阅读说明：本技术 医药中间体3-溴邻苯二酚的制备新方法 (Novel preparation method of medical intermediate 3-bromocatechol ) 是由 王建 叶刚 陈波 朱向宏 黄鹿 于 2020-07-21 设计创作，主要内容包括：本发明公开了一种医药中间体3-溴邻苯二酚的合成工艺,其特征是：以便宜的邻苯二酚(儿茶酚)为原料,经一步取代反应制得到3-溴邻苯二酚。本发明合成路线简单、生产成本低,是一种适宜工业化大生产的3-溴邻苯二酚合成工艺。(The invention discloses a synthesis process of a medical intermediate 3-bromocatechol, which is characterized by comprising the following steps: cheap catechol (catechol) is used as a raw material, and the 3-bromocatechol is prepared by one-step substitution reaction. The invention has simple synthetic route and low production cost, and is a 3-bromocatechol synthetic process suitable for industrial mass production.)

1. A synthesis process of a medical intermediate 3-bromocatechol is characterized in that catechol (catechol) is used as a raw material, and the 3-bromocatechol is obtained through one-step substitution reaction.

2. The process for the synthesis of 3-bromocatechol according to claim 1, comprising the following steps in sequence:

firstly, mixing organic alkali and aromatic organic solvent, cooling to a certain temperature, dripping bromine,

dropping organic solvent solution of catechol into the first step, and maintaining the temperature to react;

thirdly, post-processing: and after the reaction in the step II, quenching the mixture by using a saturated inorganic salt solution at room temperature, adjusting the pH value to 1 by using dilute acid, adding an aromatic hydrocarbon organic solvent for extraction, washing the extract by using water, concentrating the extract under reduced pressure to obtain a crude compound I, and rectifying the crude compound I to obtain a refined compound I.

3. The synthetic process according to claim 2,

in the first step, the organic base comprises one or a mixture of any two of triethylamine, tert-butylamine, pyridine, N-diisopropylethylamine, butylamine and isobutylamine;

the aromatic hydrocarbon organic solvent comprises one or a mixture of any two of toluene, chlorobenzene, xylene and trimethylbenzene.

4. The synthetic process according to claim 2,

in the step (II), the organic solvent comprises one or a mixture of any two of dichloromethane, chloroform, dichloroethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol and ethanol.

5. The synthetic process according to claim 2,

in the third step, the saturated inorganic salt solution comprises one or a mixture of any two of saturated sodium bisulfite, saturated sodium thiosulfate and saturated sodium bicarbonate;

the dilute acid comprises one or a mixture of any two of dilute hydrochloric acid, dilute sulfuric acid, dilute nitric acid and dilute phosphoric acid.

6. The synthetic process according to claim 2,

in the process, the feeding molar ratio of catechol to organic alkali is 1: 1-5;

in the process, the feeding molar ratio of catechol to bromine is 1: 1-5;

in the process, the feeding molar ratio of the catechol to the aromatic hydrocarbon solvent is 1: 20-50.

7. The synthesis process according to claim 2, wherein in the process, in the step (r), the reaction temperature is-40 to-20 ℃; the reaction time is 0.5-2 hours.

8. The synthesis process of claim 2, wherein in the process, in the step (II), the dropping temperature is-80 to-60 ℃; the heat preservation temperature is 20-30 ℃; the dropping time is 0-2 hours; the reaction time is kept at 20-24 hours.

Technical Field

The invention relates to a new synthesis process of a medical intermediate 3-bromocatechol, belonging to the technical field of medicine synthesis.

Background

Hepatitis C is a viral hepatitis caused by Hepatitis C Virus (HCV) infection, and according to data of a 2017 global hepatitis report issued by the world health organization, about 3.25 million people worldwide are infected with chronic hepatitis B virus or hepatitis C virus at present. Along with the popularization and application of hepatitis B vaccines, the prevalence rate of hepatitis B is reduced, and compared with a prevention and control strategy of hepatitis B, hepatitis C has no vaccine for prevention, and the incidence rate of hepatitis C shows a sharp rising trend. China is the big country of hepatitis C, and the types 1,2, 3 and 6 of the gene cases account for 96 percent of all hepatitis C virus cases, which promotes the continuous expansion of the hepatitis C drug market.

According to the data of the internal network of rice, the hepatitis C resistant medicines of the key provincial public hospitals in 2018 year achieve the market scale of 6.1 million yuan. At present, the domestic anti-hepatitis C virus medicament is mainly researched and developed by foreign medicines such as Baishimeibao, Jilide, Erberwei, Moshadong and the like. The 3-bromocatechol is a key intermediate of a medicine cloparir hydrochloride for treating the hepatitis C, and the cloparir hydrochloride is a full-genotype NS5A replication complex inhibitor and can be combined with the fosbuvir to treat adult chronic hepatitis C. Therefore, the 3-bromocatechol has good market prospect.

