CN112374973B - Synthesis method of drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde - Google Patents
Synthesis method of drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde Download PDFInfo
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Abstract
The invention provides a method for synthesizing a drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde. According to the method, catechol is used as a raw material, and a formylation reaction and a bromination reaction are carried out under the action of inorganic alkali and a phase transfer catalyst, so that the 4-bromo-2, 3-dihydroxybenzaldehyde medical intermediate is successfully synthesized. The method has the advantages of high yield, less side reaction, high purity, short synthesis steps, conventional and easily available starting materials, low cost and environmental friendliness, and has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of synthesis, and particularly relates to a synthesis method of a drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde.
Background
4-bromo-2, 3-dihydroxybenzaldehyde (CAS: 73275-98-6) having the structure:
the two hydroxyl groups can be closed to form a piper-ring derivative, the piper-ring structural unit is closely related to the anti-tumor activity, the derivative has good cytotoxic activity on human colon cancer cells and nasopharyngeal carcinoma cells with multiple drug resistance, and the in vivo drug effect also shows excellent tumor inhibition activity. Thus, 4-bromo-2, 3-dihydroxybenzaldehyde is a very important pharmaceutical intermediate in the synthesis of new drugs.
However, no report on a synthesis method of 4-bromo-2, 3-dihydroxybenzaldehyde is currently seen, the price of the commercially available 4-bromo-2, 3-dihydroxybenzaldehyde is very high, thousands of gold-one gram is achieved, the purity is generally only 95% -98%, and the wide application of the 4-bromo-2, 3-dihydroxybenzaldehyde in the field of medicine synthesis is limited.
Therefore, it is of great importance to research a synthesis method of 4-bromo-2, 3-dihydroxybenzaldehyde with high yield, few side reactions, high purity, short synthesis steps, conventional and easily available starting materials, low cost and environmental friendliness.
Disclosure of Invention
The invention provides a synthesis method of a drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde, which comprises the following steps:
(1) Reacting catechol shown in the formula I with haloform under the action of a phase transfer catalyst and alkali to obtain 2, 3-dihydroxybenzaldehyde shown in the formula II;
(2) The compound shown in the formula II and bromine are subjected to substitution reaction under the action of alkali to obtain 4-bromo-2, 3-dihydroxybenzaldehyde shown in the formula III;
the reaction route is as follows:
further, the phase transfer catalyst in the step (1) is a quaternary ammonium salt catalyst, and/or the base is an inorganic base, and/or the haloform is chloroform.
Further, the quaternary ammonium salt catalyst is benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium bisulfate, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride or hexadecyl trimethyl ammonium bromide.
Further, the inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
Further, the base in the step (2) is an organic base, preferably an amine compound.
Further, the amine compound is tert-butylamine, diisopropylethylamine, triethylamine, N-methylmorpholine, triethylenediamine or tetramethylethylenediamine.
Further, the molar ratio of catechol to alkali and haloform in the step (1) is 1 (1-3): 2-5; the reaction conditions are as follows: in a mixed solvent of alcohol and water, reacting for 4-7 hours at the temperature of 40-100 ℃; preferably, the volume ratio of the alcohol to the water is 1:1, and the reaction time is 5-6 hours; more preferably, the alcohol is methanol or ethanol.
Further, the step (1) further includes the following post-processing steps: adjusting pH to 3-4, extracting with ethyl acetate, concentrating to obtain solid, adding purifying agent A, heating for reflux, cooling to room temperature, stirring, filtering, and oven drying filter cake; the purifying agent A is selected from methyl tertiary butyl ether, diethyl ether, isopropyl ether, ethyl acetate or methylene dichloride, preferably methyl tertiary butyl ether.
Further, in the step (2), the molar ratio of the 2, 3-dihydroxybenzaldehyde to the bromine to the alkali is 1 (1-2) (2-5); the reaction conditions are as follows: reacting for 1-3 hours at-10 ℃ to-50 ℃ in an organic solvent; preferably, the organic solvent is selected from toluene, xylene, methylene chloride, chloroform, carbon tetrachloride or dichloroethane, and the reaction time is 2-2.5 hours.
