CN117185896A - Preparation method of deuterated 1,2-dibromoethane - Google Patents
Preparation method of deuterated 1,2-dibromoethane Download PDFInfo
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- CN117185896A CN117185896A CN202311149576.XA CN202311149576A CN117185896A CN 117185896 A CN117185896 A CN 117185896A CN 202311149576 A CN202311149576 A CN 202311149576A CN 117185896 A CN117185896 A CN 117185896A
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- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical class BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 58
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 50
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 32
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000035484 reaction time Effects 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- 239000012074 organic phase Substances 0.000 claims description 24
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 24
- 230000001276 controlling effect Effects 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 17
- 239000000047 product Substances 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 235000010265 sodium sulphite Nutrition 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 239000012266 salt solution Substances 0.000 claims description 2
- 238000011403 purification operation Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 11
- 238000000746 purification Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- XIONUQPOXCUMMB-UHFFFAOYSA-N (2-bromophenyl)-diphenylphosphane Chemical compound BrC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 XIONUQPOXCUMMB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- -1 Deuterated 1,2-dibromoethane (1, 2-dibromoethane-d 4) compound Chemical class 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940006460 bromide ion Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Abstract
The invention discloses a preparation method of deuterated 1,2-dibromoethane, which comprises the following steps: (1) Adding tetradeuterium glycol, N-bromosuccinimide and a solvent into a reaction kettle; (2) Controlling the temperature in the reaction kettle to be between-5 and 20 ℃, and then dripping the mixture of triphenylphosphine and a solvent into the reaction kettle; (3) After the dripping is finished, the reaction kettle is restored to the room temperature, and the reaction time is controlled to be 0.5-1.5 h, so that the product containing deuterated 1,2-dibromoethane is obtained. The reaction temperature is normal temperature, the reaction operation is simple, the requirements of green chemistry are met, the industrial production can be realized, the purity of the deuterated 1,2-dibromoethane is more than 98wt%, and the yield of the deuterated 1,2-dibromoethane is more than 60 wt%.
Description
Technical Field
The invention relates to the technical field of deuterated compound production, in particular to a preparation method of deuterated 1, 2-dibromoethane.
Background
As knowledge of deuterium containing organics increases, deuterium containing organics become increasingly important. In the field of pharmaceutical chemistry, the active site of a drug, after substitution of hydrogen with deuterium, affects the absorption, distribution, metabolism and excretion of the drug, which were recognized by scientists in the 70 s and 80 s of the 20 th century and applied to the drug in the beginning of the 21 st century, is now becoming a popular field for new drug development due to its unique advantages of improving the metabolic and pharmacokinetic characteristics of the drug. While deuterated reagents are commonly used as pharmaceutical intermediates for the synthesis of deuterated drugs.
Deuterated 1,2-dibromoethane is one of deuterated reagents used for deuterated drug synthesis, and nuclear magnetic resonance pair with C was used in chiral anisotropic solvent published in American society of chemistry in 2002 3 And C 3V The preparation of deuterated 1,2-dibromoethane is disclosed in enantiomer and enantiomer analysis of symmetrical conical compounds, and is carried out by heating and stirring 24.0g of ethylene glycol (-10% deuteration) and 5.3g of red phosphorus at 140 ℃, simultaneously dropwise adding 20.0g of liquid bromine, reacting the mixture at the temperature for 1 hour, and cooling to room temperature. The mixture was diluted with water and diethyl ether, the solid residue was filtered, the diethyl ether layer was separated, and the solvent was distilled. After distillation, 23g of 1,2-dibromoethane (. About.10% deuterated) was obtained. Although the deuterated 1,2-dibromoethane is prepared by the method, the reaction conditions are harsh, the yield of the deuterated 1,2-dibromoethane is about 30 percent, and the method is low in yield and unfavorable for process amplification.
Therefore, there is a need to develop deuterated 1,2-dibromoethane with simple synthesis process and high yield.
Disclosure of Invention
The invention aims to provide a preparation method of deuterated 1,2-dibromoethane, which has simple synthesis process and high yield.
