CN114105790A - Preparation method of 3-amino-4, 5-dibromobenzoic acid methyl ester - Google Patents
Preparation method of 3-amino-4, 5-dibromobenzoic acid methyl ester Download PDFInfo
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- CN114105790A CN114105790A CN202111526334.9A CN202111526334A CN114105790A CN 114105790 A CN114105790 A CN 114105790A CN 202111526334 A CN202111526334 A CN 202111526334A CN 114105790 A CN114105790 A CN 114105790A
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- RFUDHVHZTRVLCD-UHFFFAOYSA-N methyl 3-amino-4,5-dibromobenzoate Chemical compound COC(=O)c1cc(N)c(Br)c(Br)c1 RFUDHVHZTRVLCD-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229940125782 compound 2 Drugs 0.000 claims abstract description 20
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000005893 bromination reaction Methods 0.000 claims abstract description 7
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- -1 3-nitro-4, 5-dibromobenzoic acid methyl ester Chemical compound 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- BNNDHGPPQZVKMX-UHFFFAOYSA-N methyl 4-bromo-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(Br)C([N+]([O-])=O)=C1 BNNDHGPPQZVKMX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 2
- TZFJADFQEBASQU-UHFFFAOYSA-N 3-amino-4-bromobenzoic acid Chemical compound NC1=CC(C(O)=O)=CC=C1Br TZFJADFQEBASQU-UHFFFAOYSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000012912 drug discovery process Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 3-amino-4, 5-dibromobenzoic acid methyl ester, which comprises the following steps: (1) carrying out bromination reaction on the compound 1 to obtain a compound 2; (2) and (3) carrying out reduction reaction on the compound 2 to obtain a target product, namely the 3-amino-4, 5-dibromobenzoic acid methyl ester. The synthesis route provided by the invention is simple, the operation is convenient, and the total yield is high (the total yield of the two steps is more than 80%).
Description
Technical Field
The invention relates to a synthesis method of a medical intermediate, in particular to a preparation method of 3-amino-4, 5-dibromobenzoic acid methyl ester.
Background
"building blocks" in pharmaceutical chemistry refer to building blocks of drug molecules that can synthesize drug molecules. They are essential components in the chemical synthesis of drugs and are also important fragments constituting drug molecules. The quality of the building blocks of drug molecules also strongly influences the quality of candidate drug screening. Obtaining high quality, novel, diverse building blocks of drug molecules is critical to improving and accelerating the drug discovery process.
Wolfgang Sippl et al (J.Med.chem., 2016,59, 2423-. Schistosomiasis is a major parasitic disease that is overlooked, affecting 2.65 million people worldwide. Wolfgang Sippl et al used 3-amino-4-bromobenzoate as a building block in the synthesis of potent inhibitors, and it was shown that derivatives of this molecule play an important role in drug synthesis.
At present, no report is found about the synthesis of the compound, namely 3-amino-4, 5-dibromobenzoic acid methyl ester, so that a reasonable synthetic route is designed to construct the molecular building blocks of the medicine.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 3-amino-4, 5-dibromobenzoic acid methyl ester. The synthesis route provided by the invention is simple, the operation is convenient, and the total yield is high (the total yield of the two steps is more than 80%).
The technical scheme of the invention is as follows:
a preparation method of methyl 3-amino-4, 5-dibromobenzoate is carried out according to the following flow chart:
the method comprises the following specific steps:
(1) carrying out bromination reaction on the compound 1 to obtain a compound 2;
(2) and (3) carrying out reduction reaction on the compound 2 to obtain a target product, namely the 3-amino-4, 5-dibromobenzoic acid methyl ester.
In a preferred scheme, in the step (1), the bromination reaction specifically comprises the following steps: dissolving the compound 1 in concentrated sulfuric acid, adding N-bromosuccinimide (NBS), reacting at 55-65 ℃ for 3-4h, cooling to room temperature after TLC detection (ethyl acetate: petroleum ether: 1:2) reaction is finished, slowly dropwise adding the mixture into ice water, extracting the ice water by using ethyl acetate, and concentrating the organic phase under reduced pressure to obtain the compound 2.
