- Synthesis method of 4-(4-aminophenyl)-3-morpholone
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The invention provides a synthesis method of 4-(4-aminophenyl)-3-morpholone. The method comprises the following steps: condensing p-halonitrobenzene and morpholine which are used as starting materials to generate 4-(4-nitrophenyl) morpholine, oxidizing 4-(4-nitrophenyl) morpholine by taking a halite or chlorine dioxide as an oxidizing agent and controlling the pH value of a reaction system to be less than 7 to generate 4-(4-nitrophenyl)-3-morpholone, and finally reducing to generate the target product 4-(4-aminophenyl)-3-morpholone. The synthesis method of 4-(4-aminophenyl)-3-morpholinone provided by the invention has the advantages of greenness, high efficiency, easiness in industrial application and the like.
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Paragraph 0042; 0049-0052
(2021/06/12)
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- Synthesis, Characterization, and Biological Evolution of New Pyrazole Derivatives of 4-(4-Aminophenyl)morpholin-3-one through Ugi Reaction
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A new heterocyclic library was synthesized using multicomponent reactions (MCRs). A green strategy during which a set of molecules with an excellent diversity is generated with a minimum of synthetic effort, time, and by-products formation. This new series prepared using the Ugi MCRs in which aldehyde, amine, acid, and isocyanide reacts to make α-bisamide. During this work, we practice the Ugi reaction to synthesize an extremely functionalized heterocyclic library which was characterized and tested for biological evaluation. This innovative synthetic route involves for pyrazole derivatives of 4-(4-aminophenyl)morpholin-3-one by Ugi four component reaction and methanol as a solvent in good yield and high purity. All the produced compounds of library were characterized using 1H-NMR, IR, and mass spectroscopic methods.
- Joshi, Harsh H.,Parsania, M. V.
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p. 247 - 253
(2021/08/03)
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- Activated charcoal supported copper nanoparticles: A readily available and inexpensive heterogeneous catalyst for the N-arylation of primary amides and lactams with aryl iodides
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A novel heterogeneous copper catalyst has been developed by supporting copper nanoparticles on activated charcoal via in situ reducing copper(II) with aqueous hydrazine as reductant. The characterization of Cu/C catalyst showed that the Cu0 nano-particles were formed on the surface of charcoal. This catalyst displayed good catalytic activities toward the N-arylation of primary amides and lactams with aryl iodides.
- Zhao, Rong,Dong, Wenwen,Teng, Jiangge,Wang, Zhiwei,Wang, Yunzhong,Yang, Jianguo,Jia, Qiang,Chu, Changhu
-
supporting information
(2020/12/21)
-
- 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
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4-(4-Nitrophenyl)morpholin-3-one and 4-(4-aminophenyl) morpholin-3-one are the key intermediates for rivaroxaban synthesis. A facile and economically efficient process has been developed for the preparation of these intermediates. Excellent yield of 4-(4-nitrophenyl)morpholine is obtained by condensing 4-chloro nitrobenzene and morpholine, and 4-(4- nitrophenyl)morpholine is oxidized using inexpensive sodium chlorite to achieve a good yield of the corresponding 4-(4- nitrophenyl)morpholin-3-one. Finally, the key intermediate of rivaroxaban, 4-(4-aminophenyl) morpholin-3-one, is achieved by the iron(III)-catalyzed reduction of the nitro group with aqueous hydrazine. No high-cost materials were used, and the process did not require column purification.
