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Method for synthesizing 4-amino-3-chlorophenol by means of multiple-temperature-zone continuous flow microchannel reactor

A channel reactor and chlorophenol technology, applied in the field of anticancer drug synthesis in organic synthesis, can solve the problems of difficult preparation, expensive, long reaction route, etc., and achieve the effect of inhibiting hydrolysis

Active Publication Date: 2018-02-27
HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] 1). J Chem Soc, Perkin Trans Ⅱ, 1981, (2): 1596-1598 reported a method for the synthesis of 4-amino-3-chlorophenol by Bamberger rearrangement reaction, but the method used expensive heavy metal platinum as Catalyst, simultaneously raw material N-(2-chlorophenyl) hydroxylamine is difficult for making
[0007] 2).US2446519(1944) reported a kind of with o-chloronitrobenzene as raw material, introduce the method that hydroxyl is synthesized 4-amino-3-chlorophenol under the situation that strong acid and molybdenum salt make catalyst, this method has a large amount of by-products The product exists, but the practicability is not high
Although this method has a short route, the unstable and explosive properties of diazonium salts make it difficult to produce on an industrial scale
[0009] Due to the long reaction route, harsh reaction conditions, and many by-products in the synthesis process of 4-amino-3-chlorophenol, the price of 4-amino-3-chlorophenol has remained high in the market, which has indirectly increased the price of lenvatinib and alternatives. Cost of Warzani API

Method used

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  • Method for synthesizing 4-amino-3-chlorophenol by means of multiple-temperature-zone continuous flow microchannel reactor
  • Method for synthesizing 4-amino-3-chlorophenol by means of multiple-temperature-zone continuous flow microchannel reactor
  • Method for synthesizing 4-amino-3-chlorophenol by means of multiple-temperature-zone continuous flow microchannel reactor

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Embodiment 1

[0039] Embodiment 1. The method described in this embodiment is a kind of multi-temperature zone continuous flow microchannel reactor synthetic 4-amino-3-chlorophenol, comprising the steps:

[0040] (1) Dissolving p-aminobenzenesulfonic acid, sodium nitrite and inorganic alkali I in water, the mixed solution obtained is used as material I, and the concentrated hydrochloric acid dilution is used as material II, and material I and material II carry out diazotization reaction, and the reaction The temperature is -5°C to 20°C, and the residence time is 30s to 60s to generate diazonium salt;

[0041](2) m-chlorophenol and inorganic base II are dissolved in water, and the obtained mixed solution is used as material III, and the diazonium salt obtained in step (1) is coupled with material III, and the reaction temperature is 0° C. to 30° C. The residence time is 20s~45s, and azo compounds are obtained;

[0042] (3) adding a metal reducing agent and a chemical reducing agent to the a...

Embodiment 2

[0045] Embodiment 2. The method for synthesizing 4-amino-3-chlorophenol in multi-temperature zone continuous flow microchannel reactor is described in detail below.

[0046] (1) Take by weighing 173g of p-aminobenzenesulfonic acid and add 2.2L of water, then add 53g of sodium carbonate and 69g of sodium nitrite, stir and dissolve the mixed solution as material I; take by weighing 300g of concentrated hydrochloric acid and add 2L of water, The diluted liquid obtained is as material II; Wherein, the mol ratio of p-aminobenzenesulfonic acid and sodium carbonate is 1:0.5, and the mol ratio of p-aminobenzenesulfonic acid and sodium nitrite is 1:1, and p-aminobenzenesulfonic acid and hydrogen chloride The molar ratio is 1:3.0, in a microchannel reactor, such as figure 1 As shown, material I enters preheating module 1 through liquid flow control pump A, controls metering pump A so that the flow rate of material I is 16mL / min, material II enters preheating module 2 through liquid flow...

Embodiment 3

[0052] Embodiment 3. The method for synthesizing 4-amino-3-chlorophenol in multi-temperature zone continuous flow microchannel reactor.

[0053] (1) Take by weighing 173g of p-aminobenzenesulfonic acid and add 2.2L of water, then add 69g of potassium carbonate and 69g of sodium nitrite, stir and dissolve the mixed solution as material I, take by weighing 300g of concentrated hydrochloric acid and add 2L of water, The diluted liquid obtained is as material II; Wherein, the mol ratio of p-aminobenzenesulfonic acid and salt of wormwood is 1:0.5, and the mol ratio of p-aminobenzenesulfonic acid and sodium nitrite is 1:1, and p-aminobenzenesulfonic acid and hydrogen chloride The molar ratio is 1:3.5, in a microchannel reactor, such as figure 1 As shown, material I enters preheating module 1 through liquid flow control pump A, controls metering pump A so that the flow rate of material I is 20mL / min, material II enters preheating module 2 through liquid flow control pump B, and contr...

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Abstract

The invention relates to a method for synthesizing 4-amino-3-chlorophenol by means of a multiple-temperature-zone continuous flow microchannel reactor, which belongs to the field of organic synthesisof anti-cancer drugs, and solves the problems in the prior art that in a process of synthesizing 4-amino-3-chlorophenol, the product yield is low, the purity is low, the cost is high and the safety property of the product is poor and the like as raw materials are not easily available, the catalyst is high in cost and the synthesized intermediate product is unstable in diazonium salt. By means of the microchannel reactor, sulfanilic acid is taken as an initial raw material, a target product 4-amino-3-chlorophenol is obtained by three steps of diazotization, coupling of diazonium salt and reduction of an azoic compound. The method provided by the invention can be applied to large-scale production of 4-amino-3-chlorophenol.

Description

technical field [0001] The invention belongs to the field of synthesis of anticancer drugs in organic synthesis, and in particular relates to a method for synthesizing 4-amino-3-chlorophenol. Background technique [0002] 4-Amino-3-chlorophenol is a key intermediate for the preparation of the tyrosine kinase inhibitor Tivozanib and the advanced liver cancer drug Lenvatinib, and its chemical structure is as follows: [0003] [0004] As an important pharmaceutical and chemical intermediate, 4-amino-3-chlorophenol is also widely used in the design and synthesis of anti-tumor, cardiovascular disease, neurological diseases and other drugs. [0005] The synthetic method about this compound mainly contains following several kinds at present: [0006] 1). J Chem Soc, Perkin Trans Ⅱ, 1981, (2): 1596-1598 reported a method for the synthesis of 4-amino-3-chlorophenol by Bamberger rearrangement reaction, but the method used expensive heavy metal platinum as catalyst, and the raw m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/76C07C213/02C07C303/32C07C309/46B01J19/00
CPCB01J19/0093C07C213/02C07C303/32C07C309/46C07C215/76
Inventor 任吉秋杨昆李海涛
Owner HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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