CN101875590B - Method for synthesizing acrylamide compound - Google Patents
Method for synthesizing acrylamide compound Download PDFInfo
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- CN101875590B CN101875590B CN 201010229266 CN201010229266A CN101875590B CN 101875590 B CN101875590 B CN 101875590B CN 201010229266 CN201010229266 CN 201010229266 CN 201010229266 A CN201010229266 A CN 201010229266A CN 101875590 B CN101875590 B CN 101875590B
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Abstract
The invention discloses a method for synthesizing an acrylamide derivative as shown in the synthesis formula (I). The acrylamide derivative is obtained by performing reductive acylation and isomerization on an oxime derivative and an acyl compound in the presence of a Pd, Cu or Ni transition metal catalyst and a proper reducing agent, wherein R1, R2 and R3 independently are hydrogen atoms, aryl, aryloxy, alkyl, cyclalkyl, alkoxy, heterocyclyl, carboxyl, esteryl, cyano, sulfonyl and carbamoyl; or R1 and R2 are combined into ring; or R2 and R3 are combined into a ring; R4 is hydrogen atom, alkyl or aryl; n is 1 or 2; and when n is 1, X is a leaving group and when n is 2, X is an oxygen atom. A series of high-yield substituted acrylamide compounds can be obtained under a mild condition by reducing and acylating oxime in the presence of the transition metal catalyst. The method has the characteristics of mild reaction condition, simple operation, wide application range, low production cost, high synthesis yield and the like.
Description
Technical field
The present invention relates to a kind of synthetic method of acrylamide compound, particularly a kind of synthetic method that is suitable for the scale operation acrylamide compound belongs to technical field of organic synthesis.
Background technology
In the modern pharmaceutical industry, acrylamide compound be widely used in asymmetric or symmetrical hydrogenation prepare Chiral Amine or non chiral amine compounds (T.C.Nugent, M.El-Shazly, Adv.Synth.Catal.2010,352,753-819).In organic synthesis, the alkene acid amides also can be used as the formation reaction that nucleophilic reagent participates in carbon-carbon bond and carbonnitrogen bond (R.Matsubara, S.Kobayashi, Acc.Chem.Res.2008,41,292-301).The shortcomings such as but the technology of existing synthetic acrylamide compound exists severe reaction conditions, catalyzer or the reductive agent cost is high, substrate is limited in scope, productive rate is not high are not suitable for scale operation.
Patent WO 99/18065, M.Burk (J.Org.Chem.; 1998; 63,6084) and X.Zhang (J.Org.Chem., 1999; 64; 1775) described iron powder/acetic anhydride/acetic acid reduction system, the reductive acylation ketoxime synthesizes acrylamide compound, the local superheating in the system but the iron powder of chemical quantity can induce reaction; cause reaction steadily not carry out, and productive rate is lower.Chinese patent application CN200480038602.0 has described precious metal (iridium, rhodium etc.) and has existed lower hydrogen and acid anhydrides reductive acylation ketoxime to prepare acrylamide compound, but the use of a large amount of precious metals, so that this reaction cost is too high.Chinese patent application CN200780013686.6 has described the standby acrylamide compound of alkylphosphines and acid anhydrides reductive acylation legal system, but the shortcomings such as that the alkylphosphines compound exists is large to air-sensitive, toxicity, severe reaction conditions.
In view of all deficiencies of existing preparation method, the novel method of developing the preparation acrylamide compound that a kind of reaction conditions is gentle, production cost is low, wide application range of substrates is general and productive rate is high has very strong practical application meaning.
Summary of the invention
The object of the present invention is to provide the preparation method of the acrylamide compound that a kind of reaction conditions is gentle, production cost is low, applied widely, synthetic yield is high.
Implementation procedure of the present invention is as follows:
A kind of synthetic method of alkenylamide derivative, in the presence of Pd, Cu or Ni transition-metal catalyst and suitable reductive agent, formula (II) 9 oxime derivate and formula (III) acyl compounds obtain through reductive acylation, isomerization reaction,
Wherein,
R1, R2 and R3 independently are hydrogen atom, aryl, aryloxy, alkyl, cycloalkyl, alkoxyl group, heterocyclic radical, carboxyl, ester group, cyano group, sulfuryl, formamyl;
Perhaps R1, R2 are combined into ring;
Perhaps R2, R3 are combined into ring;
R4 is hydrogen atom, alkyl or aryl;
N is 1 or 2, and when n was 1, X was leavings group; When n was 2, X was Sauerstoffatom.
