Process for producing pyridazinone compound and production intermediates thereof

Abstract

The present invention provides a process for producing a compound of the formula (1) wherein X represents a hydrogen atom, etc., and Y represents a hydrogen atom, etc., which comprises step 1 of reacting a compound of the formula (2) and a compound of the formula (3) in the presence of a Lewis acid wherein R represents a hydrogen atom, etc., to obtain an adduct, and step 2 of reacting the adduct obtained in the step 1 and hydrazine to obtain the compound of the formula (1). ##STR00001##

Claims

1. A compound of the formula (4); ##STR00050## wherein X represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, Y represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, and R represents a hydrogen atom or a C1-C4 alkyl group.

2. A process for producing a compound of the formula (1); ##STR00051## wherein X represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, and Y represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; which comprises step 1 of reacting a compound of the formula (2) and a compound of the formula (3) in the presence of a Lewis acid to obtain an adduct; ##STR00052## wherein R represents a hydrogen atom or a C1-C4 alkyl group and X has the same meaning as defined above, ##STR00053## wherein Y has the same meaning as defined above; and step 2 of reacting the adduct obtained in the step 1 and hydrazine.

3. The process according to claim 2, wherein the adduct is a compound of the formula (5); ##STR00054## wherein X and Y have the same meanings as defined above.

4. The process according to claim 2, wherein the reaction of the compound of the formula (2) and the compound of the formula (3) is conducted in the presence of a polar aprotic solvent.

5. The process according to any one of claims 2 to 4, wherein the Lewis acid is a titanium compound or a boron compound.

6. The process according to claim 2, 3 or 4, wherein the reactions both in step 1 and step 2 are carried out in the presence of an aromatic hydrocarbon solvent.

7. A process for producing a compound represented by the formula (1); ##STR00055## wherein X represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, and Y represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; which comprises reacting a compound of the formula (4) and hydrazine; ##STR00056## wherein R represents a hydrogen atom or a C1-C4 alkyl group and X and Y have the same meanings as defined above.

8. The process according to claim 7, wherein the reaction is carried out in the presence of an aromatic hydrocarbon solvent.

9. A process according to claim 7, which further comprises reacting the compound of formula (1) and a chlorinating agent to produce a compound of the formula (6); ##STR00057## wherein X and Y are the same as defined for formula (1).

10. A process for producing a compound of the formula (4); ##STR00058## wherein X represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, Y represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, and R represents a hydrogen atom or a C1-C4 alkyl group; which comprises reacting a compound of the formula (2) and a compound of the formula (3) in the presence of a Lewis acid in range of from 20 to 80 C.; ##STR00059## wherein X and R have the same meanings as defined above, ##STR00060## wherein Y has the same meaning as defined above.

11. The process according to claim 10, wherein the Lewis acid is a titanium compound or a boron compound.

12. The process according to claim 10 or 11, wherein the reaction is carried out in the presence of an aromatic hydrocarbon solvent.

13. The process according to claim 3, wherein the reaction of the compound of the formula (2) and the compound of the formula (3) is conducted in the presence of a polar aprotic solvent.

14. The process according to claim 5, wherein the reactions both in step 1 and step 2 are carried out in the presence of an aromatic hydrocarbon solvent.

Description

EXAMPLES

(1) The present invention will be explained further in detail by examples below, but the present invention is not limited to these examples.

