PROCESS FOR PRODUCING IMIDAZOPYRIDINE DERIVATIVE AND INTERMEDIATE

Abstract: The invention provides an industrially excellent process for producing a 2-alkyl-3-(biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridine derivative represented by general formula (II), serving as a precursor of the angiotensin II receptor antagonist useful as an antihypertensive, a biphenyl derivative serving as a precursor of the substituent of the imidazopyridine derivative, a process for producing the biphenyl derivative, and an intermediate useful for producing the biphenyl derivative. The imidazopyridine derivative (II) can be produced in a high yield according to the process of the invention by subjecting a 2-amino-5-halogeno-3-nitropyridine derivative to amidation, N-alkylation and reductive cyclization. This process is industrially excellent, because the halogen atom introduced into the 5-position as a protective group in the nitration step can be eliminated simultaneously in the subsequent step. The above biphenyl derivative is excellent in reactivity and product purity, thus being an intermediate suitable for industrial production.

Description: [Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to a process for the preparation of a biphenyloxazoline derivative which is an intermediate useful for the preparation of a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative which is disclosed in, e.g., Japanese Patent Publication-A Nos. 3-95181 (and European Patent Publication-A No. 420237 corresponding thereof) and 3-236377 and is a precursor of an antagonist against angiotensin II receptor useful as an antihypertensive drug and a remedy for hemal lesions. [Prior Art] As described in, e.g., Japanese Patent Publication-A No. 3-236377, it has been a practice in the prior art to form the side chain of biphenyl of a 2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative which is an antagonist against angiotensin II receptor by a method wherein the N-alkylation is conducted with a 4'-bromomethyl-2-biphenylcarboxylic ester. Such a 4'-bromomethyl-2-biphenylcarboxylic ester is prepared by a process which comprises preparing 4'-methyl-2-biphenyloxazoline in a manner described in Journal of Organic Chemistry (J. Org. Chem.), 43 (7), 1372 to 1379, 1978, then hydrolyzing it into 4'-methyl-2-biphenylcarboxylic acid, then esterifying it into a 4'-methyl-2-biphenylcarboxylic ester, and, further, brominating it in a manner disclosed in the Japanese Patent Publication-A No. 63-23868. This preparation process is represented hereinafter (reaction scheme-1): [Problem to be Solved by the Invention] The 4'-bromomethyl-2-biphenylcarboxylic ester which has hitherto been used has a high activity to react easily, but it could not be stored because it was poor in stability due to its high activity. Therefore, it had been prepared immediately before the use and was extremely poor in workability. Further, due to the high activity, the ester also has a disadvantage of being liable to cause decomposition or a side reaction in the reaction, so that the obtained N-alkylation product had a low purity and the by-products were varied to result in difficult purification.. Furthermore, all of the processes disclosed in the prior art failed in the preparation of a 4'-chloromethyl-2-biphenylcarboxylic ester exhibiting a desirable reactivity in the N-alkylation. Further, N-bromosuccinimide has been used for the bromination in the preparation of the 4'-bromomethyl-2-biphenylcarboxylic ester according to the process disclosed in the Japanese Patent Publication-A No. 63-23868. However, there has been a disadvantage that it is unsuitable for the industrial production thereof because this reagent is expensive and the bromination is a free-radical reaction and therefore is too rapid to be controlled. Further, the 4'-bromomethyl-2-biphenylcarboxylic ester which has hitherto been used has a high activity to react easily, but it could not be stored because it was poor in stability due to its high