CN103709116B - A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai - Google Patents
A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai Download PDFInfo
- Publication number
- CN103709116B CN103709116B CN201310663658.6A CN201310663658A CN103709116B CN 103709116 B CN103709116 B CN 103709116B CN 201310663658 A CN201310663658 A CN 201310663658A CN 103709116 B CN103709116 B CN 103709116B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- monoethanolamine
- alkoxycarbonylamino
- tertiary butyl
- compound
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses the preparation method of a kind of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (I).The method is starting raw material with 2-(4-nitrophenyl) monoethanolamine, obtain 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine with corresponding chloro-formic ester or Boc anhydride reaction after catalytic hydrogenation, after reacting with chloroacetyl chloride, cyclization in the basic conditions, obtains corresponding 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (I);
in formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a class chemical structure as
(I)the preparation method of shown 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds,
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl.
Background technology
4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) be the key intermediate synthesizing oral highly selective Factor Xa inhibitor razaxaban (Rivaroxaban).The small molecules anticoagulation that razaxaban is researched and developed by Bayer A.G, in September, 2008 goes on the market in Canada first with trade(brand)name Xarelto, replace patient with operation dvt for prevention and therapy knee or hip to be formed, after this get permission to sell at European Union, China and U.S.A.Larger scale clinical uses and shows, this product antithrombotic curative effect comparatively enoxaparin (Enoxaparine) is better, Platelet number can not be caused to reduce, also do not affect electrocardiogram parameters, the adverse reaction rates such as Nausea and vomiting are lower, have the good prospect of marketing.
At present, bibliographical information acquisition 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) method be for raw material with 4-(4-aminophenyl)-3-morpholone mai; obtain through acylation reaction with corresponding chloro-formic ester or Boc acid anhydrides, but there is the problems such as total recovery is low, three waste discharge is serious, production cost is high in the industrial production process of 4-(4-aminophenyl)-3-morpholone mai at present.Existing document disclosed synthesis 4-(4-aminophenyl)-3-morpholone mai mainly contains following several method: (1) morpholine-3-ketone under NaH effect with p-fluoronitrobenzene nucleo philic substitution reaction, obtain 4-(4-nitrophenyl)-3-morpholone mai, 4-(4-aminophenyl)-3-morpholone mai is obtained again through Pd/C catalytic hydrogenation, total recovery about 6.62%, the raw materials used high price of this method, severe reaction conditions, and low [Alexander S, the Thomas L of yield, Jens P
et a1.substituted oxazolidinones and their use in the field of blood coagulation:US, 2007157456. 2007-01-02], (2) morpholine-3-ketone and 4-Iodoaniline obtain 4-(4-aminophenyl)-3-morpholone mai through Ullmann linked reaction one step under CuI catalysis, yield about 37.6%, though this method step is less, but raw material is not easy to obtain, yield is low, prepares difficulty [SonyYH in a large number, Zhu BY, Wang SM
et al.tetrahydroisoquino linolines as factor Xa inhibitors:WO, 2,006 055951. 2006-05-26], (3) p-fluoronitrobenzene in the basic conditions with morpholine condensation, generate 4-(4-nitrophenyl) morpholine, through KMnO
4after morpholinyl being oxidized to morpholine-3-ketone group, use SnCl
2namely nitroreduction is obtained 4-(4-aminophenyl)-3-morpholone mai, yield about 33.4%, this method total recovery is low, oxidation step " three wastes " discharge serious [Masse CE. Substituted oxazolidinone derivatives:WO, 2,009 023233. 2009-02-19], (4) 2-β-anilino-ethanol in ethanolic sodium hydroxide solution with chloroacetyl chloride through acidylate cyclization, obtain 4-phenyl-3-morpholone mai, 4-(4-aminophenyl)-3-morpholone mai is obtained by 5% Pd/C catalytic hydrogenation again after sulfuric acid/nitric acid nitrating, total recovery about 36.5%, though the available aniline of this method 2-used β-anilino-ethanol and chloroethanol condensation obtain, but yield is low, in addition, ortho-nitration and side reaction such as two nitrated grade is there is in the method in nitration reaction step, and nitration reaction step " three wastes " discharges problem [the Thoms C such as serious, Berwe M. Method for the production of 4-(4-aminophehyl)-3-morpholinon:WO, 2005 026135. 2005-03-24], (5) take bromobenzene as starting raw material, with thanomin condensation after sulfuric acid/nitric acid nitrating, obtain 2-(4-nitrophenyl) monoethanolamine, 4-(4-aminophenyl)-3-morpholone mai is obtained with Fe powder reduction nitro after chloroacetylation and ring-closure reaction, it is gorgeous that total recovery is about 47.0%[Luo Ling, Shen Dongsheng, Zhou Zongzhou, etc. the synthesis of 4-(4-aminophenyl)-3-morpholone mai.
