CN105949106B - A kind of preparation method of the maleimide compound of 3- amino-N- substitutions - Google Patents
A kind of preparation method of the maleimide compound of 3- amino-N- substitutions Download PDFInfo
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- CN105949106B CN105949106B CN201610494207.8A CN201610494207A CN105949106B CN 105949106 B CN105949106 B CN 105949106B CN 201610494207 A CN201610494207 A CN 201610494207A CN 105949106 B CN105949106 B CN 105949106B
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- MKRBAPNEJMFMHU-UHFFFAOYSA-N O=C(C=C1)N(Cc2ccccc2)C1=O Chemical compound O=C(C=C1)N(Cc2ccccc2)C1=O MKRBAPNEJMFMHU-UHFFFAOYSA-N 0.000 description 1
- UBAHEZQPAINIOT-UHFFFAOYSA-N O=C(C=C1N2CCOCC2)N(Cc2ccccc2)C1=O Chemical compound O=C(C=C1N2CCOCC2)N(Cc2ccccc2)C1=O UBAHEZQPAINIOT-UHFFFAOYSA-N 0.000 description 1
- IIBOGKHTXBPGEI-UHFFFAOYSA-N O=CNCc1ccccc1 Chemical compound O=CNCc1ccccc1 IIBOGKHTXBPGEI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 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 other ring carbon atoms
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Abstract
The present invention relates to a kind of preparation methods of the maleimide compound of 3 amino N substitution, it is characterised in that：The structural formula of the compound is：Wherein, R1For phenyl or benzyl, NR2R3For pyrrolidinyl, morpholinyl, benzamido group or dimethylamino.It prepares：Maleimide that N is replaced, aminated compounds, catalyst are added in solvent, are heated to 25 DEG C~140 DEG C and react 1~12 hour, purification to get.The maleimide compound operation of 3 amino Ns substitution prepared by the present invention is simple, and yield is higher, and reaction route is short, and the generation three wastes are few, are easy to industrialized production.
Description
Technical field
The invention belongs to the maleimide compound of 3- amino-N- substitutions and preparation method thereof fields, more particularly to
A kind of preparation method of the maleimide compound of 3- amino-N- substitutions.
Background technology
The maleimide compound (I~IV) and its derivative of 3- amino-N- substitutions are important in pharmaceutical synthesis
Mesosome, while there is extensive antibacterial and bioactivity (Mori, the K. such as antitumor；Izawa,T.；Matsui,
S.Antifouling N-arylmaleimide derivatives.JP 53032119,1978；Augustin,M.；
Koehler,M.；Kazandji,S..Sulfurization of C-substituted maleimide,Tetrahedron,
1984,40(18),3499-502.；Patil,N.S.；Deshmukh,G.B.；Patil,S.V.；Bholay,A.D.；
Gaikwad,N.D.Synthesis and biological evaluation of novel N-aryl maleimide
derivatives clubbed withα-hydroxyphosphonates.European Journal of Medicinal
Chemistry,2014,83:490-497.；Mabrie,A.B.；Robin,M.P.；Quan,W.D.；Willcock,H.；
Stavros,G.；O’Reilly,R.K.Aminomaleimide fluorophores:a simple functional group
with bright,solvent dependent emission,Chemical Communications,2015,51(47):
9733-9736.)。
The synthetic method of the maleimide compound of document report 3- amino-N- substitutions includes mainly three kinds：
Method one：Tourteau etc. is reported by N- benzyl maleimides and bromine in methylene chloride reflux, then again
It is acted on down by triethylamine and the synthesis bromo- N- benzyl maleimides of 3-, yield 98% is stirred at room temperature in THF.Using three second
Amine acts on, and room temperature synthesizes target product morpholinyl-N- benzyl maleimides, yield 82% in methylene chloride with morpholine.
