CN113072505B - Preparation method of pentadeuterium atom substituted 2-thiophenobarbital - Google Patents
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- CN113072505B CN113072505B CN202110322429.2A CN202110322429A CN113072505B CN 113072505 B CN113072505 B CN 113072505B CN 202110322429 A CN202110322429 A CN 202110322429A CN 113072505 B CN113072505 B CN 113072505B
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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Abstract
The invention discloses a preparation method of pentadeuterium atom substituted 2-thiophenobarbital, belonging to the field of organic synthesis and analysis and detection, comprising the steps of taking methyl malonate as a raw material, carrying out Friedel-crafts alkylation reaction, cyclization reaction and nucleophilic substitution reaction, and separating and purifying to obtain pentadeuterium atom substituted-2-thiophenobarbital; the prepared deuterated 2-thiophenobarbital has the advantages of high chemical purity, stable deuterium atoms and the like; the method has the advantages of simple operation, high yield and low cost; the invention not only provides a synthetic method of the 2-thiophenobarbital substituted by the five deuterium atoms with the independent intellectual property rights, but also provides a deuterated internal standard substance for analysis and detection.
Description
Technical Field
The invention relates to the field of organic synthesis and analysis and detection, in particular to a preparation method of pentadeuterium atom substituted 2-thiophenobarbital.
Background
Barbiturates are sedatives acting on the central nervous system, belong to the derivatives of barbituric acid, and can be applied in the range from mild sedation to complete anesthesia, and can also be used as anxiolytics, hypnotics, and anticonvulsants. However, such drugs can be resistant and dependent after long-term use, and can be poisoned by multiple continuous or large-scale use. In recent years, some lawless persons illegally add the phenobarbital to sleep-aiding health-care food, and after the phenobarbital is eaten for a long time, the phenobarbital is accumulated in the body, so that the health of the human body is threatened. In addition, criminal cases such as drug administration, suicide, mistaken taking and the like caused by abuse of the drugs or the analogs occur occasionally.
However, in recent years, when foods and medicines are screened by using a rapid test strip, the barbiturate test is positive, but when the foods and medicines are checked by using HPLC/MS or UHPLC/Q-TOF, the medicine components in the catalog of narcotics and psychopharmaceuticals and the non-medicinal narcotics and psychopharmaceuticals cannot be detected, and the substances are not included in the latest version of NIST library. However, the chemical structure of the thiophenobarbital is analyzed by adopting high-resolution mass spectrometry, a liquid chromatograph-mass spectrometer, nuclear magnetic resonance and the like, and the structure of the thiophenobarbital is obtained by modifying the original chemical structure of common clinical drug phenobarbital and introducing a group.
Thiobenzbarbital compounds are not used clinically, but may be used by criminals for various criminal activities. This brings great hidden trouble to social security and social stability. Because the compounds lack reference substances and deuterated substances in the investigation and evidence-taking process and have no corresponding detection method for effective verification, great challenges are brought to forensic toxicant identification.
In order to solve the difficult problem of the inspection and identification of barbiturates and analogues in cases, provide key evidence for litigation, effectively attack crimes and develop efficient synthesis processes to realize the synthesis of the compound reference substance or deuterated substance, the synthesis is imminent. In the field of forensic science poison analysis, an internal standard detection method using a deuterated target of a detected target as an internal standard is internationally and generally adopted, and the internal standard method has higher accuracy and higher precision than an external standard method.
Based on the method, the invention develops a preparation method of the pentadeuterium atom substituted 2-thiophenobarbital with proprietary intellectual property rights.
