CN104058983B - A kind of synthetic method of medical material amides - Google Patents

A kind of synthetic method of medical material amides Download PDF

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CN104058983B
CN104058983B CN201410313564.0A CN201410313564A CN104058983B CN 104058983 B CN104058983 B CN 104058983B CN 201410313564 A CN201410313564 A CN 201410313564A CN 104058983 B CN104058983 B CN 104058983B
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compound
synthetic method
formula
auxiliary agent
reaction
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CN104058983A (en
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郑攀锋
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Gansu Hao Jun Pharmaceutical Co Ltd
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Abstract

The present invention relates to a kind of synthetic method of medicine intermediate amides, described method is with Ph 3p/CBr 4the composite catalyst system of/auxiliary agent and achieve the direct amidate action of torpescence carboxylic acid and aminated compounds, and filtering out hydrazine hydrate by experiment of single factor means and 1-benzyl-3-Methylimidazole Bromide is the best of breed of auxiliary agent, this synthesis technique reduces triphenylphosphine/CBr 4the consumption of catalyzer, reduces temperature of reaction and shortens the reaction times, achieves the technique effect of high yield simultaneously, is a kind of initiative catalytic preparation process of amides, has wide industrial applications prospect and marketable value.

Description

A kind of synthetic method of medical material amides
Technical field
The present invention relates to a kind of synthetic method of medical material amides, relate more specifically to a kind of method being prepared amides by torpescence carboxylic acid and amine catalyzed reaction, belong to organic synthesis field.
Background technology
Amides structure is the important feature fragment building bioprotein, medicine (as penicillin etc.), synthesis polymer (as nylon), it is prevalent among various bioactive molecule, and is subject to the extensive concern of medicine, biology, organic field research staff.
The carboxylic acid derivative (activation products as acyl chlorides, acid anhydrides or coupling reagent) that tradition prepares the method for amides mainly active reacts to prepare corresponding amide compound to aminated compounds, these methods reach its maturity, but are limited to the kind of active carboxylic acid derivative and applied environment and security.
As everyone knows, organic catalysis has become the mainstay in contemporary organic synthesis field, thus the method catalyzing and synthesizing amides has become modern vitochemical a major challenge, and also developed numerous catalysis synthesizing technologies [see " Metal-catalysedapproachestoamidebondformation ", C.LianaAllen etc., Chem.Soc.Rev., 2011,40,3405-3415], such as:
TommasoMarcelli (" MechanisticInsightsintoDirectAmideBondFormationCatalyzed byBoronicAcids:HalogensasLewisBases ", Angew.Chem.Int.Ed., 2010,49,6840-6843) report the synthesis technique of amides that a kind of amine and carboxylic acid are raw material, boric acid catalysis, its reaction formula is as follows:
In addition, HayleyCharville etc. (" Thethermalandboron-catalyseddirectamideformationreaction s:mechanisticallyunderstudiedyetimportantprocess ", Chem.Commun., 2010,46,1813-1823) also review the acid amides preparation technology of all kinds of thermocatalytic direct amido linkage forming reactions and boric acid catalysis.
C.LianaAllen etc. (" Directamideformationfromunactivatedcarboxylicacidsandami des ", Chem.Commun., 2012,48,666-668) disclose the direct amidate action of torpescence carboxylic acid and amine, it directly adopts torpescence carboxylic acid and amine to be raw material, directly amidate action is carried out under toluene, 110 DEG C of environment, it is without the need to catalyzer, and adopts Zirconium compound to be the successful preparation that catalyzer can realize amides in 4 hours.Its reaction formula is as follows:
LeonE.Barstow etc. (" ASimpleMethodfortheSynthesisofAmides ", J.Org.Chem., 1971,36 (9), 1305-1306) report a kind of simple method for synthesizing of acid amides, it adopts carboxylic acid and amine to be raw material, at triphenylphosphine and the CCl of 2 times of equivalents 4under system, in THF, back flow reaction directly prepares amide compound, but it need adopt a large amount of triphenyl phosphine catalyst systems, and its reaction formula is as follows: R'
Although prior art has existed the synthesis technique of multiple acid amides, there is many defects and still can not meet the demand of industrial application in existing technique, such as, temperature of reaction is too high and need consume mass energy; Catalytic reagent consumption is excessive and increase production cost; The use of noble metal catalyst and on the high side, etc.The present inventor is for above-mentioned problems, be intended to design a kind of composite catalyst system, it effectively reduces the consumption and temperature of reaction that reduce catalyzer by the interpolation of auxiliary agent, and significantly improve product yield, thus provide a kind of new and effective preparation technology for the production in the fields such as chemical and medicine industry.
Summary of the invention
