WO2022218348A1 - Method for synthesizing lactam compounds - Google Patents

Method for synthesizing lactam compounds Download PDF

Info

Publication number
WO2022218348A1
WO2022218348A1 PCT/CN2022/086645 CN2022086645W WO2022218348A1 WO 2022218348 A1 WO2022218348 A1 WO 2022218348A1 CN 2022086645 W CN2022086645 W CN 2022086645W WO 2022218348 A1 WO2022218348 A1 WO 2022218348A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
morpholine
water
added
minutes
Prior art date
Application number
PCT/CN2022/086645
Other languages
French (fr)
Inventor
Changhu CHU
Tianhua Ma
Jinjin YANG
Dongke SHI
Qiang JIA
Original Assignee
Seasons Biotechnology (Taizhou) Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Seasons Biotechnology (Taizhou) Co., Ltd. filed Critical Seasons Biotechnology (Taizhou) Co., Ltd.
Publication of WO2022218348A1 publication Critical patent/WO2022218348A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms

Definitions

  • This invention belongs to the technical field of chemical synthesis, in particular to a new synthesis method for oxidizing cyclic amine compounds to lactam compounds.
  • Lactam compounds are key intermediates of many drugs and have a wide range of applications in the field of drug synthesis.
  • Rivaroxaban and Apixaban both have lactam structures in their molecular structures.
  • the lactam compounds can be introduced into the target drug structure as an intermediate, and its synthesis method can be obtained by directly oxidizing the cyclic amine compounds, so as to achieve the purpose of simplifying the synthesis process of the APIs.
  • transition metal catalytic oxidation uses transition heavy metals as catalysts, resulting in high process costs and the risk of residual metal elements exceeding the standard in the product, not suitable for industrial application;
  • the non-metallic catalytic method uses a non-metallic oxidant to oxidize cyclic amines.
  • the use of heavy metals is avoided, the process cost is relatively reduced, and it is more suitable for industrial application.
  • TEMPO is expensive, toxic, and can be absorbed through the skin. It is irritating and has certain risks for experimenters, and its structure is unstable under acid-base conditions and easy to decompose, resulting in many impurities in the product, which is difficult to recycle and easily pollutes the environment. Therefore, the cost of this method is relatively high, and it does not meet the current environmental protection chemical requirements.
  • the patent provides a method for synthesizing 4- (4-aminophenyl) -3-morpholine-3-one, comprising the steps: using p-halo-nitrobenzene and morpholine as starting materials, condensing to generate 4- (4-aminophenyl) -3-morpholine, then use halite or chlorine dioxide as oxidant, adjust and control the pH value of the reaction system to be less than 7 by acid or acid salt, 4- (4-nitrophenyl) -morpholine is oxidized to generate 4- (4-nitrophenyl) -morpholine-3-one, and finally reduced to generate the target product 4- (4-aminophenyl) -morpholine-3-one.
  • the synthesis method shows good application value.
  • the purpose of the present invention is to provide a method for synthesizing lactam compounds which is green and efficient, mild reaction conditions, high yield and high purity, and convenient work-up and easy to industrialize.
  • carbon dioxide is used for the first time as a catalyst to participate in the oxidation reaction.
  • Carbon dioxide is a cheap and easy-to-obtain weak acid gas, which can stably control the pH value of the reaction system at about 6, which can well control the reaction process and reaction selectivity, and is an effective supplement and a great improvement to the existing technology.
  • the present invention provides a new method for synthesizing lactam compounds, which is characterized in that, the method uses sodium chlorite as an oxidant, and under the catalysis of carbon dioxide, oxidizes cyclic amine compounds to lactam compounds.
  • the method for synthesizing lactam compounds of the present invention is not limited to oxidizing a specific cyclic amine compound into lactam compound. And as a more preferred solution of the present invention, the method of the present invention oxidizes the cyclic amine compounds shown in formula II to lactam compounds shown in formula I, and the chemical reaction equation is as follows:
  • X is O or CH 2 ;
  • R is phenyl, benzyl or pyridyl which optionally substituted with one or multiple selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy. Wherein “multiple” means substituted with two or more groups.
  • the cyclic amine compounds are, for example, 4- (4-nitrophenyl) -morpholine, 4-phenyl-morpholine, 4- (2-methyl-4-nitrophenyl) -morpholine, 4- (4-cyanophenyl) -morpholine, 4- (2-chloro-4-nitrophenyl) -morpholine, 4- (4-nitrobenzyl) -morpholine, 4- (4-chlorophenyl) -morpholin e, 4- (2-nitro-4-cyanophenyl) -morpholine, 4- (pyridin-2-yl) -morpholine, 4- (2-nitro-4-trifluoromethane phenyl) -morpholine, 4- (3-nitro-5-trifluoromethylphenyl) -morpholine, 1- (4-nitrophenyl) -piperidine, 4- (3-nitrophenyl) -morpholine, 1- (4-nitrophenyl) -tetrahydropyrrole, 1- (2-methylphenyl)
  • the reaction system does not react without introducing carbon dioxide, and the reaction can be catalyzed and carried out rapidly in the presence of carbon dioxide.
  • the carbon dioxide gas can be directly introduced into the reaction vessel below the reaction liquid level, and can also be introduced into the reaction vessel above the reaction liquid surface.
  • continuously introduce carbon dioxide to the reaction system optionally continue to introduce carbon dioxide to the reaction system after dripping, stop introducing carbon dioxide, or intermittently introducing carbon dioxide. Any of the above carbon dioxide introduction methods can achieve the purpose of carbon dioxide catalytic reaction, and there is no obvious difference in the reaction effect.
  • the molar ratio of the cyclic amine compound to the oxidant sodium chlorite is 1: 1-1: 10, preferably 1: 2-1: 6, such as 1: 2, 1: 3, 1: 4, 1: 5, 1: 6.
  • sodium chlorite is widely used in industrial fields. It is readily available, inexpensive, and easily soluble in water, and can be easily removed by washing and layering after work-up; In addition, sodium chlorite as alkali metal salts will not cause excessive metal element impurities.
  • reaction temperature is 0-100°C, preferably 20-80°C, such as 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C and 80°C.
  • the used solvents are aprotic solvents such as nitrile solvents, ether solvents, toluene, acetone, and dichloromethane.
  • the nitrile solvents can be selected from acetonitrile, propionitrile, butyronitrile, etc.
  • the ether solvents can be selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, etc..
  • the present invention provides a method for synthesizing lactam compounds shown in formula I, the method uses sodium chlorite as an oxidant, and under the catalysis of carbon dioxide, the cyclic amine compounds shown in formula II is oxidization to lactam compounds as shown in formula I
  • X is O or CH 2 ;
  • R is phenyl, benzyl or pyridyl which optionally substituted with one or multiple selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy.
  • “multiple” refers to being substituted by two or more groups, and the type of the cyclic amine compounds, the method of introducing catalyst carbon dioxide, the molar ratio of the cyclic amine compounds to the oxidant sodium chlorite, the reaction temperature and the solvent used are as previously described.
  • reducing agents such as sodium bisulfite or sodium sulfite are added to quench the reaction, concentrate and recover the solvent, filter and wash to obtain lactam compounds with yield of 85-98%, and the maximum HPLC purity can reach more than 99%.
  • the method for synthesizing lactam compounds of the present invention has significant advantages: using sodium chlorite as an oxidant and CO 2 as a catalyst, the whole reaction process is mild and controllable, with high reaction selectivity and complete reaction, and high product yield, high purity.
  • the work up is convenient and simple, the added salt is only the oxidant, the usage is controllable, the oxidant is easily soluble in water, and can be removed by conventional water washing and layering operation, avoiding the generation of a large amount of solid waste; the whole reaction operation process is simple, and the product is easy manufacture, more efficient and greener.
  • the preparation of cyclic amine compounds can refer to the method described in J. Org. Chem. (2018, 83, 15333-15346) .
  • Reagents and solvents both are commercially available; the solvents used are domestic analytical reagents, purchased from Sinopharm Chemical Reagent Co., Ltd., used as received.
  • Commercially available sodium chlorite is a solid with 80%content, and can be prepare into an aqueous solution with a content of 10-60%as required, such as 10%, 20%, 30%, 40%, 50%or 60%aqueous solution.
  • HPLC Chromatography Agilent 1206.
  • NMR instrument Bruker DRX-400FT (Germany) , 1 HNMR was measured in CDCl 3 , chemical shifts were based on tetramethylsilane (TMS) , and the unit was ppm.
  • Example 16 Compared with Example 16, the catalyst was changed from CO 2 to formic acid.
  • the aqueous phase was extracted twice with 500ml of ethyl acetate.
  • the organic phases were combined again, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid.
  • the purity of the reaction solution was 76.6%
  • the raw material was left about 8.23%
  • the maximum impurity was 1.5%.
  • the purity of the reaction solution was 83.8%, the raw material was left about 5.11%, and the maximum impurity was 2.6%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

