CN104058983A - Method for synthesizing medicine raw material amide compounds - Google Patents
Method for synthesizing medicine raw material amide compounds Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 20
- -1 amide compounds Chemical class 0.000 title abstract description 8
- 239000003814 drug Substances 0.000 title abstract description 5
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- 239000002994 raw material Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 25
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims abstract description 22
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 11
- ZVSNCWPOEUHDNE-UHFFFAOYSA-N 3-benzyl-1-methyl-1,2-dihydroimidazol-1-ium;bromide Chemical compound [Br-].C1=C[NH+](C)CN1CC1=CC=CC=C1 ZVSNCWPOEUHDNE-UHFFFAOYSA-N 0.000 claims abstract description 11
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000010189 synthetic method Methods 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012752 auxiliary agent Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 8
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 238000010025 steaming Methods 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 230000009435 amidation Effects 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 150000001408 amides Chemical class 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 5
- 239000002131 composite material Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012567 medical material Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229940059260 amidate Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 238000007171 acid catalysis Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000010976 amide bond formation reaction Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000002153 concerted effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 125000005620 boronic acid group Chemical group 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 150000003755 zirconium compounds Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing medicine midbody amide compounds. The compound catalytic system of Ph3P/CBr4/assistants is utilized in the method, and therefore the direct amidation of inert carboxylic acid and amine compounds can be achieved, and hydrazine hydrate and 1-benzyl-3-methylimidazole bromide are screened out through the single-factor experiment measures to be used as the optimal combination of the assistants. According to the synthesizing process, the use amount of triphenylphosphine/CBr4 catalysts is reduced, the reaction temperature is reduced, the reaction time is shortened, and meanwhile the high-yield technical effect is obtained, and the method is the pioneering catalyst preparation process of the amide compounds and has the wide industrial application prospect and the market value.
Description
Technical field
The present invention relates to a kind of synthetic method of medical material amides, relate more specifically to a kind of method of being prepared amides by torpescence carboxylic acid and amine catalyzed reaction, belong to organic synthesis field.
Background technology
Amides structure is the important structure fragment that builds bioprotein, medicine (as penicillin etc.), synthetic polymer (as nylon), it is prevalent among various bioactive molecules, and is subject to medicine, biology, organic field research staff's extensive concern.
The method that tradition is prepared amides is mainly that active carboxylic acid derivative (as the activation products of acyl chlorides, acid anhydrides or coupling reagent) reacts to prepare corresponding amide compound with aminated compounds, these methods reach its maturity, but are limited to kind and applied environment and the security of active carboxylic acid derivative.
As everyone knows, organic catalysis has become the mainstay in contemporary organic synthesis field, thereby the method that catalyzes and synthesizes amides has become modern vitochemical a major challenge, and also develop numerous catalysis synthesizing technologies [referring to " Metal-catalysedapproaches to amide bond formation ", C.Liana Allen etc., Chem.Soc.Rev., 2011,40,3405-3415], for example:
Tommaso Marcelli (" Mechanistic Insights into Direct Amide BondFormation Catalyzed by Boronic Acids:Halogens as Lewis Bases ", Angew.Chem.Int.Ed., 2010,49,6840-6843) reported that a kind of amine and carboxylic acid are the synthesis technique of the amides of raw material, boric acid catalysis, its reaction formula is as follows:
In addition, Hayley Charville etc. (" The thermal and boron-catalysed directamide formation reactions:mechanistically understudied yet importantprocess ", Chem.Commun., 2010,46,1813-1823) also summarize all kinds of thermocatalytic direct amido linkages and formed the acid amides preparation technology of reaction and boric acid catalysis.
C.Liana Allen etc. (" Direct amide formation from unactivatedcarboxylic acids and amides ", Chem.Commun., 2012,48,666-668) the direct amidate action of torpescence carboxylic acid and amine is disclosed, it directly adopts torpescence carboxylic acid and amine is raw material, under toluene, 110 DEG C of environment, directly carry out amidate action, it is without catalyzer, and employing Zirconium compound is the successful preparation that catalyzer can be realized amides in 4 hours.Its reaction formula is as follows:
Leon E.Barstow etc. (" A Simple Method for the Synthesis of Amides ", 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 is 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 triphenylphosphine catalyst system, 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, and for example, temperature of reaction is too high and need to consume mass energy; Catalytic reagent consumption excessive and increase production cost; The use of noble metal catalyst and on the high side, etc.The inventor is for above-mentioned problems, be intended to design a kind of composite catalyst system, its interpolation by auxiliary agent has effectively reduced the consumption and the temperature of reaction that have reduced catalyzer, and significantly improved product yield, thereby 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 inventor conducts in-depth research this, is paying after a large amount of creative works, thereby is developing a kind of synthetic method of medical material amides, and then completing the present invention.
