Title of Invention	PROCESS FOR PREPARING TERT-BUTYL 4 -METHYL-2-BIPHENYLCABOXYLATE
Abstract	ABSTRACT This invention relates to a process for preparing tert-butyl 4'methyl1-2lphenyl-carboxylate, comprising reacting 4-methyl-2-biphenyl--carboxylic add with Isobutene in the presence of an acid catalyst selected from the group consisting of a phosphorus hallde, a sulfonic acid and sulfuric acid, therein the amount of isobutene is 1.5 to 10 mol per one mol of 4'-methyl-2-bipheny-carboxyllc acid, and the amount of the acid catalyst is 0.1 to 1.2 mol per one mol of 4'methyl-2-biphenyl-carboxyllc acid and recovering the tert-butyl 4'-nethyl-2-blphenyl-carboxylate In a known manner.

Title of Invention

PROCESS FOR PREPARING TERT-BUTYL 4 -METHYL-2-BIPHENYLCABOXYLATE

Abstract

ABSTRACT This invention relates to a process for preparing tert-butyl 4'methyl1-2lphenyl-carboxylate, comprising reacting 4-methyl-2-biphenyl--carboxylic add with Isobutene in the presence of an acid catalyst selected from the group consisting of a phosphorus hallde, a sulfonic acid and sulfuric acid, therein the amount of isobutene is 1.5 to 10 mol per one mol of 4'-methyl-2-bipheny-carboxyllc acid, and the amount of the acid catalyst is 0.1 to 1.2 mol per one mol of 4'methyl-2-biphenyl-carboxyllc acid and recovering the tert-butyl 4'-nethyl-2-blphenyl-carboxylate In a known manner.