The C atomicity of described R1, R2 and R3≤20, the C atomicity of R4≤10.
Among the present invention, catalyst levels is 1～30mol% of formula (II) 9 oxime derivate consumption; The consumption of formula (III) compound is at least 1 times of mole dosage of formula (II) 9 oxime derivate, preferentially selects 2～3 times of mole dosage.
Catalyzer of the present invention is Pd, Cu or Ni transition metal simple substance, halogenide or acetate, is preferably cuprous halide salt or cuprous acetate, and most preferred is cuprous iodide or cuprous bromide.
The present invention carries out in suitable solvent, and solvent is such as toluene, DMF, Isosorbide-5-Nitrae-dioxane, ethyl acetate or 1,2-ethylene dichloride (DCE) etc.
The present invention implements in 20～150 ℃ temperature range, and optimum temperature range is 80～130 ℃.Described reductive agent is selected from S-WAT, sodium bisulfite, Sodium Hydrosulphite, sodium sulphite, potassium sulphide, sulphur; Be preferably sodium bisulfite or Sodium Hydrosulphite, and the consumption of reductive agent is based on 1～3 times of mole dosage of formula (II) 9 oxime derivate.
Described leavings group is halogen (such as Cl, Br, I), acid group (such as carbonate, sulfonate radical).
The inventive method has the reaction conditions gentleness, simple to operate, applied widely, production cost is low, the synthetic yield high.
Embodiment
For a better understanding of the present invention, now illustrate, but these embodiment also limit scope of the present invention never in any form.
Embodiment 1: prepare the alkene acid amides by acetophenone oxime
In the 250mL round-bottomed flask, add acetophenone oxime (13.5g, 0.1mol), sodium bisulfite (31.2g, 0.3mol), acetic anhydride (20.4g, 0.2mol), cuprous iodide (1.91g, 0.01mol, 10mol%) and 100mL1, the 2-ethylene dichloride.In argon gas, heated and stirred was cooled to room temperature after refluxing 20 hours, added 200mL water, with methylene dichloride (100mL) extraction three times.Merge organic phase, use respectively again 200mL sodium hydroxide solution (20%), saturated common salt water washing, drying, be spin-dried for and obtain the thick product (14.5g of alkene acid amides, 90%), column chromatography or recrystallization obtain white alkene acid amides crystallization (12.6g, 78%).
Structural analysis
1H NMR(400MHz，CDCl
3)δ7.42-7.34(m，5H)，6.89(bs，1H)，5.87(s，1H)，5.09(s，1H)，2.13(s，3H).
13C NMR(100MHz，CDCl
3)δ169.2，140.5，138.3，128.6，126.0，102.6，24.4.
Embodiment 2: prepare the alkene acid amides by indanone oxime
In the 25mL round-bottomed flask, add indanone oxime (0.15g, 0.001mol), sodium bisulfite (0.31g, 0.003mol), acetic anhydride (0.2g, 0.002mol), cuprous iodide (0.02g, 0.0001mol, 10mol%) with 5mL 1, the 2-ethylene dichloride.In argon gas, heated and stirred was cooled to room temperature after refluxing 12 hours, added 20mL water, with methylene dichloride (10mL) extraction three times.Merge organic phase, use respectively 20mL sodium hydroxide solution (20%), saturated common salt water washing again, drying is spin-dried for, and column chromatography obtains white alkene acid amides crystallization (0.13g, 74%).
Structural analysis
1H NMR(400MHz，CDCl
3)δ7.49(d，J＝8Hz，1H)，7.36(s，1H)，7.2(d，J＝7.6Hz，1H)，7.28-7.25(m，2H)，6.88(s，1H)，3.44(s，2H)，2.25(s，3H).
13C NMR(100MHz，CDCl
3)δ169.3，142.6，139.7，135.6，125.8，125.2，124.0，116.6，115.8，36.4，23.9.
Embodiment 3: prepare the alkene acid amides by the naphthane ketoxime
In the 25mL round-bottomed flask, add naphthane ketoxime (0.16g, 0.001mol), sodium bisulfite (0.31g, 0.003mol), acetic anhydride (0.2g, 0.002mol), cuprous iodide (0.02g, 0.0001mol, 10mol%) and 5mL1, the 2-ethylene dichloride.In argon gas, heated and stirred was cooled to room temperature after refluxing 12 hours, added 20mL water, with methylene dichloride (10mL) extraction three times.Merge organic phase, use respectively 20mL sodium hydroxide solution (20%), saturated common salt water washing again, drying is spin-dried for, and column chromatography obtains white alkene acid amides crystallization (0.17g, 92%).