- Chu, Changhu,Jia, Qiang,Liu, Chaoyang,Qin, Cheng,Sun, Haozhou,Yang, Tiannuo,Yu, Tao
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p. 2633 - 2638
(2020/12/29)
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- PROCESS FOR THE PREPARATION OF 4-(4-AMINOPHENYL)MORPHOLIN-3-ONE
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The field of this invention relates to a novel process, suitable for industrial scale manufacture, for the preparation of 4-(4-aminophenyl)morpholin-3-one of Formula (I), the key intermediate of rivaroxaban according to the scheme. In the process 2-(2-chloroethoxy)ethanol of Formula (XI) is oxidized to 2-(2-chloroethoxy)- acetic acid with aqueous sodium- or calcium-hypochlorite and a catalyst. The 2-(2~ chloroethoxy)acetic acid of Formula (X) is reacted with 4-nitro-aniline of Formula (VII) with phenylboronic acid catalyst. Then the 2-(2-chloroetoxy)-N-(4-nitrophenyl)acetamide of Formula (IX) is transformed to 4-(4-nitrophenyl)morpholin-3-one of Formula (IV) in a ?one- pot" procedure. The 4-(4-nitrophenyl)morpholin-3-one of Formula (IV) is hydrogenated to get 4-(4-aminophenyl)morpholin-3-one of Formula (I).
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Page/Page column 10
(2019/08/20)
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- A high-purity 4 - (4 - aminophenyl) morpholine -3 - ketone (by machine translation)
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The invention relates to a low-cost, high-purity of 4 - (4 - aminophenyl) morpholine - 3 - one (II) of the preparation method. The use of hydroxy acetonitrile and 1, 2 - dihalo substituted ethane in the reaction process for preparing halogenated ethyl oxygen radical second grade nitrile IV, then with the para-nitroaniline III substituted reaction, acid lower ring becomes a 4 - (4 - nitrophenyl) morpholine - 3 - ketone V, 4 - (4 - nitrophenyl) morpholine - 3 - ketone V obtained by hydrogenating and reducing 4 - (4 - aminophenyl) morpholine - 3 - one II. The present invention the used raw materials are cheap and easily obtained, and the cost is low; the process route is simple, safety and environmental protection; the design of each step the reaction selectivity is high, high yield, high purity for the 4 - (4 - aminophenyl) morpholine - 3 - ketone preparation provides a guarantee, to industrial production of high-purity [...]. (by machine translation)
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Paragraph 0077; 0078
(2019/03/15)
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- Synthesis of substituted 4-(4-((3-Nitro-2-oxo-2H-chromene-4-yl)amino)phenyl)morpholine-3-one coumarin derivatives
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A series of novel 4-(4-amino phenyl) morpholine-3-one substituted coumarin derivatives have been prepared by chloramine coupling reaction and were identified. The novel synthetic route involves nucleophilic substitution reaction of 4-chloro-3-nitro-2H-chromene-2- one with 4-(4-amino phenyl)morpholine-3-one. Due to the presence of nitro group in coumarin derivatives make substitution reaction easy and convenient at low temperature. Using DMF as solvent and K2CO3 as base various substituted 4-(4-((3-nitro-2-oxo-2H-chromen- 4-yl)amino)phenyl)morpholine-3-one derivatives (YS-1 to YS-10) can be obtain in good yield and high purity. Structural characterization of all synthesized compound was done by NMR, Mass and IR spectra.
- Sanghani, Yogesh J.,Koradiya, Suresh B.,Patel, Anilkumar S.
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p. 1461 - 1464
(2019/06/11)
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- Preparation method of 4-(4-aminophenyl)-3-molindone
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The invention provides a preparation method of 4-(4-aminophenyl)-3-molindone. The preparation method has the advantages that reaction steps with high risk and high environmental pressure are omitted,especially the use of mixed acid and chloroacetyl chloride is avoid, so that the pressure of environmental protection is reduced; in addition, the use of strong oxidants such as potassium permanganateis avoided, so that the production of by-products is reduced, the synthesis yield is high, the product quality is good and the purification of reaction post treatment is facilitated; besides, all thesteps related in the reaction process are easy to carry out, so that the reaction in which passivation effect of functional groups and the like are difficult to generate in an existing method is avoided, for example, the route which takes p-nitroaniline as a raw material to carry out substitution reaction is almost impossible to perform; besides, the selected raw materials such as p-fluoronitrobenzene and bromoethylamine hydrobromide, disclosed by the invention are easy to obtain; compared with the molindone and other raw materials involved in the existing method, the preparation method is low in price and is suitable for industrialized production.
