CN104860904A - Preparation method and uses of N-epoxypropyl-N-acylaniline compounds - Google Patents

Preparation method and uses of N-epoxypropyl-N-acylaniline compounds Download PDF

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CN104860904A
CN104860904A CN201410057203.4A CN201410057203A CN104860904A CN 104860904 A CN104860904 A CN 104860904A CN 201410057203 A CN201410057203 A CN 201410057203A CN 104860904 A CN104860904 A CN 104860904A
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reaction
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morpholinyl
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solvent
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CN104860904B (en
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邓勇
李岩
肖柑媛
邱玥珩
武梅
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Abstract

The present invention discloses a class of N-epoxypropyl-N-acylaniline compounds represented by a formula (I), and further discloses a preparation method of the N-epoxypropyl-N-acylaniline compounds, and applications of the N-epoxypropyl-N-acylaniline compounds in preparation of oxazolidinone treating drugs including but being not limited to linezolid and rivaroxaban racemate or optical isomers, wherein R1 represents morpholinyl or 3-O-4-morpholinyl, R2 represents H or F, R3 represents C1-12 alkyl, thien-2-yl or 5-chlorothiophen-2-yl, and the compounds are racemates, (S)-optical isomers, or (R)-optical isomers.

Description

N-epoxypropyl-N-anilid compounds Preparation Method And The Use
Technical field
The invention belongs to medicinal chemistry art, relate to n-epoxypropyl- n-anilid compounds ( i), the application in its preparation method and oxazolidinones class medicine raceme or optical isomer,
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; Described compound be raceme, (S)-optical isomer or (R)-optical isomer.
Background technology
Linezolid (linezolid), chemistry is called ( s)-5-(ethanamide methyl)-3-[(the fluoro-4-morpholinyl of 3-) phenyl]-1,3-oxazolidine-2-ketone, it is the novel oxazolidinone class antimicrobial drug of Pharmacia & Upjohn company development, in April, 2000 goes on the market in the U.S. first, trade(brand)name Zyvox, clinically be used for the treatment of the pneumonia and comprehensive skin infections that are caused by Methicillin resistant Staph. aureus (MRSA), and the microbemia etc. caused by vancomycin-resistant enterococcus (VREF) or penicillin resistance pneumococcus (PRSP).
Razaxaban (Rivaroxaban), 5-by name is chloro-for chemistry n-[[(5 s)-2-oxygen-3-[4-(3-oxygen-4-morpholinyl) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, it is the direct inhibitor of German Bayer company exploitation oxazolidinone factor Xa, go on the market in Canada first in September, 2008, trade(brand)name Xarelto, be mainly used in prevention hip or knee replacements Venous Blood bolt embolism clinically, it is high that this product has bioavailability as new oral anticoagulation medicine, dose-effect relationship is stablized, the low feature of bleeding risk, has become the choice drug of prevention of thromboembolic disorders.
At present, existing document respectively to Linezolid [(1) Chen Wei, Hu Jianliang, Zhang Xingxian. Linezolid graphical Synthetic Routes. chinese Journal of Pharmaceuticals, 2010, 41(1): 62-63; (2) He Biao, Zhang Le. the synthesis of oxazolidinone antibacterials. external medicine---microbiotic fascicle,2009, 30(2): 82-88] and razaxaban [(3) Wang Haiyan, Guo Fei, Gong Ping. razaxaban graphical Synthetic Routes. china's pharmaceutical chemistry magazine, 2012, 22(3): 249-251; (4) soar, Liang Bin, Ni Guowei, Wang Huan, etc. razaxaban graphical Synthetic Routes. chinese Journal of New Drugs, 2012, 21(4): 371-374; (4) Fu Limei, Jiang Xiangrui, Shen Jingshan. razaxaban graphical Synthetic Routes. chinese Medicine Leader, 2012, 9(13): 112-113; (5) Rivaroxaban. drugs of the Future2006,31 (6): 484-493] synthetic method is summarized.
But there is severe reaction conditions (low temperature and waterless operation) in the existing synthetic technology preparing Linezolid and razaxaban, reactions steps is many, total recovery is low, in preparation process, " three wastes " discharge is serious, operation and last handling process loaded down with trivial details etc. not enough, make the preparation cost of Linezolid and razaxaban higher, a large amount of preparation is restricted.Therefore, this area still need that exploitation raw material is cheap and easy to get, reaction conditions is gentle, easy and simple to handle, chemical yield and optical purity is high, the Linezolid of " environmental protection " and razaxaban new synthetic method.
Summary of the invention
The object of the invention is to disclose a class n-epoxypropyl- n-anilid compounds ( i).
Another object of the present invention is to disclose such n-epoxypropyl- n-anilid compounds ( i) preparation method.
Another object of the present invention is to disclose such n-epoxypropyl- n-anilid compounds ( i) oxazolidinones class medicine---include but not limited to the application in Linezolid (Linezolid) and razaxaban (Rivaroxaban) raceme or optical isomer.
Disclosed in this invention n-epoxypropyl- n-anilid compounds ( i) chemical structure of general formula be:
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; Described compound be raceme, (S)-optical isomer or (R)-optical isomer.