Structural analysis
1H NMR(400MHz，DMSO)δ9.12(s，1H)，7.20-7.16(m，4H)，6.16(s，1H)，2.70-2.68(t，J＝8Hz，2H)，2.27(s，2H)，2.01(s，3H).
13C NMR(100MHz，DMSO)δ174.0，141.2，137.6，136.9，132.6，132.3，131.3，127.3，124.2，32.3，28.5，26.9.
Embodiment 4: prepare the alkene acid amides by cyclohexanone-oxime
In the 25mL round-bottomed flask, add cyclohexanone-oxime (0.11g, 0.001mol), sodium bisulfite (0.31g, 0.003mol), acetic anhydride (0.2g, 0.002mol), cuprous iodide (0.02g, 0.0001mol, 10mol%) and 5mL1, the 2-ethylene dichloride.In argon gas, heated and stirred was cooled to room temperature after refluxing 6 hours, added 20mL water, with methylene dichloride (10mL) extraction three times.Merge organic phase, use respectively 20mL sodium hydroxide solution (20%), saturated common salt water washing again, drying is spin-dried for, and column chromatography obtains white alkene acid amides crystallization (0.09g, 67%).
Structural analysis
1H NMR(400MHz，CDCl
3)δ6.31(bs，1H)，6.06(s，1H)，2.11-2.04(m，4H)，2.01(s，3H)，1.70-1.65(m，2H)，1.59-1.54(m，2H).
13C NMR(100MHz，CDCl
3)δ168.7，132.7，113.1，27.7，24.0，23.8，22.3，21.7.
Embodiment 5:
Use different formula (II) 9 oxime derivates and formula (III) acyl compounds to prepare alkenylamide derivative with reference to above-mentioned case method, its result is as shown in the table.
Formula (II) 9 oxime derivate that table 1 is different and formula (III) acyl compounds reaction example
Claims (4)
1. the method for alkenylamide derivative shown in the synthesis type (I); it is characterized in that: in the presence of cuprous iodide catalyst and sodium bisulfite reductive agent; formula (II) 9 oxime derivate and formula (III) acyl compounds obtain through reductive acylation, isomerization reaction
Wherein,
R
1Be H, alkyl, ester group;
R
2Be H, alkyl, cyano group;
R
3Be aryl, heterocyclic radical;
Or R
1, R
2Be combined into ring;
Or R
2, R
3Be combined into ring;
R
4Be alkyl;
N is that 2, X is Sauerstoffatom;
Described R
1, R
2And R
3C atomicity≤20, R
4C atomicity≤10.
2. the method for synthetic alkenylamide derivative according to claim 1, it is characterized in that: catalyst levels is 1 ~ 30 mol% of formula (II) 9 oxime derivate consumption, and the consumption of formula (III) compound is at least 1 times of mole dosage of formula (II) 9 oxime derivate.
3. the method for synthetic alkenylamide derivative according to claim 2, it is characterized in that: the reaction solvent for use is toluene, DMF, Isosorbide-5-Nitrae-dioxane, ethyl acetate or 1,2-ethylene dichloride.
4. the method for synthetic alkenylamide derivative according to claim 1 is characterized in that: react 20 ~ 150
oImplement in the temperature range of C.
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| CN 201010229266 CN101875590B (en) | 2010-07-19 | 2010-07-19 | Method for synthesizing acrylamide compound |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999018065A1 (en) * | 1997-10-03 | 1999-04-15 | Chirotech Technology Limited | Chiral amines |
| CN1898194A (en) * | 2003-12-22 | 2007-01-17 | Ppg-Sipsy公司 | New process for the synthesis of eneamide derivatives |
| CN101421228A (en) * | 2006-03-31 | 2009-04-29 | 塞普拉柯公司 | Preparation of chiral amides and amines |
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2010
- 2010-07-19 CN CN 201010229266 patent/CN101875590B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999018065A1 (en) * | 1997-10-03 | 1999-04-15 | Chirotech Technology Limited | Chiral amines |
| CN1898194A (en) * | 2003-12-22 | 2007-01-17 | Ppg-Sipsy公司 | New process for the synthesis of eneamide derivatives |
| CN101421228A (en) * | 2006-03-31 | 2009-04-29 | 塞普拉柯公司 | Preparation of chiral amides and amines |
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