CN112939893B - Synthesis method of 4- (4-aminophenyl) -3-morpholinone - Google Patents
Synthesis method of 4- (4-aminophenyl) -3-morpholinone Download PDFInfo
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- CN112939893B CN112939893B CN201911264060.3A CN201911264060A CN112939893B CN 112939893 B CN112939893 B CN 112939893B CN 201911264060 A CN201911264060 A CN 201911264060A CN 112939893 B CN112939893 B CN 112939893B
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- 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
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- 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
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- 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
- C07D295/12—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 singly or doubly bound nitrogen atoms
- C07D295/135—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a method for synthesizing 4- (4-aminophenyl) -3-morpholone, which comprises the following steps: condensing p-halonitrobenzene and morpholine serving as starting materials to generate 4- (4-nitrophenyl) morpholine, then oxidizing the 4- (4-nitrophenyl) morpholine to generate 4- (4-nitrophenyl) -3-morpholinone by using a hypohalite or chlorine dioxide serving as an oxidizing agent and controlling the pH value of a reaction system to be less than 7, and finally reducing to generate a target product, namely the 4- (4-aminophenyl) -3-morpholinone. The method for synthesizing 4- (4-aminophenyl) -3-morpholone provided by the invention has the advantages of greenness, high efficiency, easiness in industrial application and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of 4- (4-aminophenyl) -3-morpholinone.
Background
Rivaroxaban, chemical name: 5-chloro-N- (((5S) -2-oxo-3- (4- (3-oxomorpholin-4-yl) phenyl) -1, 3-oxazolin-5-yl) methyl) thiophene-2-carboxamide, an oral antithrombotic drug developed for bayer corporation, english name: rivaroxaban, trade name: xarelto, has obtained marketing approval for canada and the european union on days 9, 15 and 10, 1, 2008, respectively. The product is marketed in the United states in 2011, and the United states market is developed by Qiangsheng corporation; approved by China for sale in 2009 at 6/18 th, under the trade name of Bylermon.
The chemical structural formula of rivaroxaban is as follows:
4- (4-aminophenyl) -3-morpholinone is a key intermediate for the synthesis of rivaroxaban, a compound of formula I, having the following structure:
chinese patent CN1926148 discloses a synthetic method of 4- (4-aminophenyl) -3-morpholinone, and the synthetic route is as follows:
the preparation process comprises the steps of reacting p-fluoronitrobenzene with morpholine to generate 4- (4-nitrophenyl) morpholine, oxidizing the 4- (4-nitrophenyl) morpholine with potassium permanganate and TEBA (benzyltriethylammonium chloride) to generate 4- (4-nitrophenyl) -3-morpholone, and finally, using tin chloride to prepare the 4- (4-nitrophenyl) -3-morpholone as a target product. The method has the advantages of easily-reached reaction conditions, fewer reaction steps, higher price of the used reagent, use of potassium permanganate containing heavy metal in the oxidation reaction, use of toxic heavy metal tin in the reduction reaction, no environmental pollution and higher requirement on subsequent heavy metal residue detection.
European patent EP1479675 discloses a synthesis method of 4- (4-aminophenyl) -3-morpholinone similar to the above patent except that potassium permanganate is used as an oxidizing agent and sodium sulfite is used as a reducing agent in the oxidation to produce 4- (4-nitrophenyl) -3-morpholinone.
Chinese patent CN101610767 discloses a synthesis method of 4- (4-aminophenyl) -3-morpholinone, the synthesis route is as follows:
the preparation method adopts 4-fluoronitrobenzene to condense with 3-morpholinone under the action of NaH as an alkali to obtain 4- (4-nitrophenyl) -3-morpholinone with the yield of only 17.6 percent, and finally, the 4- (4-aminophenyl) -3-morpholinone is obtained by reduction through Pd/C. The method has fewer steps, but uses NaH, and the reagent generates hydrogen when meeting water, has certain danger in industrial use and is not suitable for industrialization; moreover, the raw material 4- (4-aminophenyl) -3-morpholone is difficult to prepare, the market price is very high (about 5000/kg), and no mass production factory exists.