More preferably, the mass concentration of the concentrated sulfuric acid is 98%, and the volume consumption is 2.5-3 times of the mass of the compound 1.
Further preferably, the molar ratio of compound 1 to NBS is 1: 1.1-1.2.
Preferably, in the step (2), the specific process of the reduction reaction is as follows:
dissolving the compound 2 in a mixed solvent of water and ethanol, sequentially adding concentrated hydrochloric acid and Fe powder, reacting at 85-90 ℃ for 3-4h, after TLC detection (ethyl acetate: petroleum ether ═ 1:2) reaction is finished, filtering with diatomite while hot, extracting the filtrate with ethyl acetate, concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography to obtain a white solid, namely the methyl 3-amino-4, 5-dibromobenzoate.
Further preferably, the volume ratio of water to ethanol in the mixed solvent is 1: 8.
More preferably, the mass concentration of the concentrated hydrochloric acid is 36 to 38%, and the molar ratio of the compound 2 to the concentrated hydrochloric acid is 1:0.11 to 0.12.
Further preferably, the molar ratio of the compound 2 to the Fe powder is 1: 2.5-3.0.
The invention has the technical effects that:
the synthetic route of the invention is reported for the first time. The product is synthesized through bromination reaction and reduction reaction, the synthetic route is simple, and the raw materials are cheap. The product can be directly used for reduction reaction without purification after bromination reaction, and the treatment after reaction is simple. Few by-products of the reduction reaction are easy to purify, the total yield of the two-step reaction can reach 80 percent, and the total yield of the reaction is high.
Drawings
FIG. 1 shows the preparation of methyl 3-amino-4, 5-dibromobenzoate according to example 1 of the invention1H NMR spectrum.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A preparation method of methyl 3-amino-4, 5-dibromobenzoate, which comprises the following steps:
(1) in a 100mL three-necked flask, 4-bromo-3-nitrobenzoic acid methyl ester (5.0g, 19.2mmol,1.0eq) and concentrated H were added in this order2SO4(12.5mL), after dissolution, N-bromosuccinimide (3.8g, 21.2mmol,1.1eq) was added and the mixture was reacted at 60 ℃ for 3h with TLC detectionMeasuring (ethyl acetate: petroleum ether: 1:2), cooling to room temperature after the reaction is finished, then slowly dropwise adding the mixture into 20mL of ice water, extracting the mixture for 3 times by using ethyl acetate, and concentrating the organic phase under reduced pressure to obtain 6.1g of white solid, namely the compound 2 (3-nitro-4, 5-dibromobenzoic acid methyl ester), wherein the yield of a crude product is 93.5 percent, and LCMS (ESI) comprises M/z 339.9[ M + H)]+。
(2) In a 250mL three-necked flask, Compound 2(6.1g, 18.0mmol,1.0eq), H were added in that order2O (4mL) and ethanol (32mL), then Fe powder (2.5g, 45.0mmol,2.5eq) and concentrated hydrochloric acid (concentration 37%, 0.2mL) are added, the mixture is reacted at 90 ℃ for 3h, TLC detection (ethyl acetate: petroleum ether ═ 1:2) is performed, after the reaction is finished, the mixture is filtered through kieselguhr while hot, the filtrate is extracted with ethyl acetate for 3 times, the organic phase is dried through anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude product, and the crude product is separated through column chromatography to obtain 4.8g of a white solid, namely the methyl 3-amino-4, 5-dibromobenzoate (yield of two steps is 81%, and HPLC purity is 98%).
