the combination process of deacetylate reaction, column chromatography purification, phenolic hydroxyl group acetylization reaction, recrystallization technology realizes the preparation technology of morphine base, heroinbase standard substance.Detect through Gc-ms, morphine purity >=97%, heroine purity >=98%.Provide a kind of operational path becoming drugs and be medicine: the heroine placed under arrest (drugs) is reduced into morphine, morphine monomethyl ether, and then synthesis of high purity diacetylmorphine, reduce the cost (cost is less than one of the percentage of import reference material) of opium class drugs reference material.
The present invention is achieved by the following technical solutions, a kind of technique preparing heroinbase, morphine base standard substance, and step is as follows:
(1) get and capture drugs heroine 10.0g, solvent extraction heroine, add the methyl alcohol of 500 ~ 600ml, stir extraction at 20 ~ 35 DEG C 3 times, extract 1h at every turn, often extract once, filter and heroine is leached; United extraction liquid (about 1350 ~ 1700ml), at 30 ~ 45 DEG C, rotary evaporation under-0.07 ~-0.09Mpa, obtains heroine crude product (about 8.5 ~ 10g);
(2) the heroine crude product to step (1) gained dissolves with appropriate hydrochloric acid, 80 DEG C of water-bath 1 ~ 2h, NaOH or Na
2cO
3be adjusted to pH10, (about 100ml water liquid) heating volatilizes to 50ml, and chloroform 100ml × 3 are extracted, and fling to chloroform and obtain morphine crude product (about 2 ~ 7g);
(3) to the morphine crude product of step (2) gained with proper amount of methanol or dissolve with ethanol, in add 1 ~ 3 times (refer to quality volume multiple, namely 1g crude product add 1 ~ 3 times of solid, silica gel down together), stir at 20 ~ 35 DEG C, evaporate under normal temperature, must containing the silica gel sample of morphine;
(4) preparation of chromatography column: take 650 ~ 750g silica gel, activates 6 ~ 10h at 110 ~ 120 DEG C; In silica gel, add 3 times of chloroforms (quality volume multiple), stir into pulpous state; Adopt wet method dress post method that silica gel is encased in 6 × 60cm
2in chromatography column, leave standstill, make silica gel fully be settled down to volume stability constant;
(5) get step (3) gained and mix sample silica gel 15 ~ 30g containing morphine sample, slowly join upper end in chromatography column, use chloroform elution, flow velocity is 2 ~ 3ml/min, collects elutriant by every part of 100 ~ 300ml; Concentrated by each part elutriant collected, each part eluant component of gas chromatography mass spectrometry Qualitative Identification is to no longer detecting morphine monomethyl ether, and use meoh eluate wash-out, flow velocity is 2 ~ 3ml/min, collects elutriant by every part of 100 ~ 300ml;
(6) each part meoh eluate collected is concentrated, the each part eluant component of gas chromatography mass spectrometry Qualitative Identification, the concentrated solution of single for tool morphine base component is merged, evaporation of solvent, with methyl alcohol or ethyl alcohol recrystallization secondary, obtain morphine base (Morphine alkloid, MA) standard substance (about 2 ~ 7g), detect through Gc-ms, purity >=97% of morphine base.
(7) be dissolved in reaction solvent aceticanhydride with the sodium acetate of step (6) gained concentrated solution and 1 ~ 5 times amount, utilize acetylization reaction, 50 ~ 100 DEG C of heated and stirred, react 1 ~ 5 hour, be 1:(2 ~ 5 in reaction solution and distilled water) ratio, reaction solution is poured in distilled water, 4 DEG C of refrigerators are placed and are spent the night, adularescent solid is separated out, precipitation washes with water to neutrality, with methyl alcohol or ethyl alcohol recrystallization, obtain morphine diacetyl compound heroinbase (heroin alkloid, HA) sterling (about 2 ~ 5g), detect through Gc-ms, purity >=98% of heroinbase.