Disclosed in this invention n-epoxypropyl- n-anilid compounds ( i) prepare by following methods:
Method one:
Method two:
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; X represents chlorine, bromine or iodine; Compound be raceme, (S)-optical isomer or (R)-optical isomer.
Its concrete preparation method is as follows:
Method one:
A) with amino benzenes compounds ( 1) be starting raw material, solvent-free or under having solvent and alkaline condition, corresponding carboxylic acid halides or anhydride reaction, obtain accordingly n-anilid compounds ( 4); Wherein, solvent for use is: C 3-8aliphatic ketone, C 5-10fat alkane or C 5-10naphthenic hydrocarbon (as: normal hexane, normal heptane, hexanaphthene etc.), n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, glycol dimethyl ether, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, mixed solvent volume ratio is 1:0.1 ~ 10, and preferred solvent is: tetrahydrofuran (THF), n,N-dimethyl formamide, methylene dichloride, chloroform, acetone, ethyl acetate, acetonitrile or toluene; Reacting alkali used is: alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, Tributylamine, pyridine, n-methylmorpholine, n-methyl piperidine or triethylene diamine, preferred bases is: sodium bicarbonate, salt of wormwood, triethylamine, n-methylmorpholine or pyridine; Amino benzenes compounds ( 1): carboxylic acid halides ( 2) or acid anhydrides ( 3): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0, is preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5; Temperature of reaction is-60 DEG C ~ 100 DEG C, is preferably 0 ~ 80 DEG C; Reaction times is 20 minutes ~ 24 hours, is preferably 30 minutes ~ 12 hours.
B) by steps A) obtain n-anilid compounds ( 4) under solvent and alkaline condition with racemization or optically active epoxy chloropropane ( 5) reaction, obtain accordingly n-epoxypropyl- n-anilid compounds ( i); Wherein, solvent for use is: C 3-8aliphatic ketone, C 5-10fat alkane or C 5-10naphthenic hydrocarbon (as: normal hexane, normal heptane, hexanaphthene etc.), n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, glycol dimethyl ether, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, mixed solvent volume ratio is 1:0.1 ~ 10, and preferred solvent is: tetrahydrofuran (THF), n,N-dimethyl formamide, methylene dichloride, chloroform, acetone, ethyl acetate, acetonitrile or toluene; Reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, basic metal and C 1-12the salt that alcohol is formed, alkaline-earth metal and C 1-12the salt that alcohol is formed, NaH or KH, preferred bases is: sodium bicarbonate, salt of wormwood, trimethyl carbinol lithium or NaH; n-anilid compounds ( 4): epoxy chloropropane ( 5): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0, is preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5; Temperature of reaction is-20 DEG C ~ 120 DEG C, is preferably 0 ~ 80 DEG C; Reaction times is 1 ~ 24 hour, is preferably 2 ~ 12 hours.
Method two:
With racemization or optically active n-(2,3-epoxy-1-propyl group)-amino benzenes compounds ( 6) be starting raw material, under solvent and alkaline condition with corresponding carboxylic acid halides ( 2) reaction, obtain accordingly n-epoxypropyl- n-anilid compounds ( i); Wherein, solvent for use is: C 3-8aliphatic ketone, C 5-10fat alkane or C 5-10naphthenic hydrocarbon (as: normal hexane, normal heptane, hexanaphthene etc.), n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, glycol dimethyl ether, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, mixed solvent volume ratio is 1:0.1 ~ 10, and preferred solvent is: tetrahydrofuran (THF), n,N-dimethyl formamide, methylene dichloride, chloroform, acetone, ethyl acetate, acetonitrile or toluene; Reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, Tributylamine, pyridine, n-methylmorpholine, n-methyl piperidine or triethylene diamine, preferred bases is: sodium bicarbonate, salt of wormwood, triethylamine, diisopropylethylamine, n-methylmorpholine or pyridine; n-(2,3-epoxy-1-propyl group)-amino benzenes compounds ( 6): carboxylic acid halides ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0, is preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5; Temperature of reaction is-60 DEG C ~ 100 DEG C, is preferably 0 ~ 60 DEG C; Reaction times is 20 minutes ~ 24 hours, is preferably 30 minutes ~ 12 hours.
Aforesaid method is utilized to obtain n-epoxypropyl- n-anilid compounds ( i) available following methods Jiang its Zhuanization Wei oxazolidinone medicine ( iI), Zhe Xie oxazolidinone medicine includes but not limited to Linezolid (Linezolid) and razaxaban (Rivaroxaban) raceme or optical isomer, and its synthetic route is as follows:
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; Described compound be raceme, (S)-optical isomer or (R)-optical isomer.
