JPS59167568A - Preparation of pyrrole derivative containing perfluoroalkyl group at beta-position - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a raw material for various kinds of pyrrole derivative in high yield, by oximating a reaction product of a perfluorocarboxylic ester and an acetic ester with a strong acid, etc. reducing and condensing the resultant compound with zinc powder. CONSTITUTION:A perfluorocarboxylic ester shown by the formula II (Rf is perfluoroalkyl; R<4> is alkyl) is reacted with an acetic ester shown by the formula III[R<1> is (substituted) alkyl] in an ether in the presence of NaH, etc. to give a perfluoroacetoacetic ester shown by the formula IV, which is treated with a strong acid such as trifluoroacetic acid or sulfuric acid, etc. alone or with it and a weak acid such as acetic acid, propionic acid, etc. and a nitrous acid gas to give an oximated substance shown by the formula V. This substance is reduced and condensed with a beta-diketone shown by the formula VI (R<2>=R<1>; R<3> is alkyl, or alkoxy) and zinc powder, to give the desired compound shown by the formula I . USE:A base substance such as a phenyl-substituted pyrrole derivative, etc. having an anti-inflammatory action.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the following formula: The present invention relates to a method for producing a virol derivative having a perfluoroalkyl group at the β-position as shown.

According to the method of the present invention, perfluorocarbon Yoshinisuru R,C0OR', (R4 represents an alkyl group)
and 62 ester CH3000R", , l to perfluoroacetomonoacid ester COCH2000R
” , !L is combined with “ H , and β-diketones R2000H, COR3, f
In the method for producing virol derivatives having a perfluoroalkyl group at the β-position by condensation with By using it in combination with a weak enemy such as , propionic acid, etc., and further reducing and condensing it with powdered zinc, pyrrole=m-form having a perfluoroalkyl group at the β-position can be obtained in good yield.

These reaction formulas are shown below.

4 Shiba: In the above reaction equation, the general reaction conditions are reaction conditions (1): Place metallic sodium or sodium hydride in ether, and add an equimolar mixture of 4
After dropping for ~5 hours, reflux for 3-4 hours. The ether layer is distilled off, the reaction mixture is neutralized with 30% sulfuric acid, water and ether are added, the ether layer is separated, washed with water, dried, and then the ether is distilled off and distilled under reduced pressure.

Reaction conditions [1 [)] The mixture of 4 and trifluoroester acid was cooled on ice, dried hydrogen chloride was introduced, the hydrogen chloride gas was saturated, nitrite gas was blown in, the mixture was stirred, and then condensed under reduced pressure. get this.

Reaction conditions CU After adding β-diketones to the trifluoroacetic acid solution and adding powdered zinc little by little, it was heated, sodium acetate was added and stirred at 100°C, and this was poured into ice water to remove the product. Filter.

It is done by

The present inventors presented a method for producing virol derivatives having a trifluoromethyl group at the β-position at the 1981 Spring Annual Meeting of the Chemical Society of Japan, but the yield was less than 10%;
It was extremely low. Therefore, the present inventors conducted intensive studies on a method for obtaining a virol derivative having a perfluoroalkyl group at the β-position at a higher yield, and found that virol having a perfluoroalkyl group at the β-position is stable to strong acids. It is possible to use a strong acid as a solvent in the process of obtaining oxime depletion, which moves the ketoenol grains of 4 into the keto form, and reacts this with nitrite residue to obtain the corresponding oxime compound, which is then converted into a strong acid. inside β
-We have discovered a method of obtaining cylindrical action by conducting reductive condensation with dictones, leading to the present invention.

The virol derivative of the present invention can be obtained in 0 units by reducing it with diborane or sodium borohydride.

Depending on the amount of sulfuryl chloride added, II M can be obtained, which can be hydrolyzed to lead to (X=OH20H, C!HO'l'ta0).

On the other hand, (where R5 represents a benzyl group, P (0 by hydrogenolysis using a 1-0 system)
It can be converted into each virol derivative by carrying out a chemical reaction.