This invention provides a new synthesis method of lactam compounds, which is characterized in that, the method uses sodium chlorite as an oxidant, and under the catalysis of carbon dioxide, oxidizes cyclic amine compounds to lactam compounds. The synthesis method provided by the invention has the characteristics ofgreen, high efficiency, mild reaction conditions, high yield, high purity, convenient work-up and easy to industrialize.

Description

METHOD FOR SYNTHESIZING LACTAM COMPOUNDS FIELD OF THE INVENTION
This invention belongs to the technical field of chemical synthesis, in particular to a new synthesis method for oxidizing cyclic amine compounds to lactam compounds.
BACKGROUND OF THE INVENTION
Lactam compounds are key intermediates of many drugs and have a wide range of applications in the field of drug synthesis. For example, Rivaroxaban and Apixaban, the commonly used clinical antithrombotic drugs, both have lactam structures in their molecular structures. The lactam compounds can be introduced into the target drug structure as an intermediate, and its synthesis method can be obtained by directly oxidizing the cyclic amine compounds, so as to achieve the purpose of simplifying the synthesis process of the APIs.
Figure PCTCN2022086645-appb-000001
Commonly methods for obtaining lactam compounds by oxidizing cyclic amine compounds include transition metal catalytic oxidation and non-metal catalytic oxidation. The transition metal catalytic method uses transition heavy metals as catalysts, resulting in high process costs and the risk of residual metal elements exceeding the standard in the product, not suitable for industrial application; the non-metallic catalytic method uses a non-metallic oxidant to oxidize cyclic amines. Compared with the metal catalytic oxidation method, the use of heavy metals is avoided, the process cost is relatively reduced, and it is more suitable for industrial application.
The article by Fernando Sartillo-Piscil et al. published in J. Org. Chem. (2018, 83, 15333-15346) in 2018 describes a method for oxidizing morpholines to morpholinones using a non-metallic catalytic oxidation method. This method uses sodium chlorite (3 equiv. ) and sodium hypochlorite (0.7 equiv. ) as oxidants, TEMPO (tetramethylpiperidine nitrogen oxide) (0.1 equiv. ) as catalyst, and pH adjuster  NaH 2PO 4 (3 equiv. ) as oxidation system and realizes non-metallic catalytic oxidation. However, the disadvantage ofthis reaction is also obvious. Too many salts are added to the whole reaction system, and a large amount of solid waste or waste liquid will be generated during industrialization. In addition, TEMPO is expensive, toxic, and can be absorbed through the skin. It is irritating and has certain risks for experimenters, and its structure is unstable under acid-base conditions and easy to decompose, resulting in many impurities in the product, which is difficult to recycle and easily pollutes the environment. Therefore, the cost of this method is relatively high, and it does not meet the current environmental protection chemical requirements.
The article by Eric P.A. Talbot et al. published in Org. Lett. (2017, 19, 870-873) in 2017 describes a method for oxidizing cyclic amines to lactams using a non-metallic catalytic oxidation method. The method uses up to 7.5 equivalents of iodine as the oxidant, and the price of iodine is high and the usage is large, resulting in high process cost; and using 10 equivalents of NaHCO 3 as the pH regulator, a large amount of solid waste will be generated during industrialization, and it does not meet the current green chemical requirements.
The above-mentioned processes have disadvantages such as high production cost, many "three wastes" , not environmentally friendly, poor reaction selectivity and incomplete reaction when the process is scaled up, which is not conducive to industrialized production. Therefore, the research on the synthesis of lactam compounds has very important practical value and significance.
In the patent CN201911264060.3 filed by the applicant in 2019, using acid or acid salt as pH adjuster and sodium chlorite as oxidant, the synthesis of 4- (4-aminophenyl) -3-morpholinone, an intermediate of Rivaroxaban, was successfully achieved. Specifically, the patent provides a method for synthesizing 4- (4-aminophenyl) -3-morpholine-3-one, comprising the steps: using p-halo-nitrobenzene and morpholine as starting materials, condensing to generate 4- (4-aminophenyl) -3-morpholine, then use halite or chlorine dioxide as oxidant, adjust and control the pH value of the reaction system to be less than 7 by acid or acid salt, 4- (4-nitrophenyl) -morpholine is oxidized to generate 4- (4-nitrophenyl) -morpholine-3-one, and finally reduced to generate the target product 4- (4-aminophenyl) -morpholine-3-one. The synthesis method shows good application value. But in this method, pH control is more difficult. At the beginning of the reaction, the reaction rate is too fast and the heat is released more, resulting in poor selectivity, and at the later stage of the reaction, the pH increases and the reaction rate decreases. The reaction speed is not very stable in the whole reaction process. When the process is scaled up, there are outstanding  problems such as poor reaction selectivity and incomplete reaction, which are not conducive to industrial production. Therefore, the alternative synthesis of lactam compounds still needs further improvement.
SUMMARY OF THE INVENTION
In view of the above-mentioned deficiencies in the synthesis of lactam compounds, the purpose of the present invention is to provide a method for synthesizing lactam compounds which is green and efficient, mild reaction conditions, high yield and high purity, and convenient work-up and easy to industrialize. In the present invention, carbon dioxide is used for the first time as a catalyst to participate in the oxidation reaction. Carbon dioxide is a cheap and easy-to-obtain weak acid gas, which can stably control the pH value of the reaction system at about 6, which can well control the reaction process and reaction selectivity, and is an effective supplement and a great improvement to the existing technology.