Example 1

(2) ##STR00028##

(3) Two hundred and five (205) mg of 2,6-difluorobenzoylformic acid and 208 mg of 4-chlorophenylacetone were mixed with 0.5 ml of toluene, and 1.5 ml of 1 M toluene solution of titanium tetrachloride was added thereto at 50 C. under nitrogen atmosphere. The mixture was stirred at 50 C. for 4 hours. The stirred mixture was analyzed with high performance liquid chromatography to find out that area percentage of 3-(4-chlorophenyl)-2-(2,6-difluorophenyl)-2-hydroxy-4-oxopentanoic acid (hereinafter, referred to as compound (4-a-3)) is 76.1%, and area percentage of a compound of the formula (B-a-3) is 0.8%. The reaction mixture was left to cool, about 3 ml of ice water was added thereto, and then the liquid was subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. Four hundred and twenty (420) mg of the residue was subjected to silica gel column chromatography (elution solvent: hexane-methyl tert-butyl ether (hereinafter, methyl tert-butyl ether is referred to as MTBE)), to obtain 312 mg of the compound (4-a-3)) (yield: 80%).

(4) Compound (4-a-3)

(5) .sup.1H-NMR (CDCl.sub.3, TMS) (ppm): 2.22 (3H, br s), 4.80 (1H, br), 5.30 (1H, br), 6.82-6.87 (3H, m), 7.13-732 (5H, m).

(6) LC-MS (ESI+APCI) MS-353 (M-1)

Example 2

(7) ##STR00029##

(8) Two hundred and five (205) mg of 2,6-difluorobenzoylformic acid and 165 mg of phenylacetone are mixed with 0.5 ml of toluene, and 1.5 ml of a 1 M toluene solution of titanium tetrachloride is added thereto at 50 C. under nitrogen atmosphere. The mixture is stirred at 50 C. for 4 hours, then, left to cool, about 3 ml of ice water is added thereto, and the liquid is subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer is dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain 2-(2,6-difluorophenyl)-2-hydroxy-4-oxo-3-phenylpentanoic acid (hereinafter, referred to as compound (4-a-1)).

Example 3

(9) ##STR00030##

(10) Two hundred twenty (220) mg of methyl 2,6-difluorobenzoylformate and 0.17 g of 4-chlorophenylacetone were mixed with 6 ml of toluene, and 1.73 g of titanium tetrachloride was added thereto at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 1 day, then, 6 ml of toluene was additionally added thereto and the mixture was further stirred at room temperature for 3 days. Ice water was added thereto, and extraction with MTBE was performed. The organic layer obtained in the extraction was washed with water twice, dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. Zero point three seven (0.37) g of the residue obtained was subjected to silica gel column chromatography (elution solvent: hexane-ethyl acetate), to obtain 0.22 g of methyl 3-(4-chlorophenyl)-2-(2,6-difluorophenyl)-2-hydroxy-4-oxopentanoate (hereinafter, referred to as compound (4-b-3)) (yield: 60%).

(11) Compound (4-b-3)

(12) .sup.1H-NMR (CDCl.sub.3, TMS) (ppm): 2.30 (3H, s), 3.80 (3H, s), 4.46 (1H, s), 6.29 (1H, s), 6.67-6.73 (2H, m), 7.07 (2H, d), 7.07-7.16 (1H, m), 7.16 (2H, d).

Example 4

(13) ##STR00031##

(14) Two hundred and twenty three (223) mg of methyl 2,6-difluorobenzoylformate and 192 mg of 4-chlorophenylacetone were mixed with 1.0 mL of toluene, and 1.1 mL of a 1 M toluene solution of titanium tetrachloride was added thereto at 50 C. under nitrogen atmosphere. The mixture was stirred with heating at 50 C. for 3.5 hours, then, at 80 C. for 2 hours, then, left to cool, and about 1 mL of water and about 1 mL of ethyl acetate were added thereto, the mixture was allowed to stand still at room temperature overnight, then, the liquid was subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. Four hundred and thirty five (435) mg of the residue obtained was subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain 306.1 mg of a compound (4-b-3) (yield: 75.2%).