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Paragraph 0067; 0071
(2018/11/03)
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- The preparation method of the [...] (by machine translation)
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The invention provides a method for preparing [...], using 4 - (4 - aminophenyl) - 3 - morpholone and 5 - chloro - N - (2 - ethylene oxide-based methyl) - 2 - thiophene carboxamide reaction to obtain 5 - [...] - 2 - {(R)- 2 - hydroxy - 3 - [4 - (3 - oxo - 4 - morpholinyl) phenyl amino] - propyl} amide, then adding N, N' - carbonyl di-imidazole, 4 - dimethylamino pyridine, begins to stir, heating reaction to obtain the - 5 - chloro - N - (( (5 S) - 2 - oxo - 3 - (4 - (3 - oxo-morpholine - 4 - yl) phenyl) - 1, 3 - Oxacillin - 5 - yl) methyl) thiophene - 2 - carboxamide. The technique of the invention route after the condition is optimized, mild reaction, high yield. (by machine translation)
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- A the advantage cuts down Sha Ban preparation method of the midbody and intermediate
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The invention discloses a preparation method of a rivaroxaban intermediate and an intermediate. The invention discloses a preparation method of a compound represented by the formula 4. The preparation method comprises a step of making a compound 3 carry out a ring closing reaction, which is represented in the description, so as to obtain the compound 4. The invention also discloses a preparation method of a compound represented by the formula 3 and a preparation method of a compound represented by the formula 1. The invention also discloses a compound represented by the formula 3 and a compound represented by the formula 5. The preparation method has the advantages of easily-available and cheap raw materials, simple technology and post-treatment, easy purification of intermediate and end products, high total yield, and high purity, and is easy for being applied to industrial production.
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Paragraph 0238; 0242; 0243; 0244
(2017/08/25)
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- 4 - (nitro-phenyl) - 3-preparation of morpholinones the advantage cuts down Sha Ban method and using the same method of preparation
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The invention relates to the technical field of preparation of rivaroxaban and an intermediate thereof and particularly relates to a preparation method of 4-(nitrobenzophenone)-3-morpholone which is prepared from halogenated nitrobenzene, ethanolamine and chloroacetyl chloride through a one-pot method. The method for preparing rivaroxaban comprises the steps of reducing 4-(nitrobenzophenone)-3-morpholone into 4-(aminophenyl)-3-morpholone; enabling 4-(aminophenyl)-3-morpholone to react with R-epichlorohydrin to obtain a product; enabling the product to react with N, N-carbonyldiimidazole to obtain a product; enabling the product to react with tert-butyl iminodicarboxylate; preparing hydrochloride; enabling hydrochloride to react with 5-penphene-2-carbonyl chloride. The preparation method of 4-(nitrobenzophenone)-3-morpholone is capable of realizing one-pot production and free of purifying intermediate products in the process, so that the operation process is simplified, the time is saved, and the labor cost is reduced; the preparation method of 4-(nitrobenzophenone)-3-morpholone is low in raw material price, high in obtained product yield and easy to realize large-scale industrial production; in addition, the method for preparing rivaroxaban is cheap, nontoxic and harmless in raw material, simple in process and high in product yield.
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Paragraph 0054; 0055
(2017/02/02)
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- A 4 - (4-amino-phenyl) - 3-morpholinon process and intermediates for the preparation of
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The invention belongs to the technical field of preparing 4-(4-amino phenyl)-3-morpholone, especially relates to a preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of the 4-(4-amino phenyl)-3-morpholone. The method comprises the following steps: amide intermediate cyclization, nitration, and reduction. The raw material aniline is a low-cost chemical, and the acylation raw material is easy to synthetize and low in cost. Compared with documents in which acylation is directly carried out after nitration, in the method disclosed by the invention, nitration is carried out after acylation, so that the method disclosed by the invention has the advantages no substituted group protection, high selectivity, less steps, high yield and the like. The preparation process does not need harsh reaction conditions such as high pressure, high temperature and deep cooling and also does not need an expensive palladium-carbon catalyst, and meets the requirements of industrial production.