chinese Journal of Pharmaceuticals, 2011,42 (2): 93-95], when repeating the method, we find, compound 2-(4-nitrophenyl) monoethanolamine is that under the reaction conditions of alkali, its product is at triethylamine with chloroacetyl chloride
o-chloroacetylation and
o,
nthe mixture of-bis-chloroacetylation, to generate without cyclised products 4-(4-nitrophenyl)-3-morpholone mai at all, even if triethylamine used for reaction is replaced with aqueous sodium hydroxide solution, also generate without cyclised products 4-(4-nitrophenyl)-3-morpholone mai, (6) p-Nitrobromobenzene is in anhydrous K
2cO
3under condition with thanomin condensation after, through Pd/C catalytic hydrogenation, obtain 2-(4-aminophenyl) monoethanolamine, then with excess chlorine excess acetyl chloride, corresponding tribromo-acetyl product is obtained through purification by silica gel column chromatography, gained tribromo-acetyl product is after aqueous sodium hydroxide solution cyclization/hydrolysis, 4-(4-aminophenyl)-3-morpholone mai is obtained through purification by silica gel column chromatography, the bright peak of total recovery 67.2%[grandson, woods Guoqiang. 4-(4-aminophenyl)-3-morpholone mai midbody acid amide, preparation method and use: CN, 102320988A. 2011-06-03], when repeating the method, we find, p-Nitrobromobenzene and thanomin react incomplete, the yield data reported is the p-Nitrobromobenzene after deduction reclaims, in addition, catalytic hydrogenation product 2-(4-aminophenyl) monoethanolamine is Ursol D structure, very easily oxidation by air in last handling process, cause reaction solution color burn, by product increases greatly, during with aqueous sodium hydroxide solution cyclization/hydrolysis, due to the more difficult hydrolysis of chloro-acetophenone amido, reaction times is extended, more established morpholine-3-keto-amide key is caused to be hydrolyzed, because in crude product, by product is many, recrystallization method purified product cannot be passed through, and overall yield of reaction is only about 20%.
In sum, existing preparation 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) method there is the problems such as preparation process is many, severe reaction conditions, operation and last handling process are loaded down with trivial details, environmental pollution is serious, yield is low, make its in a large number preparation be restricted.Therefore, develop simple and effective 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) synthetic method is significant.
Summary of the invention
The object of the invention is to be to avoid now methodical deficiency, provide that a kind of reaction conditions is gentle, aftertreatment is easy, reaction environment is friendly, yield is high, cost is low, can prepare 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds in a large number (
i) new synthetic method.
Preparation 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds proposed by the invention (
i) new synthetic method, be with 2-(4-nitrophenyl) monoethanolamine (
2) be starting raw material, in appropriate solvent through catalytic hydrogenation obtain 2-(4-aminophenyl) monoethanolamine (
3), without separation and purification directly with corresponding chloro-formic ester or Boc acid anhydrides through acylation reaction obtain 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
4), compound
4react with chloroacetyl chloride in the basic conditions, obtain 2-chloracetyl-2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
5a) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-alkoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b) mixture or compound
5bsingle compound, gained compound
5aor
5bwithout separation and purification, directly cyclization, then enters recrystallization operation in the basic conditions, can obtain corresponding 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i), its synthetic route is as follows:
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl.
For said synthesis route, its each step specifically describes as follows:
a)with 2-(4-nitrophenyl) monoethanolamine (
2) be starting raw material, in appropriate solvent through catalytic hydrogenation obtain 2-(4-aminophenyl) monoethanolamine (
3); Wherein, reacting solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol is formed, ethers are (as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, 1,4-dioxane etc.), benzene, toluene or chlorobenzene, preferred solvent is toluene, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate or methyl tertiary butyl ether; Catalytic hydrogenation used catalyst is: the Pd (OH) that the Pd-C that weight ratio is 1% ~ 30%, weight ratio are 1% ~ 30%
2-C, Raney-Ni, preferred catalyst is: Raney-Ni, 5% ~ 20%Pd-C, 5% ~ 20% Pd (OH)
2-C; Compound (
2) be 1.0:0.01 ~ 1.0 with the mass ratio of catalyzer; Reaction pressure is normal pressure ~ 10.0 MPa, preferred normal pressure ~ 2.0 MPa; Temperature of reaction is room temperature ~ 150 DEG C, is preferably room temperature ~ 80 DEG C; Reaction times is 1 ~ 48 hour, is preferably 1 ~ 24 hour.