Full Text	The present invention relates to a process for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate. More particularly, the present invention relates to a process for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate, which is useful as an intermediate of pharmaceuticals such as antihypertensives. BACKGROUND ART Conventionally, there have been known processes for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate, including (A) a method of reacting p-methylphenylzinc chloride with 2-tert-butoxycarbonyliodobenzene in the presence of NiCljCPhCphenyl group, hereinafter referred to the same]3P)2 as a catalyst (Japanese Patent Laid-Open No. Hei 6-1790); and (B) a method of reacting 4'-methyl-2-biphenylcarboxylic acid with isobutene in anhydrous ether in the presence of concentrated sulfuric acid as a catalyst (Japanese Unexamined Patent Publication No. Hei 5-506443). However, there are some defects in the process (A) such that complicated procedures are necessitated in the preparation of p-methylphenylzinc chloride as a starting material, since there is a necessity to prepare the p-methylphenylzinc chloride at an extremely low temperature of -78°C, and that relatively expensive reagents such as 2-tert-butoxycarbonyliodobenzene and NiCl2(Ph3P)2 are needed. In the process (B), since an ether is used, there has been desired to develop a process in which a highly dangerous solvent such as the ether is not used. Also, it has been known that isobutene can be reacted with sulfuric acid or a sulfonic acid to form a t-butyl ester. However, in this method, side-products and an isobutene polymer are formed together with the t-butyl ester, so that this method necessitates a purification process, thereby having making it difficult to prepare it in an industrial scale. Accordingly, in recent years, there have been desired to develop mild reaction conditions under which the t-butyl ester can be easily formed without the formation of side-products. An object of the present invention is to provide a process capable of easily preparing tert-butyl 4'-methyl-2-biphenylcarboxylate in high yield with controlling side-products and polymerization of isobutene. DISCLOSURE OF INVENTION According to the present invention, there can be provided a process for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate, comprising reacting 4'-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst. BEST MODE FOR CARRYING OUT THE INVENTION According to the present invention, tert-butyl 4'-methyl-2f-biphenylcarboxylate can be prepared by reacting 4'-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst. 4'-Methyl-2-biphenylcarboxylic acid is used as a starting material in the present invention. 4'-Methyl-2-biphenylcarboxylic acid can be prepared by hydrolyzing 2-cyano-4'-methylbiphenyl in a glycol in the presence of an alkali. The alkali includes, for instance, sodium hydroxide, potassium hydroxide, and the like. It is desired that the amount of the alkali is usually 1 to 4 mol, preferably 2 to 3 mol, per one mol of 2-cyano-4'-methylbiphenyl. The hydrolysis of 2-cyano-4'-methylbiphenyl can be carried out by dissolving 2-cyano-4'-methylbiphenyl and an alkali in a glycol to make a solution, and stirring the resulting solution with, as occasion demands, heating. In the present invention, as the solvent, a glycol can be used. It is preferable that the glycol is mixed with water from the viewpoint of speedily progressing the reaction. When the glycol is mixed with water, the amount of water used is not limited to specified ones, and it is desired that the amount of water is usually 1 to 100 parts by weight or so, preferably 5 to 50 parts by weight or so, based on 100 parts by weight of the glycol. The glycols include, for instance, ethylene glycol, propylene glycol, butanediol, diethylene glycol, and the like. Among them, glycols having high boiling points (198° to 215°C), such as ethylene glycol and propylene glycol, are preferable. It is preferable to adjust the amount of the glycol so that the amount of 2-cyano-4'-methylbiphenyl is 1 to 100 parts by weight or so, preferably 25 to 50 parts by weight or so, based on 100 parts by weight of the solvent. The hydrolysis of 2-cyano-4'-methylbiphenyl can be usually carried out in the range of 100° to 200°C. The higher the temperature is, the reaction completes in a shorter period of time. The atmosphere in which 2-cyano-4'-methylbiphenyl is hydrolyzed is not limited to specified ones. Usually, the atmosphere may be air, or an inert gas such as nitrogen gas or argon gas. In addition, it is preferable that the reaction pressure is normal pressure to 10 kgf/cm^ (gauge pressure, hereinafter referred to the same) or so. In the present invention, it is preferable to carry out hydrolysis with removing ammonia gas formed by the reaction from the reaction system. The termination of reaction can be confirmed, for instance, by high-performance liquid chromatography. After the termination of reaction, desired 4'-methyl-2-biphenylcarboxylic acid can be Isolated by, for instance, adding water, toluene, or the like to the reaction solution, removing its neutral portion by extraction; further adding hydrochloric acid to release the resulting product; and collecting the product as crystals by filtration. Further, 4'-raethyl-2-biphenylcarboxylic acid having a higher purity can be obtained by dissolving the resulting crystals in toluene, or the like, and recrystallizing the crystals therefrom. tert-Butyl 4'-methyl-2-biphenylcarboxylate can be prepared by reacting the resulting 4'-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst. The amount of isobutene which is used in the reaction with 4'-methyl-2-biphenylcarboxylic acid is not limited to specified ones. It is desired that the amount of isobutene is at least 1.5 mol, preferably at least 2 mol, more preferably at least 3 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of reactivity, and that the amount of isobutene is at most 10 mol, preferably at most 7 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of economic advantages. As the acid catalyst, phosphorus halides, sulfonic acids and sulfuric acid are preferable from the viewpoints of reactivity and economic advantages. The phosphorus halide includes, for instance, phosphorus oxytrichloride, phosphorus trichloride, phosphorus pentachloride, and the like. Among those phosphorus halides, phosphorus oxytrichloride and phosphorus trichloride are preferable from the viewpoint of reactivity. The sulfonic acid includes, for instance, methanesulfonic acid, p-toluenesulfonic acid, and the like. Incidentally, it is preferable that sulfuric acid is usually a concentrated sulfuric acid having a concentration of 96 to 98% by weight. When the reaction is carried out using a phosphorus halide or a sulfonic acid as an acid catalyst, 4'-methyl-2-biphenylcarboxylic acid can be reacted with isobutene, for instance, by mixing 4'-methyl-2-biphenylcarboxylic acid and a solvent mentioned below, adding the sulfonic acid or phosphorus halide to the resulting mixture, and introducing isobutene gas or liquid thereinto. When the reaction is carried out using a phosphorus halide as an acid catalyst, the performance of the phosphorus halide as an acid catalyst