According to the purpose of the present invention, the present invention provides a new method for synthesizing lactam compounds, which is characterized in that, the method uses sodium chlorite as an oxidant, and under the catalysis of carbon dioxide, oxidizes cyclic amine compounds to lactam compounds.
The method for synthesizing lactam compounds of the present invention is not limited to oxidizing a specific cyclic amine compound into lactam compound. And as a more preferred solution of the present invention, the method of the present invention oxidizes the cyclic amine compounds shown in formula II to lactam compounds shown in formula I, and the chemical reaction equation is as follows:
Figure PCTCN2022086645-appb-000002
Wherein:
When n=0 or 1, X is CH 2,
When n=2, X is O or CH 2;
R is phenyl, benzyl or pyridyl which optionally substituted with one or multiple selected from  hydrogen, halogen, nitro, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy. Wherein "multiple" means substituted with two or more groups.
As an example, the cyclic amine compounds are, for example, 4- (4-nitrophenyl) -morpholine, 4-phenyl-morpholine, 4- (2-methyl-4-nitrophenyl) -morpholine, 4- (4-cyanophenyl) -morpholine, 4- (2-chloro-4-nitrophenyl) -morpholine, 4- (4-nitrobenzyl) -morpholine, 4- (4-chlorophenyl) -morpholin e, 4- (2-nitro-4-cyanophenyl) -morpholine, 4- (pyridin-2-yl) -morpholine, 4- (2-nitro-4-trifluoromethane phenyl) -morpholine, 4- (3-nitro-5-trifluoromethylphenyl) -morpholine, 1- (4-nitrophenyl) -piperidine, 4- (3-nitrophenyl) -morpholine, 1- (4-nitrophenyl) -tetrahydropyrrole, 1- (2-methylphenyl) -piperidine, 1- (3-fluoro-4-bromophenyl) -piperidine, 1- (4-trifluoromethylphenyl) -piperidine, 1- (4-nitrophenyl) -azeti dine, and so on.
In the method for synthesizing lactam compounds of the present invention, add sodium chlorite dropwise to the reaction system in the form of sodium chlorite aqueous solution.
In the method for synthesizing lactam compounds of the present invention, the reaction system does not react without introducing carbon dioxide, and the reaction can be catalyzed and carried out rapidly in the presence of carbon dioxide. On the one hand, the carbon dioxide gas can be directly introduced into the reaction vessel below the reaction liquid level, and can also be introduced into the reaction vessel above the reaction liquid surface. On the other hand, in the process of dripping the sodium chlorite aqueous solution, continuously introduce carbon dioxide to the reaction system, optionally continue to introduce carbon dioxide to the reaction system after dripping, stop introducing carbon dioxide, or intermittently introducing carbon dioxide. Any of the above carbon dioxide introduction methods can achieve the purpose of carbon dioxide catalytic reaction, and there is no obvious difference in the reaction effect.
In the method for synthesizing lactam compounds of the present invention, the molar ratio of the cyclic amine compound to the oxidant sodium chlorite is 1: 1-1: 10, preferably 1: 2-1: 6, such as 1: 2, 1: 3, 1: 4, 1: 5, 1: 6. As a stable oxidant, sodium chlorite is widely used in industrial fields. It is readily available, inexpensive, and easily soluble in water, and can be easily removed by washing and layering after work-up; In addition, sodium chlorite as alkali metal salts will not cause excessive metal element impurities.
In the method for synthesizing lactam compounds of the present invention, reaction temperature is 0-100℃, preferably 20-80℃, such as 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃,  65℃, 70℃, 75℃ and 80℃.
In the method for synthesizing lactam compounds of the present invention, the used solvents are aprotic solvents such as nitrile solvents, ether solvents, toluene, acetone, and dichloromethane. The nitrile solvents can be selected from acetonitrile, propionitrile, butyronitrile, etc. The ether solvents can be selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, etc..
Preferably, the present invention provides a method for synthesizing lactam compounds shown in formula I, the method uses sodium chlorite as an oxidant, and under the catalysis of carbon dioxide, the cyclic amine compounds shown in formula II is oxidization to lactam compounds as shown in formula I
Figure PCTCN2022086645-appb-000003
Wherein:
When n=0 or 1, X is CH 2,
When n=2, X is O or CH 2;
R is phenyl, benzyl or pyridyl which optionally substituted with one or multiple selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy. Wherein "multiple" refers to being substituted by two or more groups, and the type of the cyclic amine compounds, the method of introducing catalyst carbon dioxide, the molar ratio of the cyclic amine compounds to the oxidant sodium chlorite, the reaction temperature and the solvent used are as previously described.
In the method for synthesizing lactam compounds of the present invention, high conversion rate and selectivity of the reaction can be realized under the catalysis CO 2 during the reaction process. Using CO 2 as a catalyst is an accidental discovery by the applicant, that CO 2 itself as a common gas in nature, has various applications, but it has never been directly used as a catalyst in oxidation reactions; CO 2 is a stable gas, which is soluble in water. Carbonic acid is then generated, and the reaction itself is also a reversible reaction. The generated trace amount of carbonic acid catalyzes the oxidation reaction, and the reaction system can maintain a stable carbonic acid microenvironment under the catalysis of CO 2, thereby ensuring a stable and gentle reaction. That is,  it leaves the reaction system, reduces work-up steps, does not cause environmental pollution, and is more suitable for industrial application.
After the reaction is completed, reducing agents such as sodium bisulfite or sodium sulfite are added to quench the reaction, concentrate and recover the solvent, filter and wash to obtain lactam compounds with yield of 85-98%, and the maximum HPLC purity can reach more than 99%.
In the prior art, when a non-metallic catalytic oxidation method is used to synthesize lactam compounds, the oxidation method in the literature is not suitable for industrial application. On the one hand, a large amount of oxidant is used, resulting in a large amount of waste, which increases the cost of process and is not environmentally friendly; On the other hand, when the process is scaled up, problems such as poor reaction selectivity and incomplete reaction are prominent, resulting in poor product quality.