Its synthetic method specifically describes as follows:
n-epoxypropyl- n-anilid compounds ( i) in a solvent with ammonia through the rearrangement reaction of ammonia solution, obtain 2-hydroxyl-1,3-propylene diamine compounds ( 7); Gained compound 7recycling prior art, carry out with acylating reagent in suitable solvent ring-closure reaction ， get oxazolidinone medicine ( iI); Wherein, ammonia solution rearrangement reaction ammonia used is: the C of ammonia, ammonia soln, ammonia 1-8fatty alcohol solution, liquefied ammonia or heat decompose compound (as: volatile salt, bicarbonate of ammonia, ammonium acetate etc.) or the hexamethylenetetramine that can discharge ammonia; Ammonia solution rearrangement reaction solvent for use is: water, C 1-8fatty alcohol, C 3-8aliphatic ketone, n,N-dimethyl formamide, ethers (as: ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane etc.), C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, ethylene glycol monomethyl ether, ethylene glycol, halohydrocarbon (as: methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene etc.), benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, mixed solvent volume ratio is 1:0.1 ~ 10, and preferred solvent is: water, methyl alcohol, ethanol, tetrahydrofuran (THF), n,N-dimethyl formamide, methylene dichloride, chloroform, acetonitrile, ethylene glycol monomethyl ether, acetone or Isosorbide-5-Nitrae-dioxane; n-epoxypropyl- n-anilid compounds ( i): the molar feed ratio of ammonia is 1.0:1.0 ~ 1000, is preferably 1.0:5.0 ~ 100; Ammonia solution rearrangement reaction temperature is-40 DEG C ~ 100 DEG C, is preferably 0 DEG C ~ 60 DEG C; The ammonia solution rearrangement reaction time is 20 minutes ~ 24 hours, is preferably 2 hours ~ 12 hours; In acidylate ring-closure reaction step, acylating reagent used is: phosphinylidyne diimidazole (CDI), phosgene, superpalite, two (trichloromethyl) carbonic ether, chloroformic acid C 1-8the C of aliphatic alcohol ester compounds (as: Vinyl chloroformate, isobutylchloroformate, chloroformic acid benzyl ester etc.), carbonic acid 1-8aliphatic alcohol ester compounds (as: methylcarbonate, diethyl carbonate etc.) or two succinimdyl carbonates (DSC).
The present invention's starting raw material used---racemization or optically active n-(2,3-epoxy-1-propyl group)-amino benzenes compounds ( 6) available art methods prepares, that is: amino benzenes compounds and racemization or optically active epichlorohydrin reaction, then cyclization in the basic conditions, n-(2,3-epoxy-1-propyl group)-amino benzenes compounds ( 6), two step total recovery >90%.
The invention has the advantages that: compared with prior art, it is cheap and easy to get that the method has raw material, and reaction conditions is gentle, reactions steps is few, easy and simple to handle, do not use hazardous agents, and yield is high, cost is low, optical purity of products is high, is applicable to the features such as fairly large oxazolidinones class medicine processed.
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.
IA6304 type melting point apparatus, thermometer is not calibrated; (solvent is CDCl to Varian INOVA-400 nuclear magnetic resonance analyser 3or DMSO- d 6 , interior mark TMS); Agilent-6210 TOF LC/MS high-resolution mass spectrometer; Perkin-Elmer model 341 automatic polarimeter.HPLC chiral column: Chiralcel OD-H (250mm × 4.6mm), moving phase: normal hexane-Virahol-trifluoroacetic acid.
embodiment 1
( r)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (( r)-Ia) and preparation
The fluoro-4-morpholinyl phenylamine of 3-(0.01 mol), methylene dichloride 100 ml, triethylamine (0.02 mol) is added successively in reaction flask, after stirring, add Acetyl Chloride 98Min. (0.012 mol), react 3 hours in stirring at room temperature, reaction is finished, and reaction solution uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, and resistates, through ethyl alcohol recrystallization, obtains n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide, yield 98%;
Will n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (8.0 mmol), n,N-dimethyl formamide 30 ml and NaH(9.0 mmol) add in reaction flask, stirring at room temperature adds after reacting 20 minutes ( r)-epoxy chloropropane (10.0 mmol), be warming up to 50-60 DEG C of reaction 3 hours, reaction is finished, and remove solvent under reduced pressure, resistates is dissolved in ethyl acetate 100 ml, uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, ( r)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide, yield 82.5%; HR-TOF-MS (+Q) m/z: 295.1450 ([C 15h 19fN 2o 3+ H] +calculated value: 295.1458).
embodiment 2
( s)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (( s)-Ia) and preparation
The fluoro-4-morpholinyl phenylamine of 3-(0.01 mol), ethyl acetate 100 ml, triethylamine (0.02 mol) is added successively in reaction flask, after stirring, add diacetyl oxide (0.015 mol), react 8 hours in stirring at room temperature, reaction is finished, and reaction solution uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, through ethyl alcohol recrystallization, n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide, yield 99.0%;
By gained n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (8.0 mmol), acetone 50 ml, salt of wormwood (12.0 mmol) and ( s)-epoxy chloropropane (12.0 mmol) adds in reaction flask, and temperature rising reflux reacts 10 hours, and reaction is finished, and filters, and filtrate decompression is steamed and desolventized, and resistates is dissolved in ethyl acetate 100 ml, uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, ( s)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide, yield 68.9%; HR-TOF-MS (+Q) m/z: 295.1456 ([C 15h 19fN 2o 3+ H] +calculated value: 295.1458).