Example 5

(15) ##STR00032##

(16) Two hundred and twenty three (223) mg of methyl 2,6-difluorobenzoylformate and 153 mg of phenylacetone are mixed with 1.0 mL of toluene, and 1.1 mL of a 1 M toluene solution of titanium tetrachloride is added thereto at 50 C. under nitrogen atmosphere. The mixture is stirred with heating at 50 C. for 3.5 hours, and at 80 C. for 2 hours, then, left to cool, and about 1 mL of water and about 1 mL of ethyl acetate are added thereto, the mixture is allowed to stand still at room temperature overnight, then, the liquid is subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer is dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue obtained is subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain a compound of the formula (4-b-1) (hereinafter referred to as compound (4-b-1)).

Example 6

(17) ##STR00033##

(18) One hundred and eighty seven (187) mg of 2,6-difluorobenzoylformic acid and 180 mg of 4-chlorophenylacetone were mixed with 1.0 mL of DMI, and 0.2 mL of 1 M toluene solution of titanium tetrachloride was added thereto at 140 C. under nitrogen atmosphere. The mixture was stirred with heating at 140 C. for 2 hours, then, left to cool. Water and toluene were added thereto and the added mixture was stirred for a while, then, was allowed to stand still at room temperature overnight, and the liquid was subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer was analyzed with high performance liquid chromatography to find out that area percentage of 4-(4-chlorophenyl)-3-(2,6-difluorophenyl)-5-hydroxy-5-methyl-2(5H)-furanone (hereinafter referred to as compound (5-3)) was 58.0%, area percentage of a compound of the formula (A-3) (hereinafter referred to as compound (A-3)) was 0.1%, and area percentage of a compound of the formula (C-3) (hereinafter referred to as compound (C-3)) was 6.8%. The organic layer was dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. Five hundred and fifty three (553) mg of the residue obtained was subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain 229 mg of the compound (5-3) (yield: 67.5%).

(19) Compound (5-3)

(20) .sup.1H-NMR (CDCl.sub.3, TMS) (ppm): 1.77 (3H, s), 4.36 (1H, s), 6.84 (1H, t, J=8.6 Hz), 7.04 (1H, t, J=8.6 Hz), 7.28-7.32 (2H, m), 7.34-7.42 (1H, m), 7.47-7.51 (2H, m).

(21) Compound (C-3)

(22) 1H-NMR (CDCl3, TMS) (ppm): 6.11 (1H, s), 7.01 (2H, t, J=8.1 Hz), 7.44-7.37 (3H, m), 7.62 (1H, s), 7.80-7.75 (2H, m).

Example 7

(23) ##STR00034##

(24) Nine hundred and eighty (980) mg of 2,6-difluorobenzoylformic acid, 4.0 g of toluene and 1.0 g of NMP were mixed, and 0.16 mL of titanium tetraisopropoxide was added thereto under nitrogen atmosphere. Nine hundred and eighty (980) mg of p-chlorophenylacetone was added dropwise thereto at 100 C. under reduced pressure with refluxing and dehydrating the mixture using Dean-Stark apparatus. The added mixture was stirred at 100 C. for 8 hours with reflux and dehydration. The resultant mixture was analyzed with high performance liquid chromatography to find out that area percentage of the compound (5-3) was 50.4%.

Example 8

(25) ##STR00035##

(26) Nine hundred and eighty (980) mg of 2,6-difluorobenzoylformic acid, 4.0 g of toluene and 1.1 g of NMP were mixed, and 0.53 mL of 1.1 M toluene solution of boron trichloride was added thereto under nitrogen atmosphere. Seven hundred and eighty (780) mg of phenylacetone was added dropwise thereto at 100 C. under reduced pressure with refluxing and dehydrating the mixture using Dean-Stark apparatus. One point five nine (1.59) mL of 1.1 M toluene solution of boron trichloride was further added thereto at 100 C. for 39 hours with stir, reflux and dehydration. The added mixture was left to cool, 20% hydrochloric acid and toluene were added thereto, the resultant mixture was subjected to liquid separation to obtain an organic layer and an aqueous layer, and then the organic layer was concentrated to obtain 3-(2,6-difluorophenyl)-5-hydroxy-5-methyl-4-phenyl-2(5H)-furanone (hereinafter, referred to as compound (5-1)) (color and condition: brown liquid, yield: 63.8%).

