CN104860904B - N-glycidyl-N-anilid compounds Preparation Method And The Use - Google Patents

N-glycidyl-N-anilid compounds Preparation Method And The Use Download PDF

Info

Publication number
CN104860904B
CN104860904B CN201410057203.4A CN201410057203A CN104860904B CN 104860904 B CN104860904 B CN 104860904B CN 201410057203 A CN201410057203 A CN 201410057203A CN 104860904 B CN104860904 B CN 104860904B
Authority
CN
China
Prior art keywords
reaction
solvent
compounds
morpholinyl
glycidyl
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
Application number
CN201410057203.4A
Other languages
Chinese (zh)
Other versions
CN104860904A (en
Inventor
邓勇
李岩
肖柑媛
邱玥珩
武梅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan University
Original Assignee
Sichuan University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sichuan University filed Critical Sichuan University
Priority to CN201410057203.4A priority Critical patent/CN104860904B/en
Publication of CN104860904A publication Critical patent/CN104860904A/en
Application granted granted Critical
Publication of CN104860904B publication Critical patent/CN104860904B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a classNGlycidylNAnilid compounds (I), also discloses the preparation method of this compounds and is preparing (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine, including but not limited to the application in Linezolid and razaxaban raceme or optical isomer,In formula: R1Represent morpholinyl or 3 oxygen 4 morpholinyls；R2Represent H or F；R3Represent C1‑12Alkyl, thiophene 2 base or 5 chlorothiophene 2 bases；Described compound be raceme,(S)Optical isomer or(R)Optical isomer.