Disclosure of Invention
The invention aims to provide a preparation method of 2-thiophenobarbital substituted by pentadeuterium atoms, so as to solve the problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the compound prepared by the invention is D5-deuterated-2-thiophenobarbital, as shown in a compound (III), and has a Chinese name: 5- (ethyl-d 5 ) -5-phenyl-2-thiodihydroPyrimidine-4, 6 (1)H,5H) -a diketone; the chemical formula is as follows:
a preparation method of 2-thiophenobarbital substituted by pentadeuterium atoms comprises the following steps:
(1) taking 2-halogenated malonate as a raw material, and carrying out Friedel-crafts alkylation reaction with benzene under the catalysis of Lewis acid at the temperature of 75-80 ℃ to obtain a compound 5-phenylmalonate of a formula I;
(2) in an alcohol solvent system, under the reflux condition, the compound of the formula I and thiourea are subjected to amine ester exchange reaction under the action of alkali to obtain a compound of a formula II, namely 2-sulfo-5-phenyl barbituric acid;
(3) the compound of formula II and deuterobromoethane are subjected to nucleophilic substitution reaction in an ether solvent under the action of alkali, and the compound of formula III is separated and purified to obtain 2-thiophenobarbital substituted by pentadeuterium atom,
the compound and the reaction formula are as follows:
as a preferable technical scheme, in the step (1): in the raw material 2-halogenated malonate, a halogen substituent is selected from chlorine, bromine and iodine atoms, and an ester group is selected from methyl ester, ethyl ester and isopropyl ester;
dimethyl 2-chloromalonate is further preferred because of its low cost and higher yield.
As a preferable technical scheme, in the step (1): the Lewis acid is selected from aluminum trichloride, boron trifluoride diethyl etherate, titanium tetrachloride and ferric trichloride;
aluminum trichloride is further preferred because of safe and convenient operation, lower cost and higher yield.
As a preferable technical scheme, in the step (1): the solvent is selected from benzene, mononitrobenzene or dinitrobenzene;
benzene is further preferred because of its lower boiling point and easier recovery.
As a preferable technical scheme, in the step (2): the alcohol solvent system is selected from methanol, ethanol, isopropanol and tert-butanol;
ethanol is further preferred because of its low toxicity and low cost.
As a preferable technical scheme, in the step (2): the alkali is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and potassium tert-butoxide;
sodium ethoxide is further preferred because of low cost and higher yield.
As a preferable technical scheme, in the step (2): the molar ratio of the thiourea to the compound shown in the formula I is 1:1-2: 1;
further, 1.2:1 is preferable because of more economical raw materials and higher yield.
As a preferable technical scheme, in the step (2): the molar ratio of the base to the compound of formula I is 4:1-1.5: 1;
further, 2:1 is preferable because of more economical raw materials and higher yield.
As a preferable technical solution, in the step (3): the molar ratio of the deuterated bromoethane to the compound shown in the formula II is 1:1-2: 1;
further, 1.1:1 is preferable because of more economical raw materials and higher yield.
As a preferable technical solution, in the step (3): the alcohol solvent system is selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and 1, 4-dioxane;
tetrahydrofuran is further preferred because of lower cost and higher yield;
as a preferable technical solution, in the step (3): the alkali is selected from NaH, KOH, NaOH, Cs2CO3，
NaH is further preferred, and the yield is higher;
as a preferable technical solution, in the step (3): the molar ratio of the inorganic base to the compound of the formula II is 1.5:1-3: 1;
further preferably 1.5:1 because of lower cost and higher yield.
Compared with the prior art, the invention has the advantages that: the invention provides a preparation method of pentadeuterium atom substituted 2-thiophenobarbital which can be used as an internal standard substance, and the synthesized deuterated 2-thiophenobarbital has the advantages of high chemical purity, stable deuterium atom and the like; the method has the advantages of simple operation, high yield and low cost; the invention not only provides a synthetic method of the 2-thiophenobarbital substituted by the five deuterium atoms with the independent intellectual property rights, but also provides a deuterated internal standard substance for analysis and detection.
