CN113292405A - Preparation method of 2-bromo-4-chlorobenzaldehyde - Google Patents

Preparation method of 2-bromo-4-chlorobenzaldehyde Download PDF

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CN113292405A
CN113292405A CN202110606052.3A CN202110606052A CN113292405A CN 113292405 A CN113292405 A CN 113292405A CN 202110606052 A CN202110606052 A CN 202110606052A CN 113292405 A CN113292405 A CN 113292405A
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何光明
金艳娟
陈仔玲
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Hunan Huateng Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
    • C07C17/14—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the side-chain of aromatic compounds
    • 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
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
    • C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
    • C07C209/365—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

The invention relates to a preparation method of 2-bromo-4-chlorobenzaldehyde, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of taking p-nitrotoluene as a starting material, and carrying out substitution, reduction, substitution, hydrolysis and elimination reaction to obtain 2-bromo-4-chlorobenzaldehyde; compared with the prior art, the method shortens the reaction time, reduces the reaction temperature from more than 120 ℃ to normal temperature, milds the reaction conditions, and improves the yield of the obtained product from about 70 percent to more than 90 percent; because the reaction temperature is reduced, a high-boiling point solvent is not needed to participate in the reaction, the post-treatment is simple, and the method is more suitable for the safety and environmental-friendly industrial production which is stricter day by day.

Description

Preparation method of 2-bromo-4-chlorobenzaldehyde
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method of 2-bromo-4-chlorobenzaldehyde.
Background
2-bromo-4-chlorobenzaldehyde, CAS: 84459-33-6, is an important organic synthesis intermediate and medical intermediate, and is widely applied to the laboratory research and development process and the chemical production process. The chemical structural formula is shown as the following formula I:
Figure BDA0003094142390000011
the Journal of Organic Chemistry,85(1), 248-276; 2020 discloses a synthetic route of the compound I, wherein silver nitrate is used in the last step of the route, the post-treatment is complex, the product purity is not high, and the reaction yield is low.
Patent WO2009158426 discloses a synthetic route for intermediate I: 2-bromo-4-chlorotoluene is used as a starting material, an intermediate I is obtained through substitution, hydrolysis and elimination reactions, the reaction yield is low, each step in the route involves post-treatment, the generated three wastes are more, the method is not environment-friendly, and the method is not suitable for industrial amplification.
Therefore, research on a preparation method of 2-bromo-4-chlorobenzaldehyde is still needed to obtain a preparation method which is simple and convenient to operate, easy to implement, high in yield, high in purity, low in cost, environment-friendly and suitable for industrial large-scale production.
Disclosure of Invention
Aiming at the technical problems of low yield, more three wastes and environmental pollution of the preparation method of the 2-bromo-4-chlorobenzaldehyde, the invention provides the preparation method of the 2-bromo-4-chlorobenzaldehyde, and the method has the characteristics of mild reaction conditions, high yield, six-step total yield up to 79.5%, less three wastes and suitability for industrial amplification.
The invention provides a preparation method of 2-bromo-4-chlorobenzaldehyde. 2-bromo-4-chlorobenzaldehyde, designated compound I, has the following structure:
Figure BDA0003094142390000012
according to the preparation method provided by the invention, a compound A is used as a starting material, a compound B is obtained through a substitution reaction, a compound C is obtained through a reduction reaction of the compound B, a compound D is obtained through a substitution reaction of the compound C, a compound E is obtained through a substitution reaction of the compound D, a compound F is obtained through a further substitution reaction of the compound E, and a compound I is obtained through hydrolysis and elimination reactions of the compound F; the specific reaction route is as follows:
Figure BDA0003094142390000021
in one aspect, the present invention provides a process for the preparation of compound I, comprising: hydrolyzing and eliminating the compound F in a reaction solvent at the reaction temperature in the presence of acid to obtain a compound I,
Figure BDA0003094142390000022
the reaction solvent is an organic solvent and may be selected from at least one of DCM, EA, MTBE, IPAC and toluene. In some embodiments, the reaction solvent is DCM, facilitating reaction and work-up.