embodiment 3
( dl)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (( dl)-Ia) and preparation
The same embodiment of working method 1, just incite somebody to action ( r)-epoxy chloropropane is used ( dl)-epoxy chloropropane substitutes, and can obtain corresponding target compound yield 78.0%.
embodiment 4
( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-(( r)-Ib) and preparation
4-(3-morpholine ketone group) aniline (0.01 mol), tetrahydrofuran (THF) 60 ml, triethylamine (0.015 mol) is added successively in reaction flask, after stirring, add the chloro-2-thiophene chloride of 5-(0.012 mol), stirring at room temperature reacts 5 hours, reaction is finished, pressurization steaming desolventizes, and resistates is dissolved in methylene dichloride 100 ml, uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, and resistates, through ethyl alcohol recrystallization, obtains n-[4-[(3-morpholine ketone group) phenyl] the chloro-2-thenoyl amine of-5-, yield 97.5%;
Will n-[4-[(3-morpholine ketone group) phenyl] the chloro-2-thenoyl amine of-5-(8.0 mmol), n,N-dimethyl formamide 50 ml and NaH(9.0 mmol) add in reaction flask, stirring at room temperature adds for 20 minutes ( r)-epoxy chloropropane (10.0 mmol), be warming up to 50-60 DEG C of reaction 3 hours, reaction is finished, and remove solvent under reduced pressure, resistates is dissolved in ethyl acetate 100 ml, uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, ( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-, yield 95.5%; HR-TOF-MS (+Q) m/z: 393.0682 ([C 18h 17clN 2o 4s+H] +calculated value: 393.0676).
embodiment 5
( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-(( s)-Ib) and preparation
The same embodiment of working method 4, just incite somebody to action ( r)-epoxy chloropropane is used ( s)-epoxy chloropropane substitutes, n,N-dimethyl formamide tetrahydrofuran (THF) substitutes, and NaH trimethyl carbinol lithium substitutes, and can obtain corresponding target compound yield 96.0%; Its structure is confirmed through HR-TOF-MS.
embodiment 6
( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-(( dl)-Ib) and preparation
The same embodiment of working method 4, just incite somebody to action ( r)-epoxy chloropropane is used ( dl)-epoxy chloropropane substitutes, n,N-dimethyl formamide tetrahydrofuran (THF) substitutes, and NaH trimethyl carbinol lithium substitutes, and can obtain corresponding target compound yield 90.0%; Its structure is confirmed through HR-TOF-MS.
embodiment 7
( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine (( r)-Ic) and preparation
The same embodiment of working method 4, just chloro-for 5-2-thiophene chloride 2-thiophene chloride is substituted, ( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine, yield 93.0%; HR-TOF-MS (+Q) m/z: 359.1058 ([C 18h 18n 2o 4s+H] +calculated value: 359.1066).
embodiment 8
( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine (( s)-Ic) and preparation
The same embodiment of working method 4, just chloro-for 5-2-thiophene chloride 2-thiophene chloride is substituted, ( r)-epoxy chloropropane is used ( s)-epoxy chloropropane substitutes, n,N-dimethyl formamide tetrahydrofuran (THF) substitutes, and NaH trimethyl carbinol lithium substitutes, and can obtain corresponding target compound yield 98.0%; Its structure is confirmed through HR-TOF-MS.
embodiment 9
( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine (( dl)-Ic) and preparation
The same embodiment of working method 4, just chloro-for 5-2-thiophene chloride 2-thiophene chloride is substituted, ( r)-epoxy chloropropane is used ( dl)-epoxy chloropropane substitutes, n,N-dimethyl formamide tetrahydrofuran (THF) substitutes, and NaH trimethyl carbinol lithium substitutes, and can obtain corresponding target compound yield 86.3%; Its structure is confirmed through HR-TOF-MS.
embodiment 10
( r)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (( r)-Ia) and preparation
Add successively in reaction flask ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline (0.01 mol), methylene dichloride 80 ml, triethylamine (0.012 mol), after stirring, add Acetyl Chloride 98Min. (0.012 mol), 5 hours are reacted in stirring at room temperature, reaction is finished, and reaction solution uses deionized water, saturated NaHCO successively 3the aqueous solution and saturated nacl aqueous solution washing, filter after anhydrous sodium sulfate drying, filtrate decompression boils off solvent, ( r)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide, yield 98.5%; HR-TOF-MS (+Q) m/z: 295.1466 ([C 15h 19fN 2o 3+ H] +calculated value: 295.1458).
embodiment 11
( s)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (( s)-Ia) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( s)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline substitutes, and methylene dichloride tetrahydrofuran (THF) substitutes, and triethylamine pyridine substitutes, ( s)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide, yield 92.8%; HR-TOF-MS (+Q) m/z: 295.1449 ([C 15h 19fN 2o 3+ H] +calculated value: 295.1458).
embodiment 12
( dl)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide (( dl)-Ia) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( dl)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline substitutes, and can obtain corresponding target compound yield 95.5%.