(8) the HPLC quantitative detecting method of described heroinbase, morphine base is:
Adopt U.S. Agilent company 7890A-5975C gas chromatograph-mass spectrometer, band 7683B automatic sampler, chromatographic column 30m × 0.25mm × 0.25 μm DB-5MS (Agilent); Column temperature 180 DEG C keeps lmin, 15 DEG C/min to rise to 300 DEG C and keeps 15min; Gasification temperature 260 DEG C; Interface temperature 280 DEG C; Ion source temperature 230 DEG C, EI source 70eV, Multiplier voltage 1500V, carrier gas He1.2mL/min, splitting ratio 20:1.Sample size 1ul, morphine appearance time is ~ 10.2 minutes, detects purity 97% ~ 98%.Heroine appearance time is ~ 11.4 minutes, detects purity 98% ~ 98.9%.
First the present invention sets out with capturing drugs, through the methanol extraction removal of impurity, the combination process of deacetylate alcoholysis, column chromatography purification, acetylating hydroxyl groups, recrystallization technology realizes the preparation technology of heroinbase, morphine base standard substance, detect through Gc-ms, MA purity >=97%, HA purity >=98%; The present invention has prepared heroinbase, morphine base standard substance, provide a kind of operational path (heroine (drugs) being reduced into morphine, morphine monomethyl ether (drugs, medicine)) becoming poison and be medicine, reduce the cost (cost is less than the thousandth of import reference material) of the reference material of opium class drugs.
Accompanying drawing illustrates:
Fig. 1 is the compound schematic diagram of heroine that different substituents is corresponding and similar;
Fig. 2 is technological line schematic diagram.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.
Embodiment 1: preparation heroinbase, morphine base standard substance
Prepared by morphine:
Acid hydrolysis: experiment crude product heroine 50 grams, with 3molL
-1hydrochloric acid 300ml deacetylation; after gained solution filters; 80 DEG C of heating 60min, after cooling, solid sodium hydroxide adjusts pH neutrality (having Precipitation), then adjusts pH ~ 9(no longer to produce precipitation to dripping sodium carbonate with saturated aqueous sodium carbonate); precipitation places 5h; suction filtration, washing, precipitation infrared drying; obtain morphine crude product 35 grams, transformation efficiency 70%.
Morphine is refined: morphine crude product with dry after 10 times amount ether supersound washings, suction filtration 3 times, silica gel column chromatography preparative column purifying, recrystallizing methanol 4 times.Obtain morphine base standard substance 17.6 grams, detect through Gc-ms, purity >=97%.
Prepared by heroine:
The diacetylation of morphine: get 10 grams, refining morphine; be placed in 125ml round bottom distilling flask; add diacetyl oxide 60 grams; 80 DEG C of water-bath 2h; 15% acetic acid aqueous solution 60ml is added after cooling; solution is transferred in 500ml beaker; pH neutrality (having Precipitation) is adjusted with solid sodium hydroxide; pH ~ 9(is adjusted no longer to produce precipitation to dripping sodium carbonate with saturated aqueous sodium carbonate again); suction filtration after precipitation placement 30min, more meticulously wash 3 times with deionized water, precipitate with infrared rays instrument dry; obtain diacetylmorphine crude product 9 grams, transformation efficiency 90%.
The purifying of diacetylmorphine: prepare gained diacetylmorphine, with recrystallizing methanol 4 times, obtains purifying diacetylmorphine 2.8 grams, detects, purity >=98% through Gc-ms.
The quantitative detecting method of described morphine base, heroinbase is:
Adopt U.S. Agilent company 7890A-5975C gas chromatograph-mass spectrometer, band 7683B automatic sampler, chromatographic column 30m × 0.25mm × 0.25 μm DB-5MS (Agilent); Column temperature 180 DEG C keeps lmin, 15 DEG C/min to rise to 300 DEG C and keeps 15min; Gasification temperature 260 DEG C; Interface temperature 280 DEG C; Ion source temperature 230 DEG C, EI source 70eV, Multiplier voltage 1500V, carrier gas He1.2mL/min, splitting ratio 20:1.Sample size 1ul, morphine appearance time is ~ 10.2 minutes, detects purity 97% ~ 98%.Heroine appearance time is ~ 11.4 minutes, detects purity 98% ~ 98.9%.
