CN105152947A

CN105152947A - Preparation method of 2-amino-3,5-dibromobenzaldehyde

Info

Publication number: CN105152947A
Application number: CN201510566994.8A
Authority: CN
Inventors: 李新辈
Original assignee: Jiangsu Chia Tai Qingjiang Pharmaceutical Co Ltd
Current assignee: Jiangsu Chia Tai Qingjiang Pharmaceutical Co Ltd
Priority date: 2015-09-09
Filing date: 2015-09-09
Publication date: 2015-12-16

Abstract

The invention discloses a preparation method of 2-amino-3,5-dibromobenzaldehyde. The yield of the method is higher (greater than 90 percent) and the purity is higher (greater than 99.0 percent). In the method, o-nitrobenzaldehyde is used as a raw material, nitro is reduced by using an iron powder/glacial acetic acid system to obtain o-aminobenzaldehyde mixture, and the mixture is not subjected to any treatment, is cooled and is directly dropped with bromine to obtain 2-amino-3,5-dibromobenzaldehyde. Since the intermediate product o-aminobenzaldehyde is not treated in the method, the process is simplified, the workload is reduced, the loss of o-aminobenzaldehyde during treatment is eliminated and the yield is improved; iron powder and bromine produce iron bromide, catalytic bromination is realized, the bromination efficiency is improved, the consumption of iron powder reduces the amount of iron sludge and the pollution is reduced.

Description

The preparation method of amino-3, the 5-dibromo benzaldehydes of a kind of 2-

Technical field

The invention belongs to pharmaceutical intermediate synthesis field, relate to the preparation method of amino-3, the 5-dibromo benzaldehydes of a kind of 2-.

Background technology

Amino-3, the 5-dibromo benzaldehydes of 2-are a kind of conventional pharmaceutical intermediates, are widely used in the synthesis of expelling phlegm drugs Ambroxol HCl.The route of synthesis of Ambroxol HCl is a lot, but the approach of widespread use is the most: with amino-3, the 5-dibromo benzaldehydes of 2-for raw material, with trans-carry out condensation to Trans-4-Amino Cyclohexanol to form intermediate imine class product, again through hydro-reduction and acidifying salify, obtain Ambroxol HCl.As the important intermediate of Ambroxol HCl, amino-3, the 5-dibromo benzaldehydes of 2-have larger demand.

In existing technological process, commonly use and obtain o-Aminobenzaldehyde with iron powder reducing Ortho Nitro Benzaldehyde, after the post-processing steps such as extraction, drip bromine or N-bromo-succinimide on bromine and carry out bromination reaction.Have that iron mud is difficult, environmental pollution is large, the problems such as complex process; And intermediate product o-Aminobenzaldehyde alkalescence is unstable, treating processes condensation may generate the problems such as by product.

Also have people to take methyl o-aminobenzoate as raw material, bromo-reaction generates amino-3,5 methyl-dibromobenzoates of 2-, then reacts to obtain 2-base-3,5 dibromobenzene formyl hydrazine with hydrazine hydrate, then through K ₃fe (CN) ₆oxidation obtains target product.The method needs three-step reaction, and productive rate is lower, complex process.

Summary of the invention

Synthetic route of the present invention is as follows:

The preparation of amino-3, the 5-dibromo benzaldehydes of 2-is carried out according to following route:

First, Ortho Nitro Benzaldehyde is placed in reaction vessel, adds ethanol/water mixed system, then add appropriate iron powder and Glacial acetic acid, after dripping several concentrated hydrochloric acids, back flow reaction 40-60min.After completion of the reaction, be placed in cold-trap to cool.Directly drip bromine after cooling, under room temperature, react 120-150min.After completion of the reaction, with the extraction of methylene dichloride equal solvent, then wash organic layer with saturated sodium bicarbonate, water etc., organic layer after drying, is spin-dried for and obtains crude product.Again after acetone solvent recrystallization, obtain amino-3, the 5-dibromo benzaldehydes of highly purified 2-.

beneficial effect:

1, reduction, bromination two-step reaction organically combine by this reaction, eliminate the process obtaining intermediate product o-Aminobenzaldehyde, simplify technique, decrease workload.

2, keep the acidity of reaction process, avoid the weakly alkaline in former process intermediates o-Aminobenzaldehyde treating processes, thus avoid the partial condensates reaction of intermediate o-Aminobenzaldehyde self, improve purity and productive rate.

3, remaining iron powder can be used for bromine on catalysis bromine, improves reaction efficiency.And the iron bromide generated is soluble in water, can extract removing, avoid a large amount of iron mud produced in former reaction process, decrease environmental pollution.

