CN1176075C - Pyrrole derivative preparation method - Google Patents
Pyrrole derivative preparation method Download PDFInfo
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- CN1176075C CN1176075C CNB011402350A CN01140235A CN1176075C CN 1176075 C CN1176075 C CN 1176075C CN B011402350 A CNB011402350 A CN B011402350A CN 01140235 A CN01140235 A CN 01140235A CN 1176075 C CN1176075 C CN 1176075C
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- pyrrole derivative
- methyl
- sodium
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Abstract
The present invention relates to a method for preparing pyrrole derivatives, which comprises: an acyl ester compound (R2COCH2COOR) reacts with halogenated aldehyde oe halogenated ketone (R4CHXCOR5) in polar solvent containing alkali to obtain formic ether substituted dione (R5COCH(R4)CH(COOR)COR2); then the acyl ester compound (R2COCH2COOR)reacts with ammonia water or ammonium salts which can release ammonia when heated for 1 to 10 hours at 50 to 100 DEG C, wherein R and R2 respectively are an alkyl group of which the carbon number is from 1 to 5; R4 and R5 respectively are hydrogen or an alkyl group of which the carbon number is from 1 to 5; X is chlorine, bromine or iodine. By using the method of the present invention, high-purity pyrrole derivatives can be obtained with high yields.
Description
Technical field
The present invention relates to a kind of preparation method of pyrrole derivative, relate more specifically to a kind of pyrroles's of formic acid ester group alkyl replacement preparation method.
Background technology
The pyrrole derivative that formic acid ester group alkyl replaces is the important intermediate of preparation alkyl substituted azole, and the alkyl substituted azole is as 2, and the 5-dimethyl pyrrole is a kind of important catalyst aid.Canadian Journal of Chemistry (CANADIAN JOURNAL OF CHEMISTRY VOL.48P1689-1697,1970) discloses a kind of preparation method of pyrrole derivative of formic acid ester group alkyl replacement, and this method is that ammoniacal liquor is added acyl ester cpds R
2COCH
2COOR and halogenated compound R
4Among the CHXCOH, obtain the pyrrole derivative that formic acid ester group alkyl replaces after the reaction.Its shortcoming is that the reaction product yield is low.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of pyrrole derivative.Can obtain highly purified pyrrole derivative with high yield with method of the present invention.
The invention provides a kind of preparation method with pyrrole derivative of following general formula,
Comprise a kind of acyl ester cpds R
2COCH
2COOR in having alkali or alkali-metal polar solvent with halogenated aldehyde or halogenated ketone R
4CHXCOR
5Reaction obtains the diketone R that manthanoate replaces
5COCH (R
4) CH (COOR) COR
2, and then the ammonium salt that the time can discharge ammonia with ammoniacal liquor or heating is at 50-100 ℃ of reaction 1-10 hour down, wherein R, R
2Be the alkyl of 1-5 independently for carbonatoms, R
4, R
5Be that hydrogen or carbonatoms are the alkyl of 1-5 independently, X is chlorine, bromine or iodine, preferred chlorine or bromine.
The preparation method of pyrrole derivative of the present invention comprises beta substitution reaction, annulation etc.Detailed process can be expressed as follows:
(1) acyl ester cpds and alkali or basic metal generation beta substitution reaction generates the acyl ester alkali metal
Its consumption is: the mol ratio of alkali or basic metal and acyl ester cpds is 1-5, is best with about equally mole number.
(2) acyl ester alkali metal and halogenated aldehyde or halogenated ketone reaction generates the diketone that manthanoate replaces
The consumption of halogenated aldehyde or halogenated ketone is: the mol ratio of halogenated aldehyde or halogenated ketone and acyl ester cpds is 0.1-10, is best with about equally mole number.
(3) the direct and ammonia react Cheng Huan of the diketone of manthanoate replacement generates the pyrroles that formic acid ester group alkyl replaces
Because ammonia is easy to get, low price and volatile, so the diketone that manthanoate replaces directly becomes in the ring process with ammonia react is advisable so that ammonia is excessive, with excessive more than 2 times for well, doubly be best with excessive 2-10.
Acyl ester sodium of the present invention can be with " the disclosed method of organic preparation chemistry handbook (compilings such as middle volume, Han Guang pasture, in November, 1977 first version, petrochemical industry press, the 158th page) makes, also can be made by the disclosed method of JP56-169639A.