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- Identification of anthranilamide derivatives as potential factor Xa inhibitors: Drug design, synthesis and biological evaluation
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The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 Combining double low line 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM.
- Xing, Junhao,Yang, Lingyun,Li, Hui,Li, Qing,Zhao, Leilei,Wang, Xinning,Zhang, Yuan,Zhou, Muxing,Zhou, Jinpei,Zhang, Huibin
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p. 388 - 399
(2015/04/14)
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- PROCESSES AND INTERMEDIATES FOR PREPARING RIVAROXABAN
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The invention discloses processes for the preparation of rivaroxaban and its pharmaceutically acceptable salts, solvates, and hydrates thereof. The invention also relates to novel intermediates for the preparation of rivaroxaban.
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- PROCESSES AND INTERMEDIATES FOR PREPARING RIVAROXABAN
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The invention discloses processes for the preparation of rivaroxaban and its pharmaceutically acceptable salts, solvates, and hydrates thereof. The invention also relates to novel intermediates for the preparation of rivaroxaban.
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- Studies towards the synthesis of alkyl N-(4-nitrophenyl)-3/2-oxomorpholine- 2/3-carboxylates
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The syntheses of methyl 4-(4-nitrophenyl)-3-oxomorpholine-2-carboxylate (3a) and ethyl 4-(4-nitrophenyl)-2-oxomorpholine-3-carboxylate (5b), important building blocks for the synthesis of factor Xa inhibitor rivaroxaban analogs with potential dual antithrombotic activity, via Rh2(OAc) 4-catalyzed O-H and N-H carbene insertion reactions are described.
- Trstenjak, Uros,Ilas, Janez,Kikelj, Danijel
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p. 2160 - 2172
(2013/12/04)
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- PROCESSES FOR CRYSTALLIZATION OF RIVAROXABAN
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The invention relates to rivaroxaban, more particularly to a process for preparation of rivaroxaban or a pharmaceutically acceptable salt or solvate thereof and its crystallization in order to obtain product having desired quality properties.
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- PROCESS FOR THE PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
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A process for the preparation of rivaroxaban, or a pharmaceutically acceptable salt thereof, or a solvate thereof, including a hydrate, comprising submitting an amine compound of formula (III) wherein R1 is a (C4-C10)-alkyl radical which is attached to the N atom by a tertiary C atom, first to an acylation reaction and then to a dealkylation reaction.
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- An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate
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A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the key step, in 22% overall yield.
- Li, Chao,Liu, Yingshuai,Zhang, Yongjun,Zhang, Xingxian
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p. 400 - 401
(2011/10/08)
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- MICROANGIOPATHY TREATMENT AND PREVENTION
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The present invention relates to the use of selective factor Xa inhibitors, in particular of oxazolidinones of the formula (I) for the treatment and/or prophylaxis of microangiopathies and also their use for the production of medicaments for the treatment and/or prophylaxis of microangiopathies.
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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Novel [1,2,4]triazolo[1,5-a]pyridine compounds are disclosed that have a Formula represented by the Formula (I). These compounds may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotox in states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) and proliferative diseases.
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Page/Page column 55
(2010/04/03)
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- COMBINATION THERAPY OF SUBSTITUTED OXAZOLIDINONES
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The present invention relates to combinations of A) oxazolidinones of the formula (I) with B) acetylsalicylic acid (aspirin) and C) an ADP receptor antagonist, in particular P2Y12 purinoreceptor blocker, to a process for producing these combinations and to the use thereof as medicaments, in particular for the prophylaxis and/or treatment of thromboembolic disorders.
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- Combination Therapy Comprising Substituted Oxazolidinones for the Prevention and Treatment of Cerebral Circulatory Disorders
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The present invention relates to combinations of A) oxazolidinones of the formula (I), with B) antiarrhythmics, processes for the production of these combinations, their use for the prophylaxis and/or treatment of diseases, and their use for the manufacture of medicaments for the prophylaxis and/or treatment of diseases, especially of thromboembolic disorders and/or complications.