The technical scheme adopted for solving the technical problems is as follows:
a method for preparing deuterated 1,2-dibromoethane, which comprises the following steps:
(1) Adding tetradeuterium glycol, N-bromosuccinimide and a solvent into a reaction kettle; the solvent dosage in the step is 40-60% (volume) of the total solvent dosage;
(2) Controlling the temperature in the reaction kettle to be between-5 and 20 ℃, and then dripping the mixture of triphenylphosphine and a solvent into the reaction kettle; (3) After the dripping is finished, the reaction kettle is restored to the room temperature, and the reaction time is controlled to be 0.5-1.5 h, so that the product containing deuterated 1,2-dibromoethane is obtained.
The dosage ratio of the tetradeuterium glycol, the N-bromosuccinimide, the triphenylphosphine and the solvent is 1mol:2.0 to 3mol:2.0 to 3mol: 0.8-1.5L. The amount of solvent refers to the total amount of solvent.
The solvent is selected from one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
In the invention, triphenylphosphine reacts with N-bromosuccinimide to be activated, and then oxygen atoms of tetradeuterium glycol attack bromotriphenylphosphine to obtain a phosphinium salt intermediate. And (3) carrying out SN2 reaction on the bromide ion, and leaving the triphenylphosphine oxide as a leaving group to obtain deuterated 1, 2-dibromoethane. In the process, the configuration is turned over, the reaction driving force is the generation of triphenylphosphine oxide, the triphenylphosphine oxide contains a P=O double bond with stronger bond energy, and the whole reaction system is driven to smoothly carry out, so that the reaction can be carried out at normal temperature.
In the invention, the adding amount of the tetradeuterium glycol and the N-bromosuccinimide satisfies 1mol:2.0 to 3mol, compared with tetradeuterium ethylene glycol, N-bromosuccinimide is added in excess, the purpose is to fully bromize hydroxyl groups in the tetradeuterium ethylene glycol, but when the addition amount of the N-bromosuccinimide is excessive, the purity of the obtained product is reduced, and the purification difficulty of the subsequent obtained product is increased.
In the invention, triphenylphosphine is added in excess like N-bromosuccinimide, and is matched with the added amount of N-bromosuccinimide, so that N-bromosuccinimide can be fully activated, but the added amount is excessive, so that the subsequent purification is difficult.
The adding amount of the tetradeuterium glycol and the solvent satisfies 1mol: 0.8-1.5L, in the range, tetradeuterium glycol and N-bromosuccinimide can be fully mixed, and the reaction efficiency can be improved.
The reaction time is controlled to be 0.5-1.5 h, when the reaction time is less than 0.5h, the reaction is incomplete, more raw materials remain, and the product yield is low; when the reaction time is more than 1.5 hours, the risk of side reactions increases, while the energy consumption increases.
In the step (2), triphenylphosphine is added dropwise for 0.05-0.15 h when 1mol is used. The reaction is exothermic, so that triphenylphosphine and part of solvent are mixed and added in a dropwise manner, the temperature in the reaction kettle is controlled at-5-20 ℃ to avoid a large amount of heat generation, and meanwhile, the dropwise speed is controlled, the dropwise addition is too fast, the heat release of the system is serious, and the side reaction is increased. The dripping is too slow, the whole reaction time is prolonged, and the energy consumption is improved.
The method also comprises the operation of purifying the product, specifically:
(4) Washing the product containing deuterated 1,2-dibromoethane obtained in the step (3) with inorganic salt solution and/or water, standing for liquid separation, and taking out a lower organic phase; the objective is to isolate excess N-bromosuccinimide.
(5) Adding the organic phase into a rectifying still, controlling the internal temperature of the rectifying still at 43-50 ℃, controlling the top temperature at 35-42 ℃, evaporating part of the solvent under normal pressure, then dropwise adding n-hexane, simultaneously continuously evaporating the solvent under normal pressure for the second time, and keeping the volume ratio of the dropwise adding n-hexane to the solvent obtained by the second evaporation at 1.5-3: 1, a step of;
(6) After the dripping is finished, controlling the internal temperature of the rectifying still at 35-42 ℃, stirring, controlling the internal temperature of the rectifying still at below 30 ℃, and filtering the organic phase to obtain filtrate; in the step, after the dripping is finished, the internal temperature of the rectifying kettle is controlled at 35-42 ℃ firstly, and the growth of triphenyl phosphorus oxide crystal nucleus is facilitated at the temperature; the internal temperature of the rectifying still is controlled below 30 ℃ so as to crystallize and separate out the triphenylphosphine oxide.