An otherwise similar process was used to prepare 4- (4-aminophenyl) -3-morpholinone using p-iodonitrobenzene or p-bromonitrobenzene as starting material.
The process has the defects of use of toxic heavy metals, low yield, high production cost, environmental pollution and the like, and is not beneficial to industrial production.
Disclosure of Invention
The invention provides a method for synthesizing 4- (4-aminophenyl) -3-morpholone (a compound shown in a formula I), which is green, efficient and easy for industrial application, for overcoming the defects in the prior art.
According to an object of the present invention, there is provided a method for synthesizing a compound of formula I, comprising the steps of:
(1) p-halonitrobenzene and morpholine are used as starting materials to generate 4- (4-nitrophenyl) morpholine (a compound in a formula III) through a condensation reaction;
(2) using a halide or chlorine dioxide as an oxidant, adjusting and controlling the pH value of a reaction system to be less than 7 by acid or acid salt, and oxidizing 4- (4-nitrophenyl) morpholine (a compound in a formula III) to generate 4- (4-nitrophenyl) -3-morpholone (a compound in a formula II);
(3) reducing to generate the target product 4- (4-aminophenyl) -3-morpholone (the compound of the formula I).
The method for synthesizing the compound of the formula II is characterized in that the method for synthesizing the compound of the formula II uses an oxidant, namely, a halite or chlorine dioxide, and oxidizes the compound of the formula III into the compound of the formula II by adjusting and controlling the pH value of a reaction system to be less than 7 through acid or acid salt, wherein the halite comprises sodium halite, potassium halite, lithium halite, calcium halite, magnesium halite and the like; the hypohalite includes chlorite and bromate; the chemical reaction equation is as follows:
the pH value of the reaction system can be adjusted by adding acid or acid salt, wherein the acid or acid salt comprises small-molecule organic acid such as dihydrogen phosphate, sodium hydrogen sulfate, formic acid, acetic acid and the like, hydrochloric acid, sulfuric acid, phosphoric acid and the like.
The molar ratio of the compound shown in the formula III to the oxidant is 1: 1-1: 10, and the molar ratio of the oxidant to the acid or the acid salt is 1: 0.1-1: 5.
The reaction solvent is nitrile solvents such as acetonitrile, propionitrile, butyronitrile and the like, and aprotic solvents such as tetrahydrofuran, toluene, N-dimethylformamide, N-dimethylacetamide and the like.
The reaction time is 0.5-24 hours.
The reaction temperature is 10-120 ℃.
After the reaction is finished, reducing agents such as sodium bisulfite or sodium sulfite are added to quench the reaction, the solvent is concentrated and recovered, and the light yellow solid, namely the compound shown in the formula II, can be obtained by filtering and washing the water, wherein the yield can reach more than 95 percent, and the HPLC purity can reach more than 98 percent.
In the prior art: literature methods for preparing compounds of formula II using the oxidant KMnO 4 And the post-treatment is complicated, a large amount of solid waste and waste water containing heavy metal manganese can be generated, and the environment is not protected.
The compound of formula II prepared by the invention has the remarkable advantages that: the method has the advantages that the halite or the chlorine dioxide is used as the oxidant, the reaction can be carried out when the pH is adjusted to be less than 7 by acid or acid salt, the post-treatment is convenient and simple, the oxidants are metal salts and are easily soluble in water, the oxidants can be removed by the conventional washing layering operation, the generation of a large amount of solid wastes is avoided, and the method is more green and environment-friendly; the product can be obtained by using conventional post-treatment, the operation is simple, and the product is easy to obtain.
