CN112812009B - Preparation method of 2-bromo-dibutyl glutarate - Google Patents
Preparation method of 2-bromo-dibutyl glutarate Download PDFInfo
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- CN112812009B CN112812009B CN202011630552.2A CN202011630552A CN112812009B CN 112812009 B CN112812009 B CN 112812009B CN 202011630552 A CN202011630552 A CN 202011630552A CN 112812009 B CN112812009 B CN 112812009B
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- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
The application provides a preparation method of 2-bromo-dibutyl glutarate, which belongs to the field of biological medicine and has the design key points that: the method comprises the following steps: 1) taking sulfuric acid as a catalyst, glutamic acid as a raw material and n-butyl alcohol as a solvent, adding triethylamine after the reaction is finished, and separating out a solid for suction filtration; 2) diazotizing the prepared solid, adding sodium bromide, hydrobromic acid, sodium nitrite and water, adding dichloromethane for extraction after the reaction is finished, and drying and concentrating; 3) and (3) carrying out esterification reaction on the prepared liquid by using catalytic amount of p-toluenesulfonic acid and n-butyl alcohol, washing with water, drying and concentrating to obtain the 2-bromo-dibutyl glutarate. By adopting the preparation method, the generation of sulfur waste gas and wastewater in other synthesis methods can be greatly avoided.
Description
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to a preparation method of 2-bromo-dibutyl glutarate.
Background
Gadopilacenol, a diagnostic agent suitable for use in performing rapid analytical determinations of the presence and/or concentration of hydrogen peroxide, substances which react with hydrogen peroxide, peroxidase or peroxide-active substance release, includes chromogens which are oxidized by hydrogen peroxide in the presence of peroxidase.
For Gadopiclenol, dibutyl 2-bromoglutarate is an important starting material for its production.
For the preparation method of 2-bromo-dibutyl glutarate, the prior art comprises the following steps: WO2020/030618A1 discloses: preparing acyl chloride from thionyl chloride and esterifying. However, such a method generates a large amount of sulfur waste gas and waste water, and how to dispose the sulfur waste gas and waste water is always a problem in the industry, namely, the method of WO2020/030618A1 faces severe environmental protection pressure.
Disclosure of Invention
The application aims to provide a preparation method of dibutyl 2-bromoglutarate aiming at the defects of the prior art.
A preparation method of dibutyl 2-bromoglutarate comprises the following steps:
1) taking sulfuric acid as a catalyst, glutamic acid as a raw material and n-butanol as a solvent, adding triethylamine after the reaction is finished, separating out a solid, and performing suction filtration
2) Diazotizing the prepared solid, adding sodium bromide, hydrobromic acid, sodium nitrite and water, extracting by adding dichloromethane after the reaction is finished, drying and concentrating.
3) Carrying out esterification reaction on the prepared liquid by using catalytic amount of p-toluenesulfonic acid and n-butyl alcohol, washing with water, drying and concentrating to obtain a product;
the chemical synthesis route is as follows:
further, in the step 1), after triethylamine is added, the temperature range of crystallization is controlled between 0 ℃ and 5 ℃.
Further, in step 2), sodium bromide can be replaced by potassium bromide or ammonium bromide; the temperature range of the diazotization reaction is between 0 and 15 ℃.
Further, in step 3), at the end of the reaction, the reaction mixture is washed to neutrality with water and then dried and concentrated.
The beneficial effect of this application does:
first, the technical problem to be solved by the present application is that diazonium salts formed from glutamic acid have a high solubility in water and are prone to side reactions.
One of the inventive concepts of the present application resides in: in order to solve the problems, monobutyl ester of glutamic acid is used as a raw material, and then bromination reaction is completed through corresponding diazonium salt, because the existence of the butyl ester group reduces the water solubility of diazonium salt intermediate, thereby reducing side reaction, and the main reaction yield is improved from 40% to 80%.
Secondly, one of the inventive concepts of the present application resides in: the obtained bromide has higher solubility in butanol due to the existence of ester group, the esterification is successfully completed under the catalysis of p-toluenesulfonic acid, the discharge of sulfur-containing three wastes is eliminated, the previous two-step reaction is completed in one step, and the production cost is greatly reduced.