Description

N-glycidyl-N-anilid compounds Preparation Method And The Use
Technical field
The invention belongs to medicinal chemistry art, relate toN-glycidyl-N-anilid compounds (I), its preparation method and the application in preparing (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine raceme or optical isomer,
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, thiophene-2-base or 5-chlorothiophene-2-base；Described compound be raceme,(S)-optical isomer or(R)-optical isomer.
Background technology
Linezolid (linezolid), chemistry entitled (S)-5-(acetamide methyl)-3-[(3-fluoro-4-morpholinyl) phenyl]-1,3-oxazolidine-2-ketone, it it is the novel oxazolidinone antibacterial medicine developed of Pharmacia & Upjohn company, in April, 2000 lists in the U.S. first, trade name Zyvox, it is clinically used for pneumonia and comprehensive skin infection that treatment is caused, and the bacteremia etc. caused by vancomycin-resistant enterococcus (VREF) or penicillin resistance pneumococcus (PRSP) by Methicillin resistant Staph. aureus (MRSA).
Razaxaban (Rivaroxaban), chemical entitled 5-is chloro-N-[[(5S)-2-oxygen-3-[4-(3-oxygen-4-morpholinyl) phenyl]-1,3-oxazolidine-5 base] methyl]-2-thenoyl amine, it it is the direct inhibitor of (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides factor Xa of Bayer company of Germany exploitation, list in Canada first in JIUYUE, 2008, trade name Xarelto, it is mainly used in clinically preventing hip or knee replacements Venous Blood bolt thromboembolism, it is high that this product has bioavailability as new oral anticoagulation medicine, dose-effect relationship is stable, the low feature of bleeding risk, it has also 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 antibacterial medicine.External medicine antibiotic 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 reviewed.
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 are loaded down with trivial details etc. not enough, the preparation cost making Linezolid and razaxaban is higher, and a large amount of preparations are restricted.Therefore, this area still need to exploitation raw material be cheap and easy to get, reaction condition is gentle, easy and simple to handle, chemical yield and optical purity high, the Linezolid of " environmental protection " and razaxaban new synthetic method.
Summary of the invention
It is an object of the invention to disclose a classN-glycidyl-N-anilid compounds (I).
Another object of the present invention is to disclose suchN-glycidyl-N-anilid compounds (I) preparation method.
A further object of the present invention is to disclose suchN-glycidyl-N-anilid compounds (I) include but not limited to the application in Linezolid (Linezolid) and razaxaban (Rivaroxaban) raceme or optical isomer preparing (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine.
Disclosed in this inventionN-glycidyl-N-anilid compounds (I) chemical structure of general formula be:
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, thiophene-2-base or 5-chlorothiophene-2-base；Described compound be raceme,(S)-optical isomer or(R)-optical isomer.
Disclosed in this inventionN-glycidyl-N-anilid compounds (I) can be prepared by the following method and obtain:
Method one:
Method two:
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, 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) it is initiation material, solvent-free or under the conditions of having solvent and alkalescence, corresponding carboxylic acid halides or anhydride reaction, obtain accordinglyN-anilid compounds (4)；Wherein, solvent for use is: C3-8Aliphatic ketone, C5-10Fat alkane or C5-10Cycloalkane (such as: normal hexane, normal heptane, hexamethylene etc.),N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, halogenated hydrocarbons (such as: dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene 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: oxolane,N,N-dimethylformamide, dichloromethane, chloroform, acetone, ethyl acetate, acetonitrile or toluene；Reaction alkali used is: alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine,N-methyl morpholine,N-methyl piperidine or triethylene diamine, preferably alkali be: sodium bicarbonate, potassium carbonate, triethylamine,N-methyl morpholine or pyridine；Amino benzenes compounds (1): carboxylic acid halides (2) or anhydride (3): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0, preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5；Reaction temperature is-60 DEG C ~ 100 DEG C, preferably 0 ~ 80 DEG C；Response time is 20 minutes ~ 24 hours, preferably 30 minutes ~ 12 hours.
B) by step A) obtainN-anilid compounds (4) under the conditions of solvent and alkalescence with racemization or optically active epoxychloropropane (5) reaction, obtain accordinglyN-glycidyl-N-anilid compounds (I)；Wherein, solvent for use is: C3-8Aliphatic ketone, C5-10Fat alkane or C5-10Cycloalkane (such as: normal hexane, normal heptane, hexamethylene etc.),N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, halogenated hydrocarbons (such as: dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene 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: oxolane,N,N-dimethylformamide, dichloromethane, chloroform, acetone, ethyl acetate, acetonitrile or toluene；Reaction alkali used is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, alkali metal and C1-12Salt, alkaline-earth metal and the C that alcohol is formed1-12Salt, NaH or KH, preferably alkali that alcohol is formed be: sodium bicarbonate, potassium carbonate, tert-butyl alcohol lithium or NaH；N-anilid compounds (4): epoxychloropropane (5): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0, preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5；Reaction temperature is-20 DEG C ~ 120 DEG C, preferably 0 ~ 80 DEG C；Response time is 1 ~ 24 hour, preferably 2 ~ 12 hours.
Method two:
With racemization or optically activeN-(2,3-epoxy-1-propyl group)-amino benzenes compounds (6) be initiation material, under the conditions of solvent and alkalescence with corresponding carboxylic acid halides (2) reaction, obtain accordinglyN-glycidyl-N-anilid compounds (I)；Wherein, solvent for use is: C3-8Aliphatic ketone, C5-10Fat alkane or C5-10Cycloalkane (such as: normal hexane, normal heptane, hexamethylene etc.),N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, halogenated hydrocarbons (such as: dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene 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: oxolane,N,N-dimethylformamide, dichloromethane, chloroform, acetone, ethyl acetate, acetonitrile or toluene；Reaction alkali used is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine,N-methyl morpholine,N-methyl piperidine or triethylene diamine, preferably alkali be: sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine,N-methyl morpholine 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, preferably 1.0:1.0 ~ 2.5:1.0 ~ 2.5；Reaction temperature is-60 DEG C ~ 100 DEG C, preferably 0 ~ 60 DEG C；Response time is 20 minutes ~ 24 hours, preferably 30 minutes ~ 12 hours.
Said method is utilized to prepareN-glycidyl-N-anilid compounds (I) available following methods be translated into (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine (II), these (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicines include but not limited to Linezolid (Linezolid) and razaxaban (Rivaroxaban) raceme or optical isomer, and its synthetic route is as follows:
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, thiophene-2-base or 5-chlorothiophene-2-base；Described compound be raceme,(S)-optical isomer or(R)-optical isomer.
Its synthetic method is described in detail below:
N-glycidyl-N-anilid compounds (I) in a solvent with ammonia through ammonolysis rearrangement reaction, obtain 2-hydroxyl-1,3-propane diamine compounds (7)；Gained compound7Recycling prior art, in suitable solvent, carry out ring-closure reaction with acylating reagent, obtain (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine (II)；Wherein, ammonia used by ammonolysis rearrangement reaction is: ammonia, ammonia spirit, the C of ammonia1-8Fatty alcohol solution, liquefied ammonia or heat decompose compound (such as: ammonium carbonate, ammonium hydrogen carbonate, ammonium acetate etc.) or the hexamethylenetetramine releasably going out ammonia；Ammonolysis rearrangement reaction solvent for use is: water, C1-8Fatty alcohol, C3-8Aliphatic ketone,N,N-dimethylformamide, ethers (such as: ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, glycol dimethyl ether, 1,4-dioxane etc.), C1-6Fatty acid and C1-6The formed ester of fatty alcohol, glycol monoethyl ether, ethylene glycol, halogenated hydrocarbons (such as: dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene 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, methanol, ethanol, oxolane,N,N-dimethylformamide, dichloromethane, chloroform, acetonitrile, glycol monoethyl ether, acetone or 1,4-dioxane；N-glycidyl-N-anilid compounds (I): the molar feed ratio of ammonia is 1.0:1.0 ~ 1000, preferably 1.0:5.0 ~ 100；Ammonolysis rearrangement reaction temperature is-40 DEG C ~ 100 DEG C, preferably 0 DEG C ~ 60 DEG C；The ammonolysis rearrangement reaction time is 20 minutes ~ 24 hours, preferably 2 hours ~ 12 hours；In acylated ring-closure reaction step, acylating reagent used is: phosphinylidyne diimidazole (CDI), phosgene, trichloromethyl chloroformate, double (trichloromethyl) carbonic ester, chloro-carbonic acid C1-8Aliphatic alcohol ester compounds (such as: ethyl chloroformate, isobutylchloroformate, benzyl chloroformate etc.), the C of carbonic acid1-8Aliphatic alcohol ester compounds (such as: dimethyl carbonate, diethyl carbonate etc.) or two succinimdyl carbonates (DSC).
Initiation material racemization or optically active used by the present inventionN-(2,3-epoxy-1-propyl group)-amino benzenes compounds (6) can use art methods to prepare, it may be assumed that amino benzenes compounds and racemization or optically active epichlorohydrin reaction, cyclization the most in the basic conditions,N-(2,3-epoxy-1-propyl group)-amino benzenes compounds (6), two step total recoverys > 90%.
It is an advantage of the current invention that: compared with prior art, it is cheap and easy to get that the method has raw material, and reaction condition is gentle, reactions steps is few, easy and simple to handle, do not use hazardous agents, and yield is high, low cost, optical purity of products is high, is suitable for fairly large preparing the features such as (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine.
Detailed description of the invention
The present invention can be conducted further description by the following examples, but, the scope of the present invention is not limited to following embodiment.One of skill in the art is it is understood that on the premise of without departing substantially 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 the most calibrated；(solvent is CDCl to Varian INOVA-400 nuclear magnetic resonance analyser3Or DMSO-d 6 , internal standard 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), flow phase: normal hexane-isopropanol-trifluoroacetic acid.
Embodiment 1
(R)-N-(2,3- Epoxy -1- Propyl group )-N-(3- Fluorine -4-(4- Morpholinyl ) Phenyl ) Acetamide ( (R)-Ia ) preparation
3-fluoro-4-morpholinyl phenylamine (0.01 mol), dichloromethane 100 ml, triethylamine (0.02 mol) it is sequentially added in reaction bulb, after stirring, add chloroacetic chloride (0.012 mol), reaction 3 hour is stirred at room temperature, reaction is finished, and reactant liquor is successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, and residue, through ethyl alcohol recrystallization, obtainsN-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide, yield 98%；
WillN-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide (8.0 mmol),N,N-dimethylformamide 30 ml and NaH(9.0 mmol) add in reaction bulb, add after reaction being stirred at room temperature 20 minutes (R)-epoxychloropropane (10.0 mmol), is warming up to 50-60 DEG C and reacts 3 hours, and reaction is finished, and removes solvent under reduced pressure, and residue is dissolved in ethyl acetate 100 ml, successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, (R)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide, yield 82.5%；HR-TOF-MS (+Q)m/z:295.1450 ([C15H19FN2O3+H]+Value of calculation: 295.1458).
Embodiment 2
(S)-N-(2,3- Epoxy -1- Propyl group )-N-(3- Fluorine -4-(4- Morpholinyl ) Phenyl ) Acetamide ( (S)-Ia ) preparation
3-fluoro-4-morpholinyl phenylamine (0.01 mol), ethyl acetate 100 ml, triethylamine (0.02 mol) it is sequentially added in reaction bulb, after stirring, add acetic anhydride (0.015 mol), reaction 8 hour is stirred at room temperature, reaction is finished, and reactant liquor is successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, through ethyl alcohol recrystallization,N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide, yield 99.0%；