The above, it is only preferred embodiment of the present invention, not any pro forma restriction is done to the present invention, although the present invention discloses as above with preferred embodiment, but and be not used to limit the present invention, any those skilled in the art are not departing within the scope of technical solution of the present invention, when the technology contents that appeal can be utilized to disclose is made a little change or is modified to the Equivalent embodiments of equivalent variations, in every case be the content not departing from technical solution of the present invention, according to technical spirit of the present invention to any simple modification made for any of the above embodiments, equivalent variations and modification, all still belong in the scope of technical solution of the present invention.
Claims (2)
1. prepare a technique for morphine base, heroinbase standard substance, it is characterized in that following steps:
(1) by the heroine sample placed under arrest of banning taking addictive drugs, acid hydrolysis obtains morphine crude product;
(2) silica gel column chromatography preparative column purifying morphine;
(3) recrystallizing methanol obtains morphine standard substance, detects, morphine purity >=97.8% through Gc-ms;
(4) morphine obtains heroine sample through diacetylation;
(5) step (4) gained concentrated solution recrystallization is obtained heroinbase standard substance, detect through Gc-ms, heroine purity >=98.4%.
2. according to a kind of technique preparing morphine base, heroinbase standard substance described in claim 1, it is characterized in that: select morphine base operational path to be heroine deacetylation alcoholysis-column chromatography purification-recrystallizing technology; The selected heroinbase operational path of institute is heroine deacetylation alcoholysis-column chromatography purification-acetylize-recrystallizing technology.
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| CN201410839078.2A CN104693210A (en) | 2014-12-30 | 2014-12-30 | Preparation process of standard products of morphine base and heroin base |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107179361A (en) * | 2017-05-08 | 2017-09-19 | 公安部物证鉴定中心 | Method for preparing purified for the methadone standard substance of forensic science illicit drugs inspection |
| CN107383032A (en) * | 2017-05-08 | 2017-11-24 | 公安部物证鉴定中心 | For the morphine base of forensic science illicit drugs inspection, morphine hydrochloride, heroin hydrochloride standard substance method for preparing purified |
| CN108864122A (en) * | 2018-04-20 | 2018-11-23 | 公安部物证鉴定中心 | [2H6The synthetic method of]-diacetylmorphine |
| CN110713494A (en) * | 2019-09-20 | 2020-01-21 | 甘肃省药物碱厂 | Treatment method for removing impurities from high-purity morphine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107179361A (en) * | 2017-05-08 | 2017-09-19 | 公安部物证鉴定中心 | Method for preparing purified for the methadone standard substance of forensic science illicit drugs inspection |
| CN107383032A (en) * | 2017-05-08 | 2017-11-24 | 公安部物证鉴定中心 | For the morphine base of forensic science illicit drugs inspection, morphine hydrochloride, heroin hydrochloride standard substance method for preparing purified |
| CN107179361B (en) * | 2017-05-08 | 2019-10-25 | 公安部物证鉴定中心 | The method for preparing purified of methadone standard substance for forensic science illicit drugs inspection |
| CN107383032B (en) * | 2017-05-08 | 2020-07-28 | 公安部物证鉴定中心 | Purification preparation method of morphine base, morphine hydrochloride and heroin hydrochloride standard substances for forensic science drug detection |
| CN108864122A (en) * | 2018-04-20 | 2018-11-23 | 公安部物证鉴定中心 | [2H6The synthetic method of]-diacetylmorphine |
| CN110713494A (en) * | 2019-09-20 | 2020-01-21 | 甘肃省药物碱厂 | Treatment method for removing impurities from high-purity morphine |
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