Third, one of the inventive concepts of the present application resides in: controlling the temperature range of crystallization to be between 0 and 5 ℃: the higher the temperature, the greater the solubility of the product in n-butanol and the lower the yield. Therefore, low temperature crystallization must be selected. The yield obtained at 0 ℃ or lower is substantially equivalent to 0 to 5 ℃, so that it is not necessary to control the temperature lower for crystallization.
Fourth, one of the inventive concepts of the present application resides in: the temperature range of the diazotization reaction is between 0 and 15 ℃: the higher the temperature of the above diazotization reaction, the lower the yield of the obtained product and the lower the purity. The results obtained at 0-15 ℃ were essentially equivalent. The yield obtained below 0 ℃ is basically equal to 0-15 ℃, so that the reaction does not need to be carried out at lower temperature, and the energy is wasted.
Drawings
FIG. 1 shows dibutyl 2-bromoglutarate according to the present application1HNuclear magnetic spectrum.
Detailed Description
The following examples will help those skilled in the art to understand the manufacturing technical points of the present application, but are not intended to limit the content of the present application.
Example one
Step 1: synthesis of 1-butyl 2-aminoglutarate
Adding 233.23mL of n-butanol into a 500mL four-mouth bottle, dropwise adding 12.0g of concentrated sulfuric acid, adding 15.0g of glutamic acid once after dropwise adding, heating to 45-50 ℃, and reacting until the raw materials disappear. 24.76g of triethylamine were added dropwise to a pH of 7-8, and a large amount of white solid precipitated. The product 2-aminoglutaric acid 1-butyl ester is obtained by suction filtration, and the yield is 80 percent. (ii) a
And 2, step: synthesis of 1-butyl 2-bromoglutarate
To a 250mL four-necked flask was added 10.0g of 1-butyl 2-aminoglutarate, 60mL of water and 28.96g of NaBr, and 12.3mL of 48% aqueous HBr solution was added at controlled temperature. 13.73g of 40% NaNO2 aqueous solution were added dropwise. After the addition, the reaction is carried out until the raw materials disappear. Extracting with dichloromethane, mixing organic layers, washing, drying and concentrating to obtain 2-bromoglutaric acid 1-butyl ester with yield of 80%;
and step 3: synthesis of dibutyl 2-bromoglutarate
4g of 1-butyl 2-bromoglutarate, 13.7mL of n-butanol and a catalytic amount of p-toluenesulfonic acid were added to a 50mL four-necked flask and reacted until the starting material disappeared. Washed 3 times with water to neutrality. The organic layer is dried and concentrated to obtain the dibutyl 2-bromoglutarate with the yield of 85 percent.
Example two
Step 1: synthesis of 1-butyl 2-aminoglutarate
Adding 233.23mL of n-butanol into a 500mL four-mouth bottle, dropwise adding 12.0g of concentrated sulfuric acid, adding 15.0g of glutamic acid once after dropwise adding, heating to 45-50 ℃, and reacting until the raw materials disappear. 24.76g of triethylamine were added dropwise to a pH of 7-8, and a large amount of white solid precipitated. The product 2-aminoglutaric acid 1-butyl ester is obtained by suction filtration, and the yield is 80 percent. (ii) a
Step 2: synthesis of 1-butyl 2-bromoglutarate
Into a 250mL four-necked flask were charged 10.0g of 1-butyl 2-aminoglutarate, 60mL of water and 33.49g of KBr, and 12.3mL of 48% aqueous HBr solution was added under controlled temperature. 13.73g of 40% NaNO2 aqueous solution were added dropwise. After the addition, the reaction is carried out until the raw materials disappear. Extracting with dichloromethane, combining organic layers, washing, drying and concentrating to obtain 2-bromoglutaric acid 1-butyl ester with the yield of 65%;
and step 3: synthesis of dibutyl 2-bromoglutarate
4g of 1-butyl 2-bromoglutarate, 13.7mL of n-butanol and a catalytic amount of p-toluenesulfonic acid were added to a 50mL four-necked flask and reacted until the starting material disappeared. Washed 3 times with water to neutrality. The organic layer is dried and concentrated to obtain the dibutyl 2-bromoglutarate with the yield of 80 percent.
