CN103254109B - Benzoyl pyrrole derivative and synthetic method thereof - Google Patents
Benzoyl pyrrole derivative and synthetic method thereof Download PDFInfo
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- CN103254109B CN103254109B CN201310213721.6A CN201310213721A CN103254109B CN 103254109 B CN103254109 B CN 103254109B CN 201310213721 A CN201310213721 A CN 201310213721A CN 103254109 B CN103254109 B CN 103254109B
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- benzoyl
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- isopropylamino
- pyrrole compound
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Abstract
The invention relates to a benzoyl pyrrole derivative as a medicament intermediate and a synthetic method thereof. The synthetic method comprises the steps of synthesizing 2-isopropyl aminomethyl pyrrole by taking pyrrole as a raw material through a mannich reaction, and then synthesizing a target compound by taking aromatic aldehyde as an acylation reagent. According to the benzoyl pyrrole derivative and the synthetic method thereof, the use of non-environment-friendly chlorinated reagents such as benzoyl chloride and phosphorus oxychloride with larger toxicity can be avoided, and the problems of large potential safety hazard, serious pollution of three wastes and the like in a traditional technique can be thoroughly solved. The method is economical and environment-friendly, mild in reaction conditions, simple for product separation, abundant in raw material resources, and easy for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical intermediate pyrrole derivative, specifically belong to a kind of benzoyl pyrrole compound derivative and synthetic method thereof.
Background technology
Benzoyl pyrrole compound is a kind of important medicine intermediate and industrial chemicals; be the key intermediate of synthesizing new non-steroidal analgesia anti-inflammation medicine ketorolac, the synthesis of the pyrrole derivative at present containing benzoyl is mainly through Friedel-Crafts acylation(friedel-crafts acylation) or Vilsmeier – Haack reaction (Wei Er David Smail-Haake reaction) two kinds of approach.
1. adopt friedel-crafts acylation, (a) direct Benzoyl chloride in alkali lye carries out acidylate to pyrroles, but productive rate too low (Aus.J.Chem., 1964,17,1056); B (), under BF3 catalysis, with N-benzenesulfonyl pyrroles for raw material, carries out acidylate with Benzoyl chloride or benzoyl oxide, the method complex process; long reaction time, and isomer 3-benzoyl pyrrole can be generated, product separation difficulty (J.Org.Chem.; 1983,48 (19), 3214)
2. adopt Wei Er David Smail-Haake reaction, (a) is acylating agent with the complex compound that oxalyl chloride and the reaction of N, N-dimethyl benzamide generate; the method yield is high; but reaction and finishing time longer, the purification of product needs column chromatography (US5082951,1993; J.Org.Chem, 1977,42,4248); B () is acylating agent with the complex compound that benzoyl morpholine and phosphorus oxychloride reaction generate, then at room temperature react 17h with pyrroles and obtain product.Use more expensive morpholine in reaction, and reaction still needs the time (patent 201210044628.2) of about one day; C () is with N; the complex compound that N-dimethyl benzamide and phosphorus oxychloride reaction generate is acylating agent; then react generation benzoyl pyrrole with pyrroles, the method reaction times shortens to 8 hours, the higher (Chinese Journal of Modern Applied Pharmacy of yield; 1998; 18,36) but phosphorus oxychloride as the seriously corroded of chlorinating agent to equipment, in the product that technique obtains a large amount of phosphorus-containing wastewater be difficult to process; pollution problem is serious, and environmental problem is given prominence to.
In a word; no matter be adopt friedel-crafts acylation, or adopt Wei Er David Smail-Haake reaction to synthesize benzoyl pyrrole, there is following shortcoming: (1) complex synthetic route; product yield is low, separation difficulty (2) adopt chlorinating agent to pollute comparatively large (3) cost is high, not easily suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical intermediate benzoyl pyrrole compound derivative and preparation method thereof, the economic environmental protection of synthetic method of this derivative, reaction conditions is gentle, and product separation is simple, and raw material resources are enriched, and are easy to suitability for industrialized production.
A kind of benzoyl pyrrole compound derivative provided by the invention, its structural formula:
In formula: R can be hydrogen, alkyl, alkoxyl group, halogen etc.
Its synthesis step is as follows:
(1) 2-isopropylamino methylpyrrole is conventionally prepared, as: C.C.Hsieh, W.J.Chao, Y.C.Horng, H.M.Lee, Synthesis and characterization of Nickel (II) complex containing2-(t-Butylaminomethyl) pyrrole, Journal of the Chinese Chemical Society, 2009,56,435-442.
