CN104909982A

CN104909982A - Method for synthesizing benzyl bromide compound directly from isotope labeled benzene rings

Info

Publication number: CN104909982A
Application number: CN201510285165.2A
Authority: CN
Inventors: 蔡定龙; 伍君; 方宁静; 李刚
Original assignee: Changsha Beita Pharmatech Co Ltd
Current assignee: Changsha Beita Pharmatech Co Ltd
Priority date: 2015-05-29
Filing date: 2015-05-29
Publication date: 2015-09-16

Abstract

The present invention relates to a method for synthesizing a benzyl bromide compound directly from isotope labeled benzene rings, the steps are as follows: (1), mixing carbon tetrachloride, paraformaldehyde and concentrated sulfuric acid in sequence, then adding hydrobromide, heating, adding isotope-labeled benzene, isotope-labeled mono-substituted benzene or isotope-labeled multi-substituted benzene, wherein the isotope is labeled as deuterium, tritium, 13C or 14C; then stirring for 4 to 20 hours; (2), cooling the reaction solution to 20-30 DEG C, and then washing with water, saturated sodium bicarbonate and water in sequence, extracting aqueous phase with dichloromethane, after standing and layering, separating the lower layer organic matter, namely a crude benzyl bromide compound. The method has the advantage of direct use of the most basic benzene-ring-labeled source benzene or aromatic hydrocarbon as a raw material for one-step synthesis of the benzyl bromide compound, and the synthesis process is simple and safe.

Description

A kind of directly from the method for isotopic labeling phenyl ring complex sign bromine benzyls compound

Technical field

The present invention relates to a kind of method of complex sign bromine benzyls compound, particularly relate to a kind of directly from the method for isotopic labeling phenyl ring complex sign bromine benzyls compound.

Background technology

Bromotoluene or its substitution compound are because of the reactive behavior of its benzyl bromine, and being a very important class synthetic intermediate in organic synthesis, playing an important role in the protection to alcohols or carboxylic acid compound, is the important intermediate introducing benzyl in the molecule.Especially in isotopic labeling synthesis, be the intermediate introducing phenyl ring mark benzyl in the molecule, when the phenylalanine marked as synthesis phenyl ring or tyrosine, benzyl bromine and substitution compound thereof are use as important mark source intermediate to methoxyl group bromobenzyl.

Current synthesis bromine benzyls compound mainly contains following several method:

1, be Material synthesis benzylalcohol with benzene, and then be raw material with benzylalcohol, directly carry out bromo;

Present method first synthesizes benzylalcohol by benzene, is then raw material with benzylalcohol, adopts phosphorus tribromide to be that bromizating agent directly carries out bromo to benzylalcohol, or adopts hypobromous acid and pyridinium tribromide salt to replace, and productive rate is more than 90%.Also have a series of method can be converted into bromobenzyl from benzylalcohol in addition.But synthesize benzylalcohol by benzene and need three steps, comprehensive yied is the highest is no more than 40%.This method needs to adopt as lively as a cricket reagent such as phosphorus tribromides, and simultaneous reactions temperature is higher, and the bromobenzyl for hydrogen mark synthesizes and can cause hydrogen exchange unavoidably and reduce the abundance of bromobenzyl.

2, first synthesize toluene, take then toluene as raw material, directly carry out bromo:

Present method first synthesizes toluene by benzene or aromatic hydrocarbons, and then be that raw material directly synthesizes bromobenzyl with toluene.Bromobenzyl productive rate is synthesized also higher by toluene, but this method has not only used lead tetraacetate (to be prepared before use, two step synthesis), and employ benzene lithium intermediate in the process turning toluene at bromobenzene, need strict anhydrous and oxygen-free condition, use ether in a large number, this is also a potential dangerous matter sources simultaneously.

But above two kinds of methods are all unwell to the synthesis of the benzyl bromine compounds of phenyl ring mark, the toluene mainly marked or phenylcarbinol still need to synthesize from more basic mark source benzene, and step is long, not only the generated time of at substantial reduces combined coefficient, also makes comprehensive yied on the low side.

Summary of the invention

For above-mentioned shortcoming, the object of the present invention is to provide a kind of directly from the method for isotopic labeling phenyl ring complex sign bromine benzyls compound, namely directly adopt the most basic phenyl ring mark source benzene or aromatic hydrocarbons as raw material, a step directly synthesizes benzyl bromine compounds.

Technology contents of the present invention is a kind of directly from the method for isotopic labeling phenyl ring complex sign bromine benzyls compound, and its step is as follows:

(1), successively by tetracol phenixin, paraformaldehyde, vitriol oil mixing, stir lower insulation to 25 ~ 35 DEG C, add the Hydrogen bromide that concentration is 35 ~ 48 quality % again, be warming up to 35 ~ 60 DEG C, add isotope-labeled benzene, an isotope-labeled substituted benzene or isotope-labeled Multi substituted benzenes again, isotopic labeling be deuterium, tritium, ¹³c or ¹⁴c; Then 30 ~ 65 DEG C are maintained the temperature at, stirring reaction 4 ~ 20 hours; Wherein the add-on of tetracol phenixin is 20 ~ 35 times of the quality of paraformaldehyde, the vitriol oil add-on be 1 ~ 5 times of the quality of paraformaldehyde, hydrobromic add-on is 5 ~ 15 times of the quality of paraformaldehyde, and the add-on of isotope-labeled benzene, an isotope-labeled substituted benzene or isotope-labeled Multi substituted benzenes is 5 ~ 15 times of the quality of paraformaldehyde;

(2), above-mentioned reaction solution is down to 20 ~ 30 DEG C after, then use water, saturated sodium bicarbonate and water washing successively, use dichloromethane extraction aqueous phase, separate lower floor's organism after stratification and namely obtain mark bromine benzyls compound crude product.