Moreover, since hydrogenation using pac-c can be obtained, carboxysynthesis can also be performed.

As mentioned above, the pyrrole derivative having a perfluoroalkyl group at the β-position of the present invention is a basic chemical substance that can be converted into various virol derivatives. Since it exhibits a low anti-inflammatory effect (Japanese Patent Publication No. 47-8535), it is expected to have a wide range of applications.

The method of the present invention will be explained in more detail with reference to Examples below.

Example 1 Into a 100 td glass three-tube flask equipped with a gas inlet tube and a stirrer, 44 mm of ethyltrinoroacetoacetate and 2 (1 m/m) of trifluoroacetic acid were added, and dried at 0° C. for 30 minutes. Hydrogen gas was introduced into the reaction system through a gas introduction tube to saturate hydrogen chloride.

Freshly generated nitrite gas was introduced into the solution at 0°C until the gas absorption ceased, and the extrusion resistance was maintained at 0°C for 20 hours.
Concentrated under full vacuum.

The concentrated material is transferred to a
Transfer to a 00M glass Mitsuro flask and add 150 mmol of acetylacetone. : 13m containing trifluoroacetic acid
1 and I! A mixed solution of rl=acid 30d was added dropwise with stirring. To this, 153 mmol of powdered zinc (!72 hours was added to the reaction mixture under stirring. After stirring at 70° C. for 3 hours, the sodium hydroxide solution was added to the reaction mixture). Add Oy and heat at 100℃ for 20
After stirring for a minute, the reaction was poured into ice water. After filtering the product, it was recrystallized from n-hexane-methylene chloride to give ethyl-4-aceter-3-trifluoromethyl-5-methylpyrrole-2-carboxylate 5.49 (yield: 4
7%).

Analysis value infrared absorption spectrum νCo 169 m', 1
675c 1 proton NMR spectrum δtomi, 4o
(sH, t), 2.38 (3HIS) 2.45 (3n,
s), 4.4o (2a, q), 1o, 50 (IH, S)
Melting point 110°C Mass spectrometry m/e 263 (M) Example 2 Ethertrifluoroacetate 40,4y (o, 2a mol
) and benzyl rrP acid 98.89 (0.57 mol
) and ether 1oo-, and 14,4 y of sodium hydride (purity about 50%) was gradually added to the reactor while stirring. After refluxing for 2 hours and 1 hour, the ether was distilled off under reduced pressure, the reaction mixture was neutralized with 30% sulfuric acid, water and ether were added, and the ether layer was separated. After washing with water, it was dried over magnesium sulfate, and the mixture was dried under reduced pressure. Distillation yielded 16.9y of penzyltrifluoroacetoacethitra. This benzyl trifluoroacetoacetate 2.1 y (8,6m
9.mo:L) into a 100 ml glass flask similar to Example 1. 3.18 rd of hydrogen chloride acid was added, hydrogen chloride gas fq was introduced in the same manner as in Example 1, and then nitrous acid gas was introduced. After adding 10d1 of acetic acid and 21rLe of acetylacetone to the reaction system, 1.5y of powdered zinc was added little by little, and after the addition was completed, it was heated at 70°C for 2 hours, and rD&
35"f of sodium was added and the mixture was further stirred at 100° C. for 20 minutes. The reaction mixture was poured into ice water, and the product was completely extracted with chloroform, washed with sodium bicarbonate, washed with water, and dried over magnesium sulfate.

After distilling off methylene chloride, the product was separated by column chromatography (silica gel - methylene chloride), and then n-
Recrystallized from hexane-methylene chloride to give benzyl-4-acetyl-3-trifluoromethyl-5-methylpyrrole-2-carboxylate ytrm-h, 74051+ (yield 26.5).