Example 9

(27) ##STR00036##

(28) Nine hundred and seventy (970) mg of 2,6-difluorobenzoylformic acid, 4.0 g of toluene and 1.0 g of NMP were mixed, and 0.52 mL of 1.1 M toluene solution of titanium tetrachloride was added thereto under nitrogen atmosphere. Seven hundred and sixty (760) mg of phenylacetone was added thereto at 100 C. under reduced pressure with refluxing and dehydrating the mixture using Dean-Stark apparatus. The added mixture was left to cool, 20% hydrochloric acid and toluene were added thereto, the resultant mixture was subjected to liquid separation to obtain an organic layer and an aqueous layer, and then the organic layer was concentrated to obtain the compound (5-1) (yield: 77.4%) as brown liquid.

Example 10

(29) ##STR00037##

(30) Nine hundred and seventy (970) mg of 2,6-difluorobenzoylformic acid and 4.0 g of toluene were mixed, and 0.53 mL of 1 M toluene solution of titanium tetrachloride was added thereto under nitrogen atmosphere. Nine hundred and eighty (980) mg of p-chlorophenylacetone was added thereto at 100 C. under reduced pressure with refluxing and dehydrating the mixture using Dean-Stark apparatus, and then, the added mixture was stirred at 100 C. for 7 hours with reflux and dehydration under reduced pressure. The stirred mixture was left to cool, 20% hydrochloric acid and toluene were added thereto, the resultant mixture was subjected to liquid separation, and then the organic layer was concentrated to obtain brown solid containing the compound (5-3) (yield: 27.6%). Recovery of 2,6-difluorobenzoylformic acid was 39.9%.

Example 11

(31) ##STR00038##

(32) One hundred and eighty seven (187) mg of 2,6-difluorobenzoylformic acid and 143 mg of phenylacetone are mixed with 1.0 mL of DMI, and 0.2 mL of 1 M toluene solution of titanium tetrachloride is added thereto at 140 C. under nitrogen atmosphere. The mixture is stirred with heating at 140 C. for 2 hours, then, left to cool. Water and toluene are added thereto and the added mixture is stirred for a while, then, the stirred mixture is allowed to stand still at room temperature overnight, then, the liquid is subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer is analyzed with high performance liquid chromatography to find out the compound (5-1), a compound of the formula (A-1) and a compound of the formula (C-1). The organic layer is dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The residue obtained is subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain the compound (5-1).

Example 12

(33) ##STR00039##

(34) One hundred and ninety four (194) mg of 2,6-difluorobenzoylformic acid and 178 mg of 4-chlorophenylacetone were mixed with 1.0 mL of xylene, and 0.1 mL of a 1 M toluene solution of titanium tetrachloride, then, 0.3 ml of NMP were added thereto at room temperature under a nitrogen atmosphere. The mixture was stirred with heating at 120 C. for 4 hours, then, left to cool. Diluted hydrochloric acid and toluene were added thereto and the added mixture was subjected to liquid separation to obtain the first organic layer and an aqueous layer. The aqueous layer was extracted once more to obtain the second organic layer, and the first and second organic layers were combined, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain 253 mg of the compound (5-3) (yield: 72.0%).

Example 13

(35) ##STR00040##

(36) One hundred and ninety four (194) mg of 2,6-difluorobenzoylformic acid and 142 mg of phenylacetone are mixed with 1.0 mL of xylene, and 0.1 mL of a 1 M toluene solution of titanium tetrachloride, then, 0.3 mL of NMP are added thereto at room temperature under nitrogen atmosphere. The mixture is stirred with heating at 120 C. for 4 hours, then, left to cool, dilute hydrochloric acid and toluene are added thereto, and the liquid is subjected to liquid separation to obtain the first organic layer and an aqueous layer. The aqueous layer is extracted with toluene once more to obtain the second organic layer. The first and second organic layers are mixed, dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The resultant residue is subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain the compound (5-1).