can be adjusted by adding water. It is desired that the amount of water added is 0.1 to 1.2 mol, preferably 0.5 to 1.0 mol, per one mol of "'the phosphorus halide, from the viewpoint of reactivity. It is desired that the amount of the acid catalyst is at least 0.1 mol, preferably at least 0.2 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of reactivity, and that the amount is at most 1.2 mol, preferably at most 1.1 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of economic advantages. In the present invention, when sulfuric acid is used as an acid catalyst, it is preferable that 4'-methyl-2-biphenylcarboxylic acid is reacted with isobutene in the presence of a dehydrating agent. Incidentally, although a dehydrating agent is not particularly necessary when a sulfonic acid, a phosphorus halide, or the like is used as an acid catalyst, the dehydrating agent may be used as desired. The dehydrating agent includes, for instance, anhydrous magnesium sulfate, or the like. The anhydrous magnesium sulfate can be preferably used from the viewpoint of reactivity. It is desired that the amount of the dehydrating agent is at least 0.1 mol per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of reactivity, and that the amount is at most 3 mol, preferably'at most 2 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of economic advantages. In the present invention, when the reaction is carried out by using sulfuric acid as an acid catalyst, 4'-methyl-2-biphenylcarboxylic acid can be reacted with isobutene, for instance, by mixing the acid catalyst, a dehydrating agent, and a solvent mentioned below, adding 4'-methyl-2-biphenylcarboxylic acid to the resulting mixture, and introducing isobutene gas or liquid thereinto. Incidentally, it is preferable that the amount of isobutene gas is adjusted so that the amount of isobutene used in the reaction is that as specified above. In the present invention, during the reaction, a solvent can be used. The solvent includes, for instance. hydrocarbon solvents such as cyclohexane and toluene; halogenated solvents such as dichloromethane and dichloroethane, and the like. It is preferable that the amount of the solvent is adjusted so that the amount of 4'-methyl-2-biphenylcarboxyllc acid is 2 to 70 parts by weight or so, based on 100 parts by weight of the solvent. The reaction temperature of 4'-methyl-2-biphenylcarboxylic acid with isobutene cannot be absolutely determined because the reaction temperature can differ depending upon the presence or absence of a dehydrating agent, and the like. For instance, when the reaction is carried out in the absence of a dehydrating agent, it is desired that the reaction temperature is usually 0° to 40°C, preferably 20° to 30"C. Also, for instance, when anhydrous magnesium sulfate or the like is used as a dehydrating agent, it is desired that the reaction temperature is usually 0° to 45°C, preferably 15° to 35°C, because magnesium sulfate releases its crystal water at about 48°C, thereby losing its dehydration ability. The reaction time cannot be absolutely determined because the reaction time can differ depending upon reaction conditions such as reaction temperature. The reaction time can be a period of time necessary for completing the reaction. The reaction time is usually from I to 24 hours or so. Incidentally, the termination of reaction can be confirmed by means o^ for instance, high performance liquid chromatography (HPLC). The reaction production prepared as above can be isolated by, for instance, adding water to the resulting reaction mixture, sufficiently stirring the mixture to allow phase separation, thereafter washing the organic layer with an aqueous sodium hydroxide, or the like, and concentrating the mixture by distilling off the organic solvent. tert-butyl 4'-methyl-2-biphenylcarboxylate obtained according to the present invention can be preferably used as an intermediate of pharmaceuticals such as antihypertensives. Accordingly the present invention provides a process for preparing tert-butyl 4'-methyl-2-biphenyl-carboxylate, comprising reacting 4'-methyl-2-biphenyl-carboxylic acid in a solvent such as herein described with isobutene in the presence of an acid catalyst selected from the group consisting of a phosphorus haUde, a sulfonic acid and sulfuric acid, wherein the amount of isobutene is 1.5 to 10 mol per one mol of 4'-methyl-2-biphenyl-carbox^'Uc acid, and the amount of the acid catalyst is O.l to 1.2 mol per one mol of 4'-methyl-2-biphenyl-carboxylic acid and recovering the tert-butyl 4'-methyl-2-biphenyl-carboxylate in a known manner. The present invention will be more specifically described by the following examples, without intending to restrict the scope or spirit of the present invention thereto. Example I - I A 300-ml four neck flask equipped with a thermometer and a reflux condenser was charged with 88.76 g of ethylene glycol, 44.38 g (229.7 mmol) of 2-cyano-4'-methylbiphenyl and 18.38 g (459.4 mmol) of sodium hydroxide, and the resulting mixture was mixed and heated. The resulting reaction mixture was stirred for 8 hours at 170°C, and the mixture was cooled to QCC. To the resulting reaction mixture was added dropwise 177.5 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 52.64 g (505.3 mmol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75"C to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand and separated into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and the solution was then gradually cooled to allow sedimentation of white crystals of 4'-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0°C, and the mixture was kept at that temperature for one hour, and the crystals were filtered. The crystals were washed with 20 g of toluene at 0°C, and air-dried to give 44.1 g of white crystals of 4'-methylbiphenyl-2-carboxylic acid (yield: 90.4% to 2-cyano-4'-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.I'C. Example 1-2 A 300-ml four-neck flask equipped with a thermometer and a reflux condenser was charged with 95 g of ethylene glycol, 5 g of water, 50 g (0.259 mol) of 2-cyano-4'-methylbiphenyl and 20.7 g (0.517 mol) of sodium hydroxide, and the resulting mixture was mixed and heated. The resulting reaction mixture was stirred for 10 hours at 150°C, and the mixture was cooled to 90°C. To the resulting reaction mixture was added dropwise 185 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added dropwise 59.4 g (0.57 mol) of 35% hydrochloric acid to allow sedimentation of white crystals of 4'-methylbiphenyl-2-carboxylic acid. The resulting crystals were collected by filtration, sufficiently washed with 200 ml of water, and air-dried to give 54.4 g of brownish white crystals of 4'-methylbiphenyl-2-carboxylic acid (yield: 99% to 2-cyano-4'-methylbiphenyl, purity: 99.0%). Next, the resulting crystals were recrystallized from toluene to give 45.8 g of white crystals (yield: 83.3% to 2-cyano-4'-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.4'C. Example 1-3 A 300-ml four-neck flask equipped with a thermometer and a reflux condenser was charged with 28.99 g of ethylene glycol, 28.99 g of water, 28.99 g (0.15 mol) of 2-cyano-4'-methylbiphenyl and 12.0 g (0.30 mol) of sodium hydroxide, and the resulting mixture was mixed