By step
a)2-(4-aminophenyl) monoethanolamine that obtains (
3) without separation and purification, in appropriate solvent with corresponding chloro-formic ester or Boc acid anhydrides through acylation reaction obtain 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
4); Wherein, reacting solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol is formed, ethers (as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane etc.), benzene, toluene or chlorobenzene, preferred solvent is toluene, tetrahydrofuran (THF), ethyl acetate or methyl tertiary butyl ether; Chloro-formic ester used is: chloroformic acid benzyl ester, chloroformic acid C
1-12alkyl ester; 2-(4-aminophenyl) monoethanolamine (
3) be 1.0:0.5 ~ 5.0 with the molar feed ratio of chloro-formic ester or Boc acid anhydrides, preferred molar feed ratio is 1.0:0.8 ~ 2.0; Temperature of reaction is-20 ~ 80 DEG C, and preferable reaction temperature is 0 ~ 50 DEG C; Reaction times is 20 minutes ~ 24 hours, and the preferred reaction time is 30 minutes ~ 12 hours.
By step
b)2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine that obtains (
4) react with chloroacetyl chloride under appropriate solvent and alkaline condition, obtain 2-chloracetyl-2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
5a) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-alkoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b) arbitrary proportion mixture or compound
5bsingle compound; Wherein, reacting solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol is formed, methylene dichloride, chloroform, 1,2-ethylene dichloride, ethers are (as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, 1,4-dioxane etc.), benzene, toluene or chlorobenzene, preferred solvent is toluene, tetrahydrofuran (THF), methylene dichloride, ethyl acetate or methyl tertiary butyl ether; Reacting alkali used is: alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, Tributylamine, trioctylamine, pyridine,
n-methylmorpholine,
n-methyl piperidine, triethylene diamine, TBAH, preferred bases is: salt of wormwood, sodium bicarbonate, triethylamine or pyridine; 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
4): chloroacetyl chloride: the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0, and preferred molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is-20 ~ 100 DEG C, and preferable reaction temperature is 0 ~ 60 DEG C; Reaction times is 20 minutes ~ 24 hours, and the preferred reaction time is 30 minutes ~ 12 hours.
By step
c)2-chloracetyl-2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine that obtains (
5a) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-alkoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b) arbitrary proportion mixture or compound
5bsingle compound without separation and purification, in the basic conditions with directly cyclization in appropriate solvent, obtain corresponding 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i); Wherein, reacting solvent for use is: water, C
1-6fatty alcohol, methylene dichloride, chloroform, 1,2-ethylene dichloride, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, 1,4-dioxane, benzene, toluene or chlorobenzene, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned two kinds of mixed solvents, mixed solvent volume ratio is 1:0.1 ~ 10; Preferred solvent is water, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), methylene dichloride, ethyl acetate, methyl tertiary butyl ether or Isosorbide-5-Nitrae-dioxane; Reacting alkali used is: alkali metal hydroxide or alkaline earth metal hydroxides, and preferred bases is: lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; Compound
5aor
5barbitrary proportion mixture or compound
5bsingle compound: the molar feed ratio of alkali is 1.0:1.0 ~ 30.0, and preferred molar feed ratio is 2.0:1.0 ~ 15.0; Temperature of reaction is room temperature ~ 100 DEG C, and preferable reaction temperature is room temperature ~ 60 DEG C; Reaction times is 10 minutes ~ 12 hours, and the preferred reaction time is 20 minutes ~ 5 hours.
Gained 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) more conventionally (include but not limited to the method disclosed in WO2013120465A1, CN103012388A, WO2013105100A1) and can razaxaban be prepared; Or when R represents the tertiary butyl, prior art (as: 20%-37% aqueous hydrochloric acid or trifluoroacetic acid etc.) can be utilized to remove Boc protecting group and obtain 4-(4-aminophenyl)-3-morpholone mai, yield is greater than 95%; When R represents benzyl, prior art (as: palladium carbon catalytic hydrogenation) can be utilized to remove benzyloxycarbonyl protecting group and obtain 4-(4-aminophenyl)-3-morpholone mai, yield is greater than 98%.
The invention has the advantages that: compared with prior art, the method raw materials used cheap and easy to get, reaction conditions is gentle, aftertreatment is easy, reaction environment is friendly, yield is high, cost is low, be applicable to prepare in a large number 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) etc. feature.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.
the preparation of embodiment 1 2-(4-aminophenyl) monoethanolamine (3)
2-(4-nitrophenyl) monoethanolamine (0.15 mol) and the trimethyl carbinol (300 ml) is added in reaction flask, after stirring, (2.8 g) to add 5% palladium-carbon catalyst, reaction flask is with after hydrogen exchange three times, hydrogenation 5 h under normal temperature and pressure, after reaction terminates, suction filtration, the a small amount of washing with alcohol of filter cake, filtrate and washing lotion merge and obtain compound
3ethanolic soln, not purifiedly can be used for the next step, yield 100%.
the preparation of embodiment 2 2-(4-aminophenyl) monoethanolamine (3)
The same embodiment of operating process
1, just replaced by trimethyl carbinol tetrahydrofuran (THF), 5% palladium carbon is with 10%Pd (OH)
2-C replaces, and obtains compound
3tetrahydrofuran solution, not purifiedly can be used for the next step, yield 100%.