In order to overcome above-mentioned pointed many defects, the present inventor, to this has been further investigation, after having paid a large amount of creative work, thus develops a kind of synthetic method of medical material amides, and then completes the present invention.
Specifically, technical scheme of the present invention and content relate to a kind of synthetic method of medical material formula (III) compound, described method comprises the steps: under atmosphere of inert gases, formula (I) compound is added in reactor, formula (II) compound and dry toluene, triphenylphosphine and tetrabromomethane is added wherein under stirring, auxiliary agent is added wherein after stirring 10min, temperature reaction, vacuum distilling after completion of the reaction, resistates adds saturated sodium bicarbonate solution after being dissolved in ethyl acetate, separate organic layer, with anhydrous magnesium sulfate drying, filter, revolve steaming, through silica gel chromatography, formula (III) compound can be obtained,
Wherein, R is H, C 1-C 6alkyl, C 1-C 6alkoxyl group, halogen or nitro;
Ar is phenyl or benzyl.
In described synthetic method of the present invention, described halogen is fluorine, chlorine, bromine or iodine atom.
In described synthetic method of the present invention, described C 1-C 6alkyl refers to the alkyl with 1-6 carbon atom, and it can be straight or branched, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl etc. in non-limiting manner.
In described synthetic method of the present invention, described C 1-C 6alkoxyl group refers to C 1-C 6the group that alkyl is connected with Sauerstoffatom.
In described synthetic method of the present invention, described auxiliary agent is the mixture of hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide, and wherein hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide mass ratio are 0.2-0.5:1, preferred 0.3:1.
In described synthetic method of the present invention, in described formula (I) compound of mole (mol) and in the ratio of liter dry toluene of (L) for 1:4-8, namely every mole (mol) described formula (I) compound uses 4-8 liter (L) dry toluene, such as, can be 1:4,1:5,1:6,1:7 or 1:8.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1-1.5, can be 1:1,1:1.1,1:1.2,1:1.3,1:1.4 or 1:1.5 in non-limiting manner, be preferably 1:1.2-1.4.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and triphenylphosphine is 1:0.1-0.3, such as, can be 1:0.1,1:0.15,1:0.2,1:0.25 or 1:0.3.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and tetrabromomethane is 1:1-1.5, can be 1:1,1:1.1,1:1.2,1:1.3,1:1.4 or 1:1.5 in non-limiting manner.
In described synthetic method of the present invention, in described formula (I) compound of mole (mol) and in the ratio 1:50-60 of the auxiliary agent of gram (g), namely every mole (mol) described formula (I) compound uses 50-60 gram (g) described auxiliary agent, can be 1:51,1:52,1:53,1:54,1:55,1:56,1:57,1:58,1:59 or 1:60 in non-limiting manner.
In described synthetic method of the present invention, the reaction times is without particular limitation, such as, can be 8-12h, can be 8h, 9h, 10h, 11h or 12h in non-limiting manner.
In described synthetic method of the present invention, temperature of reaction is 60-80 DEG C, such as, can be 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C or 80 DEG C.
In described synthetic method of the present invention, silica gel column chromatography adopts the mixed solution of ethyl acetate and normal hexane as elutriant, and wherein the volume ratio of ethyl acetate and normal hexane is 1:2.In following all embodiments, all elutriants that silica gel column chromatography uses are above-mentioned elutriant.
In described synthetic method of the present invention, rare gas element can be nitrogen or argon atmosphere.
Compared with prior art, beneficial effect of the present invention is:
1, adopt the compound system of catalyzer/auxiliary agent first, achieve torpescence carboxylic acid and aminated compounds direct reaction prepares amides, achieve the technique effect of high yield.
2, the interpolation that have studied auxiliary agent reduces the consumption of catalyzer, and have studied best auxiliary combination, itself and this reaction of catalyzer concerted catalysis and obviously improve reactivity worth.
3, the temperature required reduction of this technological reaction, time are shorter, are conducive to large-scale industrial production.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
Under nitrogen gas atmosphere, 1mmol formula (I) compound is added in reactor, 1.2mmol formula (II) compound and 6ml dry toluene, 0.2mmol triphenylphosphine and 1mmol tetrabromomethane is added wherein under stirring, the agent mixture of the hydrazine hydrate that 55mg mass ratio is 0.3:1 and 1-benzyl-3-Methylimidazole Bromide is added wherein after stirring 10min, be warming up to 70 DEG C of reaction 10h, vacuum distilling after completion of the reaction, resistates adds saturated sodium bicarbonate solution after being dissolved in ethyl acetate, separate organic layer, with anhydrous magnesium sulfate drying, filter, revolve steaming, through silica gel chromatography, formula (III) compound can be obtained, yield is 99.4%, purity is 99.2% (HPLC).
1HNMR(300MHz,CDCl 3)δ4.61(d,2H,J=3Hz),6.44(bs,1H),7.24-7.36(m,5H),7.51(d,J=9.0Hz,2H),7.75(d,J=9.0Hz,2H)
Embodiment 2