Analysis value infrared absorption spectrum νNH3300crIV',
νOO1690cyn', 1675c is CF31
275cNl, lI20cnpl proton NMR spectrum δ-2,33(3H,S), 2.44'(3H
,5)5j5(2H,S) ,7.36(5H,S),
9.80(IH,S)F''IJMR spectrum (trifluoroacetic acid external standard) -23,8PPM (S) Melting point 116.0℃ Mass spectrometry ml 325 (M+) Example 3 Same as the example process, 100d 26 in a glass flask
After adding mmol of ethyltrinoroacetoacetate, trifluoroacetic acid, and sulfuric acid to saturate the mixture with hydrogen chloride gas, nitrite gas was introduced and the mixture was concentrated under reduced pressure. Transfer the product to a 500M flask, add 51 g of ethyl acetate, 100 mmol of trifluoroacetic acid, and a small amount of acetic acid (transfer so that the product dissolves), and add 89 g
After adding mmol of powdered zinc in small amounts, it was treated with sodium acetate in the same manner as in Example 1 to give 3.07 mmol of diethyl-3-trifluoromethyl-5-methylpyrrole-2,4-dicarboxylate crystals ( A yield of 4I%) was obtained.

Analysis value infrared absorption spectrum νCo 1710cm',
1690cm "νOF31285CILL', 1
120d” proton NMR spectrum δ-1,37(
3H, t), 1.41 (3H, t) 2.49 (3L
S), 4.28 (2H, q), 4j7 (2H,
q) 10.03 (IH,S) Melting point 98°C Mass spectrometry mle 298 (M+) Example 4 10.5 mm0 of ethyl-4-acetyl-3- was placed in a 300-mm glass three-piece flask with a magnetic stirrer. )
8 m of boron trifluoride was added to 30 g of dry tetrahydrofuran containing 17 fluoromethane-5-methylpyrrole-2-carboxylate and 57 mmol of sodium borohydride at -10°C under a nitrogen stream.
Molk added. The reaction mixture was stirred at 20°C for 4 hours,
It was treated with 5q6 hydrochloric acid and neutralized with sodium hydrogen carbonate. This was extracted with ether, isolated by silica gel chromatography, recrystallized from n-hexane, and ether-4-ethyl-3
-Trifluoromethyl-5-methylpyrrole-2-carboxylate was obtained in an amount of 2.19% (yield: 83%).

Analysis value infrared absorption spectrum νCo 16aoc,, 1ν
OF11280c@”, 1120Li’ proton N
MR spectrum δ=1.07 (3H,'l:,)
,1.34(3E(,su2.23(3H,S),
2.53(2H,q), 4.35(2H,q
) 9.50 (IH, S) - point 113℃ Mass spectrometry mle 248C (M-1)
:] Example 5 Sodium borohydride (28.9 mmol) and 30 rxl of tetrahydrofuran were placed in 300 glass Mitsuro flasks, and 11 ml of borane ether solution was added dropwise under a nitrogen stream, and diborane was added. caused it to occur.

To this, 15 NJ of tetrahydro7rane containing 835 g (2,57 mmol) of benzyl-4-acetyl-3-fluoromethyl-5-methylpyrrole-2-carboxylate was added dropwise over 30 minutes.

- In the evening, leave the mixture under a nitrogen blanket and add 5% aqueous hydrochloric acid solution to decompose the borane complex. The reaction mixture was extracted with ether, neutralized with sodium hydrogen carbonate, washed with water and dried, and the ether was distilled off to give a crude product of benzyl-4-ether-3-trifluoromethyl-5-meterbyrol-2-carboxylate (754). (Roughness rate: 94%) was obtained.

Analysis value infrared absorption spectrum H3295cm', νC
o 1680cm'OF31275cm' Proton NMR spectrum δ-1,13(3H,t)
, 2.19 (3H, S) 2.54 (2H, (1), 5.
32 (2H, B), 7.33 (5H, S) 9.56
(IH, bs) Mass spectrometry m/e 311 (M+) Example 6 Pencil-4-ethyl-
3-) Lifluoromethyl-5-methylvirol-2-
Add 200 grams of carboxylate and 10 tyl of butyric acid,
After reacting with lead tetraoxide at 40°C, the reaction mixture was poured into water, extracted with ether, washed with water, dried, and concentrated under reduced pressure. 220 g of the crude product was crystallized with methanol to obtain 5 g of benzyl-4-ethyl-3-)lifluoromethyl-5-acetoxymethylpyrrole-2-carboxylate (yield: 74.5%).