The method for synthesizing lactam compounds of the present invention has significant advantages: using sodium chlorite as an oxidant and CO 2 as a catalyst, the whole reaction process is mild and controllable, with high reaction selectivity and complete reaction, and high product yield, high purity. The work up is convenient and simple, the added salt is only the oxidant, the usage is controllable, the oxidant is easily soluble in water, and can be removed by conventional water washing and layering operation, avoiding the generation of a large amount of solid waste; the whole reaction operation process is simple, and the product is easy manufacture, more efficient and greener.
DETAILED DESCRIPTION OF THE INVENTION
The embodiments of the present invention will be described in detail below with reference to specific examples, but those skilled in the art should understand that the examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.
The preparation of cyclic amine compounds can refer to the method described in J. Org. Chem. (2018, 83, 15333-15346) .
Reagents and solvents: both are commercially available; the solvents used are domestic analytical reagents, purchased from Sinopharm Chemical Reagent Co., Ltd., used as received. Commercially  available sodium chlorite is a solid with 80%content, and can be prepare into an aqueous solution with a content of 10-60%as required, such as 10%, 20%, 30%, 40%, 50%or 60%aqueous solution. HPLC Chromatography: Agilent 1206.
NMR instrument: Bruker DRX-400FT (Germany) ,  1HNMR was measured in CDCl 3, chemical shifts were based on tetramethylsilane (TMS) , and the unit was ppm.
EXAMPLES
Example 1: Synthesis of 4- (4-nitrophenyl) -morpholine-3-one
2.08g (0.01mol) 4- (4-nitrophenyl) -morpholine and 20ml acetonitrile were added to the 100ml reaction flask, and the temperature was raised to 50℃, an aqueous solution prepared by dissolving 2.26g (0.02mol) sodium chlorite in 5g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 3 hours. After completion of the reaction, 2.5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 30ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.14g 4- (4-nitrophenyl) -morpholine-3-one. Yield 96.4%, HPLC purity 99.7%.
1HNMR (CDCl 3, 400MHz) : δ8.21 (d, J=8.8Hz, 2H) , 7.55 (d, J=9.2Hz, 2H) , 4.31 (s, 2H) , 4.01 (t, J=5.2Hz, 2H) , 3.79 (t, J=5.2Hz, 2H) .
Example 2: Synthesis of 4-phenyl-morpholine-3-one
1.63g (0.01mol) 4-phenyl-morpholine and 20ml THF were added to the 100ml reaction flask, the temperature was raised to 60℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 1.5 hours. After completion of the reaction, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 15 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 25ml water, stir for 20 minutes, filter, wash the filter cake with appropriate amount water, and dry to obtain 1.53 g 4-phenyl-morpholine-3-one. Yield 86.4%, HPLC purity 98.1%.
1HNMR (CDCl 3, 400MHz) : δ7.48-7.36 (m, 2H) , 7.38-7.24 (m, 3H) , 4.35 (s, 2H) , 4.08-3.99 (m,  2H) , 3.82-3.72 (m, 2H) .
Example 3: Synthesis of 4- (2-methyl-4-nitrophenyl) -morpholine-3-one
2.22g (0.01mol) of 4- (2-methyl-4-nitrophenyl) -morpholine and 25ml dichloromethane were added to the 100ml reaction flask, the temperature was raised to 30℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 3 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 30ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.18g 4- (2-methyl-4-nitrophenyl) -morpholine-3-one. Yield 92.4%, HPLC purity 98.9%.
1HNMR (CDCl 3, 400MHz) : δ8.22-8.10 (m, 2H) , 7.35 (d, J=8.6Hz, 1H) , 4.37 (s, 2H) , 4.08 (s, 2H) , 3.67 (d, J=71.8Hz, 2H) , 2.35 (s, 3H) .
Example 4: Synthesis of 4- (4-cyanophenyl) -morpholine-3-one
1.88g (0.01mol) 4- (4-cyanophenyl) -morpholine and 15ml dioxane were added to the 100ml reaction flask, the temperature was raised to 45℃, an aqueous solution prepared by dissolving 3.38g (0.03mol) sodium chlorite in 10.62g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 3 hours. After the reaction was completed, 3.8g sodium sulfite was added, and the mixture was stirred at room temperature for 12 minutes. Concentrate under reduced pressure to obtain a white solid, add 25ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 1.87g 4- (4-cyanophenyl) -morpholine-3-one. Yield 92.6%, HPLC purity 98.1%.
1HNMR (CDCl 3, 400MHz) : δ7.75-7.67 (m, 2H) , 7.59-7.50 (m, 2H) , 4.36 (s, 2H) , 4.10-4.03 (m, 2H) , 3.86-3.78 (m, 2H) .
Example 5: Synthesis of 4- (2-chloro-4-nitrophenyl) -morpholine-3-one
2.42g (0.01mol) 4- (2-chloro-4-nitrophenyl) -morpholine and 25ml toluene were added to the 100ml  reaction flask, and the temperature was raised to 80℃, an aqueous solution prepared by dissolving 3.38g (0.03mol) sodium chlorite in 10.62g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 5 hours. After completion of the reaction, 3.8g sodium sulfite was added, and the mixture was stirred at room temperature for 15 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 40 ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 2.51g 4- (2-chloro-4-nitrophenyl) -morpholine-3-one. Yield 98.0%, HPLC purity 99.1%.
1HNMR (CDCl 3, 400MHz) : δ8.42 (d, J=2.5Hz, 1H) , 8.24 (dd, J=8.7, 2.5Hz, 1H) , 7.54 (d, J=8.6Hz, 1H) , 4.41 (s, 2H) , 4.11 (dd, J=5.8, 4.2Hz, 2H) , 3.74 (t, J=5.0Hz, 2H) .
Example 6: Synthesis of 4- (4-chlorophenyl) -morpholine-3-one
1.98g (0.01mol) 4- (4-chlorophenyl) -morpholine and 20ml acetone were added to the 100ml reaction flask, and the temperature was raised to 20℃, an aqueous solution prepared by dissolving 5.65g (0.05mol) sodium chlorite in 8.35g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 2.5 hours. After completion of the reaction, 6.3g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 50ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 1.81g 4- (4-chlorophenyl) -morpholine-3-one. Yield 85.4%, HPLC purity 98.1%.
1HNMR (CDCl 3, 400MHz) : δ7.43-7.32 (m, 2H) , 7.32-7.26 (m, 2H) , 4.34 (s, 2H) , 4.07-4.00 (m, 2H) , 3.79-3.71 (m, 2H) .
Example 7: Synthesis of 4- (2-nitro-4-cyanophenyl) -morpholine-3-one
