CN104211653A - Preparation method of 4-(4-aminophenyl)-morpholine-3-one - Google Patents

Preparation method of 4-(4-aminophenyl)-morpholine-3-one Download PDF

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Publication number
CN104211653A
CN104211653A CN201310206684.6A CN201310206684A CN104211653A CN 104211653 A CN104211653 A CN 104211653A CN 201310206684 A CN201310206684 A CN 201310206684A CN 104211653 A CN104211653 A CN 104211653A
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CN
China
Prior art keywords
preparation
aminophenyl
morpholone mai
palladium
reactions
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Pending
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CN201310206684.6A
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Chinese (zh)
Inventor
王磊
钟静芬
刘永强
韩强
时惠麟
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Priority to CN201310206684.6A priority Critical patent/CN104211653A/en
Publication of CN104211653A publication Critical patent/CN104211653A/en
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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

Abstract

The invention relates to the technical filed of preparation method of intermediate of rivaroxaban for treating thrombotic diseases. The preparation method of 4-(4-aminophenyl)-morpholine-3-one (I) comprises the following steps: taking 4-(4-nitrophenyl)-morpholine-3-one as the raw materials, taking anhydrous ammonium formate as the reducing agent, and finally carrying out reduction reactions in the presence of a palladium-carbon catalyst so as to obtain the target product. In the preparation method, ammonium formate taken as the hydrogen donor replaces the hydrogen gas as a reaction gas source; in the presence of a catalyst, all reactants are dissolved in a polar solvent; the reactions can be carried out in a normal pressure container, and thus the safety hazards existing in pressurized reduction reactions in a high pressure reactor are avoided. The provided preparation method has the advantages of mild reaction conditions, complete reactions at a room temperature, shortened reaction time, safe and convenient operation, and high product purity. Moreover, the ammonium formate taken as the reducing agent is environment-friendly, and is converted into water and carbon dioxide in the reduction process; no by-product is introduced into the system, and thus the post treatment is more convenient, so the preparation method is more suitable for industrial production.