the preparation of embodiment 3 2-(4-aminophenyl) monoethanolamine (3)
The same embodiment of operating process
1, just replaced by trimethyl carbinol methyl tertiary butyl ether, 5% palladium carbon Raney-Ni replaces, and obtains compound
3t-butyl methyl ether solution, not purifiedly can be used for the next step, yield 100%.
the preparation of embodiment 4 2-(4-aminophenyl) monoethanolamine (3)
The same embodiment of operating process
1, just trimethyl carbinol toluene is replaced, obtains compound
3toluene solution, not purifiedly can be used for the next step, yield 100%.
the preparation of embodiment 5 2-(4-aminophenyl) monoethanolamine (3)
The same embodiment of operating process
1, just trimethyl carbinol Isosorbide-5-Nitrae-dioxane is replaced, obtains compound
3isosorbide-5-Nitrae-dioxane solution, not purifiedly can be used for the next step, yield 100%.
the preparation of embodiment 6 2-[4-(t-butoxycarbonyl amino) phenyl] monoethanolamine (4a)
Add by embodiment in reaction flask
1preparation-obtained compound
3t-butanol solution (0.15 mol) and Boc acid anhydrides (0.15 mol), stirring at room temperature reacts 8 h, after reaction terminates, obtains compound
4at-butanol solution, not purifiedly can be used for the next step.Take a morsel compound
4at-butanol solution, remove solvent under reduced pressure, obtain pale yellowish oil liquid,
1hNMR (400 MHz, CDCl
3) 1.50 (s, 9H, 3 × CH
3), 2.95 (brs, 2H, OH+NH), 3.28 (t,
j=5.6Hz, 2H, CH
2), 3.83 (t,
j=5.6Hz, 2H, CH
2), 6.31 (brs, 1H, CONH), 6.66 (d,
j=8.4Hz, 2H, ArH), 7.17 (d,
j=8.4Hz, 2H, ArH); ESI-MS (
m/z,+Q): 253.2 [M+H]
+.
the preparation of embodiment 7 2-[4-(t-butoxycarbonyl amino) phenyl] monoethanolamine (4a)
The same embodiment of operating process
6, just by compound
3t-butanol solution compound
3tetrahydrofuran solution replace, obtain compound
4atetrahydrofuran solution, not purifiedly can be used for the next step.
the preparation of embodiment 8 2-[4-(benzyloxycarbonyl amino) phenyl] monoethanolamine (4b)
Operate same embodiment
6, just by compound
3t-butanol solution compound
3t-butyl methyl ether solution replace, Boc acid anhydrides chloroformic acid benzyl ester is replaced, and obtains compound
4bt-butyl methyl ether solution, not purifiedly can be used for the next step.
the preparation of embodiment 9 2-[4-(ethoxycarbonylamino) phenyl] monoethanolamine (4c)
The same embodiment of operating process
6, just by compound
3t-butanol solution compound
3toluene solution replace, Boc acid anhydrides Vinyl chloroformate is replaced, and obtains compound
4ctoluene solution, not purifiedly can be used for the next step.
the preparation of embodiment 10 2-[4-(isobutyl boc is amino) phenyl] monoethanolamine (4d)
The same embodiment of operating process
6, just by compound
3t-butanol solution compound
3isosorbide-5-Nitrae-dioxane solution is replaced, and Boc acid anhydrides isobutyl chlorocarbonate is replaced, and obtains compound
4disosorbide-5-Nitrae-dioxane solution, not purifiedly can be used for the next step.
embodiment 11 2-chloracetyl-2-[(4-tert-butoxycarbonylamino) phenyl] monoethanolamine (5a-1) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-tert-butoxycarbonylamino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-1)
Add by embodiment in reaction flask
6preparation-obtained compound
4at-butanol solution (about 0.15 mol) and triethylamine (0.30 mol), after stirring, be cooled to-5 ~ 0 DEG C, drips chloroacetyl chloride (0.2 mol), control reacting liquid temperature and be no more than 5 DEG C, drip and finish, insulated and stirred reacts 2 h, after reaction terminates, suction filtration, filtrate is compound
5a-1with
5b-1the t-butanol solution of mixture, can be directly used in the next step.
embodiment 12 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-tert-butoxycarbonylamino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-1)
Add by embodiment in reaction flask
7preparation-obtained compound
4atetrahydrofuran solution (about 0.15 mol) and pyridine (0.50 mol), after stirring, be cooled to-5 ~ 0 DEG C, drips chloroacetyl chloride (0.4 mol), control reacting liquid temperature and be no more than 5 DEG C, drip and finish, insulated and stirred reacts 3 h, after reaction terminates, suction filtration, filtrate is compound
5b-1tetrahydrofuran solution, can the next step be directly used in.Take a morsel compound
5b-1tetrahydrofuran solution, remove solvent under reduced pressure, residue by silicagel column chromatography purification (elutriant: petrol ether/ethyl acetate=40:1 (v/v)), obtains colourless oil liquid,
1hNMR (400 MHz, CDCl
3) d:1.52 (s, 9H, 3 × CH
3), 3.82 (s, 2H, CH
2cl), 3.98 (t,
j=5.6Hz, 2H, CH
2), 4.00 (s, 2H, CH
2cl), 4.37 (t,
j=5.6Hz, 2H, CH
2), 6.64 (brs, 1H, CONH), 7.20 (d,
j=8.8Hz, 2H, ArH), 7.46 (d,
j=8.8Hz, 2H, ArH); ESI-MS (
m/z,+Q): 406.2 [M+H]
+.