2.33g (0.01mol) 4- (2-nitro-4-cyanophenyl) -morpholine and 35ml propionitrile were added to the 100ml reaction flask, and the temperature was raised to 55℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 6 hours. After completion of the reaction, 4.2g sodium bisulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 30ml  water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.42g 4- (2-nitro-4-cyanophenyl) -morpholine-3-one. Yield 98.0%, HPLC purity 99.1%.
1HNMR (CDCl 3, 400MHz) : δ8.30 (d, J=1.9Hz, 1H) , 7.97 (dd, J=8.3, 1.9Hz, 1H) , 7.54 (d, J=8.3Hz, 1H) , 4.33 (s, 2H) , 4.12 (t, J=5.0Hz, 2H) , 3.87 (s, 2H) .
Example 8: Synthesis of 4- (2-nitro-4-trifluoromethylphenyl) -morpholine-3-one
2.76g (0.01mol) 4- (2-nitro-4-trifluoromethylphenyl) -morpholine and 40ml butyronitrile were added to the 100ml reaction flask, the temperature was raised to 65℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 4 hours. After completion of the reaction, 4.2g sodium bisulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 20ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.85g 4- (2-nitro-4-trifluoromethylphenyl) -morpholine-3-one. Yield 98.3%, HPLC purity 99.1%.
1HNMR (CDCl 3, 400MHz) : δ8.29 (d, J=2.0Hz, 1H) , 7.96 (ddd, J=8.3, 2.0, 0.7Hz, 1H) , 7.56 (dd, J=8.3, 0.9Hz, 1H) , 4.33 (s, 2H) , 4.12 (t, J=5.0Hz, 2H) , 3.87 (s, 2H) .
Example 9: Synthesis of 4- (3-nitro-5-trifluoromethylphenyl) -morpholine-3-one
2.76g (0.01mol) 4- (3-nitro-5-trifluoromethylphenyl) -morpholine and 40ml 2-methyltetrahydrofuran were added to the 100ml reaction flask, the temperature was raised to 60℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO2. After dripping, the reaction was continued for about 4.5 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 35ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 2.82g 4- (3-nitro-5-trifluoromethylphenyl) -morpholine-3-one. Yield 97.2%, HPLC purity 99.1%
1HNMR (CDCl 3, 400MHz) : δ8.49 (s, J=2.1Hz, 1H) , 8.38 (s, 1H) , 8.10 (s, 1H) , 4.40 (s, 2H) , 4.15-4.07 (m, 2H) , 3.91 (dd, J=5.9, 4.1Hz, 2H) .
Example 10: Synthesis of 1- (4-nitrophenyl) -2-piperidone
2.06g (0.01mol) 1- (4-nitrophenyl) -piperidine and 30ml butyronitrile were added to the 100ml reaction flask, the temperature was raised to 55℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 3 hours. After completion of the reaction, 4.2g sodium bisulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 30ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 1.98g 1- (4-nitrophenyl) -2-piperidone. Yield 90.0%, and HPLC purity 98%.
1HNMR (CDCl 3, 400MHz) : δ8.29-8.20 (m, 2H) , 7.53-7.45 (m, 2H) , 3.77-3.69 (m, 2H) , 2.61 (t, J=6.5Hz, 2H) , 2.07-1.92 (m, 4H) .
Example 11: Synthesis of 1- (4-nitrophenyl) -2-tetrahydropyrrolidone
1.92g (0.01mol) of 1- (4-nitrophenyl) -tetrahydropyrrole and 30ml dichloromethane were added to the 100ml reaction flask, and the temperature was raised to 30℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 6 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a light yellow solid, add 35ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.02g 1- (4-nitrophenyl) -2-tetrahydropyrrolidone. Yield 98.1%, and HPLC purity 99.1%.
1HNMR (CDCl 3, 400MHz) : δ8.28-8.19 (m, 2H) , 7.89-7.81 (m, 2H) , 3.93 (t, J=7.1Hz, 2H) , 2.68 (dd, J=8.6, 7.7Hz, 2H) , 2.23 (tt, J=7.8, 6.9Hz, 2H) .
Example 12: Synthesis of 1- (4-nitrophenyl) -azetidin-2-one
1.78g (0.01mol) 1- (4-nitrophenyl) -azetidine and 25ml tetrahydrofuran were added to the 100ml reaction flask, heat up to 45℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium  chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 2.5 hours. After completion of the reaction, 4.2g sodium bisulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount of water, and dry to obtain 1.68g 1- (4-nitrophenyl) -azetidin-2-one. Yield 87.5%, and HPLC purity 99.1%.
1HNMR (CDCl 3, 400MHz) : δ8.30-8.22 (m, 2H) , 7.51-7.43 (m, 2H) , 3.76 (t, J=4.7Hz, 2H) , 3.25 (t, J=4.7Hz, 2H) .
Example 13: Synthesis of 1- (3-fluoro-4-bromophenyl) -piperidin-2-one
2.57g (0.01mol) 1- (3-fluoro-4-bromophenyl) -piperidine and 40ml toluene were added to the 100ml reaction flask, and the temperature was raised to 80℃, an aqueous solution prepared by dissolving 2.26g (0.02mol) sodium chlorite in 5g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 3 hours. After completion of the reaction, 2.5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure, add 20 ml water, extract with dichloromethane (20ml*3) , combine the organic phase, and concentrate to obtain 2.33g 1- (3-fluoro-4-bromophenyl) piperidin-2-one as a colorless oil. Yield 85.7%, and HPLC purity 99.3%.
1HNMR (CDCl 3, 400MHz) : δ7.55 (t, J=8.1Hz, 1H) , 7.16-7.09 (m, 1H) , 6.99 (dd, J=8.5, 2.3Hz, 1H) , 3.64 (t, J=5.5Hz, 2H) , 2.57 (t, J=6.3Hz, 2H) , 2.03-1.88 (m, 4H) .
Example 14: Synthesis of 1- (4-trifluoromethylphenyl) -piperidin-2-one
2.29g (0.01mol) 1- (4-trifluoromethylphenyl) -piperidine and 40ml propionitrile were added to the 100ml reaction flask, the temperature was raised to 65℃, an aqueous solution prepared by dissolving 3.38g (0.03mol) sodium chlorite in 10.62g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 1.5 hours. After completion of the reaction, 3.8g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 60ml  water, stir for 20 minutes, filter and dry to obtain 2.17g 1- (4-trifluoromethylphenyl) piperidin-2-one as white solid. Yield 89.3%, and HPLC purity 99.6%.
1HNMR (CDCl 3, 400MHz) : δ7.66 (t, J=8.3Hz, 2H) , 7.42 (d, J=8.2Hz, 2H) , 3.69 (t, J=5.5Hz, 2H) , 2.60 (t, J=6.3Hz, 2H) , 2.00 (ddt, J=11.7, 8.54.5Hz, 4H) .
Example 15: Synthesis of 4- (3-nitrophenyl) -morpholine-3-one
2.08g (0.01mol) 4- (3-nitrophenyl) -morpholine and 20ml dichloromethane were added to the 100ml reaction flask, the temperature was raised to 30℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 5 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.01g yellow solid 4- (3-nitrophenyl) -morpholine-3-one. Yield 90.5%, and HPLC purity 99.7%.
1HNMR (CDCl 3, 400MHz) : δ8.27 (t, J=2.2Hz, 1H) , 8.16 (ddd, J=8.2, 2.2, 1.0Hz, 1H) , 7.82 (ddd, J=8.1, 2.1, 1.0Hz, 1H) , 7.62 (t, J=8.1Hz, 1H) , 4.40 (s, 2H) , 4.11 (dd, J=5.9, 4.1Hz, 2H) , 3.88 (dd, J=5.9, 4.1Hz, 2H) .
Example 16: Synthesis of 4- (pyridin-2-yl) -morpholine-3-one