By gainedN-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide (8.0 mmol), acetone 50 ml, potassium carbonate (12.0 mmol) and (S)-epoxychloropropane (12.0 mmol) adds in reaction bulb, and temperature rising reflux reacts 10 hours, and reaction is finished, and filters, and filtrate decompression is evaporated off solvent, and residue is dissolved in ethyl acetate 100 ml, successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, (S)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide, yield 68.9%；HR-TOF-MS (+Q)m/z:295.1456 ([C15H19FN2O3+H]+Value of calculation: 295.1458).
Embodiment 3
(dl)-N-(2,3- Epoxy -1- Propyl group )-N-(3- Fluorine -4-(4- Morpholinyl ) Phenyl ) Acetamide ( (dl)-Ia ) preparation
The same embodiment of operational approach1, simply incite somebody to action (R)-epoxychloropropane use (dl)-epoxychloropropane substitutes, and i.e. can get corresponding object yield 78.0%.
Embodiment 4
(R)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-5- Chlorine -2- Thenoyl amine ( (R)-Ib ) preparation
4-(3-morpholine ketone group) aniline (0.01 mol), oxolane 60 ml, triethylamine (0.015 mol) it is sequentially added in reaction bulb, after stirring, add 5-chloro-2-thiophene chloride (0.012 mol), reaction 5 hour is stirred at room temperature, reaction is finished, pressurization is evaporated off solvent, and residue is dissolved in dichloromethane 100 ml, successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, and residue, through ethyl alcohol recrystallization, obtainsN-[4-[(3-morpholine ketone group) phenyl]-5-chloro-2-thenoyl amine, yield 97.5%；
WillN-[4-[(3-morpholine ketone group) phenyl]-5-chloro-2-thenoyl amine (8.0 mmol),N,N-dimethylformamide 50 ml and NaH(9.0 mmol) add in reaction bulb, be stirred at room temperature addition in 20 minutes (R)-epoxychloropropane (10.0 mmol), is warming up to 50-60 DEG C and reacts 3 hours, and reaction is finished, and removes solvent under reduced pressure, and residue is dissolved in ethyl acetate 100 ml, successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, (R)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine, yield 95.5%；HR-TOF-MS (+Q)m/z:393.0682 ([C18H17ClN2O4S+H]+Value of calculation: 393.0676).
Embodiment 5
(S)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-5- Chlorine -2- Thenoyl amine ( (S)-Ib ) preparation
The same embodiment of operational approach4, simply incite somebody to action (R)-epoxychloropropane use (S)-epoxychloropropane substitutes,N,N-dimethylformamide oxolane substitutes, and NaH tert-butyl alcohol lithium substitutes, and i.e. can get corresponding object 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 ]]-5- Chlorine -2- Thenoyl amine ( (dl)-Ib ) preparation
The same embodiment of operational approach4, simply incite somebody to action (R)-epoxychloropropane use (dl)-epoxychloropropane substitutes,N,N-dimethylformamide oxolane substitutes, and NaH tert-butyl alcohol lithium substitutes, and i.e. can get corresponding object 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 ) preparation
The same embodiment of operational approach4, simply 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 ([C18H18N2O4S+H]+Value of calculation: 359.1066).
Embodiment 8
(S)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-2- Thenoyl amine ( (S)-Ic ) preparation
The same embodiment of operational approach4, simply chloro-for 5-2-thiophene chloride 2-thiophene chloride is substituted, (R)-epoxychloropropane use (S)-epoxychloropropane substitutes,N,N-dimethylformamide oxolane substitutes, and NaH tert-butyl alcohol lithium substitutes, and i.e. can get corresponding object 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 ) preparation
The same embodiment of operational approach4, simply chloro-for 5-2-thiophene chloride 2-thiophene chloride is substituted, (R)-epoxychloropropane use (dl)-epoxychloropropane substitutes,N,N-dimethylformamide oxolane substitutes, and NaH tert-butyl alcohol lithium substitutes, and i.e. can get corresponding object yield 86.3%；Its structure is confirmed through HR-TOF-MS.
Embodiment 10
(R)-N-(2,3- Epoxy -1- Propyl group )-N-(3- Fluorine -4-(4- Morpholinyl ) Phenyl ) Acetamide ( (R)-Ia ) preparation
Reaction bulb is sequentially added into (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline (0.01 mol), dichloromethane 80 ml, triethylamine (0.012 mol), after stirring, add chloroacetic chloride (0.012 mol), reaction 5 hour is stirred at room temperature, reaction is finished, and reactant liquor is successively with deionized water, saturated NaHCO3Aqueous solution and saturated nacl aqueous solution washing, anhydrous sodium sulfate filters after drying, and filtrate decompression boils off solvent, (R)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide, yield 98.5%；HR-TOF-MS (+Q)m/z:295.1466 ([C15H19FN2O3+H]+Value of calculation: 295.1458).
Embodiment 11
(S)-N-(2,3- Epoxy -1- Propyl group )-N-(3- Fluorine -4-(4- Morpholinyl ) Phenyl ) Acetamide ( (S)-Ia ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (S)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline substitutes, and dichloromethane oxolane substitutes, and triethylamine pyridine substitutes, (S)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide, yield 92.8%；HR-TOF-MS (+Q)m/z:295.1449 ([C15H19FN2O3+H]+Value of calculation: 295.1458).
Embodiment 12
(dl)-N-(2,3- Epoxy -1- Propyl group )-N-(3- Fluorine -4-(4- Morpholinyl ) Phenyl ) Acetamide ( (dl)-Ia ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (dl)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline substitutes, and i.e. can get corresponding object yield 95.5%.
Embodiment 13
(R)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-5- Chlorine -2- Thenoyl amine ( (R)-Ib ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (R)-N-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and dichloromethane ethyl acetate substitutes, and chloroacetic chloride 5-chloro-2-thiophene chloride substitutes, (R)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine, yield 98.0%；HR-TOF-MS (+Q)m/z:393.0674 ([C18H17ClN2O4S+H]+Value of calculation: 393.0676).
Embodiment 14
(S)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-5- Chlorine -2- Thenoyl amine ( (S)-Ib ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (S)-N-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and chloroacetic chloride 5-chloro-2-thiophene chloride substitutes, (S)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine, yield 95.0%；HR-TOF-MS (+Q)m/z:393.0670 ([C18H17ClN2O4S+H]+Value of calculation: 393.0676).