(Tourteau,A.；Merlet,E.；Bontemps,A.；Leland,M.；Helissey,P.；Giorgi-Renault,S.；
Desbene-Finck,S..Easy access to 1H-pyrrolo[3’4’:5,6]pyrido[2,3-d]pyrimidine-
2,4-6,8(3H,7H)-tetraone and selectively N7-substituted analogues through key
synthons.European Journal of Organic Chemistry,2015,2015(32):7028-7035.)
Method two：Patil etc. reports N-phenylmaleimide and obtains 3,4- with bromine generation addition reaction in DMF
Two bromo- N-phenylmaleimides then obtain the maleimide of 3- amino substitution without isolation with amine reaction intermediate
Compound, yield is up to 90%.(Patil,N.S.；Deshmukh,G.B.；Mahale,K.A.；Gosavi,K.S.；Patil,
S.V..Synthesis of novel N-aryl-3-dialkyamino-4-substituted maleimides.Indian
journal of Chemistry,Section B:Organic Chemistry Medicinal Chemistry,2015,54B
(2):272-278.)
Method three：Tamura etc. is reported using diphenyl sulfilimine and halogenated alkyl hydrocarbon as raw material, synthesizes nucleopilic reagent N-
Addition elimination reaction again then occurs with maleimide compound, obtains 3- ammonia again for alkyl diphenyl base sulfilimine compound
The maleimide compound of base substitution, yield is up to 79%.(Tamura,Y.；Matsushima,H.；and Ikeda,
M.Syntheses and nucleophilic reactions of N-
alkyldiphenylsulfilimines.Tetrahedron,1976,32(4):431-435.)
The shortcomings of above-mentioned three kinds of synthetic methods all have reaction route long, and by-product is more, low yield, meanwhile, the third
Raw material used in method is not easy to obtain, expensive, increases production cost.Therefore, these three methods are all unsuitable for large quantities of
Amount synthesis.
Invention content
Technical problem to be solved by the invention is to provide a kind of maleimide compounds of 3- amino-N- substitutions
Preparation method, the N-substituted maleimide of this method and aminated compounds are raw material, using mantoquitas such as copper acetates as catalyst,
It is heated to the maleimide compound that 120 DEG C of reactions obtain the-N- substitutions of 3- amino for 1~12 hour in chlorobenzene solution, receives
Rate is up to 55~95%.
A kind of maleimide compound of 3- amino-N- substitutions of the present invention, the structural formula of the compound are：Wherein, R1For phenyl or benzyl, NR2R3For pyrrolidinyl, morpholinyl, benzamido group or dimethylamino.
The compound is： In one kind.
A kind of preparation method of the maleimide compound of 3- amino-N- substitutions of the present invention, including：
Maleimide, aminated compounds, the catalyst that N- is replaced are added in solvent, are heated to 25 DEG C~140 DEG C instead
It answers 1~12 hour, purifies the maleimide compound to get the-N- substitutions of 3- amino；Wherein maleimide, amine
Close object, the molar ratio of catalyst is 1.0:1.0~2.0:0.1~1.0.
The catalyst is mantoquita.
The mantoquita is one or more of cuprous iodide, stannous chloride, cuprous bromide, copper acetate.
The solvent is chlorobenzene and/or dimethyl sulfoxide (DMSO)；Aminated compounds is in pyrrolidines, morpholine, benzylamine, dimethylamine
It is a kind of.The w/v of N- substituted maleimides amine and solvent is 1 gram：1 milliliter~100 milliliters.
The purification is：Water is added to stir 3-5min, ethyl acetate extraction, organic phase anhydrous sodium sulfate is dry, it is molten to boil off
Agent, obtained solid are recrystallized.
N- substituted maleimides amine, water, ethyl acetate w/v be 1 gram：4 milliliters~100 milliliters：4 milliliters~
100 milliliters.
Recrystallization solvent for use is 95% ethyl alcohol.