and then heated. The resulting reaction mixture was stirred for 8 hours at a pressure of 1 to 2 kgf/cm^ and a temperature of 150 °C, and the mixture was cooled to gCC. To the resulting reaction mixture was added dropwise 28.99 g of water. After the completion of dropwise addition, the mixture was" stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 34.4 g (0.33 mol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75"C to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand and separated into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and the solution was then gradually cooled to allow sedimentation of white crystals of 4'-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0°C, and the mixture was kept at that temperature for one hour, and the crystals were filtered. The crystals were washed with 15 g of toluene at O'C and then air-dried to give 28.8 g of white crystals of 4'-methylbiphenyl-2-carboxylic acid (yield: 90.6% to 2-cyano-4'-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.2°C. Example 1-4 A 300-ml four-neck flask equipped with a thermometer and a reflux condenser was charged with 87.9 g of ethylene glycol, 43.5 g (0.244 mol) of 2-cyanobiphenyl and 24.4 g (0.610 mol) of sodium hydroxide, and the resulting mixture was mixed and then heated. The resulting reaction mixture was stirred for 16 hours at 150° to 155"C, and the mixture was cooled to 90°C. To the resulting reaction mixture was added dropwise 175.8 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 64 g of toluene, and 69.9 g (0.671 mol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75°C to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand and separated into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate. Thereafter, to the resulting mixture was added 32 g of normal-heptane, and the resulting mixture was treated with activated charcoal. Subsequently, the solution was gradually cooled to allow sedimentation of white crystals of biphenyl-2-carboxylic acid. The temperature was lowered to 0°C, and the mixture was kept at that temperature for one hour, and the crystals were filtered. The crystals were washed with 20 g of a mixed solvent of toluene/normal-heptane = 2/1 (weight ratio) at 0°C and then air-dried to give 45.6 g of white crystals of biphenyl-2-carboxylic acid (yield: 94.2% to 2-cyanobiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 114.9°C. It can be seen from the above results that according to the process in Examples I-l to 1-4, biphenyl-2-carboxylic acid can be prepared from 2-cyano-4'-methylbiphenyl in high yield and at high purity. Example II-l A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid, and the mixture was vigorously stirred. To the resulting mixture was added 0.18 ml (2 mmol) of phosphorus oxytrichloride, and isobutene gas (98 mmol) was introduced thereinto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4'-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction mixture was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.63 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals (yield: 98% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound was identified as tert-butyl 4'-raethyl-2-biphenylcarboxylate by the following properties: (1) Melting point: 51'-53'C. (2) IR (neat) v(cm-M: 2976, 2928, 1708, 1478, 1446, 1368, 1302, 1250, 1174, 1128, 848, 820, 760. (3) ^H-NMR (CDCI3) 6 (ppm): 7.08-7.74 (m, 8H), 2.34 (s, 3H), 1.27 (s, 9H). Example II-2 A 500-ml flask was charged with 50 ml of toluene and 53.42 g (0.25 mol) of 4'-methyl-2-biphenylcarboxylic acid, 0.45 ml (0.025 mol) of water and 32.63 g (0.58 mol) of isobutene. To the above mixture was added 7.74 g (0.05 mol) of phosphorus oxytrichloride, and the mixture was stirred for 6 hours. The reaction mixture was added to 50 ml of a 10%-aqueous sodium hydroxide and washed. The organic layer was dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 64.2 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals (yield: 95% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-l. Example II-3 A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid, and the mixture was vigorously stirred. To the resulting mixture was added 0.32 ml (5 mmol) of methanesulfonic acid, and isobutene gas (98 mmol) was introduced thereinto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 20 minutes. After having confirmed that almost all of the peaks ascribed to 4'-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction mixture was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.52 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals (yield: 94% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Example II-4 A 100-ml flask was charged with 5 ml of toluene, 0.24 g (2 mmol) of anhydrous magnesium sulfate, and 0.11 ml (2 mmol) of concentrated sulfuric acid, and the mixture was vigorously stirred. To the above mixture was added 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid, and isobutene gas (98 mmol) was introduced into the mixture at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4'-methyl-2-biphenylcarboxylic acid disappeared by HPLC, 4 ml of deionized water was poured thereinto. The mixture was sufficiently stirred, and then allowed to stand to form separated layers. The upper toluene layer was taken out, washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.54 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals (yield: 95% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-l. It can be seen from the above results that according to the processes in Examples II-l to II-4, tert-butyl 4'-methyl-2-biphenylcarboxylate can be simply prepared in high yield and high quality. As explained above, according to the present invention, "tert-butyl 4'-methyl-2-biphenylcarboxylate can be industrially advantageously, easily prepared in high yield and high quality under mild reaction conditions of the level of ambient temperature without complicated procedures or any dangerous solvents. INDUSTRIAL APPLICABILITY tert-Butyl 4'-methyl-2-biphenylcarboxylate obtained by the process of the present invention can be preferably used as intermediates of antihypertensives. We Claim: 1. A process for preparing tert-butvl 4'-methyl-2-biphenyl-carboxylIate, comprising reacting 4'-metliyl-2-biphenyl-carboxylic acid in a solvent such as herein described with isobutene in the presence of an acid catalyst selected from the group consisting of a phosphorus halide, a sulfonic acid and sulfuric acid, wherein the amount of isobutene is 1.5 to 10 mol per one mol of 4'-methyl-2-biphenyl-carbox\'lic acid, and the amount of the acid catalyst is 0.1 to 1.2 mol per one mol of 4'-methyl-2-biphenyl-carboxylic acid and recovering the tert-butyl 4'-methyl-2-biphenyl-carboxylate in a known manner. 2. The process according to claim 1 wherein said phosphorus halide is phosphorus oxytrichloride. 3. The process according to claim 1 wherein the acid catalyst is sulphuric acid and the reaction is carried out in the presence of a dehydrating agent such as herein described. 4. The process according to claim 3 wherein said dehydrating agent is anhydrous magnesium sulfate. 5. A process for preparing tert-butyl 4'-methyl-2ibiphenyl-carboxylate, substantially as herein described and exemplified.