The nuclear magnetic spectrum of the product obtained in this example is shown in FIG. 1, wherein,1H NMR(400MHz,DMSO-d6)：δ7.38(d,J＝1.8Hz,1H),7.34(d,J＝1.8Hz,1H),6.01(s,2H),3.82(s,3H)。
example 2
A preparation method of methyl 3-amino-4, 5-dibromobenzoate, which comprises the following steps:
(1) in a 100mL three-necked flask, 4-bromo-3-nitrobenzoic acid methyl ester (5.0g, 19.2mmol,1.0eq) and concentrated H were added in this order2SO4(14.0mL), dissolving, adding N-bromosuccinimide (3.9g, 22.0mmol,1.15eq), reacting the mixture at 60 ℃ for 3H, detecting by TLC (ethyl acetate: petroleum ether: 1:2), cooling to room temperature after the reaction is finished, slowly dropping into 20mL of ice water, extracting for 3 times by ethyl acetate, concentrating the organic phase under reduced pressure to obtain 6.2g of white solid, namely compound 2 (methyl 3-nitro-4, 5-dibromobenzoate), the crude product yield is 95.0%, LCMS (ESI) M/z 339.9[ M + H ] M/z]+。
(2) In a 250mL three-necked flask, Compound 2(6.2g, 18.3mmol,1.0eq), H were added in that order2O (4mL) and ethanol (32mL), then Fe powder (2.8g, 49.4mmol,2.7eq) and concentrated hydrochloric acid (37% concentration,0.2mL), reacting the mixture at 90 ℃ for 3h, detecting by TLC (ethyl acetate: petroleum ether: 1:2), filtering the mixture with kieselguhr while the mixture is hot after the reaction is finished, extracting the filtrate with ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product. The crude product was isolated by column chromatography to give 4.9g of the methyl 3-amino-4, 5-dibromobenzoate as a white solid (82% yield over two steps, 97% HPLC purity).
1H NMR(400MHz,DMSO-d6)：δ7.38(d,J＝1.8Hz,1H),7.34(d,J＝1.8Hz,1H),6.01(s,2H),3.82(s,3H)。
Example 3
A preparation method of methyl 3-amino-4, 5-dibromobenzoate, which comprises the following steps:
(1) in a 100mL three-necked flask, 4-bromo-3-nitrobenzoic acid methyl ester (5.0g, 19.2mmol,1.0eq) and concentrated H were added in this order2SO4(15.0mL), dissolving, adding N-bromosuccinimide (4.1g, 23.0mmol,1.2eq), reacting the mixture at 60 ℃ for 3H, detecting by TLC (ethyl acetate: petroleum ether: 1:2), cooling to room temperature after the reaction is finished, slowly dropping into 20mL of ice water, extracting for 3 times by ethyl acetate, concentrating the organic phase under reduced pressure to obtain 6.2g of white solid, namely compound 2 (3-nitro-4, 5-dibromobenzoic acid methyl ester), the yield of the crude product is 95.0%, LCMS (ESI) M/z 339.9[ M + H ] M/z]+。
(2) In a 250mL three-necked flask, Compound 2(6.2g, 18.3mmol,1.0eq), H were added in that order2O (4mL) and ethanol (32mL), followed by addition of Fe powder (3.0g, 54.9mmol,3.0eq) and concentrated hydrochloric acid (37% concentration, 0.2mL), reaction of the mixture at 90 ℃ for 3h, detection by TLC (ethyl acetate: petroleum ether ═ 1:2), filtration through celite while hot after the reaction is complete, extraction of the filtrate with ethyl acetate for 3 times, drying of the organic phase over anhydrous sodium sulfate and concentration under reduced pressure to give the crude product. The crude product was isolated by column chromatography to give 4.8g of the methyl 3-amino-4, 5-dibromobenzoate as a white solid (81% yield in two steps, 97% HPLC purity).