Embodiment 15
(dl)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-5- Chlorine -2- Thenoyl amine ( (dl)-Ib ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (dl)-N-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and chloroacetic chloride 5-chloro-2-thiophene chloride substitutes, (dl)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine, 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 ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (R)-N-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and chloroacetic chloride 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 ([C18H18N2O4S+H]+Value of calculation: 359.1066).
Embodiment 17
(S)-N-(2,3- Epoxy -1- Propyl group )-N-[4-[(3- Morpholine ketone group ) Phenyl ]]-2- Thenoyl amine ( (S)-Ic ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (S)-N-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and chloroacetic chloride 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 ) preparation
The same embodiment of operational approach10, simply incite somebody to action (R)-N-(2,3-epoxy-1-propyl group) the fluoro-4-of-3-(4-morpholinyl) aniline use (dl)-N-(2,3-epoxy-1-propyl group)-4-(3-morpholine ketone group) aniline substitutes, and chloroacetic chloride 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 -[(2R)-3-[[3- Fluorine -4-(4- Morpholinyl ) Phenyl ] Amino ]-2- Hydroxypropyl ]- Acetamide ( R -7a ) preparation
Reaction bulb adds (R)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide ((R)-Ia) (5.0 mmol), methanol 40 ml, commercially available 25%-28% ammonia 30 ml, be stirred at room temperature reaction 8 hours, reaction terminate after, removing methanol under reduced pressure, residue dissolves with 100 milliliters of dichloromethane, successively with deionized water 50 milliliters, saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na2SO4It is dried, removes solvent under reduced pressure, obtain whiteN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide, 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, CH3OH), 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×-CH2O), 3.62(m, 1H, CHOH), 3.15(m, 1H, CH2NHCO), 3.04(m, 1H, CH2NHCO), 2.98(m, 1H, CH2NHAr), 2.87(m, 1H, CH2NHAr), 2.82(t,J = 4.8Hz, 4H, 2×CH2N), 1.82(s, 3H, CH3)。
Embodiment 20
N -[(2S)-3-[[3- Fluorine -4-(4- Morpholinyl ) Phenyl ] Amino ]-2- Hydroxypropyl ]- Acetamide ( S- 7a ) preparation
Reaction bulb adds (S)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide ((S)-Ia) (5.0 mmol), oxolane 30 ml, methanol saturated solution 30 ml of ammonia, be stirred at room temperature reaction 8 hours, after reaction terminates, remove solvent under reduced pressure, residue dissolves with 100 milliliters of dichloromethane, successively with deionized water 50 milliliters, saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na2SO4Be dried, remove solvent under reduced pressure, obtain white solid, yield 95.0%, its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 21
(dl)-N-[-3-[[3- Fluorine -4-(4- Morpholinyl ) Phenyl ] Amino ]-2- Hydroxypropyl ]- Acetamide ( dl- 7a ) preparation
Reaction bulb adds (dl)-N-(2,3-epoxy-1-propyl group)-N-(the fluoro-4-of 3-(4-morpholinyl) phenyl) acetamide ((dl)-Ia) (5.0 mmol), methanol 50 ml and ammonium carbonate (0.05 mol), temperature rising reflux stirring reaction 5 hours, after reaction terminates, filtered while hot, filtrate decompression is evaporated off solvent, and residue dissolves with 60 milliliters of dichloromethane, successively with deionized water 50 milliliters, saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, residue, through conventional method purification, obtains white solid, yield 85.0%, its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 22
(R)-5- Chlorine -N-[2- Hydroxyl -3-[[4-(3- Morpholine ketone group ) Phenyl ] Amino ] Propyl group ]-2- Thenoyl amine ( R -7b ) preparation
Reaction bulb adds (R)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine ((R)-Ib) (5.0 mmol), acetonitrile 20 ml, commercially available 25%-28% ammonia 20 ml, be stirred at room temperature reaction 8 hours, reaction terminate after, removing solvent under reduced pressure, residue dissolves with 80 milliliters of dichloromethane, successively with deionized water 30 milliliters, saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, obtain white solid, yield 99.0%, chemical purity 99.8%, optical purity is more than 99.8%ee；M.p. 195.5-196.5 DEG C, [a]= +5.5o(c 0.5, 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, OCH2CO), 3.92(t,J=4.8 Hz, 2H, CH2N), 3.81-3.78(m, 1H, CHOH), 3.60(t,J=4.8 Hz, 2H, CH2O), 3.39-3.30(m, 1H, CH2N), 3.28-3.21(m, 1H, CH2N), 3.14-3.08(m, 1H, CH2N), 3.00-2.94(m, 1H, CH2N)。
Embodiment 23
(S)-5- Chlorine -N-[2- Hydroxyl -3-[[4-(3- Morpholine ketone group ) Phenyl ] Amino ] Propyl group ]-2- Thenoyl amine ( S -7b ) preparation
Reaction bulb adds (S)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine ((S)-Ib) (5.0 mmol), 1,4-dioxane 20 ml, commercially available 25%-28% ammonia 20 ml, reaction 6 hour is stirred at room temperature, after reaction terminates, removing solvent under reduced pressure, residue dissolves with 60 milliliters of dichloromethane, successively with deionized water 30 milliliters, saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, residue, through conventional method purification, obtains white solid, yield 96.8%, its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 24
(dl)-5- Chlorine -N-[2- Hydroxyl -3-[[4-(3- Morpholine ketone group ) Phenyl ] Amino ] Propyl group ]-2- Thenoyl amine ( dl -7b ) preparation
Reaction bulb adds (dl)-N-(2,3-epoxy-1-propyl group)-N-[4-[(3-morpholine ketone group) phenyl]]-5-chloro-2-thenoyl amine ((dl)-Ib) (5.0 mmol), deionized water 20 ml, ethanol alcohol saturated solution 20 ml of ammonia, be stirred at room temperature reaction 8 hours, after reaction terminates, remove solvent under reduced pressure, residue dissolves with 80 milliliters of dichloromethane, successively with deionized water 30 milliliters, saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, residue, through conventional method purification, 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 ] Amino ] Propyl group ]-2- Thenoyl amine ( R -7c ) preparation