Particularly, technical scheme of the present invention and content relate to the synthetic method of a kind of medical material formula (III) compound, described method comprises the steps: under atmosphere of inert gases, in reactor, add formula (I) compound, formula (II) compound and dry toluene, under stirring, add wherein triphenylphosphine and tetrabromomethane, after stirring 10min, add wherein auxiliary agent, 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, can obtain formula (III) compound,
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, for example can be to indefiniteness methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl etc.
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, preferably 0.3:1.
In described synthetic method of the present invention, in described formula (I) compound of mole (mol) with taking the ratio of liter dry toluene of (L) as 1:4-8, be that every mole of (mol) described formula (I) compound uses 4-8 liter (L) dry toluene, for example, 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 to indefiniteness 1:1,1:1.1,1:1.2,1:1.3,1:1.4 or 1:1.5, 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, for example, 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 to indefiniteness 1:1,1:1.1,1:1.2,1:1.3,1:1.4 or 1:1.5.
In described synthetic method of the present invention, in described formula (I) compound of mole (mol) with in the ratio 1:50-60 of gram auxiliary agent of (g), be that every mole of (mol) described formula (I) compound uses 50-60 gram of (g) described auxiliary agent, can be to indefiniteness 1:51,1:52,1:53,1:54,1:55,1:56,1:57,1:58,1:59 or 1:60.
In described synthetic method of the present invention, the reaction times is without particular limitation, for example, can be 8-12h, can be to indefiniteness 8h, 9h, 10h, 11h or 12h.
In described synthetic method of the present invention, temperature of reaction is 60-80 DEG C, for example, 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 embodiment, 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 first the compound system of catalyzer/auxiliary agent, realized torpescence carboxylic acid and aminated compounds direct reaction prepares amides, obtained the technique effect of high yield.
2, the interpolation of having studied auxiliary agent has reduced the consumption of catalyzer, and has studied best auxiliary combination, and this reacts itself and catalyzer concerted catalysis and obviously promoted 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 real protection scope of the present invention is formed to any type of any restriction, more non-protection scope of the present invention is confined to this.
Embodiment 1
Under nitrogen gas atmosphere, in reactor, add 1mmol formula (I) compound, 1.2mmol formula (II) compound and 6ml dry toluene, under stirring, add wherein 0.2mmol triphenylphosphine and 1mmol tetrabromomethane, after stirring 10min, adding wherein 55mg mass ratio is the agent mixture of hydrazine hydrate and the 1-benzyl-3-Methylimidazole Bromide of 0.3:1, 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, can obtain formula (III) compound, yield is 99.4%, purity is 99.2% (HPLC).
1H NMR(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, in reactor, add 1mmol formula (I) compound, 1.4mmol formula (II) compound and 7ml dry toluene, under stirring, add wherein 0.1mmol triphenylphosphine and 1.5mmol tetrabromomethane, after stirring 10min, adding wherein 50mg mass ratio is the agent mixture of hydrazine hydrate and the 1-benzyl-3-Methylimidazole Bromide of 0.3:1, 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, can obtain formula (III) compound, yield is 99.1%, purity is 99.3% (HPLC).
1H NMR(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, in reactor, add 1mmol formula (I) compound, 1.3mmol formula (II) compound and 8ml dry toluene, under stirring, add wherein 0.3mmol triphenylphosphine and 1.3mmol tetrabromomethane, after stirring 10min, adding wherein 60mg mass ratio is the agent mixture of hydrazine hydrate and the 1-benzyl-3-Methylimidazole Bromide of 0.3:1, 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, can obtain formula (III) compound, yield is 99.5%, purity is 99.1% (HPLC).
1H NMR(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, in reactor, add 1mmol formula (I) compound, 1.2mmol formula (II) compound and 5ml dry toluene, under stirring, add wherein 0.2mmol triphenylphosphine and 1.2mmol tetrabromomethane, after stirring 10min, adding wherein 54mg mass ratio is the agent mixture of hydrazine hydrate and the 1-benzyl-3-Methylimidazole Bromide of 0.3:1, 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, can obtain formula (III) compound, yield is 99.2%, purity is 98.9% (HPLC).