activity. Therefore, it had been prepared immediately before the use and was extremely poor in workability. Furthermore, due to the high activity, the ester also has a disadvantage of being liable to cause decomposition or a side reaction in the reaction, so that the obtained N-alkylation product had a low purity and the by-products were varied to result in difficult purification. Under these circumstances, an active 4'-chloromethyl-2-biphenylcarboxylic ester and the like excellent in operatablity have also been expected, but the process disclosed in the Japanese Patent Pubilication-A No. 63-23868 failed in the preparation thereof. As described above, the 4'-bromomethyl-2-biphenylcarboxylic ester which has hitherto been used took much labor to separate and purify the N-alkylation product and had disadvantages in economic efficiency and safeness, in addition to its poor working efficiency as an intermediate. Thus, the ester was not always, satisfactory as an intermediate for industrial production. Under these circumstances, an industrially advantageous active biphenyl intermediate with which the imidazopyridine derivative useful as an antagonist against angiotensin II receptor can be prepared safely in a high yield at a high purity and a high economic efficiency has been expected. [Description of the Invention] The present inventors have extensively studied to find an active biphenyl intermediate improved on the above disadvantages. As a result, they have found that a biphenyloxazoline derivative (III) represented by the following general formula is an excellent industrial intermediate satisfying the above requirements, and have accomplished the present invention: In the formula, R 2 represents a lower alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen atom. The biphenyloxazoline derivative (III) is prepared by the following process protecting 4-bromobenzyl alcohol to form a 4-bromobenzyl ether derivative (V), coupling it with oxazolylanisole to form an alkoxymethyl-biphenyloxazoline derivative (IV) through the Grignard reaction, eliminating the protective group to form a hydroxymethyl-biphenyloxazoline derivative (II), and then conducting sulfonylation or halogenation. The outline of the reaction path according to the present invention is represented by the following chemical reaction scheme (reaction scheme-2): Accordingly, an object of the present invention is to provide a process for the preparation a biphenyloxazoline derivative (III) which is an active intermediate useful for introducing the side chain of biphenyl in the preparation of a 2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative which is an antagonist against angiotensin II receptor useful as an antihypertensive drug or a remedy for hemal lesions. The hydroxymethyl-biphenyloxazoline derivative (II) used in the present invention has the following general formula: Specific examples thereof include the following compounds. (1) 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)-oxazoline (2) 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-3-yl)-oxazoline (3) 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-4-yl)-oxazoline Then, the active biphenyloxazoline derivative (III) has the following chemical structural formula: In the formula, R 2 represents a lower alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen atom. Specific examples of the lower alkylsulfonyloxy group include those having a lower alkyl group of 1 to 6 carbon atoms, such as a methanesulfonyloxy group and an ethanesulfonyloxy group; those of the arylsulfonyloxy group include a benzenesulfonyloxy group and a toluenesulfonyloxy group; and those of the halogen atom include a chlorine atom, a bromine atom, an iodine atom and a fluorine atom. Further specific examples of the active biphenyloxazoline derivative (III) include the following compounds, though the active biphenyloxazoline derivative (III) prepared in accordance with the present invention is not limited to them. (1) 4,4-dimethyl-2-(4'-chloromethylbiphenyl-2-yl)oxazoline (2) 4,4-dimethyl-2-(4'-bromomethylbiphenyl-2-yl)oxazoline (3) 4,4-dimethyl-2-(4'-iodomethylbiphenyl-2-yl)oxazoline (4) 4,4-dimethyl-2-(4'-methanesulfonyloxymethylbiphenyl-2-yl)oxazoline (5) 4,4-dimethyl-2-(4'-ethanesulfonyloxymethylbiphenyl-2-yl)oxazoline (6) 4,4-dimethyl-2-(4'-p-toluenesulfonyloxymethylbiphenyl-2-yl)oxazoline (7) 4,4-dimethyl-2-(4'-benzenesulfonyloxymethylbiphenyl-2-yl)oxazoline Further, the alkoxymethyl-biphenyloxazoline derivative (IV) used in the present invention has the following chemical structural formula: In the formula, R 3 represents a lower alkoxyalkyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, a lower thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl group or a triphenylmethyl group. Further specific examples of the lower alkoxyalkyl group include a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group and a propoxypropyl group; those of the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethyl group and a tolyloxymethyl group; those of the aralkyloxyalkyl group include a benzyloxymethyl group and a phenethyloxymethyl group; those of the lower alkoxyalkoxyalkyl group include a methoxyethoxymethyl group and an ethoxyethoxymethyl group; those of the lower thioalkoxyalkyl group include a methylthiomethyl group, a methylthioethyl group, an ethylthiomethyl group, a phenylthiomethyl group and a benzylthiomethyl group; those of the cycloether group include a tetrahydropyranyl group and a tetrahydrofuranyl group; those of the trialkylsilyl group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an i-propyldimethylsilyl group and a phenyldimethylsilyl group; that of the triarylsilyl group includes a triphenylsilyl group; those of the lower alkyl group include a methyl group, an ethyl group, a propyl group and a t-butyl group; and those of the aralkyl group include a benzyl group, a phenethyl group, a methylbenzyl group, a trimethylbenzyl group, a nitrobenzyl group and a phenacyl group. Further, specific and representative examples of the alkoxymethyl-biphenyloxazoline derivative (IV) include the following compounds, though the alkoxymethyl-biphenyloxazoline derivative (IV) used in the present invention is not limited to them. (1) 4,4-dimethyl-2-(4'-methoxymethoxymethylbiphenyl-2-yl)oxazoline (2) 4,4-dimethyl-2-(4'-methoxyethoxymethoxymethylbiphenyl-2-yl)oxazoline (3) 4,4-dimethyl-2-(4'-thiomethoxymethoxymethylbiphenyl-2-yl)oxazoline (4) 4,4-dimethyl-2-(4'-tetrahydropyranyloxymethylbiphenyl-2-yl)oxazoline (5) 4,4-dimethyl-2-(4'-tetrahydrofurabyloxymethylbiphenyl-2-yl)oxazoline (6) 4,4-dimethyl-2-(4'-trimethylsilyloxymethylbiphenyl-2-yl)oxazoline (7) 4,4-dimethyl-2-(4'-t-butoxymethylbiphenyl-2-yl)oxazoline (8) 4,4-dimethyl-2-(4'-benzyloxymethylbiphenyl-2-yl)oxazoline Further, the 4-bromobenzyl ether derivative (V) used in the present invention has the following chemical structural formula: In the formula, R 3 is as defined above. Further specific examples of the 4-bromobenzyl ether derivative (V) include the following compounds, though the 4-bromobenzyl ether derivative (V) used in the present invention is not limited to them. (1) 4-bromobenzyl-methoxymethyl ether (2) 4-bromobenzyl-methoxyethoxymethyl ether (3) 4-bromobenzyl-thiomethoxymethyl ether (4) 4-bromobenzyl-tetrahydropyranyl ether (5) 4-bromobenzyl-tetrahydrofuranyl ether (6) 4-bromobenzyl-trimethylsilyl ether (7) 4-bromobenzyl-t-butyl ether (8) 4-bromobenzyl-benzyl ether Next, each step of the process according to the present invention will be described in detail hereinafter (see the above reaction scheme-2). Step 1 This step is one wherein 4-bromobenzyl alcohol is protected to obtain a 4-bromobenzyl ether derivative (V). This step can be conducted according to the conventional process for introducing a protective group for a hydroxyl group in organic synthesis. Specific examples of the reagent for introducing a protective group usable in this step include chloromethyl methyl ether, 2-chloroethyl methyl ether, chloromethyl