embodiment 13
( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-(( r)-Ib) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( r)- n-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and methylene dichloride ethyl acetate substitutes, and the chloro-2-thiophene chloride of Acetyl Chloride 98Min. 5-substitutes, ( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-, yield 98.0%; HR-TOF-MS (+Q) m/z: 393.0674 ([C 18h 17clN 2o 4s+H] +calculated value: 393.0676).
embodiment 14
( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-(( s)-Ib) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( s)- n-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and the chloro-2-thiophene chloride of Acetyl Chloride 98Min. 5-substitutes, ( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-, yield 95.0%; HR-TOF-MS (+Q) m/z: 393.0670 ([C 18h 17clN 2o 4s+H] +calculated value: 393.0676).
embodiment 15
( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-(( dl)-Ib) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( dl)- n-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and the chloro-2-thiophene chloride of Acetyl Chloride 98Min. 5-substitutes, ( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-, yield 93.6%; Its structure is confirmed through HR-TOF-MS.
embodiment 16
( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine (( r)-Ic) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( r)- n-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and Acetyl Chloride 98Min. 2-thiophene chloride substitutes, ( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine, yield 96.2%; HR-TOF-MS (+Q) m/z: 359.1052 ([C 18h 18n 2o 4s+H] +calculated value: 359.1066).
embodiment 17
( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine (( s)-Ic) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( s)- n-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and Acetyl Chloride 98Min. 2-thiophene chloride substitutes, ( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine, yield 97.8%; Its structure is confirmed through HR-TOF-MS.
embodiment 18
( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine (( dl)-Ic) and preparation
The same embodiment of working method 10, just incite somebody to action ( r)- n-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline is used ( dl)- n-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and Acetyl Chloride 98Min. 2-thiophene chloride substitutes, ( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine, yield 94.8%; Its structure is confirmed through HR-TOF-MS.
embodiment 19
n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a) preparation
Add in reaction flask ( r)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide ( ( r)-Ia ) (5.0 mmol), methyl alcohol 40 ml, commercially available 25%-28% ammoniacal liquor 30 ml, stirring at room temperature reacts 8 hours, reaction terminate after, remove methyl alcohol under reduced pressure, resistates 100 milliliters of methylene dichloride dissolve, and use deionized water 50 milliliters successively, the saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, obtains white n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide, yield 93.0%, chemical purity 99.8%, optical purity 99.9%ee; M.p. 124.2-125.7 DEG C, [a] =-0.95 (c 1.0, CH 3oH), HRMS-ESI (m/z): 312.1718 [M+H] +; 1h-NMR (DMSO- d 6 , 400MHz) δ: 7.86 (t, j=4.8Hz, 1H, NHCO), 6.82 (t, j=9.6Hz, 1H, Ar-H), 6.41 (dd, j=2.4,15.2Hz, 1H, Ar-H), 6.33 (dd, j=2.4,8.4Hz, 1H, Ar-H), 5.47 (t, j=5.6Hz, 1H, Ar-NH), 4.97 (d, j=5.2Hz, 1H, OH), 3.69 (t, j=4.8Hz, 4H, 2 ×-CH 2o), 3.62 (m, 1H, CHOH), 3.15 (m, 1H, CH 2nHCO), 3.04 (m, 1H, CH 2nHCO), 2.98 (m, 1H, CH 2nHAr), 2.87 (m, 1H, CH 2nHAr), 2.82 (t, j=4.8Hz, 4H, 2 × CH 2n), 1.82 (s, 3H, CH 3).
embodiment 20
n-[(2 s)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( s-preparation 7a)
Add in reaction flask ( s)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide ( ( s)-Ia ) (5.0 mmol), tetrahydrofuran (THF) 30 ml, methyl alcohol saturated solution 30 ml of ammonia, stirring at room temperature react 8 hours, after reaction terminates, remove solvent under reduced pressure, resistates 100 milliliters of methylene dichloride dissolve, use deionized water 50 milliliters successively, the saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, obtains white solid, yield 95.0%, its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 21
( dl)- n-[-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( dl-preparation 7a)
Add in reaction flask ( dl)- n-(2,3-epoxy-1-propyl group)- n-(the fluoro-4-of 3-(4-morpholinyl) phenyl) ethanamide ( ( dl)-Ia ) (5.0 mmol), methyl alcohol 50 ml and volatile salt (0.05 mol), temperature rising reflux stirring reaction 5 hours, after reaction terminates, filtered while hot, filtrate decompression is steamed and is desolventized, and resistates 60 milliliters of methylene dichloride dissolve, and use deionized water 50 milliliters successively, the saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, and resistates, through ordinary method purifying, obtains white solid, yield 85.0%, its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 22
( r)-5-is chloro- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( r-7b) preparation
Add in reaction flask ( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-( ( r)-Ib ) (5.0 mmol), acetonitrile 20 ml, commercially available 25%-28% ammoniacal liquor 20 ml, stirring at room temperature reacts 8 hours, reaction terminate after, remove solvent under reduced pressure, resistates 80 milliliters of methylene dichloride dissolve, and use deionized water 30 milliliters successively, the saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, obtains white solid, yield 99.0%, chemical purity 99.8%, and optical purity is greater than 99.8%ee; M.p. 195.5-196.5 DEG C, [a] =+5.5 o( c0.5, DMSO), HRMS-ESI (m/z): 410.0945 [M+H] +; 1h-NMR (DMSO- d 6 , 400MHz) δ: 8.61 (t, j=5.6Hz, 1H, NHCO), 7.68 (d, j=4.0 Hz, 1H, Thiophene-H), 7.18 (d, j=4.0 Hz, 1H, Thiophene-H), 7.01 (d, j=8.4 Hz, 2H, Ph-H), 6.59 (d, j=8.4 Hz, 2H, Ph-H), 5.65 (t, j=5.6Hz, 1H, Ar-NH), 5.08 (d, j=4.8Hz, 1H, OH), 4.13 (s, 2H, OCH 2cO), 3.92 (t, j=4.8 Hz, 2H, CH 2n), 3.81-3.78 (m, 1H, CHOH), 3.60 (t, j=4.8 Hz, 2H, CH 2o), 3.39-3.30 (m, 1H, CH 2n), 3.28-3.21 (m, 1H, CH 2n), 3.14-3.08 (m, 1H, CH 2n), 3.00-2.94 (m, 1H, CH 2n).