1H NMR(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
Except tetrabromomethane being replaced with following component, implement respectively embodiment 5-8 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
"--" represents not add.
From the result of embodiment 1-4 and table 1, the inventor studies discovery by experiment: CBr in this composite catalyzing/adjuvant system
4can bring into play important concerted catalysis effect, and in the time adopting other similar methyl halide compounds, cause the significantly reduction of yield.
Embodiment 9-12
Except the hydrazine hydrate in auxiliary agent is replaced with following component, implement respectively embodiment 9-12 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
Except the 1-benzyl-3-Methylimidazole Bromide in auxiliary agent is replaced with following component, implement respectively embodiment 13-16 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
"--" represents not add.
Embodiment 17-20
Except not adding auxiliary agent, implement respectively embodiment 17-20 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
"--" represents not add.
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 by a large amount of literature research and experimental exploring the combination of hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide is only the most applicable auxiliary agent mixture, the change of its kind even can make reaction be difficult to carry out; The experiment of single factor that does not add auxiliary agent by research has proved that auxiliary agent is indispensable in whole compound system.The inventor has built and Ph
3p/CBr
4the New-type adjuvant mixture system that catalyzer is composite, and obtained the technique effect of significant high yield.
In sum, the inventor, by a large amount of creative works, has researched and developed a kind of new catalytic synthesis technique of amides, and it is with Ph
3p/CBr
4the composite catalyst system of/auxiliary agent and realized the direct amidate action of torpescence carboxylic acid and aminated compounds, and the classification to component and best of breed screen by experiment of single factor means.This novel Catalytic processes has reduced the consumption of the catalyzer such as triphenylphosphine, and under auxiliary agent auxiliary, has improved the overall yield of reaction, effectively reduces the suitable temp of reaction simultaneously and has reduced production cost, has industrial application value and market outlook.
The purposes that should be appreciated that these embodiment only limits the scope of the invention for the present invention being described but not being intended to.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various changes, amendment and/or modification to the present invention, within these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. the synthetic method of a formula (III) compound, described method comprises the steps: under atmosphere of inert gases, in reactor, add formula (I) compound, formula (II) compound and dry toluene, under stirring, add wherein triphenylphosphine and tetrabromomethane, after stirring 10min, add wherein auxiliary agent, 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, can obtain formula (III) compound,
Wherein, R is H, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen or nitro;
Ar is phenyl or benzyl.
2. synthetic method as claimed in claim 1, is characterized in that: described auxiliary agent is the mixture of hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide.
3. the synthetic method as described in claim 1-2 any one, is characterized in that: in described auxiliary agent, hydrazine hydrate and 1-benzyl-3-Methylimidazole Bromide mass ratio are 0.2-0.5:1, preferably 0.3:1.
4. the synthetic method as described in claim 1-3 any one, is characterized in that: in described formula (I) compound of mole (mol) with taking the ratio of liter dry toluene of (L) as 1:4-8.
5. the synthetic method as described in claim 1-4 any one, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1-1.5.
6. the synthetic method as described in claim 1-5 any one, is characterized in that: the mol ratio of described formula (I) compound and triphenylphosphine is 1:0.1-0.3.
7. the synthetic method as described in claim 1-6 any one, is characterized in that: the mol ratio of described formula (I) compound and tetrabromomethane is 1:1-1.5.
8. the synthetic method as described in claim 1-7 any one, is characterized in that: in described formula (I) compound of mole (mol) with in the ratio 1:50-60 of gram auxiliary agent of (g).
9. the synthetic method as described in claim 1-8 any one, is characterized in that: temperature of reaction is 60-80 DEG C.
10. the synthetic method as described in claim 1-9 any one, is characterized in that: the reaction times is 8-12h.
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| CN106045870A (en) * | 2016-07-07 | 2016-10-26 | 上海应用技术学院 | Method for preparing amide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| DANNY C. LENSTRA等: "Triphenylphosphine-catalysed amide bond formation between carboxylic acids and amines", 《CHEM. COMMUN.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106045870A (en) * | 2016-07-07 | 2016-10-26 | 上海应用技术学院 | Method for preparing amide |
| CN106045870B (en) * | 2016-07-07 | 2018-07-03 | 上海应用技术学院 | A kind of method for preparing amide |
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