Example 14

(37) ##STR00041##

(38) Six point eight eight (6.88) g of 2,6-difluorobenzoylformic acid, 8.1 mL of toluene and 7.2 mL of NMP were mixed, and 3.69 mL of 1 M toluene solution of titanium tetrachloride was added thereto under nitrogen atmosphere. Five point five two (5.52) g of phenylacetone was added thereto at 75 C. under reduced pressure with refluxing and dehydrating the mixture using Dean-Stark apparatus. The added mixture was stirred at 75 C. for 22 hours under reduced pressure with reflux and dehydration. The stirred mixture was left to cool, 7.0 g of 20% hydrochloric acid and 6.9 g of toluene were added thereto, and the resultant mixture was stirred, and then, subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer was concentrated to obtain the compound (5-1) (yield: 91.4%) brown liquid.

Example 15

(39) ##STR00042##

(40) Zero point two zero (0.20) g of the compound (4-a-3) was added to 4 ml of n-butanol and 0.4 ml of acetic acid, and 35 mg of hydrazine mono-hydrate was added thereto, and the mixture was stirred at room temperature for 1 hour. Thereafter, the stirred mixture was heated at 100 C. for 6 hours, further, heated under reflux for 6 hours. After the resultant mixture was left to cool, the precipitated solid was collected by filtration, and washed with mixed liquid (1:1) of MTBE-hexane, to obtain 0.13 g of 5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methyl-2H-pyridazin-3-one (hereinafter, referred to as compound (1-3)) (yield: 69%).

(41) Compound (1-3)

(42) .sup.1H-NMR (CDCl.sub.3, TMS) (ppm): 2.12 (3H, s), 6.77-6.81 (2H, m), 7.01-7.04 (2H, m), 7.19-7.28 (3H, m), 11.61 (1H, br s)

(43) The compound of the formula (1) was isolated as by product.

(44) ##STR00043##
Compound (1)

(45) 1H-NMR (CDCl3, TMS) (ppm): 3.94 (2H, s), 6.94-7.00 (2H, m), 7.14-7.18 (3H, m), 7.26-7.40 (3H, m), 11.12 (1H, br s)

Example 16

(46) ##STR00044##

(47) Zero point one eight (0.18) g of the compound (4-a-1) is added to 4 ml of n-butanol and 0.4 ml of acetic acid, and 35 mg of hydrazine mono-hydrate is added thereto, and the mixture is stirred at room temperature for 1 hour. Thereafter, the reaction mixture is heated at 100 C. for 6 hours, further, heated under reflux for 6 hours. After the resultant mixture was left to cool, the precipitated solid is collected by filtration, and washed with mixed liquid (1:1) of MTBE-hexane, to obtain 4-(2,6-difluorophenyl)-5-methyl-6-phenyl-2H-pyridazin-3-one (hereinafter, referred to as compound (1-1)).

Example 17

(48) ##STR00045##

(49) A mixture of 400 mg of 2,6-difluorobenzoylformic acid and 388 mg of 4-chlorophenylacetone was stirred under nitrogen atmosphere, and 2.2 mL of 1 M toluene solution of titanium tetrachloride was added thereto at room temperature. The mixture was stirred with heating at 50 C. for 2.5 hours, then, 1.0 mL of water was added, and the mixture was further stirred for 0.5 hours, then, left to cool to room temperature, and the liquid was subjected to liquid separation to obtain an organic layer and an aqueous layer. One hundred and forty five (145) mg of hydrazine monohydrate was added to the organic layer while stirred, and the mixture was stirred with heating at 100 C. for 5.5 hours, then, 0.2 mL of acetic acid was added, and the added mixture was further stirred with heating for 5.5 hours. After the resultant mixture was left to cool to room temperature, ethyl acetate and dilute hydrochloric acid were added thereto, and the liquid was subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer was dried over anhydrous sodium sulfate, then, concentrated under reduced pressure. The resultant residue was dispersed in about 5 mL of methanol, and filtration thereof was performed. The residue on the filter was dried under reduced pressure, to obtain 281 mg of the compound (1-3). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: hexane-MTBE), to obtain 281 mg of the compound (1-3). Total amount of the compound (1-3): 562 mg. Yield: 78%.