The acid is inorganic or organic acid, and can be at least one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid and acetic acid. In some embodiments, the acid is hydrochloric acid, which facilitates the reaction and processing.
The reaction temperature of the hydrolysis and elimination reaction can be 10-50 ℃. In some embodiments, the reaction temperature of the hydrolysis, elimination reaction is between 20 ℃ and 40 ℃; or the reaction temperature of hydrolysis and elimination reaction is 25-35 ℃.
The reaction time of the hydrolysis and elimination reaction can be 30min-6 h. In some embodiments, the reaction time for the hydrolysis, elimination reaction is 1h to 5 h; or the reaction time of hydrolysis and elimination reaction is 2-4 h; or the reaction time of hydrolysis and elimination reaction is 2.5h-3 h.
The preparation method of the compound I can be carried out under the protection of nitrogen.
The preparation method of the compound I is characterized in that after the reaction is completed, the compound I is optionally subjected to post-treatment. In some embodiments, the method of preparation of compound I, the post-treatment comprises: and after the reaction is completed, adding water, layering, collecting an organic layer, removing the organic solvent, adding at least one of DCM, MTBE, petroleum ether, toluene, methanol, ethanol and water, crystallizing, filtering and drying to obtain the compound I.
In some embodiments, a method of preparing the foregoing compound F, can further comprise: the compound E and morpholine are subjected to substitution reaction in a reaction solvent at the reaction temperature, and after the reaction is completed, a compound F is prepared,
Figure BDA0003094142390000031
the reaction solvent is an organic solvent and can be selected from at least one of DCM, IPAC, EA, MTBE and tetrachloroethylene. In some embodiments, the reaction solvent is tetrachloroethylene, which facilitates the reaction.
In some embodiments, the reaction temperature is from 50 ℃ to 115 ℃. In some embodiments, the reaction temperature is 80 ℃.
The preparation method of the compound F can be carried out under the protection of nitrogen.
The molar ratio of morpholine to compound E may be 2:1 to 20: 1. In some embodiments, the molar ratio of morpholine to compound E is from 3:1 to 10:1, which facilitates the formation and availability of the product.
The reaction time of the substitution reaction can be 10min-36 h. In some embodiments, the reaction time for the substitution reaction is from 30min to 24 h; or the reaction time of the substitution reaction is 1h-10 h; or the reaction time of the substitution reaction is 3h-8 h.
The preparation method of the compound F optionally carries out post-treatment after the reaction is completed. In some embodiments, the method of preparation of compound F, the post-treatment comprises: and after the reaction is completed, filtering the reaction solution, concentrating the filtrate to remove the solvent, adding at least one of DCM, MTBE, EA, petroleum ether, toluene, methanol, ethanol and water for crystallization, filtering and drying to obtain the compound F.
The inventor finds that the preparation method of the compound F has unexpected technical effects, high product purity, high yield and less impurities after adopting the method.
The inventor finds that the reaction time of one-step morpholine substitution reaction, hydrolysis and elimination reaction is reduced to 2-3 hours from more than 24 hours of the prior method, so that the reaction time is greatly shortened; secondly, the reaction temperature is reduced to normal temperature from more than 120 ℃ for reaction, the reaction conditions are mild, and the yield of the obtained product is improved to more than 90 percent from about 70 percent; because the reaction temperature is reduced, a high boiling point solvent is not needed to participate in the reaction, the post-treatment is simple, in the existing method, the using amount of the high boiling point solvent is more than 20 times of the volume, the method only needs 3 to 5 times of the amount of the common solvent, and the method is more suitable for the safety and environmental-friendly industrial production which is stricter day by day.
In some embodiments, a method of making compound E, as described above, can further comprise: the compound D and a brominating reagent are subjected to substitution reaction in a reaction solvent at the reaction temperature and in the presence of a catalyst to prepare a compound E,
Figure BDA0003094142390000041
the reaction solvent is at least one of trifluorotoluene, tetrachloroethylene and carbon tetrachloride. In some embodiments, the reaction solvent is tetrachloroethylene, which facilitates the reaction.