embodiment 13 2-chloracetyl-2-[(4-Benzyloxycarbonylamino) phenyl] monoethanolamine (5a-2) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-Benzyloxycarbonylamino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-2)
Operate same embodiment
11, just by compound
4at-butanol solution compound
4bt-butyl methyl ether solution replace, obtain 2-chloracetyl-2-[(4-Benzyloxycarbonylamino) phenyl] monoethanolamine (
5a-2) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-Benzyloxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-2) mixture t-butyl methyl ether solution, can the next step be directly used in.
embodiment 14 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-Benzyloxycarbonylamino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-2)
The same embodiment of operating process
12, just by compound
4atetrahydrofuran solution compound
4bt-butyl methyl ether solution replace, obtain 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-Benzyloxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-2) t-butyl methyl ether solution, can the next step be directly used in.
embodiment 15 2-chloracetyl-2-[(4-ethoxy carbonyl amino) phenyl] monoethanolamine (5a-3) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-ethoxy carbonyl amino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-3)
The same embodiment of operating process
11, just by compound
4at-butanol solution compound
4ctoluene solution replace, obtain 2-chloracetyl-2-[(4-ethoxy carbonyl amino) phenyl] monoethanolamine (
5a-3) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-ethoxy carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-3) toluene solution of mixture, can the next step be directly used in.
embodiment 16 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-ethoxy carbonyl amino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-3)
The same embodiment of operating process
12, just by compound
4atetrahydrofuran solution compound
4ctoluene solution replace, obtain 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-ethoxy carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-3) toluene solution, can the next step be directly used in.
embodiment 17 2-chloracetyl-2-[(4-isobutyl oxygen carbonyl amino) phenyl] monoethanolamine (5a-4) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-isobutyl oxygen carbonyl amino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-4)
Operate same embodiment
11, just by compound
4at-butanol solution compound
4disosorbide-5-Nitrae-dioxane solution replace, obtain 2-chloracetyl-2-[(4-isobutyl oxygen carbonyl amino) phenyl] monoethanolamine (
5a-4) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-isobutyl oxygen carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-4) Isosorbide-5-Nitrae-dioxane solution of mixture, can the next step be directly used in.
embodiment 18 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-isobutyl oxygen carbonyl amino) phenyl]-
n-chloracetyl] preparation of monoethanolamine ester (5b-4)
The same embodiment of operating process
12, just by compound
4atetrahydrofuran solution compound
4disosorbide-5-Nitrae-dioxane solution replace, obtain 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-isobutyl oxygen carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-4) Isosorbide-5-Nitrae-dioxane solution, can the next step be directly used in.
the preparation of embodiment 19 4-(4-t-butoxycarbonyl amino) phenyl-3-morpholone mai (Ia)
By embodiment
11preparation-obtained 2-chloracetyl-2-[(4-tert-butoxycarbonylamino) phenyl] monoethanolamine (
5a-1) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-tert-butoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-1) t-butanol solution (about 0.15 mol) and aqueous sodium hydroxide solution (70 ml of mixture, 0.55 mol) mixing, be warming up to 40-45 DEG C of insulated and stirred and react 30 min, after reaction terminates, remove the trimethyl carbinol under reduced pressure, resistates is dissolved in ethyl acetate, and use deionized water, saturated NaCl solution washing successively, organic layer is through anhydrous Na
2sO
4filter after dry, filtrate decompression is steamed and is desolventized, residue from ethanol recrystallization, obtain white solid 4-(4-t-butoxycarbonyl amino) phenyl-3-morpholone mai (
ia), three step total recoverys 50.5%, mp:193 ~ 194 DEG C;
1hNMR (400 MHz, CDCl
3) 1.52 (s, 9H, 3 × CH
3), 3.72 (t,
j=5.2Hz, 2H, CH
2), 4.02 (t,
j=5.2Hz, 2H, CH
2), 4.33 (s, 2H, CH
2cONH), 6.59 (brs, 1H, CONH), 7.23 (d,
j=8.8Hz, 2H, ArH), 7.39 (d,
j=8.8Hz, 2H, ArH);
13cNMR (100 MHz, CDCl
3) d:28.3,49.4,63.7,67.9,79.3,118.5,126.1,135.9,138.0,153.0,166.1; ESI-MS (
m/z,+Q): 293.1 [M+H]
+.