phenyl ether, chloromethyl benzyl ether, chloromethyl methoxyethyl ether, chloromethyl methyl sulfide, dihydropyrane, dihydrofuran, chlorotrimethylsilane, chlorotriethylsilane, chlorotriphenylsilane, methyl iodide, benzyl chloride and chlorotriphenylmethane. Step 2 This step is one wherein the 4-bromobenzyl ether derivative (V) is coupled with oxazolylanisole to form an alkoxymethyl-biphenyloxazoline derivative (IV) through the Grignard reaction. This reaction can be conducted by the conventional process for the Grignard reaction as described in, e.g., Journal of Organic Chemistry (J. Org. Chem.), 43 (7), 1372 to 1379, 1978. Step 3 In this step, the protective group of the alkoxymethyl-biphenyloxazoline derivative (IV) is eliminated to form a hydroxymethyl-biphenyloxazoline derivative (II). This reaction can be conducted according to a common process for eliminating the protective group such as hydrolysis and catalytic reduction. Step 4 This step is one wherein an active biphenyloxazoline derivative (III) is prepared through the sulfonylation or halogenation of the hydroxymethylbiphenyloxazoline derivative (II). The sulfonylation is conducted according to the conventional process with a reagent for sulfonylation such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride. Although the amount of the reagent for sulfonylation used is not limited, it is generally used in an amount of about 1 to 50 equivalents, more preferably about 1.2 to 20 equivalents, still preferably 1.5 to 10 equivalents per equivalent of the hydroxymethyl-biphenyloxazoline derivative (II). On the other hand, the halogenation is conducted according to the conventional process with a reagent for halogenation such as hydrochloric acid, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, phosgene, diphosgene, triphosgene, hydrobromic acid, thionyl bromide and phosphorus tribromide. Although the amount of the reagent for halogenation used is not limited, it is generally used in an amount of about 1 to 50 equivalents, more preferably about 1.5 to 20 equivalents, still preferably about 2 to 10 equivalents per equivalent of the hydroxymethyl-biphenyloxazoline derivative (II). The active biphenyloxazoline derivative (III) prepared in accordance with the present invention is highly stable and can be further purified by an ordinary method such as silica gel column chromatography and vacuum distillation. Preparative Examples for the raw materials and intermediates necessary for carrying out the present invention with now be described prior to Examples. Preparative Example 1 Synthesis of 4-bromobenzylmethoxymethyl ether 10.0 g (53.5 mmol) of 4-bromobenzyl alcohol was dissolved in tetrahydrofuran (200 ml). 6.6 g (58.8 mmol) of potassium t-butoxide was added thereto under cooling with ice, followed by stirring for one hour. Then, 5.2 g (64.6 mmol) of chloromethyl methyl ether was dropwise added thereto, followed by stirring at room temperature for 12 hours. The reaction liquid was added to a saturated aqueous solution of ammonium chloride, followed by the extraction with ethyl acetate. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography to give 11.0 g of the title compound as an oil (yield 89%). 1 H-NMR(90MHz, CDCl 3 ); δ(ppm) 3.40(3H, s), 4.52(2H, s), 4.66(2H, s), 7.16(2H, d, J=8.0Hz), 7.40(2H, d, J=8.0Hz) Preparative Example 2 Synthesis of 4-bromobenzyltetrahydropylanyl ether 10.0 g (53.5 mmol) of 4-bromobenzyl alcohol and 4.95 g (58.8 mmol) of 3,4-dihydro-2H-pyrane were dissolved in methylene chloride (50 ml). Under cooling with ice, 100 mg of p-toluenesulfonic acid monohydrate was added thereto, followed by stirring for 3 hours. The reaction liquid was added to an aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was subjected to vacuum distillation (160°C/1 mmHg) to give 12.0 g of the title compound as an oil (yield 83%). 