Reaction bulb adds (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% ammonia 20 ml, be stirred at room temperature reaction 7 hours, reaction terminate after, removing solvent under reduced pressure, residue dissolves with 80 milliliters of dichloromethane, successively with deionized water 30 milliliters, saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, obtain white solid, yield 97.0%, chemical purity 99.8%, optical purity is more 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 ] Amino ] Propyl group ]-2- Thenoyl amine ( S -7c ) preparation
Reaction bulb adds (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% ammonia 20 ml, reaction 6 hour is stirred at room temperature, after reaction terminates, removing solvent under reduced pressure, residue dissolves with 60 milliliters of dichloromethane, successively with deionized water 30 milliliters, saturated NaCl aqueous solution 50 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, residue, through conventional method purification, 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 ] Amino ] Propyl group ]-2- Thenoyl amine ( dl -7c ) preparation
Reaction bulb adds (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, be stirred at room temperature reaction 8 hours, after reaction terminates, remove solvent under reduced pressure, residue dissolves with 80 milliliters of dichloromethane, successively with deionized water 30 milliliters, saturated NaCl aqueous solution 30 milliliters washing, organic layer is through anhydrous Na2SO4Being dried, remove solvent under reduced pressure, residue, through conventional method purification, obtains white solid, yield 96.5%, its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 28
(S)-N-[[3-[3- Fluorine -4-(4- Lin Ji ) Phenyl ]-2- Oxo -5- Oxazolidinyl ] Methyl ] The preparation of acetamide (Linezolid)
Reaction bulb add according to embodiment 19 preparation-obtainedN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) (0.01 mol), dichloromethane 100 ml and triethylamine (0.015 mol), after stirring, put and ice bath is cooled to 0-5 DEG C, add double (trichloromethyl) carbonic ester (0.004 mol), warming naturally to room temperature reaction 2 hours, reactant liquor uses 5%NaOH aqueous solution, saturated NaCl solution washing successively, and organic layer is dried through anhydrous sodium sulfate, filter, removal of solvent under reduced pressure, residue with ethyl acetate recrystallization, obtain white needle-like crystals, yield 95.0%, mp:178～179 DEG C；[a]= -9.2o (c 1.0, CHCl3), chemical purity 99.90%, optical purity 99.9%ee；1H NMR(CDCl3, 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, CH2CHO), 3.86(t,J=4.8 Hz, 4H, 2×OCH2), 3.75(dd, J 1=6.8 Hz,J 2=8.8 Hz, 1H, CH2CHO), 3.71～3.58 (m, 2H, CH2NH), 3.06(t,J=4.8 Hz, 4H, 2×NCH2), 2.02(s, 3H, CH3CO)；13C NMR(CDCl3, 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([C16H20FN3O4+H]+Value of calculation: 338.1516).
Embodiment 29
(R)-N-[[3-[3- Fluorine -4-(4- Lin Ji ) Phenyl ]-2- Oxo -5- Oxazolidinyl ] Methyl ] The preparation of acetamide
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) useN-[(2S)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( S- 7a) substitute, dichloromethane oxolane substitutes, and double (trichloromethyl) carbonic ester phosphinylidyne diimidazole substitutes, (R)-N-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide, yield 92.0%, mp:178～179 DEG C；Its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 30
(dl)-N-[[3-[3- Fluorine -4-(4- Lin Ji ) Phenyl ]-2- Oxo -5- Oxazolidinyl ] Methyl ] The preparation of acetamide
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (dl)-N-[-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( dl- 7a) substitute, dichloromethane ethyl acetate substitutes, and double (trichloromethyl) carbonic ester methylchloroformate substitutes, (dl)-N-[[3-[the fluoro-4-of 3-(4-Lin Ji) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide, yield 90.0%；Its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 31
(S)-5- Chlorine -N-[2- Oxygen -3-[4-(3- Morpholine ketone group ) Phenyl ]-1,3- Oxazolidine -5- Base ] Methyl ]-2- The preparation of thenoyl amine (razaxaban)
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (R)-5-is chloro-N-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] 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]= -41.0o(c 0.5, DMSO), chemical purity 99.85%, optical purity 99.8% ee；Its structure through HRMS-ESI,1H-NMR confirms.
Embodiment 32
(R)-5- Chlorine -N-[2- Oxygen -3-[4-(3- Morpholine ketone group ) Phenyl ]-1,3- Oxazolidine -5 Base ] Methyl ]-2- The preparation of thenoyl amine
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (S)-5-is chloro-N-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] amino] propyl group]-2-thenoyl amine ( S -7b) substitute, dichloromethane oxolane substitutes, and double (trichloromethyl) carbonic ester 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- Chlorine -N-[2- Oxygen -3-[4-(3- Morpholine ketone group ) Phenyl ]-1,3- Oxazolidine -5 Base ] Methyl ]-2- The preparation of thenoyl amine
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (dl)-5-is chloro-N-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] amino] propyl group]-2-thenoyl amine ( dl -7b) substitute, dichloromethane ethyl acetate substitutes, and double (trichloromethyl) carbonic ester methylchloroformate 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 ]-2- The preparation of thenoyl amine
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (R)-N-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] 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 ]-2- The preparation of thenoyl amine
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (S)-N-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] amino] propyl group]-2-thenoyl amine ( S -7c) substitute, dichloromethane oxolane substitutes, and double (trichloromethyl) carbonic ester 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 ]-2- The preparation of thenoyl amine
Operating process, with embodiment 28, simply willN-[(2R)-3-[[the fluoro-4-of 3-(4-morpholinyl) phenyl] amino]-2-hydroxypropyl]-acetamide ( R -7a) with (dl)-N-[2-hydroxyl-3-[[4-(3-morpholine ketone group) phenyl] amino] propyl group]-2-thenoyl amine ( dl -7c) substitute, dichloromethane ethyl acetate substitutes, and double (trichloromethyl) carbonic ester methylchloroformate 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 (7)