Further, the step (2) further includes the following post-processing steps: heating to room temperature, filtering to obtain solid, adding the purifying agent B, heating and refluxing, cooling to room temperature, stirring, filtering, and drying to obtain a filter cake; the purifying agent B is selected from petroleum ether, n-hexane, n-heptane, methyl tert-butyl ether, isopropyl ether, methylene chloride or toluene, preferably petroleum ether.
Experimental results show that the method for synthesizing 4-bromo-2, 3-dihydroxybenzaldehyde has the advantages of high yield, less side reaction, high purity, short synthesis steps, conventional and easily available starting materials, low cost and environmental friendliness, and has good industrial application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a schematic diagram of 4-bromo-2, 3-dihydroxybenzaldehyde prepared according to the present invention 1 H-NMR spectrum.
Detailed Description
The raw materials used in the invention are all known products and are obtained by purchasing commercial products.
EXAMPLE 1 Synthesis of 2, 3-dihydroxybenzaldehyde (Compound of formula II)
Sodium hydroxide (21.6 g,0.54 mol) and water (50 ml) were added to the reaction flask, dissolved with stirring, and then ethanol (50 ml), benzyltriethylammonium chloride (0.41 g,0.0018 mol) and ortho-diphenol (20 g,0.18 mol) were added, heated to 40℃and chloroform (43 g,0.36 mol) was added dropwise, and reacted for 5 hours at 60℃after completion of the dropwise addition. Cooling to room temperature, adding 2N hydrochloric acid to pH 3-4, extracting with ethyl acetate (100 ml×3), and concentrating to obtain crude product. Methyl tert-butyl ether (200 ml) was added, refluxed for 1h, cooled to room temperature and stirred for 1h, filtered, and the filter cake was dried to give 18.2g of 2, 3-dihydroxybenzaldehyde (formula II) in 73.2% yield. Purity of 98.9%
EXAMPLE 2 Synthesis of 2, 3-dihydroxybenzaldehyde (Compound of formula II)
Sodium hydroxide (18 g,0.45 mol) and water (42 ml) were added to the flask, dissolved with stirring, and methanol (42 ml), benzyltriethylammonium chloride (0.41 g,0.0018 mol) and o-diphenol (20 g,0.18 mol) were added, heated to 40℃and chloroform (43 g,0.36 mol) was added dropwise, and after completion of the dropwise addition, heated to 60℃for reaction for 6 hours. Cooling to room temperature, adding 2N hydrochloric acid to pH 3-4, extracting with ethyl acetate (100 ml×3), and concentrating to obtain crude product. Methyl tertiary butyl ether (200 ml) was added, the mixture was refluxed for 1h, cooled to room temperature and stirred for 1h, and the filter cake was dried to obtain 17.6g of 2, 3-dihydroxybenzaldehyde (formula II) with a yield of 70.8%. Purity of 98.4%
EXAMPLE 3 Synthesis of 2, 3-dihydroxybenzaldehyde (formula II)
Potassium hydroxide (30.2 g,0.54 mol) and water (50 ml) were added to the reaction flask, and dissolved under stirring, and ethanol (50 ml), benzyltriethylammonium chloride (0.41 g,0.0018 mol) and o-diphenol (20 g,0.18 mol) were added, heated to 40℃and chloroform (43 g,0.36 mol) was added dropwise, and after completion of the dropwise addition, heated to 60℃to react for 5 hours. Cooling to room temperature, adding 2N hydrochloric acid to pH 3-4, extracting with ethyl acetate (100 ml×3), and concentrating to obtain crude product. Methyl tert-butyl ether (200 ml) was added, refluxed for 1h, cooled to room temperature and stirred for 1h, filtered, and the filter cake was dried to give 17.1g of 2, 3-dihydroxybenzaldehyde (formula II) in a yield of 68.8%. Purity of 98.5%