Full Text

The present invention relates to a process for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate. More particularly, the present invention relates to a process for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate, which is useful as an intermediate of pharmaceuticals such as antihypertensives.
BACKGROUND ART
Conventionally, there have been known processes for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate, including (A) a method of reacting p-methylphenylzinc chloride with 2-tert-butoxycarbonyliodobenzene in the presence of NiCljCPhCphenyl group, hereinafter referred to the same]3P)2 as a catalyst (Japanese Patent Laid-Open No. Hei 6-1790); and (B) a method of reacting 4'-methyl-2-biphenylcarboxylic acid with isobutene in anhydrous ether in the presence of concentrated sulfuric acid as a catalyst (Japanese Unexamined Patent Publication No. Hei 5-506443).
However, there are some defects in the process (A)

such that complicated procedures are necessitated in the preparation of p-methylphenylzinc chloride as a starting material, since there is a necessity to prepare the p-methylphenylzinc chloride at an extremely low temperature of -78°C, and that relatively expensive reagents such as 2-tert-butoxycarbonyliodobenzene and NiCl2(Ph3P)2 are needed.
In the process (B), since an ether is used, there has been desired to develop a process in which a highly dangerous solvent such as the ether is not used.
Also, it has been known that isobutene can be reacted with sulfuric acid or a sulfonic acid to form a t-butyl ester. However, in this method, side-products and an isobutene polymer are formed together with the t-butyl ester, so that this method necessitates a purification process, thereby having making it difficult to prepare it in an industrial scale.
Accordingly, in recent years, there have been desired to develop mild reaction conditions under which the t-butyl ester can be easily formed without the formation of side-products.
An object of the present invention is to provide a process capable of easily preparing tert-butyl 4'-methyl-2-biphenylcarboxylate in high yield with controlling side-products and polymerization of isobutene.

DISCLOSURE OF INVENTION
According to the present invention, there can be provided a process for preparing tert-butyl 4'-methyl-2-biphenylcarboxylate, comprising reacting 4'-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst.
BEST MODE FOR CARRYING OUT THE INVENTION
According to the present invention, tert-butyl 4'-methyl-2f-biphenylcarboxylate can be prepared by reacting 4'-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst.
4'-Methyl-2-biphenylcarboxylic acid is used as a starting material in the present invention. 4'-Methyl-2-biphenylcarboxylic acid can be prepared by hydrolyzing 2-cyano-4'-methylbiphenyl in a glycol in the presence of an alkali.
The alkali includes, for instance, sodium hydroxide, potassium hydroxide, and the like.
It is desired that the amount of the alkali is usually 1 to 4 mol, preferably 2 to 3 mol, per one mol of 2-cyano-4'-methylbiphenyl.
The hydrolysis of 2-cyano-4'-methylbiphenyl can be carried out by dissolving 2-cyano-4'-methylbiphenyl and an alkali in a glycol to make a solution, and stirring the

resulting solution with, as occasion demands, heating.
In the present invention, as the solvent, a glycol can be used. It is preferable that the glycol is mixed with water from the viewpoint of speedily progressing the reaction. When the glycol is mixed with water, the amount of water used is not limited to specified ones, and it is desired that the amount of water is usually 1 to 100 parts by weight or so, preferably 5 to 50 parts by weight or so, based on 100 parts by weight of the glycol.
The glycols include, for instance, ethylene glycol, propylene glycol, butanediol, diethylene glycol, and the like. Among them, glycols having high boiling points (198° to 215°C), such as ethylene glycol and propylene glycol, are preferable.
It is preferable to adjust the amount of the glycol so that the amount of 2-cyano-4'-methylbiphenyl is 1 to 100 parts by weight or so, preferably 25 to 50 parts by weight or so, based on 100 parts by weight of the solvent.
The hydrolysis of 2-cyano-4'-methylbiphenyl can be usually carried out in the range of 100° to 200°C. The higher the temperature is, the reaction completes in a shorter period of time.
The atmosphere in which 2-cyano-4'-methylbiphenyl is hydrolyzed is not limited to specified ones. Usually, the atmosphere may be air, or an inert gas such as nitrogen

gas or argon gas. In addition, it is preferable that the reaction pressure is normal pressure to 10 kgf/cm^ (gauge pressure, hereinafter referred to the same) or so. In the present invention, it is preferable to carry out hydrolysis with removing ammonia gas formed by the reaction from the reaction system.
The termination of reaction can be confirmed, for instance, by high-performance liquid chromatography.
After the termination of reaction, desired 4'-methyl-2-biphenylcarboxylic acid can be Isolated by, for instance, adding water, toluene, or the like to the reaction solution, removing its neutral portion by extraction; further adding hydrochloric acid to release the resulting product; and collecting the product as crystals by filtration. Further, 4'-raethyl-2-biphenylcarboxylic acid having a higher purity can be obtained by dissolving the resulting crystals in toluene, or the like, and recrystallizing the crystals therefrom.
tert-Butyl 4'-methyl-2-biphenylcarboxylate can be prepared by reacting the resulting 4'-methyl-2-biphenylcarboxylic acid with isobutene in the presence of an acid catalyst.
The amount of isobutene which is used in the reaction with 4'-methyl-2-biphenylcarboxylic acid is not limited to specified ones. It is desired that the amount of

isobutene is at least 1.5 mol, preferably at least 2 mol,
more preferably at least 3 mol, per one mol of
4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of
reactivity, and that the amount of isobutene is at most
10 mol, preferably at most 7 mol, per one mol of
4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of
economic advantages.
As the acid catalyst, phosphorus halides, sulfonic acids and sulfuric acid are preferable from the viewpoints of reactivity and economic advantages.
The phosphorus halide includes, for instance, phosphorus oxytrichloride, phosphorus trichloride, phosphorus pentachloride, and the like. Among those phosphorus halides, phosphorus oxytrichloride and phosphorus trichloride are preferable from the viewpoint of reactivity.
The sulfonic acid includes, for instance, methanesulfonic acid, p-toluenesulfonic acid, and the like.
Incidentally, it is preferable that sulfuric acid is usually a concentrated sulfuric acid having a concentration of 96 to 98% by weight.
When the reaction is carried out using a phosphorus halide or a sulfonic acid as an acid catalyst, 4'-methyl-2-biphenylcarboxylic acid can be reacted with