(7) Adding the filtrate into another rectifying kettle, controlling the internal temperature of the rectifying kettle to be 55-65 ℃ and the vacuum degree to be 500-700 mmbar until no liquid flows out; the reasonable temperature and vacuum degree are controlled, so that the solvent is firstly distilled off, and simultaneously, the azeotropic distillation of the deuterated 1,2-dibromoethane and the solvent is avoided, and the rectification yield of the deuterated 1,2-dibromoethane is improved.
(8) Regulating the internal temperature of the rectifying still to 70-80 ℃ and the vacuum degree to be lower than 100mmbar, and obtaining the purified deuterated 1, 2-dibromoethane. And (3) controlling reasonable temperature and vacuum degree, and distilling to obtain high-purity deuterated 1, 2-dibromoethane.
The invention also needs to solve the technical difficulty that the product contains deuterated 1,2-dibromoethane, N-bromosuccinimide, triphenylphosphine oxide and a solvent, the system is mutually soluble at normal temperature, and the deuterated 1,2-dibromoethane which is a halogenated hydrocarbon has good solubility to the triphenylphosphine oxide. Thus, no product could be obtained by conventional solvent evaporation. Thus, removal of triphenylphosphine oxide from the system is a process difficulty for such purification. According to the invention, n-hexane is added in the solvent evaporation process, so that the solubility of triphenylphosphine oxide in the system is reduced, the purpose of crystallization is achieved, triphenylphosphine oxide in the system is removed, and the purpose of separation and purification is achieved through multiple operations, so that qualified deuterated 1,2-dibromoethane is obtained.
In the step (5), the solvent distilled out at one time accounts for 40 to 60 percent of the total volume of the solvent used in the reaction.
In the step (5), the addition amount of the n-hexane accounts for 40-60% of the total volume of the solvent used in the reaction.
And part of the solvent is distilled out at normal pressure, so that the solubility of the triphenylphosphine oxide is reduced, the crystallization and precipitation of the triphenylphosphine oxide are facilitated, the solvent distilled out at one time accounts for 40% -60% of the total volume of the solvent, the triphenylphosphine oxide is crystallized to form a solid better, and the filtration is facilitated.
Then dropwise adding n-hexane, and continuously evaporating the solvent for the second time, wherein the aim is to replace the solvent with the n-hexane and improve the crystallization yield of the triphenylphosphine oxide. The addition amount of the n-hexane is 40-60% of the total volume of the solvent, and the fluidity of the whole system is facilitated in the range.
The volume ratio of the volume of dropwise adding normal hexane to the volume of the secondarily distilled solvent is kept to be 1.5-3: 1, the purpose is to avoid explosion during the crystallization process of the triphenylphosphine oxide, otherwise, the solid is in a block shape, and the filtering difficulty is increased.
In the step (8), the purity of the obtained deuterated 1,2-dibromoethane is more than 98 weight percent.
The step (4) is specifically as follows:
a) Washing the product containing deuterated 1,2-dibromoethane obtained in the step (3) with sodium sulfite aqueous solution, washing with sodium bicarbonate aqueous solution, detecting pH to 7-8, standing for separating liquid, and keeping a layer organic phase;
b) Washing the organic phase obtained in the step a) with water again, detecting the pH value to 7-8, standing for separating liquid, and keeping a layer of organic phase; c) The organic phase obtained in step b) is washed with aqueous sodium chloride solution and left to stand for separation, leaving a layer of organic phase.
The dosage of the sodium sulfite aqueous solution, the sodium bicarbonate aqueous solution, the water and the sodium chloride aqueous solution is calculated by taking N-bromosuccinimide as a reference, and the N-bromosuccinimide is prepared by the following steps: aqueous sodium sulfite solution: sodium bicarbonate aqueous solution: water: sodium chloride aqueous solution = 1mol: 0.08-0.2L: 0.08-0.2L: 0.08-0.2L: 0.08-0.2L, wherein the concentration of the sodium sulfite aqueous solution is 10-25 wt%, the concentration of the sodium bicarbonate aqueous solution is 5-8 wt%, and the concentration of the sodium chloride aqueous solution is 5-30 wt%.