It is as follows that the maleimide compound of the 3- amino-N- substitutions of the present invention specifically prepares reaction equation：
The synthetic route of the maleimide compound of 3- amino-N- substitutions
The structural formula of the compound (I) is：
Fusing point：98~100 DEG C；
Character：Yellow solid；
1H NMR(400MHz,CDCl3)δ:2.02(s,4H),3.35(s,2H),3.94(s,2H),4.89(s,1H),7.32
(dd, J=18.4,7.7Hz, 3H), 7.43 (t, J=7.5Hz, 2H)
13C NMR(101MHz,CDCl3)δ:24.08,26.35,49.11,50.45,86.04,126.30(2C),
127.18,128.86(2C),132.12,148.18,165.60,170.42；
The structural formula of the compound (II) is：
Fusing point：120~122 DEG C；
Character：Yellow solid；
1H NMR(400MHz,CDCl3)δ:3.70(s,4H),3.79(s,4H),4.64(s,2H),4.98(s,1H),7.30
(d, J=12.6Hz, 2H), 7.37 (d, J=7.2Hz, 3H)
13C NMR(101MHz,CDCl3)δ:40.99(2C),47.14(2C),66.28,89.76,127.59,128.36
(2C),128.59(2C),136.83,150.06,166.90,170.34
The structural formula of the compound (III) is：
Fusing point：110~112 DEG C；
Character：Yellow solid；
1H NMR(400MHz,CDCl3)δ:4.39 (d, J=5.0Hz, 2H), 5.01 (s, 1H), 5.90 (s, 1H), 7.38
(m,10H)
13C NMR(101MHz,CDCl3)δ:48.52,85.71,125.90(2C),127.38,127.79(2C),
128.39,128.97(2C),129.08(2C),131.82,135.56,148.74,166.35,171.01；
The structural formula of the compound (IV) is：
Fusing point：132~134 DEG C；
Character：Yellow solid；
1H NMR(400MHz,CDCl3)δ:3.25 (s, 6H), 4.97 (s, 1H), 7.33 (d, J=7.5Hz, 3H), 7.44
(t, J=7.2Hz, 2H)
13C NMR(101MHz,CDCl3)δ:39.69(2C),87.71,126.43(2C),127.33,128.88(2C),
131.96,150.47,165.74,169.68.
Advantageous effect
The present invention is during preparing the maleimide compound of 3- amino-N- substitutions, using mantoquita as catalyst,
The reaction time is shortened, while improving yield；The preparation method starting material is easy to get, and at low cost, operation is simple, reaction
Route is short, is easy to industrialized production.
Description of the drawings
Fig. 1 is the nuclear magnetic resonance spectroscopy of compound 3- pyrrolidinyls-N-phenylmaleimide (I)；
Fig. 2 is the carbon-13 nmr spectra of compound 3- pyrrolidinyls-N-phenylmaleimide (I).
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, people in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1
Take N-phenylmaleimide 17.3g (0.1mol), pyrrolidines 10.6g (0.15mol), copper acetate 3.6g
(0.02mol) is added into 250mL round-bottomed flasks, and chlorobenzene 100mL is then added, and is heated to 120 DEG C of stirring 6h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 200mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, gained is solid
Body obtains yellow solid 3- pyrrolidinyls-N-phenylmaleimide 15.0g, yield 62%, mp with 95% ethyl alcohol recrystallization:98~
100℃。1H NMR(400MHz,CDCl3)δ:2.02(s,4H),3.35(s,2H),3.94(s,2H),4.89(s,1H),7.32
(dd, J=18.4,7.7Hz, 3H), 7.43 (t, J=7.5Hz, 2H)；13C NMR(101MHz,CDCl3)δ:24.08,26.35,
49.11,50.45,86.04,126.30(2C),127.18,128.86(2C),132.12,148.18,165.60,170.42。
Embodiment 2
Take N-phenylmaleimide 8.65g (0.05mol), pyrrolidines 5.3g (0.075mol), copper acetate 9.1g
(0.05mol) is added into 250mL round-bottomed flasks, and chlorobenzene 100mL is then added, and is heated to 120 DEG C of stirring 8h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 150mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, gained is solid
Body obtains yellow solid 3- pyrrolidinyls-N-phenylmaleimide 11.5g, yield 95%, mp with 95% ethyl alcohol recrystallization:98~
100℃。
Embodiment 3
Take N-phenylmaleimide 8.65g (0.05mol), pyrrolidines 5.3g (0.075mol), copper acetate 9.1g
(0.05mol) is added into 250mL round-bottomed flasks, and dimethyl sulfoxide (DMSO) 100mL is then added, and is heated to 120 DEG C of stirrings
12h, reaction are finished, and water 50mL is added, and are stirred 5 minutes, and ethyl acetate 300mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, are steamed
Solvent, obtained solid is gone to obtain brown solid 3- pyrrolidinyls-N-phenylmaleimide 9.68g with 95% ethyl alcohol recrystallization,
Yield 80%, mp:98~100 DEG C.