isobutene, for instance, by mixing 4'-methyl-2-biphenylcarboxylic acid and a solvent mentioned below, adding the sulfonic acid or phosphorus halide to the resulting mixture, and introducing isobutene gas or liquid thereinto. When the reaction is carried out using a phosphorus halide as an acid catalyst, the performance of the phosphorus halide as an acid catalyst can be adjusted by adding water. It is desired that the amount of water added is 0.1 to 1.2 mol, preferably 0.5 to 1.0 mol, per one mol of "'the phosphorus halide, from the viewpoint of reactivity.
It is desired that the amount of the acid catalyst is at least 0.1 mol, preferably at least 0.2 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of reactivity, and that the amount is at most 1.2 mol, preferably at most 1.1 mol, per one mol of 4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of economic advantages.
In the present invention, when sulfuric acid is used as an acid catalyst, it is preferable that 4'-methyl-2-biphenylcarboxylic acid is reacted with isobutene in the presence of a dehydrating agent. Incidentally, although a dehydrating agent is not particularly necessary when a sulfonic acid, a phosphorus halide, or the like is used as an acid catalyst, the

dehydrating agent may be used as desired.
The dehydrating agent includes, for instance, anhydrous magnesium sulfate, or the like. The anhydrous magnesium sulfate can be preferably used from the viewpoint of reactivity.
It is desired that the amount of the dehydrating agent is at least 0.1 mol per one mol of
4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of reactivity, and that the amount is at most 3 mol, preferably'at most 2 mol, per one mol of
4'-methyl-2-biphenylcarboxylic acid, from the viewpoint of economic advantages.
In the present invention, when the reaction is carried out by using sulfuric acid as an acid catalyst, 4'-methyl-2-biphenylcarboxylic acid can be reacted with isobutene, for instance, by mixing the acid catalyst, a dehydrating agent, and a solvent mentioned below, adding 4'-methyl-2-biphenylcarboxylic acid to the resulting mixture, and introducing isobutene gas or liquid thereinto.
Incidentally, it is preferable that the amount of isobutene gas is adjusted so that the amount of isobutene used in the reaction is that as specified above.
In the present invention, during the reaction, a solvent can be used. The solvent includes, for instance.

hydrocarbon solvents such as cyclohexane and toluene; halogenated solvents such as dichloromethane and dichloroethane, and the like. It is preferable that the amount of the solvent is adjusted so that the amount of 4'-methyl-2-biphenylcarboxyllc acid is 2 to 70 parts by weight or so, based on 100 parts by weight of the solvent.
The reaction temperature of 4'-methyl-2-biphenylcarboxylic acid with isobutene cannot be absolutely determined because the reaction temperature can differ depending upon the presence or absence of a dehydrating agent, and the like. For instance, when the reaction is carried out in the absence of a dehydrating agent, it is desired that the reaction temperature is usually 0° to 40°C, preferably 20° to 30"C. Also, for instance, when anhydrous magnesium sulfate or the like is used as a dehydrating agent, it is desired that the reaction temperature is usually 0° to 45°C, preferably 15° to 35°C, because magnesium sulfate releases its crystal water at about 48°C, thereby losing its dehydration ability.
The reaction time cannot be absolutely determined because the reaction time can differ depending upon reaction conditions such as reaction temperature. The reaction time can be a period of time necessary for completing the reaction. The reaction time is usually

from I to 24 hours or so. Incidentally, the termination of reaction can be confirmed by means o^ for instance, high performance liquid chromatography (HPLC).
The reaction production prepared as above can be isolated by, for instance, adding water to the resulting reaction mixture, sufficiently stirring the mixture to allow phase separation, thereafter washing the organic layer with an aqueous sodium hydroxide, or the like, and concentrating the mixture by distilling off the organic solvent.
tert-butyl 4'-methyl-2-biphenylcarboxylate obtained according to the present invention can be preferably used as an intermediate of pharmaceuticals such as antihypertensives.
Accordingly the present invention provides a process for preparing tert-butyl 4'-methyl-2-biphenyl-carboxylate, comprising reacting 4'-methyl-2-biphenyl-carboxylic acid in a solvent such as herein described with isobutene in the presence of an acid catalyst selected from the group consisting of a phosphorus haUde, a sulfonic acid and sulfuric acid, wherein the amount of isobutene is 1.5 to 10 mol per one mol of 4'-methyl-2-biphenyl-carbox^'Uc acid, and the amount of the acid catalyst is O.l to 1.2 mol per one mol of 4'-methyl-2-biphenyl-carboxylic acid and recovering the tert-butyl 4'-methyl-2-biphenyl-carboxylate in a known manner.
The present invention will be more specifically described by the following examples, without intending to restrict the scope or spirit of the present invention thereto. Example I - I
A 300-ml four neck flask equipped with a thermometer and a reflux
condenser was charged with 88.76 g of ethylene glycol, 44.38 g (229.7
mmol) of 2-cyano-4'-methylbiphenyl and 18.38 g (459.4 mmol) of sodium
hydroxide, and the resulting mixture was mixed and

heated.
The resulting reaction mixture was stirred for 8 hours at 170°C, and the mixture was cooled to QCC. To the resulting reaction mixture was added dropwise 177.5 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 52.64 g (505.3 mmol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75"C to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand and separated into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and the solution was then gradually cooled to allow sedimentation of white crystals of 4'-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0°C, and the mixture was kept at that temperature for one hour, and the crystals were filtered. The crystals were washed with 20 g of toluene at 0°C, and air-dried to give 44.1 g of white crystals of 4'-methylbiphenyl-2-carboxylic acid (yield: 90.4% to 2-cyano-4'-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.I'C.
Example 1-2