1. a classN-glycidyl-N-anilid compounds (I), it is characterised in that it is to have chemical structure of general formula( I )Shown compound:
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, thiophene-2-base or 5-chlorothiophene-2-base；Described compound be raceme,(S)-optical isomer or(R)-optical isomer.
The most as claimed in claim 1N-glycidyl-N-anilid compounds (I) preparation method, it is characterised in that can be prepared by following method:
Method one:
A) with amino benzenes compounds (1) be initiation material, solvent-free or under the conditions of having solvent and alkalescence, with corresponding carboxylic acid halides (2) or anhydride (3) reaction, obtain accordinglyN-anilid compounds (4)；
B) by step A) obtainN-anilid compounds (4) under the conditions of solvent and alkalescence with racemization or optically active epoxychloropropane (5) reaction, obtain accordinglyN-glycidyl-N-anilid compounds (I)；
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, 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 method as shown in method twoN-glycidyl-N-anilid compounds (I):
Method two:
With racemization or optically activeN-(2,3-epoxy-1-propyl group)-amino benzenes compounds (6) be initiation material, under the conditions of solvent and alkalescence with corresponding carboxylic acid halides (2) reaction, obtain accordinglyN-glycidyl-N-anilid compounds (I)；
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, thiophene-2-base or 5-chlorothiophene-2-base；X represents chlorine, bromine or iodine；Compound be raceme,(S)-optical isomer or(R)-optical isomer.
The most as claimed in claim 2N-glycidyl-N-anilid compounds (I) preparation method, it is characterised in that step A of method one) in, reaction solvent for use be: C3-8Aliphatic ketone, C5-10Fat alkane or C5-10Cycloalkane,N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, it is possible to carries out in two kinds of mixed solvents of above-mentioned solvent, and mixed solvent volume ratio is 1:0.1 ~ 10；Reaction alkali used is: alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine,N-methyl morpholine,N-methyl piperidine or triethylene diamine；Amino benzenes compounds (1): carboxylic acid halides (2) or anhydride (3): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0；Reaction temperature is-60 DEG C ~ 100 DEG C；Response time is 20 minutes ~ 24 hours.
The most as claimed in claim 2N-glycidyl-N-anilid compounds (I) preparation method, it is characterised in that step B of method one) in, reaction solvent for use be: C3-8Aliphatic ketone, C5-10Fat alkane or C5-10Cycloalkane,N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, it is possible to carries out in two kinds of mixed solvents of above-mentioned solvent, and mixed solvent volume ratio is 1:0.1 ~ 10；Reaction alkali used is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, alkali metal and C1-12Salt, alkaline-earth metal and the C that alcohol is formed1-12Salt that alcohol is formed, NaH or KH；N-anilid compounds (4): epoxychloropropane (5): the molar feed ratio of alkali is 1.0:1.0 ~ 5.0:1.0 ~ 5.0；Reaction temperature is-20 DEG C ~ 120 DEG C；Response time is 1 ~ 24 hour.
The most as claimed in claim 2N-glycidyl-N-anilid compounds (I) preparation method, it is characterised in that in method two react solvent for use be: C3-8Aliphatic ketone, C5-10Fat alkane or C5-10Cycloalkane,N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, 2-methyltetrahydrofuran, glycol dimethyl ether, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, it is possible to carries out in two kinds of mixed solvents of above-mentioned solvent, and mixed solvent volume ratio is 1:0.1 ~ 10；Reaction alkali used is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkali metal bicarbonates, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine,N-methyl morpholine,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；Reaction temperature is-60 DEG C ~ 100 DEG C；Response time is 20 minutes ~ 24 hours.
6. a (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine (II) preparation method, it is characterised in that with described in claim 1N-glycidyl-N-anilid compounds (I) it is raw material, prepared by following method:N-glycidyl-N-anilid compounds (I) in a solvent with ammonia through ammonolysis rearrangement reaction, obtain 2-hydroxyl-1,3-propane diamine compounds (7)；Gained compound7Recycling prior art, in suitable solvent, carry out ring-closure reaction with acylating reagent, obtain (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine (II)；
In formula: R1Represent morpholinyl or 3-oxygen-4-morpholinyl；R2Represent H or F；R3Represent C1-12Alkyl, thiophene-2-base or 5-chlorothiophene-2-base；Described compound be raceme,(S)-optical isomer or(R)-optical isomer；
Wherein, ammonia used by ammonolysis rearrangement reaction is: ammonia, ammonia spirit, the C of ammonia1-8Fatty alcohol solution, liquefied ammonia, ammonium carbonate, ammonium hydrogen carbonate, ammonium acetate or hexamethylenetetramine；Ammonolysis rearrangement reaction solvent for use is: water, C1-8Fatty alcohol, C3-8Aliphatic ketone,N,N-dimethylformamide, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane, glycol dimethyl ether, 1,4-dioxane, C1-6Fatty acid and C1-6The formed ester of fatty alcohol, glycol monoethyl ether, ethylene glycol, dichloromethane, chloroform, 1,2-dichloroethanes, o-dichlorohenzene, benzene, toluene or acetonitrile, reaction can be carried out in above-mentioned single solvent, also can carry out in the two of above-mentioned solvent kind mixed solvent, mixed solvent volume ratio is 1:0.1 ~ 10；N-glycidyl-N-anilid compounds (I): the molar feed ratio of ammonia is 1.0:1.0 ~ 1000；Ammonolysis rearrangement reaction temperature is-40 DEG C ~ 100 DEG C；The ammonolysis rearrangement reaction time is 20 minutes ~ 24 hours.
7. compound is preparing (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides medicine as claimed in claim 1, includes but not limited to the application in Linezolid and razaxaban raceme or optical isomer.
CN201410057203.4A 2014-02-20 2014-02-20 N-glycidyl-N-anilid compounds Preparation Method And The Use Expired - Fee Related CN104860904B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410057203.4A CN104860904B (en) 2014-02-20 2014-02-20 N-glycidyl-N-anilid compounds Preparation Method And The Use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410057203.4A CN104860904B (en) 2014-02-20 2014-02-20 N-glycidyl-N-anilid compounds Preparation Method And The Use