Example 18

(50) ##STR00046##
Fifty point zero zero (50.00) g of the compound (1-1) and 100.0 g of toluene were mixed, and 30.5 g of phosphorus oxychloride was added dropwise at 100 C. under nitrogen atmosphere. The added mixture was stirred at 100 C. for 8 hours. After being left to cool, the reaction mixture was added dropwise in 100.1 g of water. Forty nine point nine (49.9) g of toluene was added thereto, and 65.8 g of 48% aqueous sodium hydroxide solution was added dropwise thereto. The resultant mixture was subjected to liquid separation to obtain an organic layer and an aqueous layer. The organic layer was washed with 71.6 g of water and concentrated to obtain 2-chloro-4-phenyl-3-(2,6-difluorophenyl)-5-methyl-pyridazine (hereinafter, referred to as compound (6-1)) (yield: 100%).

Reference Production Example 1

(51) ##STR00047##

(52) One point eight six (1.86) g of 2,6-difluorobenzoylformic acid [.sup.1H-NMR (CDCl.sub.3, TMS) 6.56 (1H, br s), 6.98-7.09 (2H, m), 7.53-7.63 (1H, m)] was mixed with 21 mL of methanol, and 0.1 mL (0.184 g) of concentrated sulfuric acid was added thereto at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 2 days, then, concentrated. Ice water was added thereto, and extraction with MTBE was performed. The organic layer obtained in the extraction was washed with water twice, dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. The resultant residue (1.78 g) was subjected to silica gel column chromatography (elution solvent: hexane-ethyl acetate), to obtain 1.64 g of methyl 2,6-difluorobenzoylformate (yield: 82%) as colorless liquid.

(53) .sup.1H-NMR (CDCl.sub.3, TMS) (ppm): 3.96 (3H, s), 6.99-7.04 (2H, m), 7.52-7.60 (1H, m).

Reference Production Example 2

(54) ##STR00048##

(55) One point zero zero (1.00) g of the compound (5-1) was mixed with 5.1 g of toluene, and 0.2 g of hydrazine monohydrate was added thereto at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 10 hours. The resultant mixture was cooled by soaking the vessel containing the mixture in an ice bath to precipitate crystals, and the crystals were collected by filtration, washed with toluene, and dried to obtain a compound of the formula (J) (hereinafter referred to as compound (J)) (yield: 87.3%).

(56) Compound (J)

(57) 1H-NMR (CDCl3, TMS) (ppm): 3.18 (3H, s), 3.76 (1H, br), 4.02 (2H, br), 6.80 (1H, t), 6.99 (1H, t), 7.25-7.36 (4H, m), 7.48-7.54 (2H, m)

Reference Production Example 3

(58) ##STR00049##
Seven point eight four (7.84) g of the compound (5-1) was mixed with 12.2 g of toluene, and 2.14 g of hydrazine monohydrate was added thereto at room temperature under nitrogen atmosphere, and the mixture was heated and refluxed at 100 C. for 29 hours. The compound of the formula (J) was found out in the course of the reaction with high performance liquid chromatography. After the reaction mixture was left to cool, 6.06 g of 10% hydrochloric acid was added thereto, precipitated solid was collected by filtration. After washing with toluene and water, the solid was dried to obtain the compound (1-1) (yield: 94.5%).