(2) in the diethyl ether solution filling 2-isopropylamino methylpyrrole, the LDA adding equivalent under stirring carries out basic metal, organic amine is added as reaction promoter after stirring at room temperature 0.5-2 hour, add aromatic aldehyde subsequently, within room temperature reaction 2-6 hour, produce white precipitate, filtering separation, solid with ethyl acetate recrystallization, vacuum-drying obtains product, productive rate 80-91%.
Aromatic aldehyde in described reactions steps (2) can be all aromatic aldehyde compounds such as phenyl aldehyde, p-tolyl aldehyde, 4-chloro-benzaldehyde; Organic amine in described reactions steps (2) can be aliphatic amide or aromatic amine, preferred fragrance amine; In described reactions steps (2), the mol ratio of 2-isopropylamino methylpyrrole, organic amine, aromatic aldehyde is 1:0.1-1.0:1-1.5.
Compared with prior art, its advantage is: 1 in the present invention, does not need to adopt transition, rare metal as catalyzer, and cost is low, and technique is advanced, mild condition, and reaction yield is high; 2. adopt aromatic aldehyde to be acylating reagent, got rid of the unfriendly and use of the chlorinating agent such as the Benzoyl chloride that toxicity is larger and phosphorus oxychloride of environment, fundamentally eliminated the problems such as traditional technology potential safety hazard is large, three-waste pollution is serious.
Embodiment
Embodiment 1:
(1) preparation of 2-isopropylaminomethyl pyrroles: add isopropylamine hydrochloride (11.85g in 100mL round-bottomed flask, 0.124mol), 37% formalin ((10.05g, 0.124mol), 30mL ethanol, is cooled to 0 ° of C, dropwise drips pyrroles (8.31g, 0.124mol), dropwise and slowly return to room temperature afterwards, continue stirring 18 hours, with 30mL sodium hydroxide (4.96g, 0.124mol) neutralize, extracted with diethyl ether, anhydrous magnesium sulfate drying, is spin-dried for solvent, obtain 2-isopropylaminomethyl pyrroles 13.37g, productive rate 78%.
(2) preparation of 2-isopropylamino methyl-5-benzoyl pyrrole compound:
Reactional equation is as implied above; filling 2-isopropylaminomethyl pyrroles (6.91g; in 30mL diethyl ether solution 0.05mol); under agitation add 0.05mol LDA and carry out basic metal; stirring at room temperature adds the Isopropylamine of equivalent for 1 hour as reaction promoter; add phenyl aldehyde (5.2mL subsequently; 0.05mol); room temperature reaction produces white precipitate in 5 hours; filtering separation; solid with ethyl acetate recrystallization, vacuum-drying obtains 2-isopropylamino methyl-5-benzoyl pyrrole compound 10.3g, productive rate 85%.mp110-111°C;
1H?NMR(CDCl
3):δ(ppm)10.99(b,1H),7.85-7.88(d,2H),7.43-7.56(m,3H),6.79-6.81(d,1H),6.15-6.16(d,1H),3.91(s,2H),2.78-2.86(m,1H),1.04-1.05(d,2H);
13C?NMR(CDCl
3):δ(ppm)24.2,45.2,49.4,110.7,122.5,129.6,130.4,131.8,132.9,140.1,142.2,186.0.IR
νmax(KBr,cm
-1):3271.1,2964.4,1737.7,1606.6,1569.9,1494.7,1483.2,1407.9,1336.6,1274.9,1232.4,1176.5,1047.3,881.4,798.5,725.2,698.2,676.9,582.5.
Embodiment 2:
(1) preparation of 2-isopropylamino pyrroles as described in Example 1;
(2) 2-isopropylamino methyl-5-is to the preparation of chlorobenzene formacyl pyrroles:
Reactional equation is as implied above; filling 2-isopropylaminomethyl pyrroles (6.91g; in 30mL diethyl ether solution 0.05mol); under agitation add 0.05mol LDA and carry out basic metal; stirring at room temperature adds 2 of 0.5 equivalent in 1 hour; 6-xylidine is as reaction promoter; add 4-chloro-benzaldehyde (7.03g subsequently; 0.05mol); room temperature reaction produces white precipitate, filtering separation, solid with ethyl acetate recrystallization in 5 hours; vacuum-drying obtains 2-isopropylamino methyl-5-to chlorobenzene formacyl pyrroles 12.04g, productive rate 87%.mp129-130°C;IR
νmax(KBr,cm
-1):3274.9,1623.9,1587.3,1542.9,1427.2,1404.1,1334.7,1145.6,1068.5,1047.3,1010.6,892.9,875.6,765.7,736.8,607.5.