Under argon gas atmosphere, 1mmol formula (I) compound is added in reactor, 1.4mmol formula (II) compound and 7ml dry toluene, 0.1mmol triphenylphosphine and 1.5mmol tetrabromomethane is added wherein under stirring, the agent mixture of the hydrazine hydrate that 50mg mass ratio is 0.3:1 and 1-benzyl-3-Methylimidazole Bromide is added wherein after stirring 10min, be warming up to 60 DEG C of reaction 12h, vacuum distilling after completion of the reaction, resistates adds saturated sodium bicarbonate solution after being dissolved in ethyl acetate, separate organic layer, with anhydrous magnesium sulfate drying, filter, revolve steaming, through silica gel chromatography, formula (III) compound can be obtained, yield is 99.1%, purity is 99.3% (HPLC).
1HNMR(400MHz,DMSO-d6)δ7.10-7.14(m,1H),7.31-7.35(m,2H),7.72-7.77(m,2H),8.13(d,J=9.0Hz,2H),8.32(d,J=9.0Hz,2H),10.52(bs,1H)。
Embodiment 3
Under nitrogen gas atmosphere, 1mmol formula (I) compound is added in reactor, 1.3mmol formula (II) compound and 8ml dry toluene, 0.3mmol triphenylphosphine and 1.3mmol tetrabromomethane is added wherein under stirring, the agent mixture of the hydrazine hydrate that 60mg mass ratio is 0.3:1 and 1-benzyl-3-Methylimidazole Bromide is added wherein after stirring 10min, be warming up to 80 DEG C of reaction 8h, vacuum distilling after completion of the reaction, resistates adds saturated sodium bicarbonate solution after being dissolved in ethyl acetate, separate organic layer, with anhydrous magnesium sulfate drying, filter, revolve steaming, through silica gel chromatography, formula (III) compound can be obtained, yield is 99.5%, purity is 99.1% (HPLC).
1HNMR(300MHz,CDCl 3)δ3.83(s,3H),4.62(d,2H,J=6Hz),6.42(bs,1H),6.91(d,J=9.0Hz,2H),7.24-7.35(m,5H),7.76(d,J=9.0Hz,2H)。
Embodiment 4
Under argon gas atmosphere, 1mmol formula (I) compound is added in reactor, 1.2mmol formula (II) compound and 5ml dry toluene, 0.2mmol triphenylphosphine and 1.2mmol tetrabromomethane is added wherein under stirring, the agent mixture of the hydrazine hydrate that 54mg mass ratio is 0.3:1 and 1-benzyl-3-Methylimidazole Bromide is added wherein after stirring 10min, be warming up to 75 DEG C of reaction 10h, vacuum distilling after completion of the reaction, resistates adds saturated sodium bicarbonate solution after being dissolved in ethyl acetate, separate organic layer, with anhydrous magnesium sulfate drying, filter, revolve steaming, through silica gel chromatography, formula (III) compound can be obtained, yield is 99.2%, purity is 98.9% (HPLC).
1HNMR(400MHz,CDCl 3)δ1.34(s,9H),4.56(d,2H,J=2Hz),6.42(bs,1H),7.26-7.37(m,5H),7.45(dt,2H,J=4Hz,J=8Hz),7.74(dt,2H,J=4Hz,J=8Hz)。
Embodiment 5-8
Replace with except following component except by tetrabromomethane, implement embodiment 5-8 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 1 below.
Table 1
"--" expression is not added.
From the result of embodiment 1-4 and table 1, the present inventor studies discovery by experiment: CBr in this composite catalyzing/adjuvant system 4important concerted catalysis effect can be played, and cause the significantly reduction of yield when adopting other similar methyl halide compounds.
Embodiment 9-12
Replace with except following component except by the hydrazine hydrate in auxiliary agent, implement embodiment 9-12 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 2 below.
Table 2
Embodiment 13-16
Replace with except following component except by the 1-benzyl-3-Methylimidazole Bromide in auxiliary agent, implement embodiment 13-16 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 3 below.
Table 3
"--" expression is not added.
Embodiment 17-20
Except not adding auxiliary agent, implement embodiment 17-20 respectively in the mode identical with embodiment 1-4, the corresponding relation of component and experimental result is as shown in table 4 below.
Table 4
"--" expression is not added.
From the result of embodiment 1-4 and table 2-4, the kind of adjuvant component has apparent impact to whole composite catalyst system.Find that the combination of hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide is only the auxiliary agent mixture be applicable to the most by a large amount of literature research and experimental exploring, the change of its kind even can make reaction be difficult to carry out; The experiment of single factor of auxiliary agent is not added and to demonstrate auxiliary agent in whole compound system be indispensable by research.The present inventor constructs and Ph 3p/CBr 4the New-type adjuvant mixture system that catalyzer is composite, and obtain the technique effect achieving significant high yield.
In sum, the present inventor is by a large amount of creative works, and have developed a kind of new catalytic synthesis technique of amides, it is with Ph 3p/CBr 4the composite catalyst system of/auxiliary agent and achieve the direct amidate action of torpescence carboxylic acid and aminated compounds, and by experiment of single factor means, the classification of component and best of breed are screened.This novel Catalytic processes reduces the consumption of the catalyzer such as triphenylphosphine, and auxiliary agent auxiliary under improve the overall yield of reaction, effectively reduce the suitable temp of reaction simultaneously and reduce production cost, having industrial application value and market outlook.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.