Description

A kind of preparation method of 4-(4-aminophenyl)-3-morpholone mai
Technical field
The present invention relates to preparation method's technical field of medicine razaxaban key intermediate 4-(4-the aminophenyl)-3-morpholone mai for the treatment of thrombotic diseases.
Background technology
Razaxaban develops jointly by Bayer A.G and Johnson Co. first the oral direct Xa factor inhibitor developed.It high selectivity and competitiveness can not only directly suppress in unbound state Xa factor, but also can suppress Xa factor and the prothrombin activity of bonding state, does not have direct effect to platelet aggregation.
Compare with warfarin with heparin, razaxaban has more advantages, and main manifestations is: 1, onset is rapid, and every day only needs once oral, and dosage is fixed, and without the need to adjusting dosage under periodic monitoring, compliance improves; 2, by the impact of age, sex, body weight and food, even if also can use with renal insufficiency (CrCl is greater than 30ml/min), relative side effect is little; 3, in the body after taking medicine, bioavailability is high, and with other common drugs, such as the interaction of acetylsalicylic acid, non-steroidal anti-inflammatory drugs and digoxin etc. is little; 4, clinical observation research shows, razaxaban is used for the treatment of the thrombotic diseases such as atrial fibrillation stroke prevention, deep venous thrombosis, and curative effect is reliable, can stablize and play anticoagulation and anti thrombotic action, reduces the risk of vascular reocclusion.Its treatment window width and the advantage of monitoring without the need to conventional coagulation function be institute's active demand clinically just.
Visit auspicious appropriate at present (razaxaban) prevents VTE after more than 120, whole world state approval selects a time full hip-joint or total knee arthroplasty for adult patients; Can be used for carrying adult NVAF (AF) patient's preventing apoplectic of one or more risk factors and systemic embolism in global 60 families of Duo Ge state; In global 50 families of Duo Ge state for adult patients in treat deep venous thrombosis (DVT) and prevention DVT recurrence and acute DVT after pulmonary infarction (PE).According to Bayer annual report, within 2011, visiing auspicious appropriate global marketing volume is 1.1 hundred million, and within 2012, to visit auspicious appropriate sales volume be 4.1 hundred million, and due to the approval of razaxaban new indication, it is very considerable to visit auspicious appropriate market outlook, can become a heavy bomb drugs from now on.
The razaxaban synthetic route of current report has a lot, great majority all with 4-(4-aminophenyl)-3-morpholone mai (I) for raw material, therefore it is the key intermediate preparing razaxaban.
The bibliographical information of preparation 4-(4-aminophenyl)-3-morpholone mai (I) also has a lot, and the most common is obtained by the nitroreduction in 4-(4-nitrophenyl)-3-morpholone mai (II) structure.This route has many sections of bibliographical informations at present.As described below:
Supporting under the existence of the palladium on gac, preparing 4-(4-aminophenyl)-3-morpholone mai (I) by 4-(4-nitrophenyl)-3-morpholone mai (II) with hydrogen reaction is the most frequently used method.It is solvent that W00147919 and US2004242660 discloses with tetrahydrofuran (THF), and compound (II) is incorporated in 70 DEG C with under the hydrogenation pressure of 50bar with palladium carbon (5%) is mixed, and yield is 37.6%; It is solvent that W02005026135 discloses with ethanol, and compound (II) is incorporated in 80 DEG C with under the hydrogenation pressure of 5bar with palladium carbon (5%) is mixed, and yield is 93%; Heterocycles, 2007,74,437-445 report that compound (II) and palladium carbon (5%) are mixed and are incorporated in 40 DEG C with under the hydrogenation pressure of 2bar, and yield is 95%; Chinese Journal of New Drugs, 2010,19 (23): 2185-2187 reports are with N, and N '-dimethyl methane amide is solvent, logical H-H reaction under compound (II) is incorporated in atmospheric pressure at room with palladium carbon (5%) is mixed, yield 83.17%.Hydrogen-palladium carbon reduction nitro is a kind of green method of reducing, select suitable solvent, temperature of reaction and reaction pressure can obtain good yield, but reaction often needs to pressurize in autoclave to carry out, hydrogen is again inflammable and explosive gas, in industrialized production, need great care safety problem.
Chinese Journal of Pharmaceuticals, 2011,42 (2), 93-95 reports with iron powder and concentrated hydrochloric acid reaction, also can obtain good yield (86%), but iron powder reducing easily produces a large amount of iron mud, the problems such as aftertreatment is loaded down with trivial details limit its application.
It is reductive agent that EP1479675 discloses with tin protochloride, equally also can obtain compound (I), yield 92%.Tin is heavy metal, there is the problems such as contaminate environment, and quantity of solvent is very large, and the three wastes are many.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of new 4-(4-aminophenyl)-3-morpholone mai (I), to overcome the above-mentioned defect existed in prior art, the preparation technology of 4-(4-aminophenyl)-3-morpholone mai (I) is made more to be conducive to suitability for industrialized production.
Technical conceive of the present invention is such: with 4-(4-nitrophenyl)-3-morpholone mai (II) for raw material, with anhydrous formic acid ammonium for reductive agent, carry out reduction reaction in the presence of a catalyst, thus at room temperature prepare 4-(4-aminophenyl)-3-morpholone mai (I).
Technical scheme of the present invention is as described below:
The preparation method of 4-(4-aminophenyl)-3-morpholone mai (I), the method is for raw material with following formula (II) 4-(4-nitrophenyl)-3-morpholone mai, with anhydrous formic acid ammonium for reductive agent, carry out reduction reaction under the catalysis of palladium carbon and obtain target compound (I):