1.64g (0.01mol) 4- (pyridin-2-yl) -morpholinone and 25ml dioxane were added to the 100ml reaction flask, the temperature was raised to 40℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 5.5 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 35ml water, stir for 20 minutes, filter, and dry to obtain 1.52g white solid 4- (pyridin-2-yl) -morpholine-3-one. Yield 85.4%, and HPLC purity 99.6%.
1HNMR (CDCl 3, 400MHz) : δ8.44 (dd, J=5.0, 1.9Hz, 1H) , 8.11 (dt, J=8.3, 1.0Hz, 1H) , 7.73 (ddd, J=8.4, 7.3, 2.0Hz, 1H) , 7.13 (ddd, J=7.3, 4.9, 1.0Hz, 1H) , 4.37 (s, 2H) , 4.16-4.09 (m, 2H) ,  4.09-4.02 (m, 2H) .
Example 17: Synthesis of 4- (4-nitrobenzyl) -morpholine-3-one
2.22g (0.01mol) 4- (4-nitrobenzyl) -morpholine and 20ml 2-methyltetrahydrofuran were added to the 100ml reaction flask, the temperature was raised to 50℃, an aqueous solution prepared by dissolving 3.38g (0.03mol) sodium chlorite in 10.62g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 5 hours. After completion of the reaction, 3.8g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25ml water, stir for 20 minutes, and concentrate under reduced pressure to obtain 2.04g light yellow solid 4- (4-nitrobenzyl) -morpholine-3-one. Yield 86.4%, and HPLC purity 98.3%.
1HNMR (CDCl 3, 400MHz) : δ8.24 (dd, J=9.0, 2.1Hz, 2H) , 7.51-7.44 (m, 2H) , 4.74 (s, 2H) , 4.30 (s, 2H) , 3.95-3.87 (m, 2H) , 3.35 (dd, J=5.9, 4.4Hz, 2H) .
Example 18: Synthesis of 1- (2-methylphenyl) -piperidin-2-one
1.75g (0.01mol) 1- (2-methylphenyl) -piperidine and 25ml acetone were added to the 100ml reaction flask, and the temperature was raised to 30℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system in the presence of CO 2. After dripping, the reaction was continued for about 4.5 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 30 ml water, stir for 20 minutes, filter and dry to obtain 1.66g 1- (2-methylphenyl) -piperidin-2-one. Yield 87.8%, and HPLC purity 99.3%.
1HNMR (CDCl 3, 400MHz) : δ7.32-7.29 (m, 1H) , 7.27-7.22 (m, 2H) , 7.15-7.10 (m, 1H) , 4.66-4.57 (m,2H) , 2.48-2.36 (m, 4H) , 2.26 (s, 3H) , 1.96 (m, 2H) .
Example 19: Synthesis of 4- (3-nitrophenyl) -morpholine-3-one
2.08g (0.01mol) 4- (3-nitrophenyl) -morpholine and 20mL dichloromethane were added to the 100ml reaction flask, the temperature was raised to 30℃, CO2 was introduced into the system, and at the  same time the aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system. After dripping, stop the introduction of CO2, the reaction was continued for about 5 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25mL water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.05g yellow solid 4- (3-nitrophenyl) -morpholine-3-one. Yield 92.3%, and HPLC purity 99.7%.
Example 20: Synthesis of 4- (3-nitrophenyl) -morpholine-3-one
2.08g (0.01mol) 4- (3-nitrophenyl) -morpholine and 20mL dichloromethane were added to the 100ml reaction flask, the temperature was raised to 30℃, CO 2 was introduced into the system, and at the same time the aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system. After dripping, stop the introduction of CO 2, the reaction was continued for about 5 hours, CO 2 was introduced intermittently during the reaction. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 2.03g 4- (3-nitrophenyl) -morpholine-3-one. Yield 91.4%, and HPLC purity 99.6%.
Comparison Example 1: Synthesis of 4- (3-nitrophenyl) -morpholine-3-one
Compared with Example 15, no catalyst CO 2 was added.
2.08g (0.01mol) 4- (3-nitrophenyl) -morpholine and 20mL of dichloromethane were added to the 100ml reaction flask, the temperature was raised to 30℃, an aqueous solution prepared by dissolving 4.51g (0.04mol) sodium chlorite in 14.16g water was added dropwise to the reaction system. After dripping, and the reaction was continued for about 8 hours, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 25ml water, stir for 20 minutes, filter, wash the filter cake with an appropriate amount water, and dry to obtain 0.81g 4- (3-nitrophenyl) -morpholine-3-one. Yield 36.47%, and HPLC purity 20.8%.
Comparison Example 2: Synthesis of 4- (pyridin-2-yl) -morpholine-3-one
Compared with Example 16, the catalyst was changed from CO 2 to formic acid.
1.64g (0.01mol) of 4- (pyridin-2-yl) -morpholinone and 25mL dioxane, 0.27g (0.006mol) formic acid were added to the 100ml reaction flask and the temperature was raised to 40℃. An aqueous solution prepared by dissolving 4.51g (0.04mol) of sodium chlorite in 14.16g of water was added dropwise to the reaction system. After dripping, the reaction was continued for about 6 hours. After the reaction was completed, 5g sodium sulfite was added, and the mixture was stirred at room temperature for 10 minutes. Concentrate under reduced pressure to obtain a yellow solid, add 35mL water, stir for 20 minutes, filter and dry to obtain 1.42g 4- (pyridin-2-yl) -morpholine-3-one. Yield 79.8%, and HPLC purity 91.6%.
Comparison Example 3: Synthesis of 4- (3-nitrophenyl) -morpholine-3-one
Scale up according to CN201911264060.3.
104g (0.5mol) 4- (3-nitrophenyl) -morpholine, 234g sodium dihydrogen phosphate dihydrate, 3L acetonitrile were added to the reactor, the temperature was raised to 40℃, an aqueous solution prepared by dissolving 169g sodium chlorite in 650g water was added dropwise to the reaction system. After dripping, the reaction was continued, and the reaction was monitored by HPLC. After the reaction was completed, the layers were left to stand, and the organic layer was collected. The aqueous layer was extracted twice with 700ml of ethyl acetate. The organic layers were combined and placed in a cold water bath. About 1L of saturated aqueous sodium sulfite solution was added and stirred for 10 minutes. The aqueous phase was extracted twice with 500ml of ethyl acetate. The organic phases were combined again, dried by adding anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid. 240ml of mixed solvent (petroleum ether: ethyl acetate=5: 1) was added, and the mixture was fully stirred for 20 minutes. After filtration and drying, 106 g of yellow solid was obtained, the yield was 95.9%, the HPLC purity is 95.7%, the raw material was about 3.1%, and the maximum impurity was 1.1%. When reacting for 1 hour, the purity of the reaction solution was 76.6%, the raw material was left about 8.23%, and the maximum impurity was 1.5%. When reacting for 6 hours, the purity of the reaction solution was 83.8%, the raw material was left about 5.11%, and the maximum impurity was 2.6%.