According to the purpose of the invention, the invention also provides a synthesis method of the compound shown in the formula III, which is characterized in that the compound shown in the formula III is synthesized by taking parahalonitrobenzene and morpholine as starting materials, wherein the parahalonitrobenzene comprises parachloronitrobenzene, parafluoronitrobenzene, parabromonitrobenzene and paraiodonitrobenzene, and the chemical reaction equation is as follows:
the compound of formula III can be synthesized by a method of reacting in a solvent or under the condition of no solvent.
The acid-binding agent used in the method for synthesizing the compound of the formula III comprises inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, bicarbonate, sodium hydroxide and sodium hydride, and organic bases such as triethylamine, pyridine, N-diisopropylethylamine or morpholine can also be used.
In the synthesis method of the compound shown in the formula III, the molar ratio of the parahalonitrobenzene to the morpholine is 1: 2-1: 10; the molar ratio of the parahalonitrobenzene to the acid-binding agent is 1: 0-1: 2.
The reaction temperature of the synthesis method of the compound shown in the formula III is 40-130 ℃.
The reaction time of the synthetic method of the compound shown in the formula III is 1-10 hours.
After the reaction is finished, decompressing and concentrating, then adding a certain amount of water, stirring for 10-30 minutes, filtering, collecting solids, washing filter cakes with a proper amount of water, and drying to obtain the compound shown in the formula III, wherein the yield can reach more than 95%, and the HPLC purity can reach more than 99.5%.
The technical method is reported in the literature as follows: when the compound of the formula III is prepared, a strong-polarity high-boiling-point solvent such as DMSO is used, so that the post-treatment difficulty is increased, the solvent residue in the obtained product is easy to exceed the standard, the subsequent treatment steps are increased, and the production cost is increased.
The preparation of the compound of formula III according to the present invention has significant advantages: the reaction does not need to add extra reaction solvent, the starting material morpholine is both reactant and solvent, the boiling point of morpholine is not high, the morpholine can be easily removed from the reaction system by a reduced pressure distillation mode in the post-treatment, in addition, the morpholine is miscible with water, and the morpholine can be cleaned by a water washing mode, so that the residue of the morpholine in the product can be reduced to the maximum extent.
According to the object of the present invention, the present invention provides a method for synthesizing a compound of formula I, characterized in that the compound of formula I is synthesized by reducing a compound of formula II, wherein the chemical reaction equation is as follows:
the method for synthesizing the compound of formula I is characterized in that the reduction method used is a conventional reduction method, including but not limited to the following methods: palladium/carbon hydrogenation reduction, ferric trichloride/active carbon hydrazine hydrate reduction, iron powder reduction and other reduction methods.
Detailed Description
Embodiments of the present invention are described in detail below with reference to specific examples, but it should be understood by those skilled in the art that the examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.
The examples, in which specific conditions are not specified, were conducted under conventional conditions, conditions recommended by the manufacturer or supplier. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound of formula III
31.5g (0.2mol) of p-chloronitrobenzene, 87g (1mol) of morpholine and 12.7g (0.12mol) of sodium carbonate are added into a reaction bottle, the mixture is heated to 100 ℃ for reaction for 5 hours, after the reaction is monitored by HPLC, the mixture is decompressed and concentrated to obtain yellow solid, 200mL of water is added, after stirring for 20 minutes, the yellow solid is filtered, a filter cake is washed by proper amount of water, and the yellow solid is dried to obtain 41g of the compound shown in the formula III, wherein the yield is 98.5 percent and the HPLC purity is 99.7 percent.
1 HNMR(CDCl 3 ，400MHz)：δ8.15(d，J＝9.6Hz，2H)，6.84(d，J＝9.2Hz，2H)，3.87(t，J＝4.8Hz，2H)，3.38(t，J＝4.8Hz，2H)。
EXAMPLE 2 Synthesis of Compound of formula II
16.9g of 80% sodium chlorite (0.15mol) was dissolved in 65mL of water under stirring to prepare an aqueous sodium chlorite solution.