Palladium-carbon catalyst used in the present invention does not specially require, and general commercial goods all can use.Preferred technical scheme is, the consumption of palladium carbon is the 1-40% of reactant, preferred 5-20%.The weight percent of Pd in palladium-carbon catalyst is preferably as 2-10%, and more preferably the palladium carbon of 5-10% is as catalyzer.Find in experiment, the amount increasing palladium-carbon catalyst can reduce the reaction times.
Alcoholic solvent used in the present invention refers to C 1-C 3alcoholic solvent, particularly preferably methyl alcohol.The weightmeasurement ratio of reactant and alcoholic solvent is 1: 4-50, preferably 1: 10-40.The solvability of methyl alcohol to reactant and resultant is good compared with other alcohols.
The present invention, the mol ratio of reactant and reductive agent anhydrous formic acid ammonium is preferably 1: 4-15, more preferably 1: 5-12.
The raw material that the present invention uses can prepare according to the method for WO2005026135.
4-(4-the aminophenyl)-3-morpholone mai that preparation method of the present invention obtains, purity reaches more than 99%, and productive rate is 85-95%.Fusing point 170 DEG C, consistent with bibliographical information, with the structure of nucleus magnetic resonance and elemental analyses product.
Beneficial effect of the present invention:
The present invention compared with prior art, replace using ammonium formiate as hydrogen donor hydrogen as reaction hydrogen source, in the presence of a catalyst, all reactants are dissolved in polar solvent, can carry out in non-pressure vessel, avoid the unsafe factor adopting autoclave catalysis pressure reduction to exist; Reaction process mild condition, at room temperature can react completely, and the reaction times shortens, and simple and safe operation, the product purity obtained is high.In addition, ammonium formiate is environmentally friendly as reductive agent, and they are oxidized to water and carbonic acid gas in reduction process, can not introduce by product, makes aftertreatment simpler.
To sum up, 4-of the present invention (4-aminophenyl)-3-morpholone mai (I) preparation method overcomes the above-mentioned defect of prior art, is a kind of method being more suitable for suitability for industrialized production.
Embodiment
Below by embodiment, the invention will be further described, but embodiment does not limit the scope of the invention.
Embodiment 1
Under nitrogen protection; by 22g (0.1mol) 4-(4-nitrophenyl)-3-morpholone mai (II); 66g (1.0mol) ammonium formiate joins in 700ml methyl alcohol; under agitation; add 3g7% palladium carbon; at room temperature stirring reaction 1 hour, thin-layer chromatographic analysis determination reaction end.Filtering reacting liquid, revolves and steams desolventizing, with methylene dichloride and saturated aqueous common salt extraction, merges organic phase, revolves the solid steaming and obtain white, after drying, obtain 18.2g.Yield is 94.8%.Be 94.6% through high-efficient liquid phase analysis purity.Ultimate analysis (C 10h 12n 2o 2) measured value (calculated value, %): C62.54 (62.49) H6.28 (6.29); N14.35 (14.57).Nucleus magnetic hydrogen spectrum (solvent DMSO-δ 6) (ppm): δ 4.13 (s, 2H), δ 3.91-3.94 (q, 2H), δ 3.58-3.60 (t, 2H), δ 6.95-6.97 (d, 2H), δ 6.55-6.57 (d, 2H), δ 5.05 (S, 2H).
Embodiment 2
Under nitrogen protection; by 10g (0.05mol) 4-(4-nitrophenyl)-3-morpholone mai (II); 33g (0.52mol) ammonium formiate joins in 400ml methyl alcohol; under agitation; add 1g7% palladium carbon; at room temperature stirring reaction spends the night, thin-layer chromatographic analysis determination reaction end.Filtering reacting liquid, revolves and steams desolventizing, with methylene dichloride and saturated aqueous common salt extraction, merges organic phase, revolves the solid steaming and obtain white, after drying, obtain 8.0g.Yield is 93.0%.Be 93.6% through high-efficient liquid phase analysis purity.
Embodiment 3
Under nitrogen protection; by 1.0g (4.5mmol) 4-(4-nitrophenyl)-3-morpholone mai (II); 0.85g (13.5mmol) ammonium formiate joins in 40ml methyl alcohol; under agitation; add 0.1g7% palladium carbon, at room temperature stirring reaction spends the night, thin-layer chromatographic analysis; do not react completely, at input 0.85g (13.5mmol) ammonium formiate thin-layer chromatographic analysis determination reaction end.Filtering reacting liquid, revolves and steams desolventizing, with methylene dichloride and saturated aqueous common salt extraction, merges organic phase, revolves the solid steaming and obtain white, after drying, obtain 0.81g.Yield is 94.1%.Be 93.2% through high-efficient liquid phase analysis purity.
Embodiment 4
Under nitrogen protection; by 1.9g (8.6mmol) 4-(4-nitrophenyl)-3-morpholone mai (II); 5.4g (86mmol) ammonium formiate joins in 60ml ethanol; under agitation; add 0.4g7% palladium carbon; at room temperature stirring reaction spends the night, and thin-layer chromatography detects determines reaction end.Filtering reacting liquid, revolves and steams desolventizing, with methylene dichloride and saturated aqueous common salt extraction, merges organic phase, revolves the solid steaming and obtain white, after drying, obtain 1.53g.Yield is 93.5%.Be 92.0% through high-efficient liquid phase analysis purity.
Embodiment 5
Under nitrogen protection; by 1.5g (6.8mmol) 4-(4-nitrophenyl)-3-morpholone mai (II); 4.3g (68mmol) ammonium formiate joins in 30ml ethanol; under agitation; add 0.3g5% palladium carbon; at room temperature stirring reaction spends the night, and thin-layer chromatography detects determines reaction end.Filtering reacting liquid, revolves and steams desolventizing, with methylene dichloride and saturated aqueous common salt extraction, merges organic phase, revolves the solid steaming and obtain white, after drying, obtain 1.24g.Yield is 95.2%.Be 95.0% through high-efficient liquid phase analysis purity.