EXAMPLE III
Step 1: synthesis of 1-butyl 2-aminoglutarate
Adding 233.23mL of n-butanol into a 500mL four-mouth bottle, dropwise adding 12.0g of concentrated sulfuric acid, adding 15.0g of glutamic acid once after dropwise adding, heating to 45-50 ℃, and reacting until the raw materials disappear. 24.76g of triethylamine were added dropwise to a pH of 7-8, and a large amount of white solid precipitated. The product 2-aminoglutaric acid 1-butyl ester is obtained by suction filtration, and the yield is 80 percent. (ii) a
Step 2: synthesis of 1-butyl 2-bromoglutarate
Into a 250mL four-necked flask were charged 10.0g of 1-butyl 2-aminoglutarate, 60mL of water, and 27.57g of NH4Br, while 12.3mL of 48% aqueous HBr was added at controlled temperature. 13.73g of 40% NaNO2 aqueous solution were added dropwise. After the addition, the reaction is carried out until the raw materials disappear. Extracting with dichloromethane, combining organic layers, washing, drying and concentrating to obtain 2-bromoglutaric acid 1-butyl ester with a yield of 68%;
and step 3: synthesis of dibutyl 2-bromoglutarate
4g of 1-butyl 2-bromoglutarate, 13.7mL of n-butanol and a catalytic amount of p-toluenesulfonic acid were added to a 50mL four-necked flask and reacted until the starting material disappeared. Washed 3 times with water to neutrality. The organic layer was dried and concentrated to obtain dibutyl 2-bromoglutarate in 83% yield.
Example four
Step 1: synthesis of S-2-bromoglutaric acid
A1000 mL four-necked flask was charged with 40g L-glutamic acid, 192mL water and 160g NaBr, and 68mL 48% aqueous HBr at controlled temperature. 70.32g of a 40% NaNO2 aqueous solution were added dropwise. After the addition, the reaction is carried out until the raw materials disappear. Extracting with dichloromethane, combining organic layers, washing, drying and concentrating to obtain S-2-bromoglutaric acid with a yield of 40%;
step 2-Synthesis of 2-Bromoglutaryl chloride intermediate
To a 250mL four-necked flask was added 30g S-2-bromoglutaric acid, 120mL dichloromethane, and 50.74g SOCl2 was added dropwise at controlled temperature. After dripping, the temperature is raised to 50-55 ℃ for reaction until the raw materials disappear. Rotary evaporation is carried out to obtain a 2-bromoglutaryl chloride intermediate with the yield of 75 percent;
and step 3: synthesis of dibutyl 2-bromoglutarate
Adding 162mL of n-butanol into a 250mL four-mouth bottle, dropwise adding 27g of 2-bromoglutaryl chloride intermediate at controlled temperature, and reacting until the raw materials disappear. Dissolving the mixture by ethyl acetate after rotary evaporation, washing the mixture by water, and drying and concentrating an organic layer to obtain the 2-bromo-dibutyl glutarate with the yield of 100 percent.
EXAMPLE five
Step 1: synthesis of S-2-bromoglutaric acid
A1000 mL four-necked flask was charged with 40g L-glutamic acid, 192mL water and 160g NaBr, and 68mL 48% aqueous HBr at controlled temperature. 70.32g of a 40% NaNO2 aqueous solution were added dropwise. After the addition, the reaction is carried out until the raw materials disappear. Extracting with dichloromethane, combining organic layers, washing, drying and concentrating to obtain S-2-bromoglutaric acid with a yield of 40%;
step 2: synthesis of dibutyl 2-bromoglutarate
30g S-2-bromoglutaric acid and 300mL of n-butanol and a catalytic amount of p-toluenesulfonic acid are added into a 500mL four-mouth bottle, and the temperature is controlled at 60-65 ℃ to react until the raw materials disappear. Washed 3 times with water to neutrality. The organic layer is dried and concentrated to obtain the dibutyl 2-bromoglutarate with the yield of 90 percent.