EXAMPLE 4 Synthesis of 2, 3-dihydroxybenzaldehyde (formula II)
Sodium hydroxide (21.6 g,0.54 mol) and water (50 ml) were added to the flask, dissolved with stirring, and ethanol (50 ml), tetrabutylammonium bromide (0.58 g,0.0018 mol) and ortho-diphenol (20 g,0.18 mol) were added, heated to 40 ℃, chloroform (43 g,0.36 mol) was added dropwise, and reacted for 5 hours at 60 ℃ after completion of the dropwise addition. Cooling to room temperature, adding 2N hydrochloric acid to pH 3-4, extracting with ethyl acetate (100 ml×3), and concentrating to obtain crude product. Methyl tertiary butyl ether (200 ml) was added, heated under reflux for 1h, cooled to room temperature and stirred for 1h, and the filter cake was dried to give 18.8g of 2, 3-dihydroxybenzaldehyde (formula II) in a yield of 75.6%. Purity of 98.7%
EXAMPLE 5 Synthesis of 4-bromo-2, 3-dihydroxybenzaldehyde (formula III)
Tert-butylamine (28.5 g,0.3 mol) and toluene (100 ml) are added into a reaction flask, cooled to-10 to-15 ℃, bromine (12 g,0.15 mol) is added dropwise, cooled to-30 to-40 ℃ continuously after the dropwise addition, toluene (100 ml) solution of 2, 3-dihydroxybenzaldehyde (13.8 g,0.1 mol) is added dropwise, and the reaction is carried out for 2 hours at-30 to-40 ℃ after the dropwise addition. Heating to room temperature, and filtering to obtain crude product. 250ml of petroleum ether was added thereto, the mixture was refluxed for 1 hour, cooled to room temperature and stirred for 2 hours, and then filtered and dried to obtain 18.2g of 4-bromo-2, 3-dihydroxybenzaldehyde (formula III) with a yield of 84%. Purity of 99.4%
Experimental results: as shown in figure 1 of the drawings, 1 H-NMR(400MHz,DMSO-d6):δ10.12(s,1H),7.13～7.16(d,2H).
LCMS:m/z 217.3(M + H + ).
EXAMPLE 6 Synthesis of 4-bromo-2, 3-dihydroxybenzaldehyde (formula III)
Diisopropylethylamine (38.8 g,0.3 mol) and toluene (100 ml) were added to a reaction flask, cooled to-10 to-15 ℃, bromine (12 g,0.15 mol) was added dropwise, cooled to-30 to-40 ℃ after the completion of the dropwise addition, a toluene (100 ml) solution of 2, 3-dihydroxybenzaldehyde (13.8 g,0.1 mol) was added dropwise, and the reaction was carried out for 2.5 hours at-30 to-40 ℃ after the completion of the dropwise addition. Heating to room temperature, and filtering to obtain crude product. 250ml of petroleum ether is added, heating reflux is carried out for 1h, cooling to room temperature and stirring is carried out for 2h, filtering is carried out, filter cakes are washed by a small amount of petroleum ether, 17.4g of 2, 3-dihydroxyl-4-bromobenzaldehyde (formula III) is obtained after drying, and the yield is 80%. Purity of 99.2%
Experimental results: as shown in figure 1 of the drawings, 1 H-NMR(400MHz,DMSO-d6):δ10.12(s,1H),7.13～7.16(d,2H).
LCMS:m/z 217.3(M + H + ).
according to the calculation of the results, the total yield of the synthesized product 4-bromo-2, 3-dihydroxybenzaldehyde can reach 55.0-61.5%, and the purity of the final product is higher than 99.2%.
In summary, the invention provides a synthesis method of a drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde, which has the advantages of high yield, less side reaction, high purity, short synthesis step, conventional and easily available starting materials, low cost and environmental friendliness, and has good industrial application prospect.
