JPS60248665A - Fluorine-substituted pyrrole derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The fluorine-substituted pyrrole derivative of formula I (R<1> is ethyl or substituted alkyl; R<2> is methyl, formyl or methylol). EXAMPLE:2-Ethyl-4-fluoro-3,5-dimethylpyrrole-2-carboxylate. USE:A drug useful as an anti-inflammatory agent and also expected to have antitumor and antibacterial activities. Also useful as an intermediate of carboxylic acid, ester, acetal, etc. PREPARATION:The compound of formula I (R<2> is methyl) can be prepared by the photo-decomposition of the compound of formula III obtained by the reaction of the compound of formula II with sodium nitrite and hydroborofluoric acid. If necessary, the product is converted to the compound of formula I (R<2> is formyl) with lead tetraacetate, and further to the compound of formula I (R<2> is methylol) by reducing with sodium borohydride.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a fluorine-substituted pyrrole derivative and a method for producing the same.

(Industrial Application Field) Halogen-substituted pyrrole derivatives are contained in marine natural products, and some are known to have physiologically active effects. Among the pyrrole derivatives.

As shown in Japanese Patent Publication No. 47-8535, compounds having anti-inflammatory effects with few side effects are known.

(Prior Art) There have been no reports of pyrrole derivatives having a fluorine atom at the β-position of pyrrole.

A method for producing a pyrrole derivative having a trifluoromethyl group at the .beta. position is disclosed in 1% Application No. 58-41594.

(Problems to be Solved by the Invention) The present invention introduces a fluorine atom with large electron-withdrawing property into the pyrrole skeleton, thereby changing the electron distribution of the pyrrole ring and changing the basicity of the pyrrole derivative. This is expected to change various properties of pyrrole derivatives, thereby producing physiologically active effects.

As a result of intensive studies on methods for synthesizing fluorine-substituted virol derivatives, the present inventors found that 4-amino-3 represented by the general formula (wherein R' represents an ethyl group or a substituted alkyl group)
, 5-dimethylpyrrole-2-carboxylic acid ester 2 using fluoroboric acid to convert the amine group of 2 into diazonium polyfluoride, which is photodecomposed to form the general formula (wherein R1 is an ethyl group or a substituted 3,5-dimethyl-4-fluoropyrrole-2 represented by an alkyl group
- It has been found that carboxylic acid ester 4 can be obtained.

The pyrrole derivative represented by formula 2 is 4-nitro-3,5
It can be obtained by reducing -dimethylpyrrole-2-carboxylic acid ester with a tin-hydrochloric acid system, or as shown in Examples, 4-(4-nitrophenyl'7)-3,5
') It can also be obtained by reducing methylpyrrole-2-carboxylic acid ester with a stannous chloride-acetic acid system.

The pyrrole derivative represented by the general formula 2 can be produced by converting the amino group of 2 into diazonium tetrafluoroborate using sodium nitrite and hydrofluoroboric acid, and photodecomposing this to produce a fluorine-substituted pyrrole derivative represented by the general formula 2. A derivative is obtained. Moreover, by reacting the compound with lead tetraacetate, the general formula L 6' (wherein R' represents an ethyl group or a substituted alkyl group) is obtained.
4-fluoro-5-formyl-3-methylvirol-2 represented by general formula 5 through the acyl compound represented by
- A carboxylic acid ester is obtained. Further, the formyl group of compound 5 can be used to synthesize other derivatives such as carboxylic acids, esters thereof, acetals, etc. through various chemical reactions.

The compound can be easily reduced with a sodium borohydride reducing agent and induced to 4-fluoro-3-methyl-5-#ffluorol-2-carboxylic acid ester 6. Since the compound has a methylol group, it can be used as an alcohol part in many reactions such as esters, and is also useful as a synthetic intermediate.

The carboxylic acid ester group at position 2 of compound w6 can be converted to a dicarboxylic acid group by hydrolysis.

Other derivatives can also be synthesized by subjecting the carboxylic acid group to various reactions.

The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these in any way as long as the scope of snow making is not exceeded.

Example 1 Malonic acid diethyl ester 2QOILt was added to a 3L glass Mituro flask equipped with a stirrer and a dropping funnel.
(1,318 mol) and 700 d of glacial acetic acid.
An aqueous solution of sodium nitrite (183.69 m of sodium nitrite dissolved in 400 m of water) was added dropwise through a dropping funnel while stirring at °C. After the addition, the reaction mixture was stirred at room temperature for one week. The resulting reaction solution (oxime of malonic acid diethyl ester) was mixed with zinc powder using a stirrer. 50,8 p (2 mol), sodium acetate 14
The reaction solution was added dropwise to a 3β glass flask containing 168 f (1.68 mol) of 451° acetylacetone while being stirred and occasionally cooled in a water bath so that the temperature did not exceed 50°C. After the dropwise addition was completed, the reaction solution was heated to reflux for 2 hours.
The reaction solution was poured into 201 g of ice water, and after being left overnight, the obtained solid was separated. This was dissolved in methylene chloride, the methylene chloride layer was separated from the aqueous layer, and after drying over anhydrous sodium sulfate, methylene chloride was distilled off from the methylene chloride layer filtrate under reduced pressure, and the product was reconstituted with an ethanol-water mixture. crystallized,
53.59 g of 2-ethyl-3,5-dimethylpyrrole-2-carboxylate (yield 24.3%) was obtained.

