JPH04187656A - Novel 2-chloro-3,4,5-trifluorobenzoic acids - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [X is OR<1> (R<1> is H or 1-3C alkyl), Cl, CH3, -CH2C(=0)OR<2> or of formula II (R<2> and R<3> are each 1-3C alkyl)]. USE:An intermediate for the production of 1-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acids useful for the production of antifungal agents. PREPARATION:For example, 1-chloro-2,3,4-trifluorobenzene is reacted in carbon tetrachloride in the presence of aluminum chloride into benzotrichloride, which is then reacted with water in the presence of ferric chloride, thus obtaining the objective compound of the formula (where, X is Cl).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides an intermediate for producing 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-year-old xoquinoline-3-carboxylic acid. It's about the body.

These compounds are useful as antibacterial agents, such as 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-substituted quinoline-3-carboxylic acid,
128,978, JP 64-47,785, JP 61-1,682, EP343,5
24. EP342,678. EP 311, 948, etc.] has been in production for a long time.

[Prior Art] Conventionally, 1-cyclopropyl-6,7,8-)lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was converted into 2.3.4.5-tetrafluorobenzoic acid. Since it is produced as a starting material [JP-A-61-1682], HF is eliminated during quinoline ring closure, which poses a material problem.

[Problems to be Solved by the Invention] The present invention provides novel 2-chloro-3,4.5-trifluorobenzoic acids, and the material problem is solved because the liver does not come off during quinoline ring closure. It was done.

[Means for Solving the Problems] The present invention relates to compounds of the formula alkyl group, R2 and R3 are C1-C3 alkyl groups, and particularly preferred compounds are the following: 2-chloro-3,4, 5-Trifluorobenzoic acid, 2-chloro-3,4,5-trifluorobenzoyl chloride, ethyl 2-chloro-3,4,5-trifluorobenzoylacetate, 2-(2-chloro-3,4
．． Ethyl 5-trifluorobenzoyl)-3-ethoxyacrylate, ethyl 2-(2-chloro-3,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate, 2-chloro-3,4,5 -methyl trifluorobenzoylacetate, 2-(2-chloro-3,4.5-
Methyl trifluorobenzoyl)-3-ethoxyacrylate, methyl 2-(2-chloro-3,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate.

The method for producing the compound of the present invention is shown below.

Reaction formula 1 % formula %) () Reaction formula 2 Reaction formula 1 shows the production of compound (V) from 1-lytetra-2.3.4-1-lifluorobenzene.

(I) is reacted at 75° C. in 4 to 20 times the mole of carbon tetrachloride in the presence of 1.5 to 3 times the mole of aluminum chloride, followed by normal post-treatment and recrystallization separation to obtain NT). (T
When I) is hydrolyzed in 85-95% sulfuric acid, carboxylic acid (IV) is obtained.

In addition, (IV) is obtained by reacting (I) with acetyl chloride at 80 to 120°C in the presence of 1.5 to 3 times molar aluminum chloride to obtain acetophenone (III), and then reacting it with an aqueous solution of sodium hypochlorite and heroform. It can also be obtained by performing a reaction. Acid (IV) reacts with common acid chloride generating reagents such as thionyl chloride, phosphorus oxychloride, oxalyl chloride, etc. at 40 to 100°C without a solvent or in an inert solvent (benzene, methylene chloride, chloroform, etc.). This yields acid chloride (V).

(V) can also be obtained by reacting benzotrichloride (II) with equimolar amounts of water in the presence of ferric chloride at 125-135°C.

Reaction scheme 2 shows the production of a compound of formula (■) from acid chloride (V).

(V) is condensed with a magnesium salt of dialkyl malonate, which is then hydrolytically decarboxylated [R
, Filler et al., J., Crg., Cham.

35930 (1970)], it can be converted into a substituted benzoyl acetate (Vl). Formula (Vll
) is tautomeric, and its enol form also exists.

(Vl) (VI') Compound (Vl) is described by Grohe et al. [EP 78.362]
2-(2-chloro-3,4.5-trifluorobenzoyl)-3-ethoxyacrylate (■) by the method of After reaction and usual post-treatment,
Recrystallization yields the enamine compound (■) with high purity and good yield.

Examples of the present invention will be described in more detail below.

[Example 1] 20 with a stirrer, rapid flow cooler, thermometer, and dropping funnel
97 ml (1 mol) of carbon tetrachloride and 33.4 g (0.25 mol) of aluminum chloride were placed in a 140m flask, and 1-4-2.3.4-
16.6 g (0.1 mol) of 1-lifluorobenzene was added dropwise over 1.5 hours to slowly generate hydrochloric acid gas. After the dropwise addition was completed, the reaction mixture was allowed to react for 15 minutes, and after cooling to room temperature, the reaction mixture was poured into ice water (150 ml).

Separate the organic layer, wash with 50ml of water, then add 5% sodium bicarbonate in water. ? 1 (50 ml) and further washed with 50 ml of water.