Accompanying drawing illustrates: Fig. 1 is blank HPLC collection of illustrative plates;

Fig. 2 is commercially available prod HPLC collection of illustrative plates;

The HPLC collection of illustrative plates of Fig. 3 sample obtained by embodiment 1;

The HPLC collection of illustrative plates of Fig. 4 sample obtained by embodiment 2.

Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and be only limitted to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement made according to ordinary skill knowledge and customary means or the amendment of change, include within the scope of the invention .

embodiment 1

Ortho Nitro Benzaldehyde 1.5g(10mmol is added) in 100mL there-necked flask, dehydrated alcohol 34mL, distilled water 17mL, 50 DEG C are slowly warming up under stirring, after Ortho Nitro Benzaldehyde all dissolves, add acetic acid 34mL, 3.9g(70mmol again) reduced iron powder and 3 ~ 4 dense HCl, continue to be heated to 105 DEG C; After backflow 40min, stopped reaction.

There-necked flask is cooled in 0 DEG C of cold-trap, after cooling, drips bromine 3.1g(20mmol), under room temperature, react 120min at a low price.Stopped reaction, suction filtration, uses 10ml water washing, then uses 3*20ml dichloromethane extraction, then uses 2*20ml saturated sodium bicarbonate solution and 2*20ml water washing dichloromethane layer; Use anhydrous sodium sulfate drying organic layer after washing, revolve steaming and obtain yellow solid 2.76g.

Use 10ml acetone recrystallization, obtain faint yellow solid 2.54g, productive rate 91.1%, purity 99.4%, is shown in Fig. 3.

embodiment 2

Ortho Nitro Benzaldehyde 1.5g(10mmol is added in 100mL there-necked flask), dehydrated alcohol 40mL, distilled water 10mL, stirred at ambient temperature, after Ortho Nitro Benzaldehyde all dissolves, then adds acetic acid 31mL, 2.2g(40mmol) reduced iron powder and 3 ~ 4 dense HCl, continue heating 90 DEG C; After backflow 60min, stopped reaction.

There-necked flask is cooled in 0 DEG C of cold-trap, after cooling, drips bromine 6.2g(40mmol), under room temperature, react 150min at a low price.Stopped reaction, suction filtration, uses 10ml water washing, then uses 3*20ml dichloromethane extraction, then uses 2*20ml saturated sodium bicarbonate solution and 2*20ml water washing organic layer; Use anhydrous sodium sulfate drying organic layer after washing, revolve steaming and obtain yellow solid 2.76g.

Use 10ml acetone recrystallization, obtain faint yellow solid 2.59g, productive rate 92.8%, purity 99.2%, is shown in Fig. 4.

Claims

1. the preparation method of 2-amino-3, a 5-dibromo benzaldehyde, the method is raw material with Ortho Nitro Benzaldehyde, and concrete steps are as follows:

1) Ortho Nitro Benzaldehyde is dissolved in mixed solvent ethanol/water, adds iron powder after dissolving and Glacial acetic acid is some, and drip several concentrated hydrochloric acid catalysis, after reacting 40-60min at 95 ~ 105 DEG C, obtain mixed system a, directly in-10 ~ 5 DEG C of coolings; After cooling, directly drip slightly excess bromine, after reacting 120-150min under room temperature, direct filtration;

2) filter residue, dichloromethane extraction filtrate is washed by suitable quantity of water, filtrate saturated sodium carbonate or sodium hydrogen carbonate solution and saturated aqueous common salt or each twice of pure water;

3), after organic over anhydrous sodium sulfate or anhydrous magnesium sulfate drying, revolve and steam removing methylene chloride, obtain 2-amino-3,5-dibromo benzaldehyde crude product; After solvent acetone recrystallization, obtain amino-3, the 5-dibromo benzaldehydes of sterling 2-, purity is greater than 99.0%.

2. the preparation method of amino-3, the 5-dibromo benzaldehydes of 2-according to claim 1, the mixed system a containing o-Aminobenzaldehyde obtained, does not need, through any process, directly to drip bromine after cooling, carries out bromine reaction on next step.

3. the preparation method of amino-3, the 5-dibromo benzaldehydes of 2-according to claim 1, the volume ratio of the mixed solvent ethanol/water used is 2:1 ~ 4:1, and the mol ratio of institute's water consumption and Ortho Nitro Benzaldehyde is 70:1 ~ 120:1.

4. the preparation method of amino-3, the 5-dibromo benzaldehydes of 2-according to claim 1, the order number of the iron powder used is 50 ~ 100, and the molar ratio of iron powder and Ortho Nitro Benzaldehyde is 4:1 ~ 7:1.

5. the preparation method of amino-3, the 5-dibromo benzaldehydes of the 2-according to right 1, the mol ratio of bromine used and Ortho Nitro Benzaldehyde is 2:1 ~ 4:1.