The beneficial effects of the invention are as follows: the method has the advantages that the easily brominated deuterated 1,2-dibromoethane is finally realized by controlling the addition amount of tetradeuterium ethylene glycol, N-bromosuccinimide and a solvent and controlling the reaction temperature and the reaction time, the reaction temperature is normal temperature, the reaction operation is simple, the requirements of green chemistry are met, the industrial production can be realized, the purity of the deuterated 1,2-dibromoethane is more than 98wt%, and the yield of the deuterated 1,2-dibromoethane is more than 60deg.C.
Drawings
FIG. 1 is a molecular structural formula of tetradeuterium ethylene glycol of the present invention;
FIG. 2 is a molecular structural formula of deuterated 1,2-dibromoethane of the present invention;
FIG. 3 is a synthetic scheme for deuterated 1,2-dibromoethane of the present invention;
FIG. 4 is GC detection data of example 1 of the present invention;
FIG. 5 is a nuclear magnetic resonance spectrum of deuteration degree according to example 1 of the present invention.
Detailed Description
The technical scheme of the invention is further specifically described by the following specific examples.
In the present invention, the materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
Examples:
the present invention provides 15 examples for preparing deuterated 1,2-dibromoethane and 4 comparative examples, wherein the examples include the following preparation steps (fig. 3):
1) Adding tetradeuterium glycol (figure 1), N-bromosuccinimide and solvent into a reaction kettle;
2) Controlling the temperature in the reaction kettle to be between-5 and 20 ℃, and then dripping the mixture of triphenylphosphine and a solvent into the reaction kettle; triphenylphosphine and the dropwise addition time satisfied 1mol:0.05 to 0.15h;
3) After the dripping is finished, the reaction kettle is restored to normal temperature, and the reaction time is controlled to be 0.5-1.5 h, so as to obtain the obtained product containing deuterated 1, 2-dibromoethane;
the addition amount of the tetradeuterium glycol, the N-bromosuccinimide, the triphenylphosphine and the solvent satisfies 1mol:2.0 to 3mol:2.0 to 3mol: 0.8-1.5L; the solvent is selected from one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform, and the key parameter control is shown in table 1. In all embodiments of the invention, the amount of solvent used in step 1) is one half of the total amount of solvent used.
The addition amount of tetradeuterium glycol, N-bromosuccinimide, triphenylphosphine and a solvent is recorded to meet A;
and (3) recording triphenylphosphine and dropwise adding time to meet the requirement of C.
The resulting 15 examples of deuterated 1,2-dibromoethane were purified according to the purification method of the present invention, comprising the following purification steps:
4) Washing the obtained product according to the following method, and then standing and separating liquid to obtain a lower organic phase; the method comprises the following steps:
a) Washing the obtained product with sodium sulfite aqueous solution, washing with sodium bicarbonate aqueous solution, detecting pH value to 7-8, standing for separating liquid, and keeping a layer organic phase;
b) Washing the organic phase obtained in the step a) with water again, detecting the pH value to 7-8, standing for separating liquid, and keeping a layer of organic phase;
c) Washing the organic phase obtained in the step b) with sodium chloride aqueous solution, standing for separating liquid, and keeping a layer of organic phase; the addition amount of the N-bromosuccinimide, the sodium sulfite aqueous solution, the sodium bicarbonate aqueous solution, the water and the sodium chloride aqueous solution satisfies 1mol: 0.08-0.2L: 0.08-0.2L: 0.08-0.2L: 0.08-0.2L, the concentration of sodium sulfite aqueous solution is 10-25 wt%, the concentration of sodium bicarbonate aqueous solution is 5-8 wt%, and the concentration of sodium chloride aqueous solution is 5-30 wt%.