the preparation of embodiment 20 4-(4-t-butoxycarbonyl amino) phenyl-3-morpholone mai (Ia)
By embodiment
12preparation-obtained compound
5b-1tetrahydrofuran solution (about 0.15 mol) and aqueous sodium hydroxide solution (80 ml, 0.65 mol) mixing, be warming up to 40-45 DEG C of insulated and stirred and react 30 min, after reaction terminates, remove the trimethyl carbinol under reduced pressure, resistates is dissolved in ethyl acetate, and use deionized water, saturated NaCl solution washing successively, organic layer is through anhydrous Na
2sO
4filter after dry, filtrate decompression is steamed and is desolventized, residue from ethanol recrystallization, obtain white solid 4-(4-t-butoxycarbonyl amino) phenyl-3-morpholone mai (
ia), three step total recoverys 58.0%, mp:193 ~ 194 DEG C;
1hNMR data are consistent with embodiment 19.
the preparation of embodiment 21 4-(4-benzyloxycarbonyl amino) phenyl-3-morpholone mai (Ib)
The same embodiment of operating process
19, just by 2-chloracetyl-2-[(4-tert-butoxycarbonylamino) phenyl] monoethanolamine (
5a-1) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-tert-butoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-1) the t-butanol solution embodiment of mixture
13gained 2-chloracetyl-2-[(4-Benzyloxycarbonylamino) phenyl] monoethanolamine (
5a-2) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-Benzyloxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-2) mixture t-butyl methyl ether solution replace, obtain 4-(4-benzyloxycarbonyl amino) phenyl-3-morpholone mai (
ib), three step total recoverys 45.8%, mp:189 ~ 191 DEG C; Its chemical structure warp
1h NMR and HR-ESIMS confirms.
the preparation of embodiment 22 4-(4-benzyloxycarbonyl amino) phenyl-3-morpholone mai (Ib)
The same embodiment of operating process
20, just by compound
5b-1tetrahydrofuran solution embodiment
14gained 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-Benzyloxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-2) t-butyl methyl ether solution replace, obtain 4-(4-benzyloxycarbonyl amino) phenyl-3-morpholone mai (
ib), three step total recoverys 49.6%, mp:190 ~ 192 DEG C; Its chemical structure warp
1h NMR and HR-ESIMS confirms.
the preparation of embodiment 23 4-(4-ethoxycarbonylamino) phenyl-3-morpholone mai (Ic)
Operate same embodiment
19, just by 2-chloracetyl-2-[(4-tert-butoxycarbonylamino) phenyl] monoethanolamine (
5a-1) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-tert-butoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-1) the t-butanol solution embodiment of mixture
15gained 2-chloracetyl-2-[(4-ethoxy carbonyl amino) phenyl] monoethanolamine (
5a-3) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-ethoxy carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-3) mixture toluene solution replace, obtain 4-(4-ethoxycarbonylamino) phenyl-3-morpholone mai (
ic), three step total recoverys 36.7%;
1hNMR (400 MHz, CDCl
3) 1.30 (t,
j=7.6Hz, 3H, CH
3), 3.73 (t,
j=5.2Hz, 2H, CH
2), 4.02 (t,
j=5.2Hz, 2H, CH
2), 4.21 (q,
j=7.6Hz, 2H, CH
2), 4.33 (s, 2H, CH
2cONH), 6.75 (brs, 1H, CONH), 7.25 (d,
j=8.8Hz, 2H, ArH), 7.40 (d,
j=8.8Hz, 2H, ArH).
the preparation of embodiment 24 4-(4-ethoxycarbonylamino) phenyl-3-morpholone mai (Ic)
The same embodiment of operating process
20, just by compound
5b-1tetrahydrofuran solution embodiment
16gained 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-ethoxy carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-3) toluene solution replace, obtain 4-(4-ethoxycarbonylamino) phenyl-3-morpholone mai (
ic), three step total recoverys 47.0%;
1hNMR data are consistent with embodiment 23.
the preparation of embodiment 25 4-(4-isobutyl boc is amino) phenyl-3-morpholone mai (Id)
The same embodiment of operating process
19, just by 2-chloracetyl-2-[(4-tert-butoxycarbonylamino) phenyl] monoethanolamine (
5a-1) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-tert-butoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-1) the t-butanol solution embodiment of mixture
17gained 2-chloracetyl-2-[(4-isobutyl oxygen carbonyl amino) phenyl] monoethanolamine (
5a-4) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-isobutyl oxygen carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-4) Isosorbide-5-Nitrae-dioxane solution of mixture replaces, obtain 4-(4-isobutyl boc is amino) phenyl-3-morpholone mai (
id), three step total recoverys 41.5%; Its chemical structure warp
1h NMR and HR-ESIMS confirms.
the preparation of embodiment 26 4-(4-isobutyl boc is amino) phenyl-3-morpholone mai (Id)
The same embodiment of operating process
20, just by compound
5b-1tetrahydrofuran solution embodiment
18gained 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-isobutyl oxygen carbonyl amino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b-4) Isosorbide-5-Nitrae-dioxane solution replace, obtain 4-(4-isobutyl boc is amino) phenyl-3-morpholone mai (
id), three step total recoverys 50.0%; Its chemical structure warp
1h NMR and HR-ESIMS confirms.