The reaction bromination reagent is at least one of NBS, dibromohydantoin and bromine. In some embodiments, the brominating reagent is NBS, facilitating the reaction.
The catalyst for the substitution reaction is at least one of BPO and AIBN, and the generation and the obtaining of products are facilitated.
The reaction temperature of the substitution reaction may be 0 ℃ to 120 ℃. In some embodiments, the reaction temperature of the substitution reaction is 30 to 100 ℃; or the reaction temperature of the substitution reaction is 50-90 ℃.
The reaction time of the substitution reaction can be 30min-36 h. In some embodiments, the reaction time for the substitution reaction is from 1h to 24 h; or the reaction time of the substitution reaction is 2h-10 h; or the reaction time of the substitution reaction is 3h-8 h.
The preparation method of the compound E is that after the reaction is completed, the compound E is optionally subjected to post-treatment. In some embodiments, the method of preparation of compound E, the post-treatment comprises: after the reaction is completed, filtering, removing insoluble substances, washing the filtrate with water, collecting an organic phase, and concentrating under reduced pressure to obtain the compound E.
In some embodiments, a method of making compound E comprises: adding NBS and BPO into tetrachloroethylene at 0-120 ℃ for substitution reaction of the compound D, and optionally carrying out post-treatment after the reaction is finished; the post-treatment comprises the following steps: filtering insoluble substances, washing the filtrate for 2-3 times, collecting organic phase, drying with anhydrous sodium sulfate, filtering, and removing solvent to obtain compound E.
In some embodiments, a method of preparing compound D, as described above, can further comprise: dropwise adding sodium nitrite solution into hydrochloric acid at-20-80 ℃ to carry out diazotization reaction on the compound C to prepare diazonium chloride of the compound C, then adding the diazonium chloride into hydrochloric acid solution containing a catalyst at-20-80 ℃ to carry out substitution reaction to prepare a compound D,
Figure BDA0003094142390000042
the molar ratio of the compound C to the sodium nitrite is 1:1 to 2: 1. In some embodiments, the molar ratio of compound C to sodium nitrite is 1:1 to 1.1: 1.
The catalyst is CuCl or CuCl2、FeCl2、FeCl3、AlCl3In some embodiments, the catalyst is CuCl.
The reaction time of the diazotization reaction can be 30min-36 h. In some embodiments, the reaction time for the diazotization reaction is from 1h to 24 h; or the reaction time of the diazotization reaction is 1-10 h; or the reaction time of the diazotization reaction is 1h-5h
The reaction time of the substitution reaction can be 30min-36 h. In some embodiments, the reaction time for the substitution reaction is from 1h to 24 h; or the reaction time of the substitution reaction is 1h-10 h; or the reaction time of the substitution reaction is 1h-5 h.
The preparation method of the compound D is optionally post-treated after the reaction is completed. In some embodiments, the method of preparing compound D, the post-treating comprises: after the reaction is completed, adding water into the reaction solution at the temperature of-20-80 ℃ for layering, collecting an organic layer, and distilling under reduced pressure to obtain a compound D.
In some embodiments, a method of preparing compound D comprises: dissolving a compound C in hydrochloric acid, dropwise adding a sodium nitrite solution at the temperature of-20-0 ℃, reacting for 1-5h, dropwise adding the diazonium salt aqueous solution into a CuCl hydrochloric acid solution at the temperature of-20-80 ℃, reacting for 1-5h, and optionally performing post-treatment; the post-treatment comprises the following steps: after the reaction is completed, adding water into the reaction solution at the temperature of-20-80 ℃ for layering, collecting an organic layer, and distilling under reduced pressure to obtain a compound D.
In some embodiments, a method of making the foregoing compound C, comprises: the compound B is subjected to reduction reaction in a reaction solvent in the presence of a catalyst and a reducing agent at a reaction temperature to prepare a compound C,
Figure BDA0003094142390000051
the preparation method of the compound C optionally carries out post-treatment after the reaction is completed. In some embodiments, the method of preparation of compound C, the post-treatment comprises: the catalyst was removed by filtration, and the solvent was distilled off to obtain compound C.