Embodiment 3:
(1) preparation of 2-isopropylamino pyrroles as described in Example 1;
(2) 2-isopropylamino methyl-5-is to the preparation of methyl benzoyl pyrroles:
Reactional equation is as implied above; filling 2-isopropylaminomethyl pyrroles (6.91g; in 30mL diethyl ether solution 0.05mol); under agitation add 0.05mol LDA and carry out basic metal; stirring at room temperature adds the TERTIARY BUTYL AMINE of 0.5 equivalent for 1 hour as reaction promoter; add p-tolyl aldehyde (6.0g subsequently; 0.05mol); room temperature reaction produces white precipitate in 5 hours; filtering separation; solid with ethyl acetate recrystallization, vacuum-drying obtains 2-isopropylamino methyl-5-to methyl benzoyl pyrroles 11.66g, productive rate 91%.mp119-121°C;IRνmax(KBr,cm-1):3303.8,1616.2,1602.7,1564.2,1537.2,1421.4,1396.4,1176.5,1132.1,1056.9,891.1,833.2,752.2,607.5,547.8,480.2.
Embodiment 4:
(1) preparation of 2-isopropylamino pyrroles as described in Example 1;
(2) 2-isopropylamino methyl-5-is to the preparation of anisoyl pyrroles:
Reactional equation is as implied above; filling 2-isopropylaminomethyl pyrroles (6.91g; in 30mL diethyl ether solution 0.05mol); under agitation add 0.05mol LDA and carry out basic metal; stirring at room temperature adds the TERTIARY BUTYL AMINE of 0.5 equivalent for 1 hour as reaction promoter; add aubepine (6.81g subsequently; 0.05mol); room temperature reaction produces white precipitate in 5 hours; filtering separation; solid with ethyl acetate recrystallization, vacuum-drying obtains 2-isopropylamino methyl-5-to anisoyl pyrroles 10.89g, productive rate 80%.mp114-116°C，IRνmax(KBr,cm-1):3282.6,1604.7,1571.9,1544.9,1510.2,1452.3,1417.6,1402.2,1336.6,1305.7,1253.6,1172.6,1128.3,1043.4,1022.2,892.9,835.1,754.1,603.7,553.5。
Claims (4)
1. a preparation method for benzoyl pyrrole compound derivative, is characterized in that, comprises the steps:
(1) 2-isopropylamino methylpyrrole is prepared;
(2) in the diethyl ether solution filling 2-isopropylamino methylpyrrole, the LDA adding equivalent under stirring carries out basic metal, organic amine is added after stirring at room temperature 0.5-2 hour, add aromatic aldehyde subsequently, within room temperature reaction 2-6 hour, produce white precipitate, filtering separation, solid with ethyl acetate recrystallization, vacuum-drying obtains;
Described benzoyl pyrrole compound derivative, its structural formula is:
In formula: R is hydrogen, alkyl, alkoxy or halogen.
2. the preparation method of a kind of benzoyl pyrrole compound derivative as claimed in claim 1, is characterized in that, in described step (2), the mol ratio of 2-isopropylamino methylpyrrole, organic amine, aromatic aldehyde is 1:0.1-1.0:1-1.5.
3. the preparation method of a kind of benzoyl pyrrole compound derivative as claimed in claim 1, is characterized in that, the aromatic aldehyde in described step (2) is phenyl aldehyde, p-tolyl aldehyde, 4-chloro-benzaldehyde or aubepine.
4. the preparation method of a kind of benzoyl pyrrole compound derivative as claimed in claim 1, is characterized in that, the organic amine in described step (2) is aliphatic amide or aromatic amine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0115424A1 (en) * | 1983-01-26 | 1984-08-08 | McNeilab, Inc. | Pyrrole-2-acetylamino acid derivatives |
| CN102584668A (en) * | 2012-02-27 | 2012-07-18 | 蚌埠中实化学技术有限公司 | Method for preparing 2,3-dibromo-5-benzoyl pyrrole |
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2013
- 2013-05-31 CN CN201310213721.6A patent/CN103254109B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0115424A1 (en) * | 1983-01-26 | 1984-08-08 | McNeilab, Inc. | Pyrrole-2-acetylamino acid derivatives |
| CN102584668A (en) * | 2012-02-27 | 2012-07-18 | 蚌埠中实化学技术有限公司 | Method for preparing 2,3-dibromo-5-benzoyl pyrrole |
Non-Patent Citations (1)
| Title |
|---|
| 《A novel one-pot synthesis of 2-benzoylpyrroles from benzaldehydes》;Ratnesh Sharma et al;《Tetrahedron Letters》;20101231;第51卷;第2039-2043页 * |
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