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- Practical and efficient processes for the preparation of 4-(4-aminophenyl)morpholin-3-ones on a larger scale: Precursor of factor Xa inhibitors
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Factor Xa inhibitors are interesting targets for the development of antithrombotic agents. Our personal efforts in the discovery of small molecule inhibitors led to the compounds EMD 495235 and EMD 503982, which entered preclinical and clinical studies, respectively. Therefore, kilograms of both drugs in particular 4-(4-aminophenyl)morpholin-3-one moieties have to be provided. The scale-up results of these special P-4 ligands will be described herein.
- Mederski, Werner W.K.R.,Wendel, Peter Ludwig,Woissyk, Markus
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p. 437 - 445
(2008/09/17)
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- PROLINE DERIVATIVES
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The invention relates to novel compounds of formula (I), wherein X, Y, R1, R2, R3, R4 and n have the meaning cited in claim 1, are inhibitors of the coagulation factor Xa and can be used for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.
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Page/Page column 41
(2008/06/13)
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- METHOD FOR PRODUCTION OF N-ARYL MORPHOLINONES
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The invention relates to a method for production of compounds of formula (I), where X has the meaning given in claim 1 and precursors for the same.
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Page/Page column 24
(2008/06/13)
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- Beta-aminoacid-derivatives as factor Xa inhibitors
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The present invention relates to compounds of the formula I, in which R0 ; R1 ; R2 ; R3 ; R4; R5, R6, Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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- METHOD FOR THE PRODUCTION OF 4-(4-AMINOPHENYL)-3-MORPHOLINON
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The invention relates to a method for the production of 4-(4-aminophenyl)-3-morpholinon by reacting 4-(4-nitrophenyl)-3-morpholinon with hydrogen in the presence of a hydrogenation catalyst. The invention is characterised in that the reaction is carried out in an aliphatic alcohol.
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Page/Page column 6; 7
(2008/06/13)
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- Indazole-derivatives as factor Xa inhibitors
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The present invention relates to compounds of the formulae I and Ib wherein R0 ; R1 ; R2 ;Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formulae I and Ib, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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- CARBONYL COMPOUNDS
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The invention relates to the novel compounds of formula (I), wherein D, E, G, W, X, Y, T, R and R are defined as in claim 1. The inventive compounds inhibit coagulation factor Xa and can be used in the prophylaxis and/or therapy of thrombo-embolic diseases and for treating tumors.
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Page/Page column 112
(2008/06/13)
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- Benzimidazole-derivatives as factor xa inhibitors
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Benzimidazole-derivatives as factor Xa inhibitors The present invention relates to compounds of the formula I, wherein R0 ; R1 ; R2 ; R3 ; R4; Q; V, G and M have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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- Chlorothiophenecarboxamides as P1 surrogates of inhibitors of blood coagulation factor Xa
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Neutral chlorothiophenecarboxamides bearing an amino acid and a substituted aniline were synthesized and investigated for their factor Xa inhibitory activity in vitro. From selected 2-methylphenyl morpholinones the solution properties were determined. The most soluble and active compounds were then investigated in different animal species to compare the pharmacokinetic parameters. This led to a potent, water soluble and orally bioavailable candidate for further development: EMD 495235.
- Mederski, Werner W.K.R.,Cezanne, Bertram,Amsterdam, Christoph Van,Bühring, Karl-Ulrich,Dorsch, Dieter,Gleitz, Johannes,M?rz, Joachim,Tsaklakidis, Christos
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p. 5817 - 5822
(2007/10/03)
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- HETEROCYCLIC COMPOUNDS
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The invention concerns blood clotting. The invention particularly concerns certain heterocyclic compounds, methods for the production thereof, their use for treating and/or preventing diseases, and their use for producing medicaments for treating and/or preventing diseases.
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Page/Page column 31
(2010/02/09)
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- Substituted oxazolidinones and their in the field of blood coagulation
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The invention relates to the field of blood coagulation. Novel oxazolidinone derivatives of the general formula (I) processes for their preparation and their use as medicinally active compounds for the prophylaxis and/or treatment of disorders are described.
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