1H NMR(400MHz,DMSO-d6)：δ7.38(d,J＝1.8Hz,1H),7.34(d,J＝1.8Hz,1H),6.01(s,2H),3.82(s,3H)。
Claims (8)
1. A preparation method of methyl 3-amino-4, 5-dibromobenzoate is characterized by comprising the following steps:
the method comprises the following specific steps:
(1) carrying out bromination reaction on the compound 1 to obtain a compound 2;
(2) and (3) carrying out reduction reaction on the compound 2 to obtain a target product, namely the 3-amino-4, 5-dibromobenzoic acid methyl ester.
2. The preparation method according to claim 1, wherein in the step (1), the bromination reaction is carried out by the following specific steps: dissolving the compound 1 in concentrated sulfuric acid, adding NBS, reacting at 55-65 ℃ for 3-4h, cooling to room temperature after TLC detection reaction is finished, slowly dropwise adding into ice water, extracting with ethyl acetate, and concentrating organic phase under reduced pressure to obtain a compound 2.
3. The method according to claim 2, wherein the concentrated sulfuric acid has a mass concentration of 98% and is used in an amount of 2.5 to 3 times the mass of compound 1.
4. The method according to claim 2, wherein the molar ratio of Compound 1 to NBS is 1:1.1 to 1.2.
5. The preparation method according to claim 1, wherein in the step (2), the reduction reaction is carried out in the following specific process:
dissolving the compound 2 in a mixed solvent of water and ethanol, sequentially adding concentrated hydrochloric acid and Fe powder, reacting at 85-90 ℃ for 3-4h, filtering with diatomite while hot after TLC detection reaction is finished, extracting the filtrate with ethyl acetate, concentrating the organic phase under reduced pressure to obtain a crude product, and separating the crude product by column chromatography to obtain a white solid, namely the 3-amino-4, 5-dibromobenzoic acid methyl ester.
6. The production method according to claim 5, wherein the volume ratio of water to ethanol in the mixed solvent is 1: 8.
7. The method according to claim 5, wherein the mass concentration of the concentrated hydrochloric acid is 36 to 38%, and the molar ratio of the compound 2 to the concentrated hydrochloric acid is 1:0.11 to 0.12.
8. The method according to claim 5, wherein the molar ratio of the compound 2 to the Fe powder is 1: 2.5-3.0.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070225506A1 (en) * | 1997-10-27 | 2007-09-27 | Toyama Chemical Co., Ltd. | Processes for producing 7-isoindoline-quinolonecarboxylic acid derivative and its intermediate, as well as salt of 7-isoindoline-quinolonecarboxylic acid derivative, its hydrate and composition comprising the same as active ingredient |
| CN103044447A (en) * | 2013-01-16 | 2013-04-17 | 江西富祥药业股份有限公司 | Preparation method of benzhydryl s-oxopenicillanate |
| CN103402996A (en) * | 2011-01-04 | 2013-11-20 | 诺瓦提斯公司 | Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (AMD) |
| WO2016062175A1 (en) * | 2014-10-23 | 2016-04-28 | 上海雅本化学有限公司 | Preparation method for 1-substituted-1h-1,2,3-triazole-4-carboxylic acid |
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2021
- 2021-12-14 CN CN202111526334.9A patent/CN114105790A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070225506A1 (en) * | 1997-10-27 | 2007-09-27 | Toyama Chemical Co., Ltd. | Processes for producing 7-isoindoline-quinolonecarboxylic acid derivative and its intermediate, as well as salt of 7-isoindoline-quinolonecarboxylic acid derivative, its hydrate and composition comprising the same as active ingredient |
| CN103402996A (en) * | 2011-01-04 | 2013-11-20 | 诺瓦提斯公司 | Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (AMD) |
| CN103044447A (en) * | 2013-01-16 | 2013-04-17 | 江西富祥药业股份有限公司 | Preparation method of benzhydryl s-oxopenicillanate |
| WO2016062175A1 (en) * | 2014-10-23 | 2016-04-28 | 上海雅本化学有限公司 | Preparation method for 1-substituted-1h-1,2,3-triazole-4-carboxylic acid |
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