3-bromocatechol is known under the English name of 3-Bromobenzene-1,2-diol, CAS number: 14381-51-2, Chinese alias: 3-bromocatechol, molecular formula: c₆H₅BrO₂The molecular structural formula is shown as follows:

through literature research, the synthesis of 3-bromocatechol mainly has the following route:

the Synthesis methods reported by JOC (1993.58.3877) and Synthesis (2001.741) use guaiacol as raw material, and prepare 3-bromocatechol by bromine substitution and boron tribromide deprotection. The method has the defects of long process route, low atom utilization rate, low total yield and the like. In addition, a boron tribromide reagent with high price is used in the reaction, so the production cost is high.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides the synthesis process of the medical intermediate 3-bromocatechol, which has the advantages of simple process, safety, reliability, stable quality, low cost and high yield, is suitable for industrial mass production and has great social, economic and environmental benefits.

In order to solve the technical problems, the invention adopts the following technical scheme:

the invention discloses a synthesis process of a medical intermediate 3-bromocatechol, which is characterized by comprising the following steps: cheap catechol (catechol) is used as a raw material, and the 3-bromocatechol is prepared by one-step substitution reaction. The invention has simple synthetic route and low production cost, and is a 3-bromocatechol synthetic process suitable for industrial mass production.

Sequentially comprises the following steps:

mixing organic alkali and aromatic organic solvent, cooling to-30 ℃, dripping bromine,

dropping organic solvent solution of catechol into the first step, and maintaining the temperature at room temperature for reaction;

thirdly, post-processing: and step two, after the reaction is finished, quenching the mixture by using a saturated inorganic salt solution at room temperature, adjusting the pH value to 1 by using dilute acid, adding an aromatic hydrocarbon organic solvent for extraction, washing the mixture by using water, concentrating the mixture under reduced pressure to obtain a crude compound I, and rectifying the crude compound I to obtain a refined compound I.

Further, in the step I, the organic base comprises one or a mixture of any two of triethylamine, tert-butylamine, pyridine, N-diisopropylethylamine, butylamine and isobutylamine;

the aromatic hydrocarbon organic solvent comprises one or a mixture of any two of toluene, chlorobenzene, xylene and trimethylbenzene.

Further, in the step (ii), the organic solvent includes one or a mixture of any two of dichloromethane, chloroform, dichloroethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol and ethanol.

Further, in the third step, the saturated inorganic salt solution comprises one or a mixture of any two of saturated sodium bisulfite, saturated sodium thiosulfate and saturated sodium bicarbonate;

the dilute acid comprises one or a mixture of any two of dilute hydrochloric acid, dilute sulfuric acid, dilute nitric acid and dilute phosphoric acid.

Further, in the present invention,

in the process, the feeding molar ratio of catechol to organic alkali is 1: 1-5;

in the process, the feeding molar ratio of catechol to bromine is 1: 1-5;

in the process, the feeding molar ratio of catechol to aromatic solvent is 1: 20-50;

in the process, in the step I, the reaction temperature is-40 to-20 ℃;

in the process, in the second step, the dropping temperature is-80 to-60 ℃;

in the process, in the second step, the heat preservation temperature is 20-30 ℃;

in the process, in the step I, the reaction time is 0.5-2 hours.

In the second step, the dropping time is 0-2 hours.

In the second step of the process, the reaction time is kept for 20-24 hours.

In summary, the invention has the following advantages:

(1) the invention creatively provides a new technical route for preparing 3-bromocatechol by using catechol as a raw material and carrying out one-step substitution reaction. In comparison with the processes reported in the documents JOC (1993.3877) and Synthesis (2001.741)). Firstly, the process uses catechol as a raw material, can prepare a target product through one-step reaction without deprotection reaction, shortens the reaction route, and combines two steps into one step; the synthesis conditions of the invention enable the process route to be smoothly carried out, and the occurrence of side reactions is inhibited through gradient temperature control, so that the reaction yield is improved, and the operation is simpler and more convenient.

(2) The invention achieves the aim of the invention, overcomes the defects in the prior art, and provides the synthesis process of the medical intermediate 3-bromocatechol, which has the advantages of simple process, safety, reliability, high yield, suitability for industrial mass production and great social, economic and environmental benefits.

Drawings

FIG. 1 is a 3-bromocatechol H-NMR spectrum;

FIG. 2 is a 3-bromocatechol HPLC chromatogram.

Detailed Description

The technical solution of the present invention will be described in detail with reference to the following embodiments.