The diketone that manthanoate of the present invention replaces can make with the JP56-169639A method.
Ammonium salt of the present invention is volatile salt or bicarbonate of ammonia.
Alkali of the present invention can be the represented alkali metal compound of formula M Y, and M is a basic metal, and Y is hydrogen atom, alkoxyl group.Wherein basic metal M is sodium or potassium; Alkalimetal hydride is alkalimetal hydrides such as lithium hydride, sodium hydride, potassium hydride KH; Alkali metal alcoholates is alkali metal alcoholates such as sodium methylate, sodium ethylate, sodium propylate, lithium ethoxide, potassium isopropoxide, butanols potassium; Preferred hydride and alkoxide.Considering from obtaining easily and in price of industry, is ideal with sodium hydride, sodium methylate or sodium ethylate then.
The polar solvent that is used for dissolving raw material and alkali of the present invention for example can be the alcohols of water and methyl alcohol, ethanol, Virahol etc.; The polar aprotic solvent of dimethyl formamide, methyl-sulphoxide, hexamethylphosphoramide etc.; The ester class of diox, tetrahydrofuran (THF) etc.Be the occasion of solvent with water, if the alkali that uses is alkalimetal hydride or alkali metal alcoholates, then the reaction of the alkali of this class and water generates oxyhydroxide, and the result participates in reaction with oxyhydroxide as alkali, and the yield that causes reaction is low.So solvent is to use polar nonaqueous solvent for well.The preferred at least a non-aqueous solvent that is selected from methyl alcohol, ethanol, dimethyl formamide, methyl-sulphoxide and hexamethylphosphoramide of solvent of the present invention.Its consumption be there is no strict demand, raw material is fully dissolved and can stir fully and be advisable.
R of the present invention, R
2Be the alkyl of 1-3 independently for carbonatoms, more preferably methyl, ethyl, R
4, R
5Be the alkyl of 1-3 for hydrogen or carbonatoms independently, more preferably hydrogen, methyl, ethyl.Most preferably R is methyl or ethyl, R
2Methyl, R
4Be hydrogen, R
5Be methyl or hydrogen.
Acyl ester cpds R of the present invention
2COCH
2COOR and halogenated aldehyde or halogenated ketone R
4CHXCOR
5Temperature of reaction be-10-100 ℃ preferred-10-25 ℃.
When preparing the pyrroles of manthanoate alkyl replacement, have characteristics easy to operate, that product yield is high, purity is high with method of the present invention.
Embodiment
The following examples will help to illustrate the present invention, but not limit to its scope.
Embodiment 1
1, the preparation of acetonyl methyl aceto acetate
The 1000ml round-bottomed flask that will have whipping appts is placed in water-bath, add the anhydrous N of 420ml, N dimethyl formamide and 102g (1.5mol) sodium ethylate, under room temperature (20 ℃), whipped state, slowly add 195g (1.5mol) methyl aceto acetate, feed rate is no more than 25 ℃ with temperature of charge and exceeds, and dropwises, drip 140g (1.5mol) monochloroacetone again, feed rate still is no more than 25 ℃ with temperature of charge and exceeds.Then, continue to keep reaction 12 hours, make muddy shape browning reaction liquid (1).
Reaction solution (1) is filtered, remove the NaCl solid, obtain red-purple liquid 650ml (2), through chromatograph-mas spectrometer qualitative analysis, chromatographic quantitative analysis, wherein the content of acetonyl methyl aceto acetate is 33%.Red-purple liquid (2) is carried out vacuum fractionation, to remove reaction solvent and unreacted component, collect the cut (3) of temperature 80 ℃ (3.3kpa), its quality is 220 grams, through chromatographic quantitative analysis, wherein (211 grams, 1.13mol), its yield is that basic calculation is 75% with the monochloroacetone to acetonyl methyl aceto acetate content 96wt.%.
2,2, the preparation of 5-dimethyl pyrrole-3-ethyl formate
Solution (3) is placed water-bath 1000ml there-necked flask, and holding temperature stirs at 60 ℃, slowly adds the ammoniacal liquor of 400ml 28%, dropwises in 2 hours, and 60 ℃ are continued reaction 1 hour down, naturally cool to room temperature then, and placement is spent the night.Obtained golden yellow sedimentary mixed solution (4).Reaction solution (4) being filtered, obtain golden yellow crystal (5), is 2 through mass spectrometry (5), and (161 grams, 0.96mol), its yield is 85% (is basic calculation with the acetonyl methyl aceto acetate) to 5-dimethyl-3-group-4 ethyl formate pyrroles.