embodiment 23
( s)-5-is chloro- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( s-7b) preparation
Add in reaction flask ( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-( ( s)-Ib ) (5.0 mmol), 1,4-dioxane 20 ml, commercially available 25%-28% ammoniacal liquor 20 ml, stirring at room temperature reacts 6 hours, after reaction terminates, remove solvent under reduced pressure, resistates 60 milliliters of methylene dichloride dissolve, and use deionized water 30 milliliters successively, the saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, and resistates, through ordinary method purifying, obtains white solid, yield 96.8%, its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 24
( dl)-5-is chloro- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( dl-7b) preparation
Add in reaction flask ( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]] the chloro-2-thenoyl amine of-5-( ( dl)-Ib ) (5.0 mmol), deionized water 20 ml, ethanol alcohol saturated solution 20 ml of ammonia, stirring at room temperature react 8 hours, after reaction terminates, remove solvent under reduced pressure, resistates 80 milliliters of methylene dichloride dissolve, use deionized water 30 milliliters successively, the saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, and resistates, through ordinary method purifying, obtains white solid, yield 98.0%, its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 25
( r)- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( r-7c) preparation
Add in reaction flask ( r)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine ( ( r)-Ic ) (5.0 mmol), acetonitrile 20 ml, commercially available 25%-28% ammoniacal liquor 20 ml, stirring at room temperature reacts 7 hours, reaction terminate after, remove solvent under reduced pressure, resistates 80 milliliters of methylene dichloride dissolve, and use deionized water 30 milliliters successively, the saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, obtains white solid, yield 97.0%, chemical purity 99.8%, and optical purity is greater than 99.8%ee; HRMS-ESI (m/z): 376.1325 [M+H] +.
embodiment 26
( s)- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( s-7c) preparation
Add in reaction flask ( s)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine ( ( s)-Ic ) (5.0 mmol), 1,4-dioxane 20 ml, commercially available 25%-28% ammoniacal liquor 20 ml, stirring at room temperature reacts 6 hours, after reaction terminates, remove solvent under reduced pressure, resistates 60 milliliters of methylene dichloride dissolve, and use deionized water 30 milliliters successively, the saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, and resistates, through ordinary method purifying, obtains white solid, yield 96.8%, its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 27
( dl)- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( dl-7c) preparation
Add in reaction flask ( dl)- n-(2,3-epoxy-1-propyl group)- n-[4-[(3-morpholine ketone group) phenyl]]-2-thenoyl amine ( ( dl)-Ic ) (5.0 mmol), deionized water 20 ml, ethanol alcohol saturated solution 20 ml of ammonia, stirring at room temperature react 8 hours, after reaction terminates, remove solvent under reduced pressure, resistates 80 milliliters of methylene dichloride dissolve, use deionized water 30 milliliters successively, the saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na 2sO 4drying, removes solvent under reduced pressure, and resistates, through ordinary method purifying, obtains white solid, yield 96.5%, its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 28
( s)- nthe preparation of-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide (Linezolid)
Add according to embodiment 19 preparation-obtained in reaction flask n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) (0.01 mol), methylene dichloride 100 ml and triethylamine (0.015 mol), after stirring, put in ice bath and be cooled to 0-5 DEG C, add two (trichloromethyl) carbonic ether (0.004 mol), naturally room temperature reaction is warming up to 2 hours, reaction solution uses the 5%NaOH aqueous solution, saturated NaCl solution washing successively, organic layer is through anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure, residue with ethyl acetate recrystallization, obtains white needle-like crystals, yield 95.0%, mp:178 ~ 179 DEG C; [a] =-9.2 o( c1.0, CHCl 3), chemical purity 99.90%, optical purity 99.9%ee; 1h NMR (CDCl 3, 400 MHz) d: 7.43 (dd, j 1=2.8 Hz, j 2=14.4 Hz, 1H, Ar-H), 7.06 (dd, j 1=1.6 Hz, j 2=8.8 Hz, 1H, Ar-H), 6.94 (t, j=9.2 Hz, 1H, Ar-H), 6.17 (t, j=6.0 Hz, 1H, NH), 4.80 ~ 4.74 (m, 1H, CHO), 4.02 (t, j=8.8 Hz, 1H, CH 2cHO), 3.86 (t, j=4.8 Hz, 4H, 2 × OCH 2), 3.75 (dd, j 1=6.8 Hz, j 2=8.8 Hz, 1H, CH 2cHO), 3.71 ~ 3.58 (m, 2H, CH 2nH), 3.06 (t, j=4.8 Hz, 4H, 2 × NCH 2), 2.02 (s, 3H, CH 3cO); 13c NMR (CDCl 3, 100 MHz): 171.4,155.7 (d, j=245 Hz), 154.5,136.4 (d, j=8.8 Hz), 132.8 (d, j=10.4 Hz), 118.6 (d, j=3.9 Hz), 113.8 (d, j=3.0 Hz), 107.4 (d, j=26.1 Hz), 72.0,66.8,50.8,47.5,41.7,22.8; HR-TOF-MS (+Q) m/z: 338.1512 ([C 16h 20fN 3o 4+ H] +calculated value: 338.1516).