Drawings
FIG. 1 is a hydrogen spectrum of the objective product obtained in example 1;
FIG. 2 is a carbon spectrum of the objective product obtained in example 1;
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1:
2-Chloropropanedioic acid methyl ester (6.0 mmol, 1.0 g) is dissolved in benzene (10 mL), cooled to 0 ℃ in an ice bath, and AlCl is added in three portions3(18 mmol, 2.4 g), after the addition, the reaction system was heated to 80 ℃ and the reaction was continued for 5 h. Cooling to 0 ℃ in an ice bath, adding diluted 6 mol/L hydrochloric acid (10 mL), stirring for 30 minutes, filtering under reduced pressure, separating filtrate, washing an organic phase twice, drying, concentrating under reduced pressure to obtain an oily substance, purifying by column chromatography, wherein an eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 25:1, and the compound of the formula I is obtained in 1.12 g, and the yield is 90%;
dissolving a compound (5.4 mmol, 1.12 g) of a formula I in ethanol (15 mL), cooling to 0 ℃ in an ice bath, adding corresponding sodium ethoxide (10.8 mmol, 0.56 g), stirring at 0 ℃ for 10 minutes, adding thiourea (6.48 mmol, 0.49 g), after TLC monitoring reaction is completed, concentrating under reduced pressure to remove ethanol, adding dichloromethane (20 mL) to dissolve, washing an organic phase twice (2 x 20 mL), drying, concentrating under reduced pressure to obtain a white solid compound (1.11 g, the yield is 93%) of a formula II, and directly using the obtained compound (II) in the next reaction;
a compound of formula II (0.97 g, 4)4 mmol) was dissolved in tetrahydrofuran (15 mL) and NaH (6.6 mmol, 0.26 g, 60% NaH content) was dissolved at 0 deg.C, after stirring for 30 min at 25 deg.C deuterated ethyl bromide (0.55 g, 4.8 mmol) was added and the reaction monitored by TLC until the compound of formula II disappeared and quenched by addition of water (30 mL). Adding dichloromethane (2 x 20 mL) for extraction twice, drying, concentrating under reduced pressure to obtain white solid, recrystallizing the compound of formula III, i.e. the target product, to obtain 1.09 g with a yield of 98%, wherein the nuclear magnetic hydrogen spectrum of the target compound is shown in figure 1, the nuclear magnetic carbon spectrum is shown in figure 2, and the target compound is determined to be 5- (ethyl-d 5 ) -5-phenyl-2-thiodihydropyrimidine-4, 6 (1)H,5H) -a diketone.
Example 2:
dissolving 2-chloro-malonic acid methyl ester (60.0 mmol, 10.0 g) in benzene (100 mL), cooling to 0 deg.C in ice bath, and adding AlCl in three batches3(180 mmol, 24.0 g), after the addition, the reaction system was heated to 80 ℃ and the reaction was continued for 5 h. Cooling to 0 ℃ in an ice bath, adding diluted 6 mol/L hydrochloric acid (100 mL), stirring for 30 minutes, filtering under reduced pressure, separating filtrate, washing an organic phase twice, drying, concentrating under reduced pressure to obtain an oily substance, purifying by column chromatography, wherein an eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of the petroleum ether to the ethyl acetate is 25:1, and 11.90 g of the compound shown in the formula I is obtained, and the yield is 95%;
dissolving a compound (57.1 mmol, 11.90 g) of a formula I in tert-butyl alcohol (15 mL), cooling to 0 ℃ in an ice bath, adding corresponding sodium tert-butoxide (114.2 mmol, 11.0 g), stirring at 0 ℃ for 10 minutes, adding thiourea (68.5 mmol, 5.21 g), concentrating under reduced pressure to remove ethanol after TLC monitoring reaction is completed, adding dichloromethane (200 mL) for dissolving, washing an organic phase (2 x 200 mL) twice, drying, concentrating under reduced pressure to obtain a white solid compound (11.19 g, the yield is 89%, and directly using the obtained compound of the formula II in the next reaction;
after the compound of formula II (9.42 g, 42.8 mmol) was dissolved in tetrahydrofuran (150 mL), NaOH (63.9 mmol, 2.57 g) at 0 deg.C, and stirred for 30 minutes at 25 deg.C, deuterated bromoethane (5.37 g, 47.08 mmol) was added, the reaction was monitored by TLC until the compound of formula II disappeared, and the reaction was quenched by addition of water (300 mL). Dichloromethane (2 × 200 mL) was added for extraction twice, dried and concentrated under reduced pressure to give a white solid, which was recrystallized to give 9.76 g, 90% yield, of the compound of formula iii.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (21)