1 H-NMR(90MHz, CDCl 3 ); δ(ppm) 1.40-2.10 (6H, m), 3.38∼3.70(1H, m), 3.70∼4.02(1H, m), 4.41(1H, d, J=13.0Hz), 4.64(1H, s), 4.70(1H, d, J=13.0Hz), 7.18(2H, d, J=8.0Hz), 7.44(2H, d, J=8.0Hz) Next, Examples will be given hereinafter to illustrate the present invention in definite, though it is needless to say that the present invention is not limited to them. Example 1 Synthesis of 4,4-dimethyl-2-(4'-methoxymethoxymethylbiphenyl-2-yl)oxazoline Tetrahydrofuran (15 ml) was added to 408 mg (16.8 mmol) of flaky magnesium, followed by the addition of a small amount of dibromoethane under stirring. After the confirmation of bubbling, a solution of 3.23 g (14.0 mmol) of 4-bromobenzyl-methoxymethyl ether in tetrahydrofuran (15 ml) was dropwise added thereto. After the confirmation of the dissolution of the magnesium, the resulting mixture was further stirred at room temperature for one hour. Then, a solution of 2.10 g (10.2 mmol) of 4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (15 ml) was dropwise added thereto, followed by stirring for 12 hours. The reaction liquid was poured into a saturated aqueous solution of ammonium chloride, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.20 g of the title compound as an oil (yield 96%). 1 H-NMR(400MHz, CDCl 3 ); δ(ppm) 1.30(6H, s), 3.45(3H, s), 3.80(2H, s), 4.64(2H, s), 4.74(2H, s), 7.34-7.40(6H, m), 7.48(1H, ddd, J=8.5,8.0, 1.5Hz), 7.73(1H, dd, J=8.0, 1.5Hz) FAB-MS; 326(MH + ) Example 2 Synthesis of 4,4-dimethyl-2-(4'-tetrahydropyranyloxymethylbiphenyl-2-yl]oxazoline Tetrahydrofuran (15 ml) was added to 1.2 g (49.4 mmol) of flaky magnesium, followed by the addition of a small amount of dibromoethane under stirring. After the confirmation of bubbling, a solution of 11.0 g (40.6 mmol) of 4-bromobenzyl-tetrahydropyranyl ether in tetrahydrofuran (15 ml) was dropwise added thereto. After the confirmation of the dissolution of the magnesium, the resulting mixture was further stirred at room temperature for one hour. Then, a solution of 7.0 g (34.1 mmol) of 4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (5 ml) was dropwise added thereto, followed by stirring for 12 hours. The reaction liquid was poured into a saturated aqueous solution of ammonium chloride, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 6.61 g of the title compound as an oil (yield 53%). 1 H-NMR(400MHz, CDCl 3 ); δ(ppm) 1.29(6H, s), 1.50-1.94(6H. m), 3.52-3.59(1H, m), 3.80(2H, s), 3.91-3.97(1H, m), 4.55(1H, d, J=12.3Hz), 4.73(1H, t, J=3.7Hz), 4.84(1H, d, J=12.3Hz), 7.38(4H, s), 7.34-7.40(2H, m), 7.48(1H, ddd, J=8.0, 7.5, 1.5Hz), 7.72(1H, ddd, J=8.0, 1.5, 1.0Hz) FAB-MS; 366(MH + ) Example 3 Synthesis of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl]oxazoline 2.62 g (8.05 mmol) of 4,4-dimethyl-2-(4'-methoxymethoxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (20 ml). 6N hydrochloric acid (10 ml) was added thereto, followed by stirring at 40°C for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 2.20 g of the title compound as a crystal (yield 97%). m.p.; 97-100° C 1 H-NMR(400MHz, CDCl 3 ); δ(ppm) 1.30(6H, s), 1.75(1H, br-s), 3.80(2H, s), 4.75(2H, s), 7.40(4H, s), 7.35-7.42(2H, m), 7.48(1H, ddd, J=8.0, 7.5, 1.3Hz), 7.73(1H, dd, J=8.1, 1.3Hz) EI-MS; 280(M-H + ) Example 4 Synthesis of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline 4.0 g (10.9 mmol) of 4,4-dimethyl-2-(4'-tetrahydropyranyloxymethylbiphenyl-2-yl)oxazoline was dissolved in methanol (50 ml), and 6N hydrochloric acid (15 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was poured into a saturated aqueous solution of sodium hydrogencarbonate, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.0 g of the title compound (yield 98%). Example 5 Synthesis of 4,4-dimethyl-2-(4'-chloromethylbiphenyl-2-yl)oxazoline 1.0 g (3.55 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline was dissolved in methylene chloride (15 ml). Under cooling with ice, 0.51 g (4.29 mmol) of thionyl chloride was dropwise added thereto, followed by stirring for one hour. The reaction liquid was poured into an aqueous solution of sodium hydrogencarbonate, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 1.05 g of the title compound was