Claims (5)

  1. A method for synthesizing lactam compounds, which is characterized in that, the method uses sodium chlorite as an oxidant, and under the catalysis of carbon dioxide, oxidizes cyclic amine compounds to lactam compounds.
  2. The synthetic method according to claim 1, which is characterized in that, the cyclic amine compounds shown in formula II are oxidized to the lactam compounds shown in formula I:
    Figure PCTCN2022086645-appb-100001
    Wherein:
    When n=0 or 1, X is CH 2,
    When n=2, X is O or CH 2;
    R is phenyl, benzyl or pyridyl which optionally substituted with one or multiple selected from hydrogen, halogen, nitro, trifluoromethyl, cyano, C1-C6 alkyl, C1-C6 acyl, C1-C6 alkoxy.
  3. The synthetic method according to claim 1 or 2, which is characterized in that, the molar ratio of the cyclic amine compound to the oxidant sodium chlorite is 1: 1～1: 10, preferably 1: 2～1: 6.
  4. The synthetic method according to claim 1 or 2, which is characterized in that, the reaction temperature is 0-100℃, preferably 20-80℃.
  5. The synthetic method according to claim 1 or 2, which is characterized in that, the solvent used is aprotic solvents such as nitrile solvents, ether solvents, toluene, acetone, and dichloromethane.
PCT/CN2022/086645 2021-04-16 2022-04-13 Method for synthesizing lactam compounds WO2022218348A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110438690 2021-04-16
CN202110438690.9 2021-04-16