Analysis value Infrared absorption Sbestol νNH3300c@”, ν
co 167021 Melting point 125°C In a 3L Mitsuro flask equipped with a stirrer.

2-ethyl-3,5-dimethylpyrrole-2-carboxylate 16.7 P C0.01 mol), glacial acetic acid xi
.

Add sodium acetate 505E and stir, add p-nitrobenzenediazonium chloride solution prepared in advance (
P-Nitroaniline 165F, 61J-
Add hydrochloric acid and add 30% sodium nitrite aqueous solution 25
The solution was slowly added dropwise while cooling in a water bath) at room temperature over 1 hour or more. After the dripping is finished, place 1
After stirring for an hour, add 50% ethanol aqueous solution lk to this reaction solution.
added. The red colored precipitate ethyl 4-(4-nitrophenylazo) 3.5-dimethylpyrrole-2-carboxylate was filtered off and thoroughly washed with an aqueous 80% ethanol solution. Add 200ml of acetic acid to a flask equipped with a stirrer and a cooler.
m.

Tin chloride dihydrate SnO]4.2H, 02009 was added and kept at 80° C. with stirring, and the red colored precipitate was added little by little over 30 minutes.

Continue stirring until the reaction solution becomes cloudy.

3 Water in that three-sided flask 11. potassium hydroxide 50
After adding 0F and sufficiently dissolving the temperature, the temperature was raised to 20°C, and the ice-cooled cloudy liquid was slowly added dropwise thereto, and 30 minutes after the completion of the dropwise addition, the product was filtered out, and the product was extracted with methylene chloride, dried, and chlorinated. After distilling off the methylene, the residue was recrystallized from ethanol-water to obtain 10.02 jl of white crystals of 2-ethyl-4-amino-3,5-dimethyl-2-carboxylate (yield: 55.0%).

Analysis value infrared absorption spectrum νNH53so, -g' 53
oo='.

νCo 1680c23-” Proton NMR spectrum δ=x, +0(3H,t)
,2,2o(3n,su.

2.25 (3H, Eri, 2.50 (2H, Sun + ”'
(2H+q)+8~9 (IH, broad) Melting point 121~122℃ 2-ethyl-4-amino-
3,5-dimethylvirol-2-carboxylate6.
5y (0,0357 mol), HBF4563d was added, and sodium nitrite2 was dissolved in a very small amount of water under water cooling.
．． Add 95 f and leave it for 30 minutes.

Irradiation was performed using a 100 W high-pressure mercury lamp until no nitrogen was generated. The reaction solution was neutralized with an aqueous sodium hydroxide solution, extracted with ethyl acetate, and dried. Ethyl acetate was distilled off under reduced pressure and dried. This was purified by column chromatography using Silicage P to methylene chloride system to 1.295K (yield 19.5%)
2-ethyl-4-fluoro-3,5-dimethylpyrrole-2-carboxylate was obtained.

Analysis value Infrared absorption spectrum νNH3280cl? ! '
, Jloo 1670c@'νOF 1198cfi Proton NMR spectrum δ= 1.40 (3H, t
), 2.20 (6H,S).

4.35 (2H, q), 8.5 to 9.2 (IH, S) Melting point 133 to 135°C Example 2 In a 300 d Mitsuro flask, 1 part of benzyl alcohol was added.
After adding 0.5F of metallic sodium and dissolving it, 2-ethyl-5,5-dimethylpyrrole-2-
After adding carboxylate 2 J f (0,126 mol) and keeping at 100° C. for 1 hour, the ethanol is driven off under reduced pressure of 12 mHg. Repeat the decompression operation every hour 1
Confirm the completion of the reaction using thin layer chromatography. After the reaction was completed, the volatiles were distilled off at 100° C. and 1 m+Hg, and the residue was dissolved in ether.

After washing with water, add anhydrous sodium sulfate and leave it overnight in the refrigerator. After distilling off the ether, recrystallize with ethanol-water. A yield of 79.7 cm) was obtained.

Analysis value infrared absorption spectrum νNH3280cWv”,
ν001660 (i' proton NMR spectrum
δ=2.30(5H,S), 245(:5H,S
).