obtained as a crystal (yield 99%). m.p.; 72-75° C 1 H-NMR(400MHZ, CDCl 3 ); δ(ppm) 1.29(6H, s), 3.80(2H, s), 4.64(2H, s), 7.35-7.43(6H, m), 7.62(1H, td, J=7.6, 1.5Hz), 7.73(1H, ddd, J=7.6, 1.5, 1.0H FAB-MS; 300(MH + ) Example 6 Synthesis of 4,4-dimethyl-2-(4'-methanesulfonyloxymethylbiphenyl-2-yl)oxazoline 2.0 g (7.1 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline and 1.43 g (14.1 mmol) of triethylamine were dissolved in methylene chloride (20 ml). A solution of 0.98 g (8.6 mmol) of methanesulfonyl chloride in methylene chloride (10 ml) was dropwise added thereto under cooling with salt-ice. After stirring for 3 hours as such, the reaction liquid was poured into water, followed by the extraction with methylene chloride. After washing with water and drying, vacuum concentration was conducted. 2.53 g of the title compound was obtained as an oil (yield 99%). 1 H-NMR(90MHz, CDCl 3 ); δ(ppm) 1.31(6H, s), 2.94(3H, s), 3.80(2H, s), 6.26(2H, s), 7.40(4H, s), 7.14-7.80(4H, m) Example 7 Synthesis of 4,4-dimethyl-2-(4'-p-toluenesulfonyloxymethylbiphenyl-2-yl)oxazoline 0.34 g (8.5 mmol) of a 60% oily sodium hydride was suspended in tetrahydrofuran (20 ml). A solution of 2.0 g (7.1 mmol) of 4,4-dimethyl-2-(4'-hydroxymethylbiphenyl-2-yl)oxazoline in tetrahydrofuran (30 ml) was dropwise added thereto at room temperature, followed by further stirring at room temperature for one hour. After the reaction liquid was cooled with ice, a solution of 1.6 g (8.4 mmol) of p-toluenesulfonyl chloride in tetrahydrofuran (20 ml) was dropwise added thereto. After stirring for 3 hours as such, the reaction liquid was poured into a saturated aqueous solution of ammonium chloride, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.7 g of the title compound as an oil (yield 55%). 1 H-NMR(90MHz, CDCl 3 ); δ(ppm) 1.28(6H, s), 2.24(3H, s), 3.76(2H, s), 5.07(2H, s), 7.11-7.70(10H, m), 7.78(2H, d, J=8Hz) FAB-MS; 436(MH + )

Claims: A process for preparing a biphenyloxazoline derivative (III) represented by the following general formula: wherein R 2 represents a C 1 -C 6 alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen atom, comprising the step of subjecting a hydroxymethyl-biphenyl-oxazoline derivative (II) having the following general formula to sulfonylation or halogenation: ; and wherein the hydroxymethylbiphenyloxazoline derivative (II) is prepared by eliminating the protective group from an alkoxymethyl-biphenyloxazoline derivative (IV) having the following general formula: wherein R 3 represents a methoxymethyl group, an ethoxymethyl group, a propoxymethyl group, a methoxyethyl group, an ethoxyethyl group, a propoxyethyl group, a propoxypropyl group, an aryloxyalkyl group, an aralkyloxyalkyl group, a methoxyethoxymethyl group, an ethoxyethoxymethyl group, a methylthiomethyl group, a methylthioethyl group, an ethylthiomethyl group, a phenylthiomethyl group, a benzylthiomethyl group, a cycloether group, a trialkylsilyl group, a triarylsilyl group, a methyl group, an ethyl group, a propyl group, a t-butyl group, a vinyl group, an aralkyl group or a triphenylmethyl group; and wherein the alkoxymethylbiphenyloxazoline derivative (IV) is prepared by protecting 4-bromobenzyl alcohol into a 4-bromobenzyl ether derivative (V) represented by the following general formula: wherein R 3 is as defined above, and then coupling it with 4,4-dimethyl-oxazol-2-yl-anisole through the Grignard reaction.

Inventors: FURUKAWA KEN, ICHINO TOMIO, SHIMIZU TOSHIKAZU, TSURUGI TOMIO, URAWA YOSHIO, YAMAGISHI YOJI, FURUKAWA, KEN, ICHINO, TOMIO, SHIMIZU, TOSHIKAZU, TSURUGI, TOMIO, URAWA, YOSHIO, YAMAGISHI, YOJI, FURUKAWA, KEN RESIDENCE HIRO 202, ICHINO, TOMIO 2333-197, KYUCHU, SHIMIZU, TOSHIKAZU KONOIKE OHKARYO, TSURUGI, TOMIO 1-1044-130, TOYOSATODAI, URAWA, YOSHIO 16-27, KONOIKE OHKARYO
Applicants: EISAI CO LTD, EISAI KAGAKU KK, EISAI CHEMICAL CO., LTD., EISAI CO., LTD.
Application year: 1993
Main classification: C07D471
IPC codes: C07D471, C07D213, C07C63, C07C69, C07C65, C07D263, C07D413, C07D309