Embodiment 2
With the sodium ethylate in the sodium Metal 99.5 alternate embodiment 1, other condition is with embodiment 1, and test-results sees Table 1.
Embodiment 3
With the dimethyl formamide in the ethanol alternate embodiment 1, other condition is with embodiment 1, and test-results sees Table 1.
Embodiment 4
With the monochloroacetone in the martonite alternate embodiment 1, other condition is with embodiment 1, and test-results sees Table 1.
Embodiment 5
With the ammoniacal liquor in the ammonium carbonate solution alternate embodiment 1 of 500 milliliters of 50wt.%, the annulation temperature is 90 ℃, and other condition is with embodiment 1, and test-results sees Table 1.
Embodiment 6
With the monochloroacetone in the bromoacetaldehyde alternate embodiment 1, other condition obtains 2-methyl-3-group-4 ethyl formate pyrroles with embodiment 1, and test-results sees Table 1.
Embodiment 7
With the methyl aceto acetate of methyl acetoacetate alternate embodiment 1, other condition obtains 2 with embodiment 1,5-dimethyl-3-methyl-formiate base pyrroles, and test-results sees Table 1.
Comparative Examples 1
The round-bottomed flask that will have the 1000ml of whipping appts is placed in water-bath, at room temperature, adds 65g (0.5mol) methyl aceto acetate, 46g (0.5mol) monochloroacetone, the ammoniacal liquor of 250ml28% and the distilled water of 250ml.Keep 60 ℃ in water-bath, reacted 2 hours, naturally cool to room temperature then, placement is spent the night.Obtain golden yellow sedimentary mixed reaction solution.Reaction solution is carried out suction filtration, obtain golden yellow crystal 2,5-dimethyl pyrrole-3-ethyl formate 36 grams, its yield is 43% (is basic calculation with the monochloroacetone).
Table 1
| Embodiment | The yield (%) of the diketone that manthanoate replaces | The pyrroles's that formic acid ester group alkyl replaces yield (%) | Total recovery (%) |
| 1 | 75 | 85 | 64 |
| 2 | 73 | 85 | 62 |
| 3 | 70 | 82 | 57 |
| 4 | 76 | 84 | 64 |
| 5 | 76 | 87 | 66 |
| 6 | 80 | 83 | 66 |
| 7 | 69 | 80 | 55 |
| Comparative Examples 1 | 43 |
*Total recovery is that the yield (%) of the diketone of manthanoate replacement amasss with the pyrroles's of formic acid ester group alkyl replacement yield is.
Claims (8)
1, a kind of preparation method with pyrrole derivative of following general formula,
Comprise a kind of acyl ester cpds R
2COCH
2COOR in the polar solvent that has alkali or basic metal M with halogenated aldehyde or halogenated ketone R
4CHXCOR
5Reaction obtains the diketone R that manthanoate replaces
5COCH (R
4) CH (COOR) COR
2, and then the ammonium salt that the time can discharge ammonia with ammoniacal liquor or heating is at 50-100 ℃ of reaction 1-10 hour down, wherein R, R
2Be the alkyl of 1-5 independently for carbonatoms, R
4, R
5Be that hydrogen or carbonatoms are the alkyl of 1-5 independently, X is chlorine, bromine or iodine.
2, the preparation method of pyrrole derivative according to claim 1 is characterized in that described ammonium salt is volatile salt or bicarbonate of ammonia.
3, the preparation method of pyrrole derivative according to claim 1 is characterized in that described alkali is the represented alkali metal compound of formula M Y, and wherein M is that basic metal, Y are hydrogen atom or alkoxyl group.
4, the preparation method of pyrrole derivative according to claim 1 is characterized in that described basic metal M is potassium or sodium; Described alkalimetal hydride is lithium hydride, sodium hydride or potassium hydride KH; Described alkali metal alcoholates is sodium methylate, sodium ethylate, sodium propylate, lithium ethoxide, potassium isopropoxide, butanols potassium.