embodiment 29
( r)- nthe preparation of-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) use n-[(2 s)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( s-7a ) substitute, methylene dichloride tetrahydrofuran (THF) substitutes, and two (trichloromethyl) carbonic ether phosphinylidyne diimidazole substitutes, ( r)- n-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, yield 92.0%, mp:178 ~ 179 DEG C; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 30
( dl)- nthe preparation of-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( dl)- n-[-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( dl-7a ) substitute, methylene dichloride ethyl acetate substitutes, and two (trichloromethyl) carbonic ether methyl-chloroformate substitutes, ( dl)- n-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, yield 90.0%; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 31
( s)-5-is chloro- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5-base] methyl] preparation of-2-thenoyl amine (razaxaban)
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( r)-5-is chloro- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( r-7b ) substitute, ( s)-5-is chloro- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5-base] methyl]-2-thenoyl amine, yield 95.3%, mp:232 ~ 233 DEG C; [a] =-41.0 o( c0.5, DMSO), chemical purity 99.85%, optical purity 99.8% ee; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 32
( r)-5-is chloro- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl] preparation of-2-thenoyl amine
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( s)-5-is chloro- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( s-7b ) substitute, methylene dichloride tetrahydrofuran (THF) substitutes, and two (trichloromethyl) carbonic ether phosphinylidyne diimidazole substitutes, ( r)-5-is chloro- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, yield 90.0%, mp:232 ~ 233 DEG C; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 33
( dl)-5-is chloro- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl] preparation of-2-thenoyl amine
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( dl)-5-is chloro- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( dl-7b ) substitute, methylene dichloride ethyl acetate substitutes, and two (trichloromethyl) carbonic ether methyl-chloroformate substitutes, ( dl)-5-is chloro- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, yield 87.8%; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 34
( s)- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl] preparation of-2-thenoyl amine
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( r)- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( r-7c ) substitute, ( s)- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, yield 92.8%, chemical purity 99.85%, optical purity 99.8% ee; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 35
( r)- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl] preparation of-2-thenoyl amine
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( s)- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( s-7c ) substitute, methylene dichloride tetrahydrofuran (THF) substitutes, and two (trichloromethyl) carbonic ether phosphinylidyne diimidazole substitutes, ( r)- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, yield 90.0%, mp:232 ~ 233 DEG C; Its structure through HRMS-ESI, 1h-NMR confirms.
embodiment 36
( dl)- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl] preparation of-2-thenoyl amine
Operating process, with embodiment 28, just will n-[(2 r)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] is amino]-2-hydroxypropyl]-ethanamide ( r-7a ) with ( dl)- n-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] is amino] propyl group]-2-thenoyl amine ( dl-7c ) substitute, methylene dichloride ethyl acetate substitutes, and two (trichloromethyl) carbonic ether methyl-chloroformate substitutes, ( dl)- n-[2-oxygen-3-[4-(3-morpholine ketone group) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, yield 87.8%; Its structure through HRMS-ESI, 1h-NMR confirms.
  

Claims (10)

1. a class n-epoxypropyl- n-anilid compounds ( i), it is characterized in that, it has chemical structure of general formula (I)shown compound:
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; Described compound be raceme, (S)-optical isomer or (R)-optical isomer.
2. as claimed in claim 1 n-epoxypropyl- n-anilid compounds ( i) preparation method, it is characterized in that preparing by following method:
Method one:
A) with amino benzenes compounds ( 1) be starting raw material, solvent-free or under having solvent and alkaline condition, corresponding carboxylic acid halides or anhydride reaction, obtain accordingly n-anilid compounds ( 4);
B) by steps A) obtain n-anilid compounds ( 4) under solvent and alkaline condition with racemization or optically active epoxy chloropropane ( 5) reaction, obtain accordingly n-epoxypropyl- n-anilid compounds ( i);
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; X represents chlorine, bromine or iodine; Compound be raceme, (S)-optical isomer or (R)-optical isomer;
Also can prepare by such as method shown in method two n-epoxypropyl- n-anilid compounds ( i):
Method two:
With racemization or optically active n-(2,3-epoxy-1-propyl group)-amino benzenes compounds ( 6) be starting raw material, under solvent and alkaline condition with corresponding carboxylic acid halides ( 2) reaction, obtain accordingly n-epoxypropyl- n-anilid compounds ( i);
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; X represents chlorine, bromine or iodine; Compound be raceme, (S)-optical isomer or (R)-optical isomer.