EXAMPLE six
Step 1: synthesis of S-2-bromoglutaric acid
A1000 mL four-necked flask was charged with 40g L-glutamic acid, 192mL water and 160g NaBr, and 68mL 48% aqueous HBr at controlled temperature. 70.32g of a 40% NaNO2 aqueous solution were added dropwise. After the addition, the reaction is carried out until the raw materials disappear. Extracting with dichloromethane, combining organic layers, washing, drying and concentrating to obtain S-2-bromoglutaric acid with a yield of 40%;
step 2-Synthesis of 2-Bromoglutaryl chloride intermediate
To a 250mL four-necked flask was added 30g S-2-bromoglutaric acid, 120mL dichloromethane, and 50.74g SOCl2 was added dropwise at controlled temperature. After dripping, the temperature is raised to 50-55 ℃ for reaction until the raw materials disappear. Rotary evaporation is carried out to obtain a 2-bromoglutaryl chloride intermediate with the yield of 75 percent;
and step 3: synthesis of 2-bromoglutaric acid dimethyl ester
Adding 162mL of methanol into a 250mL four-mouth bottle, dropwise adding 27g of 2-bromoglutaryl chloride intermediate at controlled temperature, and reacting until the raw materials disappear. After rotary evaporation, the mixture is dissolved by ethyl acetate, washed by water, and the organic layer is dried and concentrated to obtain the 2-bromodimethyl glutarate with the yield of 100 percent.
And 4, step 4: synthesis of dibutyl 2-bromoglutarate
60mL of n-butanol and 2g of KOH are added into a 250mL four-neck flask, 10g of 2-bromoglutaric acid dimethyl ester is dropwise added at controlled temperature, and the reaction is carried out until the raw materials disappear. Dissolving the mixture by ethyl acetate after rotary evaporation, washing the mixture by water, and drying and concentrating an organic layer to obtain the 2-bromo-dibutyl glutarate with the yield of 70 percent.
The above-mentioned embodiments are merely preferred embodiments of the present application, which are not intended to limit the present application in any way, and it will be understood by those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present application.
Claims (4)
1. The preparation method of the dibutyl 2-bromoglutarate is characterized by comprising the following steps:
1) taking sulfuric acid as a catalyst, glutamic acid as a raw material and n-butanol as a solvent, adding triethylamine after the reaction is finished, separating out a solid, and performing suction filtration
2) Diazotizing the prepared solid, adding sodium bromide, hydrobromic acid, sodium nitrite and water, adding dichloromethane for extraction after the reaction is finished, drying and concentrating;
3) carrying out esterification reaction on the prepared liquid by using catalytic amount of p-toluenesulfonic acid and n-butyl alcohol, washing with water, drying and concentrating to obtain a product;
the chemical synthesis route is as follows:
2. the method for preparing dibutyl 2-bromoglutarate according to claim 1, wherein in the step 1), after triethylamine is added, the temperature for crystallization is controlled to be between 0 and 5 ℃.
3. The method for preparing dibutyl 2-bromoglutarate according to claim 1, wherein in the step 2), sodium bromide can be replaced by potassium bromide or ammonium bromide; the temperature range of the diazotization reaction is between 0 and 15 ℃.
4. The method for preparing dibutyl 2-bromoglutarate according to claim 1, wherein in the step 3), after the reaction is finished, the dibutyl 2-bromoglutarate is washed to be neutral by water and then dried and concentrated.
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Non-Patent Citations (2)
| Title |
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| Design of a New Glutamine-Fipronil Conjugate with α-Amino Acid Function and Its Uptake by A. thaliana Lysine Histidine Transporter 1 (AtLHT1);Xunyuan Jiang et al;《J. Agric. Food Chem.》;20181231;第66卷;7597-7605 * |
| Strategies for the synthesis of HBGl3, a glutamic acid derived ligand bearing phenolic and azacarboxylate donor groups at the nitrogen atom;Raminder S. Mulla et al;《Tetrahedron》;20171231;第73卷;6410-6420 * |
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