Publications (2)

Publication Number Publication Date
CN104860904A CN104860904A (en) 2015-08-26
CN104860904B true CN104860904B (en) 2016-08-17

Family

ID=53907139

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410057203.4A Expired - Fee Related CN104860904B (en) 2014-02-20 2014-02-20 N-glycidyl-N-anilid compounds Preparation Method And The Use

Country Status (1)

Country Link
CN (1) CN104860904B (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7816355B1 (en) * 2009-04-28 2010-10-19 Apotex Pharmachem Inc Processes for the preparation of rivaroxaban and intermediates thereof
CN102351807B (en) * 2011-09-03 2015-04-29 四川大学 Dibenzyl-1,3-oxazolidine-2-ketone compound and preparation method and application thereof
CN103483294B (en) * 2013-08-12 2015-01-28 四川大学 Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof

Also Published As

Publication number Publication date
CN104860904A (en) 2015-08-26

Similar Documents

Publication Publication Date Title
ES2903214T3 (en) Compounds derived from 1,3,4-oxadiazole as inhibitors of histone deacetylase 6 and the pharmaceutical composition comprising them
CA2553237C (en) Production method
EP2563781B1 (en) Processes for preparing linezolid
JP6325978B2 (en) Process for the preparation of rivaroxaban and intermediates formed in the process
EP2753619A2 (en) Processes and intermediates for preparing rivaroxaban
CN102822167A (en) Process for the preparation of rivaroxaban and intermediates thereof
EP2630143B1 (en) Processes for the preparation of rivaroxaban and intermediates thereof
CN101824012B (en) 2-(1,6,7,8-tetrahydrogen-2H-indeno-[5,4-b] furan-8-group) acetonitrile, preparation method and applciation
EP2613787A2 (en) Processes for the preparation of 4-{4-[5(s)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one
WO2013046211A1 (en) Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide and intermediates thereof
CA2771601A1 (en) Morpholinone compounds as factor ixa inhibitors
CN104487436B (en) Improved process for preparing rivaroxaban using intermediates
CN104592143B (en) The preparation method of Yi Zhong oxazolidinone compounds
ES2647607T3 (en) Procedure for the preparation of rivaroxaban
CN111699184B (en) Process for producing oxazolidinone compound
EP3565552B1 (en) An improved process for the preparation of rivaroxaban involving novel intermediate
CN102267956A (en) 1, 3-oxazolidin-2-one compound, preparation method and application thereof
CN104860904B (en) N-glycidyl-N-anilid compounds Preparation Method And The Use
WO2012041263A2 (en) A method of manufacturing 2-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l,3-oxazolidin-5-yl}methyl)-lh-isoindol-l,3(2h)-dione with a high optical purity
CN103804315B (en) A kind of preparation method of 5-An methyl oxazolidinone compounds
CN103483294B (en) Salt of 3-amino-2-propanol acetamide compound, as well as preparation method and use thereof
CN104370854B (en) 3-halogen-2-hydroxypropyl-1-anilid compounds Preparation Method And The Use
CN108250193B (en) Method for preparing rivaroxaban by one-pot method
WO2018055499A1 (en) One pot synthesis for the preparation of substituted phthalimido oxazolidinone antibacterials and oxazolidinone antiharombotics compounds by using recyclable heterogeneous catalyst
BR112018001720B1 (en) COMPOUNDS OF 1,3,4-OXADIAZOLE SULFONAMIDE DERIVATIVE AS A HISTONE DEACETYLASE 6 INHIBITOR AND THE PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate 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

Granted publication date: 20160817

CF01 Termination of patent right due to non-payment of annual fee