3. as claimed in claim 2 n-epoxypropyl- n-anilid compounds ( i) preparation method, it is characterized in that, the steps A of method one) in, reaction solvent for use be: C 3-8aliphatic ketone, C 5-10fat alkane or C 5-10naphthenic hydrocarbon, n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, glycol dimethyl ether, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, and mixed solvent volume ratio is 1:0.1 ~ 10; Reacting alkali used is: alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, Tributylamine, pyridine, n-methylmorpholine, n-methyl piperidine or triethylene diamine; Amino benzenes compounds ( 1): carboxylic acid halides ( 2) or acid anhydrides ( 3): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is-60 DEG C ~ 100 DEG C; Reaction times is 20 minutes ~ 24 hours.
4. as claimed in claim 2 n-epoxypropyl- n-anilid compounds ( i) preparation method, it is characterized in that, the step B of method one) in, reaction solvent for use be: C 3-8aliphatic ketone, C 5-10fat alkane or C 5-10naphthenic hydrocarbon, n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, glycol dimethyl ether, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, and mixed solvent volume ratio is 1:0.1 ~ 10; Reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, basic metal and C 1-12the salt that alcohol is formed, alkaline-earth metal and C 1-12the salt that alcohol is formed, NaH or KH; n-anilid compounds ( 4): epoxy chloropropane ( 5): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is-20 DEG C ~ 120 DEG C; Reaction times is 1 ~ 24 hour.
5. as claimed in claim 2 n-epoxypropyl- n-anilid compounds ( i) preparation method, it is characterized in that, reacting solvent for use in method two is: C 3-8aliphatic ketone, C 5-10fat alkane or C 5-10naphthenic hydrocarbon, n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, glycol dimethyl ether, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, and mixed solvent volume ratio is 1:0.1 ~ 10; Reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, Tributylamine, pyridine, n-methylmorpholine, n-methyl piperidine or triethylene diamine; n-(2,3-epoxy-1-propyl group)-amino benzenes compounds ( 6): carboxylic acid halides ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is-60 DEG C ~ 100 DEG C; Reaction times is 20 minutes ~ 24 hours.
6. Yi Zhong oxazolidinone medicine ( iI) preparation method, it is characterized in that, with according to claim 1 n-epoxypropyl- n-anilid compounds ( i) be raw material, prepared by following method: n-epoxypropyl- n-anilid compounds ( i) in a solvent with ammonia through the rearrangement reaction of ammonia solution, obtain 2-hydroxyl-1,3-propylene diamine compounds ( 7); Gained compound 7recycling prior art, carry out with acylating reagent in suitable solvent ring-closure reaction ， get oxazolidinone medicine ( iI);
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent C 1-12alkyl, thiophene-2-base or 5-chlorothiophene-2-base; Described compound be raceme, (S)-optical isomer or (R)-optical isomer.
7. as claim 6 Suo Shu oxazolidinone medicine ( iI) preparation method, it is characterized in that, ammonia solution rearrangement reaction ammonia used is: the C of ammonia, ammonia soln, ammonia 1-8fatty alcohol solution, liquefied ammonia, volatile salt, bicarbonate of ammonia, ammonium acetate or hexamethylenetetramine; Ammonia solution rearrangement reaction solvent for use is: water, C 1-8fatty alcohol, C 3-8aliphatic ketone, n,N-dimethyl formamide, ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane, C 1-6lipid acid and C 1-6ester that fatty alcohol is formed, ethylene glycol monomethyl ether, ethylene glycol, methylene dichloride, chloroform, 1,2-ethylene dichloride, orthodichlorobenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in above-mentioned mixed solvent, and mixed solvent volume ratio is 1:0.1 ~ 10; n-epoxypropyl- n-anilid compounds ( i): the molar feed ratio of ammonia is 1.0:1.0 ~ 1000; Ammonia solution rearrangement reaction temperature is-40 DEG C ~ 100 DEG C; The ammonia solution rearrangement reaction time is 20 minutes ~ 24 hours.
8. a compounds, it is characterized in that it be have chemical structure of general formula ( 4) shown in compound:
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent methyl, thiophene-2-base or 5-chlorothiophene-2-base.
9. a compounds, is characterized in that it has the compound shown in following chemical structure of general formula:
In formula: R 1represent morpholinyl or 3-oxygen-4-morpholinyl; R 2represent H or F; R 3represent thiophene-2-base.
10. arbitrary compound oxazolidinones class medicine as described in claim 1,8,9, includes but not limited to the application in Linezolid and razaxaban raceme or optical isomer.
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