Embodiment 4
Take N-phenylmaleimide 1.73g (0.01mol), pyrrolidines 1.07g (0.075mol), stannous chloride 0.99g
(0.01mol) is added into 250mL round-bottomed flasks, and chlorobenzene 20mL is then added, and is heated to 120 DEG C of stirring 12h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 50mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, obtained solid
Yellow solid 3- pyrrolidinyls-N-phenylmaleimide 1.57g, yield 65%, mp are obtained with 95% ethyl alcohol recrystallization:98~
100℃。
Embodiment 5
Take N-phenylmaleimide 1.73g (0.01mol), pyrrolidines 1.07g (0.075mol), cuprous bromide 1.43g
(0.01mol) is added into 250mL round-bottomed flasks, and chlorobenzene 20mL is then added, and is heated to 120 DEG C of stirring 12h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 50mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, obtained solid
Yellow solid 3- pyrrolidinyls-N-phenylmaleimide 1.65g, yield 68%, mp are obtained with 95% ethyl alcohol recrystallization:98~
100℃。
Embodiment 6
Take N-phenylmaleimide 5.0g (0.03mol), pyrrolidines 4.3g (0.06mol), cuprous iodide 1.90g
(0.01mol) is added into 250mL round-bottomed flasks, and chlorobenzene 60mL is then added, and is heated to 120 DEG C of stirring 12h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 100mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, gained is solid
Body obtains yellow solid 3- pyrrolidinyls-N-phenylmaleimide 5.4g, yield 75%, mp with 95% ethyl alcohol recrystallization:98~
100℃。
Embodiment 7
Take N- benzyl maleimides 18.7g (0.1mol), morpholine 13.05g (0.15mol), copper acetate 18.16g
(0.1mol) is added into 250mL round-bottomed flasks, and chlorobenzene 100mL is then added, and is heated to 120 DEG C of stirring 12h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 200mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, gained is solid
Body obtains yellow solid morpholinyl-N- benzyl maleimide 22.0g, yield 81%, mp with 95% ethyl alcohol recrystallization:120~
122℃。1H NMR(400MHz,CDCl3)δ:3.70(s,4H),3.79(s,4H),4.64(s,2H),4.98(s,1H),7.30
(d, J=12.6Hz, 2H), 7.37 (d, J=7.2Hz, 3H)；13C NMR(101MHz,CDCl3)δ:40.99(2C),47.14
(2C),66.28,89.76,127.59,128.36(2C),128.59(2C),136.83,150.06,166.90,170.34。
Embodiment 8
Take N-phenylmaleimide 17.3g (0.1mol), benzylamine 16.05g (0.15mol), copper acetate 18.16g
(0.1mol) is added into 250mL round-bottomed flasks, and chlorobenzene 100mL is then added, and is heated to 120 DEG C of stirring 12h, and reaction is finished, added
Water 50mL is stirred 5 minutes, and ethyl acetate 300mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, gained is solid
Body obtains yellow solid 3- benzamido groups-N-phenylmaleimide 14.18g, yield 51%, mp with 95% ethyl alcohol recrystallization:110~
112℃。1H NMR(400MHz,CDCl3)δ:4.39 (d, J=5.0Hz, 2H), 5.01 (s, 1H), 5.90 (s, 1H), 7.38 (m,
10H)；13C NMR(101MHz,CDCl3)δ:48.52,85.71,125.90(2C),127.38,127.79(2C),128.39,
128.97(2C),129.08(2C),131.82,135.56,148.74,166.35,171.0。
Embodiment 9
Take N-phenylmaleimide 17.3g (0.1mol), 33% dimethylamine agueous solution 20.45g (0.15mol), acetic acid