The reaction solvent is at least one of methanol, ethanol, isopropanol and water. In some embodiments, the reaction solvent is ethanol, which facilitates the reaction.
The catalyst is one of Pd/C, Raney/Ni. In some embodiments, the catalyst is Raney Ni, which facilitates the reaction
The reducing agent is one of hydrogen and hydrazine hydrate. In some embodiments, the reducing agent is hydrazine hydrate, which facilitates the reaction.
The preparation method of the compound C optionally carries out post-treatment after the reaction is completed. In some embodiments, the method of preparation of compound C, the post-treatment comprises: after the reaction is completed, the catalyst is filtered off at normal temperature, and the solvent is distilled off to obtain a compound C.
In some embodiments, a method of making compound C comprises: dissolving the compound B in a solvent, adding a catalyst, dropwise adding a reducing agent at 0-90 ℃, reacting for 1-10h after the addition is finished, cooling to normal temperature, filtering the catalyst, and evaporating the solvent to obtain a compound C.
In some embodiments, a method of making the foregoing compound B, comprises: the compound A is subjected to substitution reaction at the reaction temperature in the presence of acid and a brominating agent to obtain a compound B,
Figure BDA0003094142390000061
the acid is at least one of sulfuric acid, hydrochloric acid, hydrobromic acid, formic acid and acetic acid. In some embodiments, the acid is sulfuric acid, which facilitates the reaction.
The reaction bromination reagent is at least one of NBS, dibromohydantoin and bromine. In some embodiments, the brominating reagent is NBS, facilitating the reaction.
The reaction temperature of the substitution reaction may be-10 ℃ to 100 ℃. In some embodiments, the reaction temperature of the substitution reaction is from 0 ℃ to 80 ℃; or the reaction temperature of the substitution reaction is 10-50 ℃.
The reaction time of the substitution reaction can be 30min-36 h. In some embodiments, the reaction time for the substitution reaction is from 1h to 24 h; or the reaction time of the substitution reaction is 2h-10 h; or the reaction time of the substitution reaction is 3h-8 h.
The preparation method of the compound B optionally carries out post-treatment after the reaction is completed. In some embodiments, the method of preparation of compound B, the post-treatment comprises: adding water into the reaction system, stirring, filtering and drying to obtain the compound B.
In some embodiments, a method of preparing compound B comprises: dissolving the compound A in sulfuric acid, adding NBS, reacting at 0-80 ℃ for 3-8h, adding water at normal temperature, stirring, filtering and drying to obtain a compound B.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
In the present invention, "optional" or "optionally" means that it may or may not be present; or may not be performed; the phrase "optionally adding a reaction solvent to the crude product obtained in step (C)" means that the reaction solvent may or may not be added to the crude product obtained in step (C).
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol; min represents minutes; h represents an hour; g represents g; ml means ml; DCM represents dichloromethane; DMF for N, N-dimethylformamide, THF for tetrahydrofuran; MTBE represents methyl tert-butyl ether; (ii) a IPAC for isopropyl acetate; BPO represents benzoyl peroxide; AIBN represents azobisisobutyronitrile; RaneyNi represents Raney nickel; Pd/C represents palladium carbon; toluene represents Toluene; NBS represents: n-bromosuccinimide.
In the present invention, the reaction is considered complete when the remaining amount of the raw materials does not exceed 5%, 3%, 2%, 1% or 0.5% of the charged amount in the reaction.