Claims (8)
1. 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) preparation method,
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl;
It is characterized in that comprising the steps:
a)with 2-(4-nitrophenyl) monoethanolamine (
2) be starting raw material, in appropriate solvent through catalytic hydrogenation obtain 2-(4-aminophenyl) monoethanolamine (
3);
b)by step
a)2-(4-aminophenyl) monoethanolamine that obtains (
3) without separation and purification, in appropriate solvent with corresponding chloro-formic ester or Boc acid anhydrides through acylation reaction obtain 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
4);
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl;
c)by step
b)2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine that obtains (
4), react with chloroacetyl chloride under appropriate solvent and alkaline condition, obtain 2-chloracetyl-2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
5a) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-alkoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b) arbitrary proportion mixture or compound
5bsingle compound;
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl;
d)by step
c)2-chloracetyl-2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine that obtains (
5a) and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-alkoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b) arbitrary proportion mixture or compound
5bsingle compound is without separation and purification, and in the basic conditions with directly cyclization in appropriate solvent, then through recrystallization operation purifying, described recrystallization solvent is ethanol, obtain corresponding 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i).
2. 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds as claimed in claim 1 (
i) preparation method, it is characterized in that described step
a)in, reaction solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol is formed, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane, benzene, toluene or chlorobenzene; Catalytic hydrogenation used catalyst is: the Pd (OH) that the Pd-C that weight ratio is 1% ~ 30%, weight ratio are 1% ~ 30%
2-C, Raney-Ni; Compound (
2) be 1.0:0.01 ~ 1.0 with the mass ratio of catalyzer; Reaction pressure is normal pressure ~ 10.0 MPa; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 48 hour.
3. 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds as claimed in claim 1 (
i) preparation method, it is characterized in that described step
b)in, reaction solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol is formed, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane, benzene, toluene or chlorobenzene; Chloro-formic ester used is: chloroformic acid benzyl ester, chloroformic acid C
1-12alkyl ester; 2-(4-aminophenyl) monoethanolamine (
3) be 1.0:0.5 ~ 5.0 with the molar feed ratio of chloro-formic ester or Boc acid anhydrides; Temperature of reaction is-20 ~ 80 DEG C; Reaction times is 20 minutes ~ 24 hours.
4. 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds as claimed in claim 1 (
i) preparation method, it is characterized in that described step
c)in, reaction solvent for use is: C
1-6fatty alcohol, C
3-8aliphatic ketone, C
1-6lipid acid, C
1-6lipid acid and C
1-6ester that fatty alcohol is formed, methylene dichloride, chloroform, 1,2-ethylene dichloride, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane, benzene, toluene or chlorobenzene; Reacting alkali used is: alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, Tributylamine, trioctylamine, pyridine,
n-methylmorpholine,
n-methyl piperidine, triethylene diamine, TBAH; 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
4): chloroacetyl chloride: the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0; Temperature of reaction is-20 ~ 100 DEG C; Reaction times is 20 minutes ~ 24 hours.
5. 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds as claimed in claim 1 (
i) preparation method, it is characterized in that described step
d)in, reaction solvent for use is: water, C
1-6fatty alcohol, methylene dichloride, chloroform, 1,2-ethylene dichloride, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, 1,4-dioxane, benzene, toluene or chlorobenzene, or more the mixed solvent of two kinds of solvents, in mixed solvent, two kinds of solvent volume are than being 1:0.1 ~ 10; Reacting alkali used is: alkali metal hydroxide or alkaline earth metal hydroxides; Compound
5aor
5barbitrary proportion mixture or compound
5bsingle compound: the molar feed ratio of alkali is 1.0:1.0 ~ 30.0; Temperature of reaction is room temperature ~ 100 DEG C; Reaction times is 10 minutes ~ 12 hours.
6. a class 2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
4) compounds, it is characterized in that it is the compound with following chemical structure of general formula,
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl.
7. a class 2-chloracetyl-2-[(4-alkoxycarbonylamino) phenyl] monoethanolamine (
5a) compounds and 2-Mono Chloro Acetic Acid-2 '-[
n-[(4-alkoxycarbonylamino) phenyl]-
n-chloracetyl] monoethanolamine ester (
5b) compounds, it is characterized in that it is the compound with following chemical structure of general formula,
In formula: R represents the tertiary butyl, benzyl, do not comprise the C of the tertiary butyl
1-12alkyl.