Copper 18.16g (0.1mol) is added into 250mL round-bottomed flasks, and chlorobenzene 100mL is then added, and is heated to 120 DEG C of stirring 12h, instead
It should finish, add water 50mL, stir 5 minutes, ethyl acetate 200mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent,
Obtained solid obtains yellow solid 3- dimethylamino-N-phenylmaleimide 10.6g with 95% ethyl alcohol recrystallization, yield 49%,
mp:132~134 DEG C.1H NMR(400MHz,CDCl3)δ:3.25 (s, 6H), 4.97 (s, 1H), 7.33 (d, J=7.5Hz, 3H),
7.44 (t, J=7.2Hz, 2H)；13C NMR(101MHz,CDCl3)δ:39.69(2C),87.71,126.43(2C),127.33,
128.88(2C),131.96,150.47,165.74,169.68。
Embodiment 10
Take N-phenylmaleimide 17.3g (0.1mol), 33% dimethylamine agueous solution 20.45g (0.15mol), chlorination
Cuprous 9.9g (0.1mol) is added into 250mL round-bottomed flasks, and dimethyl sulfoxide (DMSO) 100mL is then added, is heated to 120 DEG C
12h is stirred, reaction is finished, and water 50mL is added, and is stirred 5 minutes, and ethyl acetate 200mL × 3 is extracted, and organic phase is dry with anhydrous sodium sulfate
It is dry, solvent is boiled off, obtained solid obtains yellow solid 3- dimethylamino-N-phenylmaleimide with 95% ethyl alcohol recrystallization
13.2g, yield 61%, mp:132~134 DEG C.
Claims (7)
1. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions, it is characterised in that：The compound
Structural formula is：Wherein, R1For phenyl or benzyl, NR2R3For pyrrolidinyl, morpholinyl, benzamido group or diformazan
Amido；
Preparation method includes：Maleimide, aminated compounds, the catalyst that N- is replaced are added in solvent, are heated to 25 DEG C
~140 DEG C are reacted 1~12 hour, and the maleimide compound to get the-N- substitutions of 3- amino is purified；Wherein maleimide
Amine, aminated compounds, catalyst molar ratio be 1.0:1.0~2.0:0.1~1.0；Wherein catalyst is cuprous iodide, chlorination
One or more of cuprous, cuprous bromide, copper acetate；Solvent is chlorobenzene and/or dimethyl sulfoxide (DMSO).
2. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special
Sign is：The compound is：
In one kind.
3. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special
Sign is：The aminated compounds is one kind in pyrrolidines, morpholine, benzylamine, dimethylamine.
4. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special
Sign is：The w/v of N- substituted maleimides amine and solvent is 1 gram：1 milliliter~100 milliliters.
5. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 1, special
Sign is：The purification is：Water is added to stir 3-5min, ethyl acetate extraction, organic phase anhydrous sodium sulfate is dry, it is molten to boil off
Agent, obtained solid are recrystallized.
6. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 5, special
Sign is：N- substituted maleimides amine, water, ethyl acetate w/v be 1 gram：4 milliliters~100 milliliters：4 milliliters~
100 milliliters.
7. a kind of preparation method of the maleimide compound of 3- amino-N- substitutions according to claim 5, special
Sign is：Recrystallization solvent for use is 95% ethyl alcohol.
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