10.4g (0.05mol) of the compound of formula III prepared in example 1, 23.4g (0.15mol) of sodium dihydrogen phosphate dihydrate and 300mL of acetonitrile were added to a reaction flask, heated to 40 ℃ and the prepared aqueous solution of sodium chlorite was added dropwise over about 10 minutes, and the reaction was carried out at 40 ℃ for 6 hours, after the reaction is monitored by HPLC, standing and layering are carried out, an organic phase is collected, 70mL ethyl acetate is added into a lower water phase for extraction twice, the organic phases are combined, the mixture was placed in a cold water bath, about 100mL of saturated aqueous sodium sulfite solution was added, the mixture was stirred for 10 minutes, the aqueous phase was extracted twice with 50mL of ethyl acetate, the organic phases were combined again, anhydrous sodium sulfate was added, the mixture was concentrated under reduced pressure to give a pale yellow solid, 240mL of a mixed organic solution (petroleum ether: ethyl acetate: 5: 1) was added, and the mixture was stirred sufficiently for 20 minutes to obtain 10.8g of a pale yellow powdery solid, the yield was 97.7%, and the HPLC purity was 98.3%.
1 HNMR(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 3 Synthesis of Compounds of formula I
11.1g (0.05mol) of the compound of formula II prepared in example 2 was added to a reaction flask, 50mL of ethanol was added, 0.5g Pd/C (5%) was added, hydrogen was added for reaction overnight, Pd/C was filtered, the filter cake was washed with an appropriate amount of ethanol, and the filtrate was concentrated under reduced pressure to dryness to give 9.1g of a yellow solid with a yield of 94.9%.
1 HNMR(CDCl 3 ，400MHz)：δ7.07(d，J＝8.8Hz，2H)，6.69(d，J＝8.8Hz，2H)，4.32(s，2H)，4.00(t，J＝4.8Hz，2H)，3.72(bs，2H)，3.69(t，J＝4.8Hz，2H)。
Claims (2)
1. The method for synthesizing the compound shown in the formula II is characterized in that an oxidant chlorite is used for oxidizing the compound shown in the formula III into the compound shown in the formula II by regulating and controlling the pH value of a reaction system to be less than 7 through acid or acid salt; the chemical reaction equation is as follows:
wherein the molar ratio of the compound III to the oxidant is 1: 1-1: 10, and the molar ratio of the oxidant to the acid or the acid salt is 1: 0.1-1: 5; the reaction solvent is acetonitrile; the reaction temperature is 10-120 ℃.
2. The synthesis method according to claim 1, wherein the reaction time is 0.5 to 24 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1429216A (en) * | 2000-05-18 | 2003-07-09 | 阿斯特拉曾尼卡有限公司 | A new process for synthesis of morpholinylbenzenes |
| CN102603665A (en) * | 2012-01-17 | 2012-07-25 | 北京贯虹科技集团有限公司 | Synthesis method of 4-(4-aminophenyl)-3-morpholone |
| CN109705068A (en) * | 2019-02-27 | 2019-05-03 | 重庆医药高等专科学校 | Protoanemonin synthetic method |
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- 2019-12-10 CN CN201911264060.3A patent/CN112939893B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1429216A (en) * | 2000-05-18 | 2003-07-09 | 阿斯特拉曾尼卡有限公司 | A new process for synthesis of morpholinylbenzenes |
| CN102603665A (en) * | 2012-01-17 | 2012-07-25 | 北京贯虹科技集团有限公司 | Synthesis method of 4-(4-aminophenyl)-3-morpholone |
| CN109705068A (en) * | 2019-02-27 | 2019-05-03 | 重庆医药高等专科学校 | Protoanemonin synthetic method |
Non-Patent Citations (2)
| Title |
|---|
| 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;Liu Chaoyang et al.;《Org. Process Res. Dev》;20200914;第24卷(第11期);第2633-2638页 * |
| Selective, Catalytic, and Dual C(sp3）-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions;Delfino Chamorro-Arenas et al.;《J.Org.Chem.》;20181115;第83卷(第24期);第15333-15346页 * |
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