5,, it is characterized in that described polar solvent is at least a non-aqueous solvent that is selected from methyl alcohol, ethanol, dimethyl formamide, methyl-sulphoxide and hexamethylphosphoramide according to the preparation method of each described pyrrole derivative of claim 1-4.
6,, it is characterized in that described R is methyl or ethyl, R according to the preparation method of each described pyrrole derivative of claim 1-4
2Be methyl, R
4Be hydrogen, R
5Be methyl or hydrogen.
7,, it is characterized in that described X is a chlorine or bromine according to the preparation method of each described pyrrole derivative of claim 1-4.
8,, it is characterized in that acyl ester cpds R according to the preparation method of each described pyrrole derivative of claim 1-4
2COCH
2COOR and halogenated aldehyde or halogenated ketone R
4CHXCOR
5Temperature of reaction be-10-25 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011402350A CN1176075C (en) | 2001-12-07 | 2001-12-07 | Pyrrole derivative preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011402350A CN1176075C (en) | 2001-12-07 | 2001-12-07 | Pyrrole derivative preparation method |
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|---|---|
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| CN1176075C true CN1176075C (en) | 2004-11-17 |
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|---|---|---|---|
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
| US7942147B2 (en) | 2001-06-05 | 2011-05-17 | Alexza Pharmaceuticals, Inc. | Aerosol forming device for use in inhalation therapy |
| US7987846B2 (en) | 2002-05-13 | 2011-08-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| US8235037B2 (en) | 2001-05-24 | 2012-08-07 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| US8333197B2 (en) | 2004-06-03 | 2012-12-18 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
| US8387612B2 (en) | 2003-05-21 | 2013-03-05 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
-
2001
- 2001-12-07 CN CNB011402350A patent/CN1176075C/en not_active Expired - Lifetime
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8235037B2 (en) | 2001-05-24 | 2012-08-07 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| US9440034B2 (en) | 2001-05-24 | 2016-09-13 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| US7645442B2 (en) | 2001-05-24 | 2010-01-12 | Alexza Pharmaceuticals, Inc. | Rapid-heating drug delivery article and method of use |
| US9211382B2 (en) | 2001-05-24 | 2015-12-15 | Alexza Pharmaceuticals, Inc. | Drug condensation aerosols and kits |
| US9308208B2 (en) | 2001-06-05 | 2016-04-12 | Alexza Pharmaceuticals, Inc. | Aerosol generating method and device |
| US7942147B2 (en) | 2001-06-05 | 2011-05-17 | Alexza Pharmaceuticals, Inc. | Aerosol forming device for use in inhalation therapy |
| US8074644B2 (en) | 2001-06-05 | 2011-12-13 | Alexza Pharmaceuticals, Inc. | Method of forming an aerosol for inhalation delivery |
| US9439907B2 (en) | 2001-06-05 | 2016-09-13 | Alexza Pharmaceutical, Inc. | Method of forming an aerosol for inhalation delivery |
| US8955512B2 (en) | 2001-06-05 | 2015-02-17 | Alexza Pharmaceuticals, Inc. | Method of forming an aerosol for inhalation delivery |
| US7987846B2 (en) | 2002-05-13 | 2011-08-02 | Alexza Pharmaceuticals, Inc. | Method and apparatus for vaporizing a compound |
| US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
| US8991387B2 (en) | 2003-05-21 | 2015-03-31 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
| US9370629B2 (en) | 2003-05-21 | 2016-06-21 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
| US8387612B2 (en) | 2003-05-21 | 2013-03-05 | Alexza Pharmaceuticals, Inc. | Self-contained heating unit and drug-supply unit employing same |
| US8333197B2 (en) | 2004-06-03 | 2012-12-18 | Alexza Pharmaceuticals, Inc. | Multiple dose condensation aerosol devices and methods of forming condensation aerosols |
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| Publication number | Publication date |
|---|---|
| CN1422846A (en) | 2003-06-11 |
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Effective date of registration: 20170125 Address after: 100027 Beijing, Chaoyangmen, North Street, No. 22, No. Patentee after: CHINA PETROLEUM & CHEMICAL Corp. Address before: 102500 Yanshan Phoenix Road, Fangshan District, No., No. 15 Patentee before: Beijing Research Inst. of Yanshan Petrochemical Corp. |
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Granted publication date: 20041117 |