Publications (1)

Publication Number Publication Date
WO2022218348A1 true WO2022218348A1 (en) 2022-10-20

Family

ID=83606612

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/086645 WO2022218348A1 (en) 2021-04-16 2022-04-13 Method for synthesizing lactam compounds

Country Status (2)

Country Link
CN (1) CN115215816B (en)
WO (1) WO2022218348A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112939893A (en) * 2019-12-10 2021-06-11 普济生物科技（台州）有限公司 Synthesis method of 4- (4-aminophenyl) -3-morpholinone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112939893A (en) * 2019-12-10 2021-06-11 普济生物科技（台州）有限公司 Synthesis method of 4- (4-aminophenyl) -3-morpholinone

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHAMORRO-ARENAS DELFINO, OSORIO-NIETO URBANO, QUINTERO LETICIA, HERNÁNDEZ-GARCÍA LUÍS, SARTILLO-PISCIL FERNANDO: "Selective, Catalytic, and Dual C(sp 3 )–H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 83, no. 24, 21 December 2018 (2018-12-21), pages 15333 - 15346, XP055947090, ISSN: 0022-3263, DOI: 10.1021/acs.joc.8b02564 *
GRIFFITHS ROBERT J., BURLEY GLENN A., TALBOT ERIC P. A.: "Transition-Metal-Free Amine Oxidation: A Chemoselective Strategy for the Late-Stage Formation of Lactams", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 19, no. 4, 17 February 2017 (2017-02-17), US , pages 870 - 873, XP055780586, ISSN: 1523-7060, DOI: 10.1021/acs.orglett.7b00021 *
LIU CHAOYANG, YU TAO, YANG TIANNUO, SUN HAOZHOU, QIN CHENG, JIA QIANG, CHU CHANGHU: "Facile Preparation of 4-(4-Nitrophenyl)morpholin-3-one via the Acid-Catalyzed Selective Oxidation of 4-(4-Nitrophenyl)morpholine by Sodium Chlorite as the Sole Oxidant", ORGANIC PROCESS RESEARCH & DEVELOPMENT, AMERICAN CHEMICAL SOCIETY, US, vol. 24, no. 11, 20 November 2020 (2020-11-20), US , pages 2633 - 2638, XP055976845, ISSN: 1083-6160, DOI: 10.1021/acs.oprd.0c00299 *
ZHANG WENZHEN, ZHANG NING, GUO CHUNXIAO, LÜ XIAOBING: "Recent Progress in the Cyclization Reactions Using Carbon Dioxide", CHINESE JOURNAL OF ORGANIC CHEMISTRY, SCIENCE PRESS, BEIJING., CN, vol. 37, no. 6, 25 June 2017 (2017-06-25), CN , pages 1309 - 1321, XP055976839, ISSN: 0253-2786, DOI: 10.6023/cjoc201701031 *

Also Published As

Publication number Publication date
CN115215816B (en) 2024-02-02
CN115215816A (en) 2022-10-21

Similar Documents

Publication Publication Date Title
CN107235923B (en) Preparation method of 3-aryl quinoxalinone derivatives
CN112442008B (en) Method for preparing 1, 4-dithiine and thiophene compounds by regulating elemental sulfur and active internal alkyne at temperature and conversion reaction of compound
CN106749071B (en) A kind of preparation method of aromatics 1,2,4,5- tetrazine compound
WO2022218348A1 (en) Method for synthesizing lactam compounds
WO2011043483A1 (en) Metal complex, pyridylphosphine compound, and method for producing alkyl methacrylate
CN109574913B (en) Method for preparing geminal dinitro compound by nitrate hydrate
CN104628653B (en) The method of synthesizing rosuvastatin spit of fland calcium key intermediate
CN114573512B (en) Method for synthesizing C2-difluoro alkyl benzimidazole derivative
CA2586931C (en) Process for preparation of isonicotinic acid derivatives
CN101891716B (en) Synthesis method of S-beta-hydroxy-gamma-butyrolactone
KR20080110729A (en) Process for the preparation of 2-(4-hydroxy-3-morfolynil)-2-cyclohexenone
CN112047842A (en) 1, 4-diene compound and preparation method and application thereof
CN112939893A (en) Synthesis method of 4- (4-aminophenyl) -3-morpholinone
CN110283129A (en) A method of synthesizing complete carbon-based substituted pyrimidines derivative
CN113651761B (en) Synthesis method of bixafen precursor
KR101554539B1 (en) Development of Method for Amide Bond Formation via Metal-Free Aerobic Oxidative Amination of Aldehydes
CN115215764B (en) Preparation method of deuterated aromatic nitrile compound
CN113651684B (en) Preparation method of 4-hydroxy-2-butynoic acid
CN112920129B (en) 1,2, 3-triazole-2-oxide and preparation method thereof
CN115677711B (en) Method for preparing spiro oxindole natural product Spirotryprostatin A
EP2327685B1 (en) Process for production of alpha-trifluoromethyl- beta-substituted- beta -amino acid
CN111303006B (en) Preparation method of amlodipine key intermediate
CN111925291B (en) Preparation method of 3, 4-disubstituted alpha-tetralone compound
KR101006737B1 (en) Process for the preparation of 2-sulfonyliminoindoline using Cu catalyst
CN116715573A (en) Synthesis method of 2, 2-dimethylbutyryl chloride

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22787570

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22787570

Country of ref document: EP

Kind code of ref document: A1