Claims (10)

  1. The preparation method of 1.4-(4-aminophenyl)-3-morpholone mai (I), the method is for raw material with following formula (II) 4-(4-nitrophenyl)-3-morpholone mai, with anhydrous formic acid ammonium for reductive agent, carry out reduction reaction under the catalysis of palladium carbon and obtain target compound (I):
  2. 2. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 1, is characterized in that: the weight percent of Pd in palladium-carbon catalyst is 2-10%.
  3. 3. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 2, is characterized in that: the weight percent of Pd in palladium-carbon catalyst is 5-10%.
  4. 4. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 1, is characterized in that: the consumption of palladium carbon is the 1-40% of reactant formula (II).
  5. 5. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 4, is characterized in that: the consumption of palladium carbon is the 5-20% of reactant formula (II).
  6. 6. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 1, is characterized in that: reactant formula (II) is 1: 4-15 with the mol ratio of reductive agent anhydrous formic acid ammonium.
  7. 7. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 6, is characterized in that: reactant formula (II) is 1: 5-12 with the mol ratio of reductive agent anhydrous formic acid ammonium.
  8. 8. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 1, is characterized in that: alcoholic solvent refers to C 1-C 3alcohol.
  9. 9. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 8, is characterized in that: alcoholic solvent is methyl alcohol.
  10. 10. the preparation method of 4-(4-aminophenyl)-3-morpholone mai (I) as claimed in claim 1, is characterized in that: reactant formula (II) is 1: 4-50 with the weightmeasurement ratio of alcoholic solvent.
CN201310206684.6A 2013-05-29 2013-05-29 Preparation method of 4-(4-aminophenyl)-morpholine-3-one Pending CN104211653A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090253723A1 (en) * 2007-11-27 2009-10-08 Abbott Laboratories Protein kinase inhibitors
WO2011131316A1 (en) * 2010-04-23 2011-10-27 Archimica Gmbh Process for preparing 4-(4-aminophenyl)morpholin-3-one
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090253723A1 (en) * 2007-11-27 2009-10-08 Abbott Laboratories Protein kinase inhibitors
WO2011131316A1 (en) * 2010-04-23 2011-10-27 Archimica Gmbh Process for preparing 4-(4-aminophenyl)morpholin-3-one
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
杨银萍，等: "利伐沙班的合成工艺改进", 《中国药物化学杂志》 *

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Application publication date: 20141217