5) Adding the organic phase into a rectifying still, controlling the internal temperature of the rectifying still at 43-50 ℃, controlling the top temperature at 35-42 ℃, evaporating part of the solvent under normal pressure, then dropwise adding n-hexane, simultaneously continuously evaporating the solvent under normal pressure for the second time, and keeping the volume ratio of the volume of dropwise adding n-hexane to the volume of the solvent obtained by the second evaporation at 1.5-3: 1, the solvent distilled out at one time accounts for 40 to 60 percent of the total volume of the solvent, and the addition amount of the n-hexane accounts for 40 to 60 percent of the total volume of the solvent;
6) After the dripping is finished, controlling the internal temperature of the rectifying still at 35-42 ℃, stirring, controlling the internal temperature of the rectifying still at below 30 ℃, and filtering the organic phase to obtain filtrate;
7) Adding the filtrate into a rectifying kettle, controlling the internal temperature of the rectifying kettle to be 55-65 ℃ and the vacuum degree to be 500-700 mmbar until no liquid flows out;
8) The internal temperature of the rectifying still is regulated to 70-80 ℃ and the vacuum degree is lower than 100mmbar, thus obtaining the purified deuterated 1,2-dibromoethane (figure 2). Deuterated 1,2-dibromoethane (1, 2-dibromoethane-d 4) compound analysis data are as follows: 1H NMR (399 MHz, chloro form-d) δ3.81 (s, 0.02H) MS (EI) 186.1.
Recording the volume ratio of the dropwise adding of n-hexane to the volume ratio of the secondarily distilled solvent as D;
recording the content of the solvent distilled out at one time accounting for the total volume of the solvent as E;
recording the content of n-hexane accounting for the total volume of the solvent as F;
after the addition of the water is recorded, the internal temperature of the rectifying still is controlled at G; stirring, and controlling the internal temperature of the rectifying still at H;
the addition amount of N-bromosuccinimide, sodium sulfite aqueous solution, sodium bicarbonate aqueous solution, water and sodium chloride aqueous solution is recorded to meet I; the key parameter control is shown in tables 2 and 3.
Comparative example 1 differs from example 1 in that: the temperature in the reaction kettle is controlled at 25 ℃;
comparative example 2 is different from example 1 in that: the reaction time is 3h;
comparative example 3 is different from example 1 in that: triphenylphosphine and the dropwise addition time satisfied 1mol:0.03h;
comparative example 4 differs from example 1 in that: step 2) of the purification step is omitted.
The following tests were carried out on the examples and comparative examples obtained:
1) And (3) purity detection: and detecting by adopting a gas chromatograph.
The GC detection data of example 1 are shown in FIG. 4.
2) And (3) yield detection: the calculation formula is 1,2-dibromoethane actual weight/1, 2-dibromoethane theoretical weight percentage.
The nuclear magnetic resonance detection pattern of deuteration degree of example 1 is shown in fig. 5.
The specific detection results are shown in Table 4.
TABLE 1 Key parameter control for the preparation of the examples of the invention
TABLE 2 critical parameter control for purification of the examples of the invention
TABLE 3 critical parameter control for purification of the examples of the invention
TABLE 4 detection results of examples and comparative examples of the present invention
| Numbering device | Yield/% | Purity/% |
| Example 1 | 70.3 | 99.4 |
| Example 2 | 87.5 | 99.0 |
| Example 3 | 88.8 | 99.2 |
| Example 4 | 80.1 | 98.8 |
| Example 5 | 78.9 | 99.2 |
| Example 6 | 78.3 | 98.3 |
| Example 7 | 87.5 | 98.7 |
| Example 8 | 89.2 | 99.1 |
| Example 9 | 83.3 | 98.5 |
| Example 10 | 88.5 | 98.2 |
| Example 11 | 89.3 | 98.8 |
| Example 12 | 79.2 | 99.5 |
| Example 13 | 78.8 | 99.0 |
| Example 14 | 88.6 | 98.5 |
| Example 15 | 87.8 | 98.9 |
| Comparative example 1 | 65 | 83.4 |
| Comparative example 2 | 68 | 85.6 |
| Comparative example 3 | 61 | 90.1 |
| Comparative example 4 | 70 | 80.7 |
。
The above-described embodiment is only a preferred embodiment of the present invention, and is not limited in any way, and other variations and modifications may be made without departing from the technical aspects set forth in the claims.