Claims (9)

1. the synthetic method of formula (III) compound, described method comprises the steps: under atmosphere of inert gases, formula (I) compound is added in reactor, formula (II) compound and dry toluene, triphenylphosphine and tetrabromomethane is added wherein under stirring, auxiliary agent is added wherein after stirring 10min, temperature reaction, vacuum distilling after completion of the reaction, resistates adds saturated sodium bicarbonate solution after being dissolved in ethyl acetate, separate organic layer, with anhydrous magnesium sulfate drying, filter, revolve steaming, through silica gel chromatography, formula (III) compound can be obtained,
Wherein, R is H, C 1-C 6alkyl, C 1-C 6alkoxyl group, halogen or nitro;
Ar is phenyl or benzyl;
Described auxiliary agent is the mixture of hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide, and in described auxiliary agent, hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide mass ratio are 0.2-0.5:1.
2. synthetic method as claimed in claim 1, is characterized in that: in described auxiliary agent, hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide mass ratio are 0.3:1.
3. synthetic method as claimed in claim 1 or 2, is characterized in that: in mole described formula (I) compound and in the ratio of the dry toluene risen for 1:4-8.
4. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1-1.5.
5. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described formula (I) compound and triphenylphosphine is 1:0.1-0.3.
6. synthetic method as claimed in claim 1 or 2, is characterized in that: the mol ratio of described formula (I) compound and tetrabromomethane is 1:1-1.5.
7. synthetic method as claimed in claim 1 or 2, is characterized in that: in mole described formula (I) compound with in gram the ratio 1:50-60 of auxiliary agent.
8. synthetic method as claimed in claim 1 or 2, is characterized in that: temperature of reaction is 60-80 DEG C.
9. synthetic method as claimed in claim 1 or 2, is characterized in that: the reaction times is 8-12h.
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US5137918A (en) * 1986-04-22 1992-08-11 Goedecke Aktiengesellschaft N-(2'-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing them
CN101434561A (en) * 2007-11-13 2009-05-20 刘起瑞 Synthesis of 3-amino-4-chlorine-N-(5-chlorine-2-methyl phenyl) benzamide
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US5137918A (en) * 1986-04-22 1992-08-11 Goedecke Aktiengesellschaft N-(2'-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing them
CN101434561A (en) * 2007-11-13 2009-05-20 刘起瑞 Synthesis of 3-amino-4-chlorine-N-(5-chlorine-2-methyl phenyl) benzamide
CN102206172A (en) * 2010-03-30 2011-10-05 中国医学科学院医药生物技术研究所 Substituted diaryl compound and preparation method and antiviral application thereof

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