8. as claimed in claims 6 or 7 arbitrary compound preparation 4-according to claim 1 (4-alkoxycarbonylamino) phenyl-3-morpholone mai compounds (
i) or razaxaban medicine in application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310663658.6A CN103709116B (en) | 2013-12-10 | 2013-12-10 | A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310663658.6A CN103709116B (en) | 2013-12-10 | 2013-12-10 | A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103709116A CN103709116A (en) | 2014-04-09 |
| CN103709116B true CN103709116B (en) | 2015-09-23 |
Family
ID=50402507
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310663658.6A Expired - Fee Related CN103709116B (en) | 2013-12-10 | 2013-12-10 | A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103709116B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829482B (en) * | 2015-04-17 | 2017-06-06 | 浙江海森药业有限公司 | The preparation method and its usage of 2 [2 chlorine N (4 aminophenyl) acetamido] chloracetates of ethyl 2 |
| CN105111163B (en) * | 2015-08-28 | 2017-10-20 | 浙江车头制药股份有限公司 | A kind of synthetic method of 4 (4 aminophenyl) 3 morpholones |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005026135A1 (en) * | 2003-09-15 | 2005-03-24 | Bayer Healthcare Ag | Method for the production of 4-(4-aminophenyl)-3-morpholinon |
| US20050182055A1 (en) * | 2004-01-15 | 2005-08-18 | Bayer Healthcare Ag | Preparation process |
| CN102320988A (en) * | 2011-06-03 | 2012-01-18 | 中国科学院上海有机化学研究所 | 4-(4-amion phenyl)-3-morpholone intermediate amide and synthesis method and application thereof |
| 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 |
-
2013
- 2013-12-10 CN CN201310663658.6A patent/CN103709116B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005026135A1 (en) * | 2003-09-15 | 2005-03-24 | Bayer Healthcare Ag | Method for the production of 4-(4-aminophenyl)-3-morpholinon |
| US20050182055A1 (en) * | 2004-01-15 | 2005-08-18 | Bayer Healthcare Ag | Preparation process |
| CN102320988A (en) * | 2011-06-03 | 2012-01-18 | 中国科学院上海有机化学研究所 | 4-(4-amion phenyl)-3-morpholone intermediate amide and synthesis method and application thereof |
| 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 (2)
| Title |
|---|
| 何洪光 等..4-(4-氨基苯基)-3-吗啉酮的制备.《中国医药工业杂志》.2014,第45卷(第2期),110-112. * |
| 王海燕 等..利伐沙班合成路线图解.《中国药物化学杂志》.2012,第22卷(第3期),249-251,256. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103709116A (en) | 2014-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102786516B (en) | Method for synthesizing rivaroxaban | |
| CN103304547A (en) | Preparation method of antidepressant drug-vilazodone | |
| CN102516122B (en) | Environment friendly method for preparing DMF (Dimethyl Formamide) solution of 2-hydroxy-benzonitril | |
| CN102002021A (en) | Novel method for synthesizing repaglinide | |
| CN100522953C (en) | Synthesis method of valsartan | |
| CN110526859A (en) | A kind of preparation method of Rui Weina new intermediate and preparation method thereof and Rui Weinaxin | |
| CN103373953A (en) | Preparation method for 3-aminopiperidine and optical isomer thereof | |
| JP2019528254A (en) | Improved 5R-benzyloxyaminopiperidine-2S-formic acid ester and process for preparing the oxalate salt thereof | |
| CN102020589B (en) | Tert-butyl carbamate derivative and preparation method and application thereof | |
| CN103204801A (en) | Synthesis method for N-Boc-3-piperidone | |
| CN103709116B (en) | A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai | |
| CN102320988B (en) | 4-(4-amion phenyl)-3-morpholone intermediate amide and synthesis method and application thereof | |
| CN102911160B (en) | Method for preparing and purifying dabigatran etexilate intermediate | |
| CN107365276A (en) | A kind of diazepam D5 preparation method | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN103864773B (en) | Razaxaban and its preparation method of intermediate | |
| CN101993426A (en) | 3-aryl glutaric acid mono-amide compound as well as preparation method and application thereof | |
| CN107501196A (en) | Intermediate for preparing diazepam D5 and diazepam D8 and preparation method thereof | |
| CN101967096A (en) | 3-[4-(alkoxy) phenyl] propionate compound and preparation method and application thereof | |
| CN110105294A (en) | A kind of preparation method of polysubstituted tetrahydroquinoxaline derivative | |
| CN103408450A (en) | Method for catalytically synthesizing tamibarotene through acenaphthene imidazole n-heterocyclic carbine allyl palladium chloride compound | |
| CN103613513B (en) | Milnacipran hydrochloride intermediate and its preparation method and application | |
| CN102807516A (en) | Intermediate in amisulpride and method for preparing amisulpride by using intermediate | |
| CN102351734B (en) | Preparation method for aliskiren | |
| CN102336676A (en) | New preparation method of dopexamine hydrochloride by ArCHR protection strategy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150923 Termination date: 20161210 |