Purified for making above-mentioned directly obtained from the method for isotopic labeling phenyl ring complex sign bromine benzyls compound mark bromine benzyls compound crude product, it adopts conventional purification process, first can add anhydrous sodium sulphate in mark bromine benzyls compound crude product or anhydrous magnesium sulfate carries out drying, then control temperature is less than 100 DEG C and steams solvent tetracol phenixin at ambient pressure; Again by raffinate underpressure distillation, collect temperature at the cut of 115 ~ 120 DEG C, namely obtain the mark cylite product after purifying.

Concrete synthetic route of the present invention is as follows:

Reaction raw materials in the present invention is cheap and easy to get, and reaction process is simple and easy to control, and reaction conditions is gentle, easy handling, and product is purified convenient, and cost is low.

The advantage that the present invention has is:

(1), the present invention avoids using mark aromatic hydrocarbons that is complicated or that be not easy to obtain as starting raw material, directly uses the commercial mark benzene be extremely easy to get for making starting raw material, the building-up process of benzyl bromine or benzalcohol derivatives is simplified.

(2), the present invention avoids using metallic lithium benzene etc. to need the operation of strict anhydrous and oxygen-frees, and whole reaction process can be opened wide, and simplifies synthetic operation step.

(3), the present invention avoids using low temperature or high temperature, and adopts one kettle way, just can react in room temperature and above portion temperature, and this for being very favorable concerning temperature than more sensitive raw material.

Embodiment

Example 1: in the there-necked flask of 100ml, add 20mL CCl successively ₄, 1.16 g paraformaldehydes, the 2.2 mL vitriol oils, stir be warming up to 40 DEG C, add the Hydrogen bromide that 8 mL concentration are 40 quality %, be warming up to 60 DEG C, then add 2.0g benzene- ¹³c ₆, then maintain the temperature at 60 DEG C of reactions, stirring reaction 8 h, take out after above-mentioned reaction solution being down to 25 DEG C after reaction terminates, then use water, saturated sodium bicarbonate, water washing successively, and with dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, must mark bromine benzyls compound crude product; In mark bromine benzyls compound crude product, add anhydrous sodium sulphate again or anhydrous magnesium sulfate carries out drying, then normal pressure steams solvent; Again by raffinate underpressure distillation, collect temperature at the cut of 115 ~ 120 DEG C, namely obtain the cylite product after purifying, i.e. colourless transparent liquid bromobenzyl- ¹³c ₆1.91 g, productive rate 43.6%; It is more than 97% that high performance liquid chromatography shows its purity.

Example 2: in the there-necked flask of 100ml, add 10mL CCl successively ₄, 0.42 g paraformaldehyde, the 1 mL vitriol oil, stir be warming up to 40 DEG C, adding 2.6 mL concentration is the Hydrogen bromide of 40%, add 1.05 g methyl-phenoxides- ¹³c ₆form mixing solutions, maintain the temperature at 40 DEG C of reactions, stirring reaction spends the night, and takes out after above-mentioned mixed solution being down to 25 DEG C after reaction terminates, then water, saturated sodium bicarbonate, water washing is used successively, and with dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, then carries out air distillation, control temperature is below 100 DEG C, and then carry out underpressure distillation, collect the cut of temperature within the scope of 115-120 DEG C, obtain colourless transparent liquid or white solid for methoxyl group bromobenzyl- ¹³c ₆0.8 g, productive rate 42.0%.It is more than 95% that high performance liquid phase shows its purity.

Example 3: in the there-necked flask of 100ml, first use air in argon replaces bottle, then add 20mL CCl successively under air-proof condition ₄, 1.16 g paraformaldehydes, the 2.2 mL vitriol oils, stir be warming up to 40 DEG C, add the Hydrogen bromide that 8 mL concentration are 40 quality %, be warming up to 50 DEG C, then add 1.6 g benzene-D ₆, then maintain the temperature at 50 DEG C of reactions, stirring reaction 10 h, take out after above-mentioned reaction solution being down to 25 DEG C after reaction terminates, then use water, saturated sodium bicarbonate, water washing successively, and with dichloromethane extraction, organic phase anhydrous magnesium sulfate drying, must mark bromine benzyls compound crude product; In mark bromine benzyls compound crude product, add anhydrous sodium sulphate again or anhydrous magnesium sulfate carries out drying, then normal pressure steams solvent; Again by raffinate underpressure distillation, collect temperature at the cut of 115 ~ 120 DEG C, namely obtain the cylite product after purifying, i.e. colourless transparent liquid bromobenzyl- ¹³c ₆1.5 g, productive rate 44.8%; It is more than 97% that high performance liquid chromatography shows its purity.

Claims

1., directly from a method for isotopic labeling phenyl ring complex sign bromine benzyls compound, its step is as follows:

2. the method for direct synthesis phenyl ring mark benzyl bromine compounds according to claim 1, it is characterized in that the purification of the mark bromine benzyls compound crude product obtained, for first adding anhydrous sodium sulphate in mark bromine benzyls compound crude product or anhydrous magnesium sulfate carries out drying, then control temperature is less than 100 DEG C and steams solvent tetracol phenixin at ambient pressure; Again by raffinate underpressure distillation, collect temperature at the cut of 115 ~ 120 DEG C, namely obtain the mark cylite product after purifying.