After carbon tetrachloride was distilled off, the residual liquid was distilled under vacuum to obtain benzotrichloride (mixture 33:67) as a yellow liquid with a concentration of 19.3%.
g was obtained. bp85-90℃/2 mmHg When this product is left in the refrigerator, crystals are precipitated, and after filtering and recrystallizing from petroleum ether, 2-chloro-3,
650 g of 4.5-h-lifluorobenzotrichloride was obtained as white crystals. m941~43°CIR(K
Br) cm-', 1607, 1500° 1420, 77
0 (C-C13) NMR (CDCI z ) δ7゜93 (IH, ddd
, J-2,0Hz, 7.3Hz.

11.7H2) Elemental analysis value: C1,49,8%; C, HCl4F3
Calculated value as: C1,49,95% [Example 2] 3[12 g of 95% sulfuric acid was charged in a 1 ml flask, and while stirring, 2-chloro-3,4,5-
) 312 g of refluorobenzotrichloride were added over 10 minutes. After reacting for 2 hours, the reaction mixture was poured into 50 ml of ice water, and the precipitated crystals were filtered off. The filtered crystals were washed with a small amount of cold water and dried to give 2.22 g of 2-chloro-3,4.5-trifluorobenzoic acid as white crystals (yield: 9
6%) was obtained. mp107~109℃ IR (KBr) cm-', 3100~2300 (0-H
), 1698((:;0).

1605.1517.1425 NMR (CDC1a) 67.81 (LHld
dd, J=0.7Hz, 8.3Hz.

9.3Hz) 12.1 (LH,s) Elemental analysis value:
C1, 16, 7%, C? Calculated value as H2CIF50□ C1, 16, 84% [Example 3] 100v 1 flask contains 1-4 rows 2.3.4-
16.6 g of trifluorobenzene and 33.4 g of aluminum chloride were charged, and 11.8 g of acetyl chloride was added dropwise with stirring at 20 to 40°C.
Allowed time to react. The mixture was diluted with 30 ml of EDC at 80°C and poured into 200 ml of ice water. Separate the organic layer and add 5 liters of water.
0ml 1.5% sodium bicarbonate 50ml and saline solution 5
After washing with 0ml, it was dried with magnesium sulfate. EDC
After distillation, the residual liquid was vacuum distilled and acetophenone (34:
mixture of 66-substituted isomers) as a pale yellow liquid at 15.6
g was obtained. b+p65-70°C/2mmHg.

Next, sodium hypochlorite aqueous solution 47 with 10% available chlorine.
．． 6.26 g of the acetophenone compound obtained above was added dropwise into the solution over 10 minutes at 50° C. or lower, and the mixture was then refluxed for 2 hours. After cooling, remove excess Na0 with sodium bisulfite.
After decomposing C1, hydrochloric acid was added to adjust the pH to 1, and crystals were precipitated. (5.67 g, mixture 1:2). This was recrystallized twice from hexane-toluene (3.1) to obtain 1.80 g of 2-chloro-3,4,5-trifluorobenzoic acid as needle-like crystals.

[Example 4] 2.10 g of 2-chloro-3,4,5-trifluorobenzoic acid and 5 ml of thionyl chloride were placed in a 20 ml flask, and heated under reflux for 6 hours while stirring.

After removing excess thionyl chloride, the residue was distilled under reduced pressure to obtain 2.06 g (yield: 90%) of 2-chloro-3,4,5-trifluorobenzoyl chloride as a colorless liquid.

bp 95-96℃ 720mmHg, no” 1.
5093TR(neat)ctrV', 176
5 (C=o), 1600.1505NMR (CD
C1a) δ7.88 (IH, ddd, J・2.2Hz
, 7.3) +z.

10.0 Hz) [Example 5] 567 g of 2-chloro-3,4,5-1-lifluorobenzotrichloride and 10 mg of anhydrous chlorinated chloride were added to a 20 ml flask, and the mixture was heated at 125 to 130°C with stirring.
0.40 ml of water was added dropwise over about 1 hour, and the mixture was allowed to react for 1 hour.

When the dark brown reaction liquid was distilled under reduced pressure, 2-chloro-3,4.5-trifluorobenzoyl chloride was obtained as 3
．． 66 g (yield: 80%) was obtained.

[Example 6] One piece of magnesium 240mg in a 20ml flask,
0.5 ml of absolute ethanol and 50 μm of carbon tetrachloride were added, and the reaction started. While stirring, 1.52 g of diethyl malonate and 0.5 ml of absolute ethanol were added to the mixture.
A solution of 84 ml and toluene 4 ml was added dropwise, and the mixture was reacted for 15 hours. Next, the solvent was distilled off from the reaction mixture under reduced pressure, and 8 ml of anhydrous THF (tetrahydrofuran) was added.

2-chloro-3,4.5-trifluorobenzoyl chloride 2.
A solution of 0.6 g in 2 ml of THF was added dropwise over 10 minutes, and the reaction was then allowed to proceed for 2 hours.