EXAMPLE 1 preparation of Compound B
Figure BDA0003094142390000071
Adding 40L of 50% sulfuric acid into a 100L reaction kettle, stirring, slowly adding a compound A (5kg) which is melted in advance, controlling the temperature to be 40-50 ℃ after the addition is finished, adding NBS (6.8kg) in batches, reacting for 4-12 h at the temperature of 40-50 ℃, monitoring the reaction end point by HPLC (high performance liquid chromatography), cooling to normal temperature after the reaction is finished, adding 40L of water, stirring for 2h, carrying out suction filtration, washing a filter cake by a small amount of water until the filter cake is neutral, pumping to dry, and drying at the normal pressure of 50-55 ℃ to obtain a compound B (7.7kg), wherein the yield is 97.8% and the purity is 98%.
EXAMPLE 2 preparation of Compound C
Figure BDA0003094142390000072
Adding 75L of ethanol and a compound B (7.5kg) into a 100L reaction kettle at normal temperature, stirring and heating to 60-80 ℃, dissolving, adding Raney Ni (0.75kg), controlling the temperature to 60-80 ℃, dropwise adding 80% hydrazine hydrate (10kg), reacting for 4-12 h, controlling the reaction end point by TLC, cooling to normal temperature after the reaction is finished, filtering to remove Raney Ni (taking care not to dry), concentrating the filtrate, and evaporating the solvent to obtain a compound C (6.3kg), wherein the yield is 97.5% and the purity is 97%.
EXAMPLE 3 preparation of Compound D
Figure BDA0003094142390000081
Adding 25L of 15% hydrochloric acid into a 50L reaction kettle, slowly adding the compound C (5kg) at the temperature of below 20 ℃, controlling the temperature to be below 10 ℃, dropwise adding a sodium nitrite aqueous solution (2kg dissolved in 6L of water) for reaction for 1-2 h, monitoring the reaction end point by HPLC, and standing after the reaction is finished.
Adding 10L of 15% hydrochloric acid into a 100L reaction kettle, adding CuCl (4kg), dripping the reaction liquid in the 50L reaction kettle into the 100L reaction kettle, controlling the temperature to be 0-10 ℃, finishing the dripping reaction for 2-5 h, monitoring the reaction end point by HPLC (high performance liquid chromatography), adding DCM (15L) for layering after the reaction is finished, extracting a water layer by DCM (5L), combining organic layers, adding 10L water for washing for 2 times, evaporating DCM from the organic layers, and distilling a crude product under reduced pressure to obtain a compound D (5kg), wherein the yield is 90.5%, and the purity is 98%.
EXAMPLE 4 preparation of Compound E
Figure BDA0003094142390000082
Adding tetrachloroethylene (25L), NBS (9.5kg) and BPO (250g) into a 50L reaction kettle, heating to 60-90 ℃, dropwise adding a compound D (5kg), reacting for 1-2 h at 60-90 ℃ after dropwise adding, monitoring the reaction end point by HPLC, cooling to normal temperature after the reaction is finished, adding 10L of water, washing for 2 times, drying organic phase anhydrous sodium sulfate, concentrating and distilling to remove tetrachloroethylene to obtain a compound E (9kg), wherein the yield is 101.8%, and the HPLC purity is 95%.
EXAMPLE 5 preparation of Compound F
Figure BDA0003094142390000083
Adding tetrachloroethylene (40L) and morpholine (10kg) into a 100L reaction kettle, heating to 20-30 ℃, slowly adding a compound E (8kg), reacting at 20-30 ℃ for 1-2 h, monitoring the reaction end point by TLC, filtering after the reaction is finished, filtering to remove a byproduct morpholine hydrobromide, adding 10L of water into the filtrate, washing for 2-3 times, drying organic phase anhydrous sodium sulfate, concentrating to remove tetrachloroethylene, and obtaining a compound F (8.3kg), wherein the yield is 100.5%, and the HPLC purity is 96%.