1. A preparation method of 2-thiophenobarbital substituted by pentadeuterium atoms is characterized by comprising the following steps:
(1) taking 2-halogenated malonate as a raw material, and carrying out Friedel-crafts alkylation reaction with benzene under the catalysis of Lewis acid at the temperature of 80 ℃ to obtain a compound 2-phenylmalonate of a formula I;
(2) in an alcohol solvent system, under the reflux condition, the compound of the formula I and thiourea are subjected to amine ester exchange reaction under the action of alkali to obtain a compound of a formula II, namely 2-sulfo-5-phenyl barbituric acid;
(3) the compound of the formula II and deuterated bromoethane are subjected to nucleophilic substitution reaction in an ether solvent under the action of alkali, and the compound of the formula III, namely 2-thiophenobarbital substituted by a pentadeuterium atom, is obtained after separation and purification, wherein the ether solvent is selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and 1, 4-dioxane;
the compound and the reaction formula are as follows:
in the formula, the X substituent is selected from one of chlorine, bromine and iodine, and the R group is selected from one of methyl, ethyl and isopropyl.
2. The method for preparing the pentadeuterium atom-substituted 2-thiophenobarbital according to claim 1, wherein in the step (1): the 2-halogenated malonate is dimethyl 2-chloromalonate.
3. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (1): the Lewis acid is selected from aluminum trichloride, boron trifluoride diethyl etherate, titanium tetrachloride and ferric trichloride.
4. The method for preparing 2-thiophenobarbital substituted by pentadeuterium atoms as claimed in claim 3, wherein the Lewis acid is aluminum trichloride.
5. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein the reaction solvent in step (1) is selected from benzene, mononitrobenzene or dinitrobenzene.
6. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 5, wherein the reaction solvent in the step (1) is benzene.
7. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (2): the alcohol solvent is selected from methanol, ethanol, isopropanol and tert-butanol.
8. The method for preparing 2-thiophenobarbital substituted by pentadeuterium atoms as claimed in claim 7, wherein the alcohol solvent is ethanol.
9. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (2): the alkali is selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide and potassium tert-butoxide.
10. The method for preparing the pentadeuterium atom-substituted 2-thiophenobarbital of claim 9, wherein the base is sodium ethoxide.
11. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (2): the molar ratio of the thiourea to the compound of the formula I is 1:1-2: 1.
12. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 11, wherein in the step (2): the molar ratio of thiourea to the compound of formula I is 1.2: 1.
13. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (2): the molar ratio of the base to the compound of formula I is 4:1 to 1.5: 1.
14. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom, as claimed in claim 13, wherein the molar ratio of the base to the compound of formula I is 2: 1.
15. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (3): the molar ratio of the deuterated bromoethane to the compound shown in the formula II is 1:1-2: 1.
16. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 15, wherein in the step (3): the molar ratio of the deuterated bromoethane to the compound of the formula II is 1.1: 1.
17. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (3): the ether solvent is tetrahydrofuran.
18. The method of claim 1A preparation method of 2-thiophenobarbital substituted by pentadeuterium atoms is characterized in that in the step (3): the alkali is selected from NaH, KOH, NaOH, Cs2CO3。
19. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 18, wherein in the step (3): the alkali is NaH.
20. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 1, wherein in the step (3): the molar ratio of the base to the compound of formula II is 1.5:1 to 3: 1.
21. The method for preparing 2-thiophenobarbital substituted by a pentadeuterium atom as claimed in claim 20, wherein in the step (3): the molar ratio of the base to the compound of formula ii is 1.5: 1.
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| US9981920B2 (en) * | 2014-06-26 | 2018-05-29 | Rodin Therapeutics, Inc. | Inhibitors of histone deacetylase |
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