5.35 (2H, S), 5.80 (IH, (1), 7.
5 (5H, S).

8.8-9.2 (IH, broad) Melting point 102-104°C Then 2-
Benzyl-3,5-dimethylpyrrole-2-carboxylate was reacted with p-nitrobenzenediazonium chloride in the same manner as in Example 1 to give benzyl-4-(4-nitrophenylazo)-3,5-dimethyl-2. -carboxylate was obtained, which was converted into benzyl-4-amino-3,5-dimethylpyrrole-2-carboxylate, and the amine group was converted into a diazonium salt of f-dorafluoroporate.

Optical fraction MINc, 2-benzyl-4-fluoro-3,
5-dimethylaminopyrol-2-carboxylate 1
．． 187 (yield 1o, 9%) was obtained.

Analysis value infrared absorption spectrum νNH3290c@',
νoo 1660 (:i ”.

νOF o94. ,,;”PutonNMRxvec)le ν=2.23(3H,S)
, 2.30 (3H,S).

5.30 (2H, S, 7.4 (5H, S), 8~9
(IH, broad) Melting point 126°C Example 3 Obtained in Example t *2-ethyl-4-fluoro-3,5-dimethylpyrrole-2-carboxylate) 1.04 i
Dissolve 0,0056 monolithic acid in acetic acid, add 4,989 (0,0112 mol) of lead 1 acetate over a total of 50 minutes, and stir at room temperature for 8 hours. After the reaction is complete, the product is poured into 2 ml of ice water.
After leaving it overnight, it was extracted with methylene chloride, and then purified with silica gel-methylene chloride column chromatography.
Recrystallize from ethanol to obtain 2-ethyl-4-fluoro-5
-Formyl-5-methylpyrrole-2-carboxylate 0.4F (yield 36.0%) was obtained.

Analysis value infrared absorption spectrum νNH327o,;7”νo
o 1690c@”, 1700c@”νOF
12003' P O ton N M R spectrum A/ δ = 1.45 (3
H, S, 2.35 (3H, S).

4.45 (2H, q), 8.5-9.5 (IH, bro
ad).

9.8 (IH,S) Melting point 133-133.5°C Example 4 2-ethyl-4-fluoro-5-formyl-3-methylvirol-2-carboxylate obtained in Example 50
．． 37 (0,0015 mol) in a mixture of 30-1 methanol and 2 d of water, and 0.0 mol of sodium borohydride.
After stirring at room temperature for 30 minutes, the mixture was made alkaline by adding an aqueous sodium hydroxide solution, the product was extracted with methylene chloride, and the mixture was diluted with anhydrous sulfuric acid.
After drying over IJum, methylene chloride was distilled off and recrystallized from ethanol-water to give 2-ethyl/L- to 4-fluoro-5-methyl-5-methylolpyrrole-2-carboxylate (0.259 g). A rate of 94 cm) was obtained.

Analysis value infrared absorption spectrum νNH3300i”, νco
t6ao,,;”νay t2oo,,-1 Proton NMR spectrum δ=1.45(3H,t
), 2.3(3H,B).

3.9 (LH, S), 4.35 (2H, q), 4.7 (
2H, d).

8.5 to 9.5 (IH, broad) (Effect of the invention) The fluorine-substituted pyrrole derivative obtained by the present invention is
In addition to being used as an anti-inflammatory agent, it is also expected to have antitumor and antibacterial activity.

Patent applicant: Central Glass Co., Ltd.

Claims (1)

[Claims] (In the formula, R1 represents an ethyl group or a substituted alkyl group, and H2 represents a methyl group, formyl group, or methylol group)
A fluorine-substituted pyrrole derivative represented by 2) A method for synthesizing a fluorine-substituted pyrrole derivative represented by the general formula: diazonium 4-amino-3,5-dimethylpyrrole-2-carboxylic acid di(in the formula, R1 represents an ethyl group or a substituted alkyl group) 3, which is salt;
5-dimethylpyrrole-2-carboxylic acid ester-4-
Fluorine substitution to obtain 3,5-dimethylpyrrole-4-fluoro-2-carboxylic acid ester 4 (in the formula, R1 is the same as above) by photolyzing diazonium tetrafluoroborate 5 (in the formula, R1 is the same as fly) A method for producing a pyrrole derivative. 3) The methyl group at the 5-position of the compound is reacted with lead tetraacetate to formyl 4-fluoro-5-formyl-3-methylbilow A/-2-carboxylic acid ester 5 (wherein R1 is 4)). (i) A patent claim for reducing the above compound with sodium borohydride to obtain 4-fluoro-3-)if-5-methylolpyrrole-2-carboxylic acid nister (in the formula, R1 is the same as above). The method described in Scope No. 2.