Claims (10)
1. A method for preparing deuterated 1,2-dibromoethane, which is characterized by comprising the following steps:
(1) Adding tetradeuterium glycol, N-bromosuccinimide and a solvent into a reaction kettle;
(2) Controlling the temperature in the reaction kettle to be between-5 and 20 ℃, and then dripping the mixture of triphenylphosphine and a solvent into the reaction kettle;
(3) After the dripping is finished, the reaction kettle is restored to the room temperature, and the reaction time is controlled to be 0.5-1.5 h, so that the product containing deuterated 1,2-dibromoethane is obtained.
2. The method of manufacturing according to claim 1, characterized in that: the dosage ratio of the tetradeuterium glycol, the N-bromosuccinimide, the triphenylphosphine and the solvent is 1mol:2.0 to 3mol:2.0 to 3mol: 0.8-1.5L.
3. The method of manufacturing according to claim 1, characterized in that: the solvent is selected from one of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
4. The method of manufacturing according to claim 1, characterized in that: in the step (2), triphenylphosphine is added dropwise for 0.05-0.15 h when 1mol is used.
5. The preparation method according to claim 1, further comprising a product purification operation, in particular:
(4) Washing the product containing deuterated 1,2-dibromoethane obtained in the step (3) with inorganic salt solution and/or water, standing for liquid separation, and taking out a lower organic phase;
(5) Adding the organic phase into a rectifying still, controlling the internal temperature of the rectifying still at 43-50 ℃, controlling the top temperature at 35-42 ℃, evaporating part of the solvent under normal pressure, then dropwise adding n-hexane, simultaneously continuously evaporating the solvent under normal pressure for the second time, and keeping the volume ratio of the dropwise adding n-hexane to the solvent obtained by the second evaporation at 1.5-3: 1, a step of;
(6) After the dripping is finished, controlling the internal temperature of the rectifying still at 35-42 ℃, stirring, controlling the internal temperature of the rectifying still at below 30 ℃, and filtering the organic phase to obtain filtrate;
(7) Adding the filtrate into another rectifying kettle, controlling the internal temperature of the rectifying kettle to be 55-65 ℃ and the vacuum degree to be 500-700 mmbar until no liquid flows out;
(8) Regulating the internal temperature of the rectifying still to 70-80 ℃ and the vacuum degree to be lower than 100mmbar, and obtaining the purified deuterated 1, 2-dibromoethane.
6. The method of manufacturing according to claim 5, wherein: in the step (5), the solvent distilled out at one time accounts for 40 to 60 percent of the total volume of the solvent used in the reaction.
7. The method of manufacturing according to claim 5, wherein: in the step (5), the addition amount of the n-hexane accounts for 40-60% of the total volume of the solvent used in the reaction.
8. The method of manufacturing according to claim 5, wherein: in the step (8), the purity of the obtained deuterated 1,2-dibromoethane is more than 98 weight percent.
9. The method of manufacturing according to claim 5, wherein: the step (4) is specifically as follows:
a) Washing the product containing deuterated 1,2-dibromoethane obtained in the step (3) with sodium sulfite aqueous solution, washing with sodium bicarbonate aqueous solution, detecting pH to 7-8, standing for separating liquid, and keeping a layer organic phase;
b) Washing the organic phase obtained in the step a) with water again, detecting the pH value to 7-8, standing for separating liquid, and keeping a layer of organic phase;
c) The organic phase obtained in step b) is washed with aqueous sodium chloride solution and left to stand for separation, leaving a layer of organic phase.
10. The method of manufacturing according to claim 9, wherein: the dosage of the sodium sulfite aqueous solution, the sodium bicarbonate aqueous solution, the water and the sodium chloride aqueous solution is calculated by taking N-bromosuccinimide as a reference, and the N-bromosuccinimide is prepared by the following steps: aqueous sodium sulfite solution: sodium bicarbonate aqueous solution: water: sodium chloride aqueous solution = 1mol: 0.08-0.2L: 0.08-0.2L: 0.08-0.2L: 0.08-0.2L, wherein the concentration of the sodium sulfite aqueous solution is 10-25 wt%, the concentration of the sodium bicarbonate aqueous solution is 5-8 wt%, and the concentration of the sodium chloride aqueous solution is 5-30 wt%.
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