EXAMPLE 6 preparation of Compound I
Figure BDA0003094142390000091
Adding DCM (40L) and a compound F (8kg) into a 100L reaction kettle, controlling the temperature to be 10-30 ℃, adding 15% hydrochloric acid (10L), reacting for 1-2 h at 10-30 ℃, monitoring the reaction end point by HNMR, layering after the reaction is finished, adding 5L of water into an organic layer to wash for 2 times, drying by anhydrous sodium sulfate, evaporating DCM to obtain a crude product of the compound I, and recrystallizing by adopting petroleum ether (30L) to obtain the compound I (4.2kg), wherein the yield is 90%, and the HPLC purity is 99.8%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (9)

1. A process for the preparation of a compound I,
Figure RE-FDA0003142693650000011
the method comprises the steps of hydrolyzing and eliminating compound F in a reaction solvent at a reaction temperature in the presence of acid to obtain a compound I; wherein the acid is selected from at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, formic acid and acetic acid.
2. The process of claim 1, wherein the reaction solvent is at least one of DCM, EA, MTBE, IPAC, and toluene.
3. The process of claim 1, wherein the reaction temperature is from 10 ℃ to 50 ℃.
4. The method of claim 1, wherein after the reaction is completed, a post-treatment is used, said post-treatment comprising: adding water, layering, collecting organic layer, removing organic solvent, adding at least one of DCM, MTBE, petroleum ether, toluene, methanol, ethanol, and water, crystallizing, filtering, and drying to obtain compound I.
5. The process according to any one of claims 1 to 4, wherein the process for the preparation of compound F further comprises: the compound E and morpholine are subjected to substitution reaction in a reaction solvent at the reaction temperature, and after the reaction is completed, a compound F is prepared,
Figure RE-FDA0003142693650000012
6. the process of claim 5, wherein the reaction solvent is at least one of DCM, IPAC, EA, MTBE, and tetrachloroethylene.
7. The process of claim 5, wherein the reaction temperature is 50 ℃ to 115 ℃.
8. The process according to claim 5, wherein the molar ratio of morpholine to compound E is 2:1-20: 1.
9. A process for preparing compound I comprising the steps of:
step 1: reacting the compound A with NBS at 0-80 ℃ in acid to obtain a compound B,
Figure RE-FDA0003142693650000021
step 2: adding hydrazine hydrate dropwise into the compound B in ethanol at the temperature of 0-90 ℃ in the presence of Raney Ni to react to obtain a compound C,
Figure RE-FDA0003142693650000022
and step 3: diazotizing the compound C with sodium nitrite solution in hydrochloric acid at-20-80 ℃ to prepare diazonium chloride of the compound C, adding the diazonium chloride into hydrochloric acid solution containing CuCl at-20-80 ℃ to perform substitution reaction to prepare a compound D,
Figure RE-FDA0003142693650000023
and 4, step 4: the compound D and NBS carry out substitution reaction in tetrachloroethylene at the temperature of 0-120 ℃ in the presence of BPO to prepare a compound E,
Figure RE-FDA0003142693650000024
and 5: the compound E and morpholine are subjected to substitution reaction in tetrachloroethylene at 50-115 ℃ to obtain a compound F after the reaction is completed,
Figure RE-FDA0003142693650000031
step 6: hydrolyzing and eliminating the compound F in DCM at 10-50 deg.C in the presence of hydrochloric acid to obtain compound I,
Figure RE-FDA0003142693650000032
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CN104159890A (en) * 2011-09-09 2014-11-19 蓝瑟斯医学影像公司 Compositions, methods, and systems for the synthesis and use of imaging agents
CN110483366A (en) * 2018-05-14 2019-11-22 中国医学科学院药物研究所 Benzazole compounds and preparation method thereof, pharmaceutical composition and purposes
WO2020156453A1 (en) * 2019-02-01 2020-08-06 南京明德新药研发有限公司 Pyrimidinyl group-containing tricyclic compound serving as c-met inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104159890A (en) * 2011-09-09 2014-11-19 蓝瑟斯医学影像公司 Compositions, methods, and systems for the synthesis and use of imaging agents
CN110483366A (en) * 2018-05-14 2019-11-22 中国医学科学院药物研究所 Benzazole compounds and preparation method thereof, pharmaceutical composition and purposes
WO2020156453A1 (en) * 2019-02-01 2020-08-06 南京明德新药研发有限公司 Pyrimidinyl group-containing tricyclic compound serving as c-met inhibitor

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