Add hydrochloric acid to the reaction solution to make p)l=1, separate the layers, extract the aqueous layer twice with 4 ml of toluene, combine the extracted layer with the organic layer, wash with water, 5% NaHCO3, and brine, then Dry with magnesium sulfate. When toluene was distilled off, 3610 g of an orange liquid was obtained, which was stirred and refluxed for 3 hours in 8 ml of water and 20 ml of p-toluenesulfonic acid. After cooling, the reaction solution was extracted with chloroform, washed with water, and then dried. When chloroform is distilled off, 2-chloro-3,4,5
-1.24 g of ethyl trifluorobenzoylacetate (
Yield: 49.2%). mp41-43℃.

IR (KBr) cm-', 1730.1700 (C=
o), 1600.151ONMR (CDCI 3)
δ1.26 (0.6X 3H,t, J=7.0Hz,)
, 1.35 (0.4x 3H,t, J=7.0Hz)
, 4.00 (0,6x 2H,S).

4.20 (0.6x 2H,q, J=7.0Hz),
4.30 (0,4X 2H,q.

J=7.0Hz), 5.60 (0.4X IH,s)
, 7.2-7.6 (LH.

m), 12. Stone (0,4xlH,b,s).

This compound exists in about 40% enol form in CDCl3.

[Example 7] A mixture of 480 mg of ethyl 2-chloro-3,4.5-)lifluorobenzoylacetate, 386 mg of ethyl orthoformate, and 11,450 mg of anhydrous acid was heated under reflux for 2 hours with stirring in a 20 ml flask. The reaction mixture was concentrated under vacuum to give 2-(2-chloro-3,4.5
Ethyl-trifluorobenzoyl)-3-ethoxyacrylate was obtained as an orange viscous liquid.

[Example 8] The crude product of Example 7 was dissolved in 3 ml of THF, and 108 mg of cyclopropylamine was dissolved in 1 ml of THF for 7 nights.
It was added dropwise at °C and stirred for 1 hour.

The reaction mixture was evaporated to dryness under vacuum, and the resulting pale yellow crystals were recrystallized from isopropyl ether-petroleum ether to give 2-(2-chloro-3,4,5-trifluorobenzoyl)-3-cyclopropyl. 480 mg (yield 80%) of amine ethyl acrylate was obtained as white crystals. mp88-89℃IR(KBr)cm-',
1680 (C=0), 1610.1510.14
25 This compound was a cis-trans mixture, and the NMR spectrum of the main component (about 90%) was as follows.

NMR (C:0C13) δ0.7-1.1 (4H, m)
, 1.16 (3H, t, J=7.0Hz,), 2.8
~3.2 (IH, m), 4.02 (2H, q, J=
7.0Hz), 6.86 (LH, ddd, J=
2.0Hz, 6.4Hz, 9.0Hz).

8.24 (IH, d, J=14.0Hz), 10.
5-11.5 (IH, b, s) Elemental analysis value: C1,1
0.1%; Calculated value as C1-H33CIF3NO3: C1,10,20% [Reference Example 1] 2-(2-chloro-3,4,5-
123 mg of ethyl (trifluorobenzoyl)-3-cyclopropylaminoacrylate and 6 ml of anhydrous THF were added, and 60% sodium hydride was added at room temperature with stirring.
8 ml of the mixture was added, the mixture was stirred for 1 hour, and then refluxed for 3 hours. After distilling off THF from the reaction mixture, the residue was diluted with 1.2 ml of acetic acid.
+nl, add 20% sulfuric acid 0, 9 [[+1 and 2
The mixture was heated to reflux for an hour.

After cooling, the reaction mixture was poured into 5 ml of ice water, and the crystals were filtered off, washed with a small amount of water, and air-dried to give 1-cyclopropyl-6,7,8-1-lifluoro-1,4-dihydro- 75 mg of 4-oxoquinoline-3-carboxylic acid was obtained. mp227-229°C [Effects of the Invention The present invention is an intermediate for producing quinolone carboxylic acid useful as a pharmaceutical, and since HF is not eliminated during quinoline IM ring closure, there are no problems with the reactor material. .

Claims (2)

[Claims] (1) Compounds represented by the general formula below; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X is OR^1, Cl, CH_3, ▲ There are mathematical formulas, chemical formulas, tables, etc. , there are tables, etc. ▼, or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼,
R^1 is hydrogen and C_1 to C_3 alkyl group, R^2
and R^3 is a C_1 to C_3 alkyl group) (2) The compound is 2-chloro-3,4,5-trifluorobenzoic acid, 2-chloro-3,4,5-trifluorobenzoyl chloride, 2-chloro-3,4,5-trifluorobenzoyl Ethyl acetate, 2-(2-chloro-3
, 4,5-trifluorobenzoyl)-3-ethoxyethyl acrylate, 2-(2-chloro-3,4,5-trifluorobenzoyl)-3-cyclopropylaminoethyl acrylate, 2-chloro-3, Methyl 4,5-trifluorobenzoylacetate, 2-(2-chloro-3,4,5
The compound according to claim 1, selected from methyl -trifluorobenzoyl)-3-ethoxyacrylate, methyl 2-(2-chloro-3,4,5-trifluorobenzoyl)-3-cyclopropylaminoacrylate.