A 300-ml four-neck flask equipped with a thermometer and a reflux condenser was charged with 95 g of ethylene glycol, 5 g of water, 50 g (0.259 mol) of
2-cyano-4'-methylbiphenyl and 20.7 g (0.517 mol) of sodium hydroxide, and the resulting mixture was mixed and heated.
The resulting reaction mixture was stirred for 10 hours at 150°C, and the mixture was cooled to 90°C. To the resulting reaction mixture was added dropwise 185 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added dropwise 59.4 g (0.57 mol) of 35% hydrochloric acid to allow sedimentation of white crystals of 4'-methylbiphenyl-2-carboxylic acid. The resulting crystals were collected by filtration, sufficiently washed with 200 ml of water, and air-dried to give 54.4 g of brownish white crystals of 4'-methylbiphenyl-2-carboxylic acid (yield: 99% to 2-cyano-4'-methylbiphenyl, purity: 99.0%). Next, the resulting crystals were recrystallized from toluene to give 45.8 g of white crystals (yield: 83.3% to 2-cyano-4'-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.4'C.
Example 1-3
A 300-ml four-neck flask equipped with a thermometer and a reflux condenser was charged with 28.99 g of

ethylene glycol, 28.99 g of water, 28.99 g (0.15 mol) of 2-cyano-4'-methylbiphenyl and 12.0 g (0.30 mol) of sodium hydroxide, and the resulting mixture was mixed and then heated.
The resulting reaction mixture was stirred for 8 hours at a pressure of 1 to 2 kgf/cm^ and a temperature of 150 °C, and the mixture was cooled to gCC. To the resulting reaction mixture was added dropwise 28.99 g of water. After the completion of dropwise addition, the mixture was" stirred for 30 minutes. To this mixture was added 66.6 g of toluene, and 34.4 g (0.33 mol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75"C to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand and separated into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate, and the solution was then gradually cooled to allow sedimentation of white crystals of 4'-methylbiphenyl-2-carboxylic acid. The temperature was lowered to 0°C, and the mixture was kept at that temperature for one hour, and the crystals were filtered. The crystals were washed with 15 g of toluene at O'C and then air-dried to give 28.8 g of white crystals of 4'-methylbiphenyl-2-carboxylic acid (yield: 90.6% to

2-cyano-4'-methylbiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 150.2°C.
Example 1-4
A 300-ml four-neck flask equipped with a thermometer and a reflux condenser was charged with 87.9 g of ethylene glycol, 43.5 g (0.244 mol) of 2-cyanobiphenyl and 24.4 g (0.610 mol) of sodium hydroxide, and the resulting mixture was mixed and then heated.
The resulting reaction mixture was stirred for 16 hours at 150° to 155"C, and the mixture was cooled to 90°C. To the resulting reaction mixture was added dropwise 175.8 g of water. After the completion of dropwise addition, the mixture was stirred for 30 minutes. To this mixture was added 64 g of toluene, and 69.9 g (0.671 mol) of 35% hydrochloric acid was further added dropwise. The temperature inside the flask was raised to 75°C to dissolve the resulting product in toluene and form into two layers. After the solution was allowed to stand and separated into layers, the lower aqueous layer was removed therefrom. The toluene layer was dehydrated over anhydrous magnesium sulfate. Thereafter, to the resulting mixture was added 32 g of normal-heptane, and the resulting mixture was treated with activated charcoal. Subsequently, the solution was gradually cooled to allow

sedimentation of white crystals of biphenyl-2-carboxylic acid. The temperature was lowered to 0°C, and the mixture was kept at that temperature for one hour, and the crystals were filtered. The crystals were washed with 20 g of a mixed solvent of toluene/normal-heptane = 2/1 (weight ratio) at 0°C and then air-dried to give 45.6 g of white crystals of biphenyl-2-carboxylic acid (yield: 94.2% to 2-cyanobiphenyl, purity: 99.9%). The resulting white crystals had a melting point of 114.9°C.
It can be seen from the above results that according to the process in Examples I-l to 1-4, biphenyl-2-carboxylic acid can be prepared from 2-cyano-4'-methylbiphenyl in high yield and at high purity.
Example II-l
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid, and the mixture was vigorously stirred. To the resulting mixture was added 0.18 ml (2 mmol) of phosphorus oxytrichloride, and isobutene gas (98 mmol) was introduced thereinto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the