Analysis value infrared absorption spectrum νNH32904'νoo 1
740 (B i, 1670c foot"1/CF3 128
0cm', 1120cm' Proton NMR spectrum δ-1,17(3H,su, 2.o(3n,s)
2.68 (2H, q), 5.013 (2H1s),
5.37 (2H, s) 7.4 t (5 n, s) Melting point 124.0°C Example 7 Benzyl-4-ethyl-3-trifluoromethyl-5 in a 500XLe glass trifluoro flask equipped with a stirrer -methylpyrrole-2-carboxylate 2,1
f and 5Pd- (320Q and 15% tetrahydrofuran)
0! Le and triethylamine 4- were added, and the mixture was stirred at room temperature under a hydrogen stream for 5 hours. At the end of the reaction, Pd-C was filtered, tetrahydrofuran was distilled off, and 4-ether-3-1-
A crude product of 1J fluoromethyl-5-methylpyrrole-2-carboxylic acid, 2.3 y (crudeness rate calculated as 104% due to the inclusion of impurities), was obtained. Since it is difficult to separate the product and to make U, it is difficult to determine the structure. Therefore, the product was further reacted, and the structure was confirmed in Example 8 shown below.

Example 8 7C4 obtained in Example 7 was placed in a 50d glass flask.
-Ether-3-trifluoromethyl-5-methylpyrrole-2-carvone fjl 100'/k and si, 10
Decomposition was carried out at 170-180° C. under reduced pressure of 0-110 mmHf to obtain 40 g of 4-etherune-trifluoromethyl-5-methylpyrrole (yield 50%).

Analysis value infrared absorption spectrum J/NH3480cm', J
/CF31110 (Near 71' proton NMR spectrum δ-1, o9 (3H, t), 2.+7 (:sn,
day) 2.50(,2H,q), 6.82(IH,b
s), 7.85 (IH,be) mass spectrometry m
/e 177 (M+) Example 9 In a 100 rLl glass flask, benzene 4-
Ethyl-3-) trifluoromethyl-5-methylpyrrole-2-carboxylate 300 Y'e was taken, dissolved in dry ether IO-, 2 equivalents of sulfuryl chloride was added, stirred at room temperature for 2 hours, and then hydrolyzed. The product was extracted with ether, washed with water, dried, concentrated under reduced pressure, and purified by column chromatography to give benzyl-4-ethyl-3-t')7)li oromether-5-formylpyrrole-2-
250 q of carboxylate (yield 77%) was obtained.

Analysis value infrared absorption spectrum i+NH3245 111'
, νoo 1705c@", 1675c@'shi0F31270c@", 1120(@"Proton NMR spectrum δ-1,27(3H,t), 2.9
5 (2H, q) 5.36 (2H, e), 7.35 (5H
, s), 9.77 (LH, s), 10.27 (5H, b
s) Patent applicant Central Glass Co., Ltd.

Claims (1)

[Claims] General formula 9% formula% (in the formula, R1 and R2 represent an alkyl group or a substituted alkyl group)
R3 also represents an alkyl group, alkoxy M-k, Rf represents a fluoroalkyl group).
R', % (R' represents an alkyl group 7) and butyrate ester cH3coou'), perfluoroacetoacetate R1-000H,C0OR' 23-f was synthesized, and further turf oxime compound R,C0C-C ○OR' was obtained, and this and β-diketone Tomonaga. R2000H200R3A is condensed with R2000H200R3A to produce a pyrrole derivative JL having a perfluoroalkyl group at the β position. In the step of obtaining an oxime compound, a strong acid such as trifluoropholic acid or sulfuric acid is used alone, or a strong acid such as another weak acid is used. 1. A method for producing a virol derivative having a perfluoroalkyl group at the β-position, the method comprising using the derivative in combination with a virol derivative and further reducing and condensing it with powdered zinc.