Claims (8)
1. The synthesis method of the drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde is characterized by comprising the following steps:
(1) Reacting catechol shown in the formula I with chloroform under the action of a phase transfer catalyst and alkali to obtain 2, 3-dihydroxybenzaldehyde shown in the formula II; the phase transfer catalyst is a quaternary ammonium salt catalyst; the molar ratio of catechol to alkali to chloroform is 1 (1-3) (2-5); the reaction conditions are as follows: in a mixed solvent of alcohol and water, reacting for 4 to 7 hours at the temperature of 40 to 100 ℃; the alkali is sodium hydroxide or potassium hydroxide; the quaternary ammonium salt catalyst is benzyl triethyl ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride or hexadecyl trimethyl ammonium bromide;
(2) The compound shown in the formula II and bromine are subjected to substitution reaction under the action of alkali to obtain 4-bromo-2, 3-dihydroxybenzaldehyde shown in the formula III; the molar ratio of the 2, 3-dihydroxybenzaldehyde to the bromine to the alkali is 1 (1-2) (2-5), and the reaction conditions are as follows: reacting for 1-3 hours at-10 ℃ to-50 ℃ in an organic solvent; the alkali is tert-butylamine, diisopropylethylamine, triethylamine, N-methylmorpholine, triethylene diamine or tetramethyl ethylenediamine; the reaction route is as follows:
2. the method of claim 1, wherein the volume ratio of alcohol to water in step (1) is 1:1 and the reaction time is 5 to 6 hours.
3. The synthetic method of claim 2 wherein the alcohol is methanol or ethanol.
4. The synthesis method according to claim 1, wherein the step (1) further comprises the following post-treatment steps: adjusting pH to 3-4, extracting with ethyl acetate, concentrating to obtain solid, adding purifying agent A, heating for reflux, cooling to room temperature, stirring, filtering, and oven drying filter cake; the purifying agent A is selected from methyl tertiary butyl ether, diethyl ether, isopropyl ether, ethyl acetate or dichloromethane.
5. The method of claim 4, wherein the purifying agent A is methyl tert-butyl ether.
6. The synthetic method according to claim 1, wherein the organic solvent in the step (2) is selected from toluene, xylene, methylene chloride, chloroform, carbon tetrachloride or dichloroethane, and the reaction time is 2 to 2.5 hours.
7. The synthesis method according to claim 1, wherein the step (2) further comprises the following post-treatment steps: heating to room temperature, filtering to obtain solid, adding the purifying agent B, heating and refluxing, cooling to room temperature, stirring, filtering, and drying to obtain a filter cake; the purifying agent B is selected from petroleum ether, n-hexane, n-heptane, methyl tertiary butyl ether, isopropyl ether, methylene dichloride or toluene.
8. The synthetic method of claim 7 wherein the purifying agent B is petroleum ether.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54128542A (en) * | 1978-03-27 | 1979-10-05 | Ube Ind Ltd | Preparation of 3-cyanocatechol derivative |
| CN109053443A (en) * | 2018-08-06 | 2018-12-21 | 杭州华东医药集团浙江华义制药有限公司 | The bromo- 3- aldehyde radical-phenoxy group of 4-(4-)-benzonitrile synthetic method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54128542A (en) * | 1978-03-27 | 1979-10-05 | Ube Ind Ltd | Preparation of 3-cyanocatechol derivative |
| CN109053443A (en) * | 2018-08-06 | 2018-12-21 | 杭州华东医药集团浙江华义制药有限公司 | The bromo- 3- aldehyde radical-phenoxy group of 4-(4-)-benzonitrile synthetic method |
Non-Patent Citations (2)
| Title |
|---|
| The ortho Bromination of Phenols;D. E. Pearson等;《J.Org.Chem.》;19670701;第32卷;第2360页实验部分 * |
| The Reimer-Tiemann reaction;Wynberg, Hans等;《Organic Reactions》;20050715;第28卷;第2页最后一段 * |
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