peaks ascribed to 4'-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction mixture was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.63 g of tert-butyl
4'-methyl-2-biphenylcarboxylate as crystals (yield: 98% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%).
Incidentally, the obtained compound was identified as tert-butyl 4'-raethyl-2-biphenylcarboxylate by the following properties:
(1) Melting point: 51'-53'C.
(2) IR (neat) v(cm-M: 2976, 2928, 1708, 1478, 1446, 1368, 1302, 1250, 1174, 1128, 848, 820, 760.
(3) ^H-NMR (CDCI3) 6 (ppm): 7.08-7.74 (m, 8H), 2.34 (s, 3H), 1.27 (s, 9H).
Example II-2
A 500-ml flask was charged with 50 ml of toluene and 53.42 g (0.25 mol) of 4'-methyl-2-biphenylcarboxylic acid, 0.45 ml (0.025 mol) of water and 32.63 g (0.58 mol) of isobutene. To the above mixture was added 7.74 g (0.05 mol) of phosphorus oxytrichloride, and the mixture was stirred for 6 hours. The reaction mixture was added

to 50 ml of a 10%-aqueous sodium hydroxide and washed. The organic layer was dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 64.2 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals (yield: 95% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-l.
Example II-3
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid, and the mixture was vigorously stirred. To the resulting mixture was added 0.32 ml (5 mmol) of methanesulfonic acid, and isobutene gas (98 mmol) was introduced thereinto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 20 minutes. After having confirmed that almost all of the peaks ascribed to 4'-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction mixture was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.52 g of tert-butyl

4'-methyl-2-biphenylcarboxylate as crystals (yield: 94% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%).
Example II-4
A 100-ml flask was charged with 5 ml of toluene, 0.24 g (2 mmol) of anhydrous magnesium sulfate, and 0.11 ml (2 mmol) of concentrated sulfuric acid, and the mixture was vigorously stirred. To the above mixture was added 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid, and isobutene gas (98 mmol) was introduced into the mixture at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4'-methyl-2-biphenylcarboxylic acid disappeared by HPLC, 4 ml of deionized water was poured thereinto. The mixture was sufficiently stirred, and then allowed to stand to form separated layers. The upper toluene layer was taken out, washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.54 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals (yield: 95% to 4'-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained

compound had the same physical properties as those of the compound obtained in Example II-l.
It can be seen from the above results that according to the processes in Examples II-l to II-4, tert-butyl 4'-methyl-2-biphenylcarboxylate can be simply prepared in high yield and high quality.
As explained above, according to the present invention, "tert-butyl 4'-methyl-2-biphenylcarboxylate can be industrially advantageously, easily prepared in high yield and high quality under mild reaction conditions of the level of ambient temperature without complicated procedures or any dangerous solvents.
INDUSTRIAL APPLICABILITY
tert-Butyl 4'-methyl-2-biphenylcarboxylate obtained by the process of the present invention can be preferably used as intermediates of antihypertensives.

We Claim:
1. A process for preparing tert-butvl 4'-methyl-2-biphenyl-carboxylIate, comprising reacting 4'-metliyl-2-biphenyl-carboxylic acid in a solvent such as herein described with isobutene in the presence of an acid catalyst selected from the group consisting of a phosphorus halide, a sulfonic acid and sulfuric acid, wherein the amount of isobutene is 1.5 to 10 mol per one mol of 4'-methyl-2-biphenyl-carbox\'lic acid, and the amount of the acid catalyst is 0.1 to 1.2 mol per one mol of 4'-methyl-2-biphenyl-carboxylic acid and recovering the tert-butyl 4'-methyl-2-biphenyl-carboxylate in a known manner.
2. The process according to claim 1 wherein said phosphorus halide is phosphorus oxytrichloride.
3. The process according to claim 1 wherein the acid catalyst is sulphuric acid and the reaction is carried out in the presence of a dehydrating agent such as herein described.
4. The process according to claim 3 wherein said dehydrating agent is anhydrous magnesium sulfate.

5. A process for preparing tert-butyl 4'-methyl-2ibiphenyl-carboxylate, substantially as herein described and exemplified.

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Patent Number

187700

Indian Patent Application Number

220/MAS/1999

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

13-Dec-2002

Date of Filing

23-Feb-1999

Name of Patentee

M/S. SUMIKA FINE CHEMICALS CO., LTD

Applicant Address

1-21 UTAJIMA 3-CHOME, NISHIYODOGAWA-KU, OSAKA-SHI, OSAKA

Inventors:

#	Inventor's Name	Inventor's Address
1	TETSUYA SHINTAKU	C/O SUMIKA FINE CHEMICALS CO., LTD., CENTRAL RESEARCH LABORATORIES, 1-21, UTAJIMA 3-CHOME NISHIYODOGAWA-KU, OSAKA-SHI, OSAKA,
2	KIYOSHI SUGI	C/O SUMIKA FINE CHEMICALS CO., LTD., CENTRAL RESEARCH LABORATORIES, 1-21, UTAJIMA 3-CHOME NISHIYODOGAWA-KU, OSAKA-SHI, OSAKA,
3	TADASHI KATSURA	C/O SUMIKA FINE CHEMICALS CO., LTD., CENTRAL RESEARCH LABORATORIES, 1-21, UTAJIMA 3-CHOME NISHIYODOGAWA-KU, OSAKA-SHI, OSAKA,
4	NOBUSHIGE ITAYA	C/O SUMIKA FINE CHEMICALS CO., LTD., CENTRAL RESEARCH LABORATORIES, 1-21, UTAJIMA 3-CHOME NISHIYODOGAWA-KU, OSAKA-SHI, OSAKA,

PCT International Classification Number

C07C69/612

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	10-193034	1998-07-08	Japan