HU226806B1 - Method of manufacturing the cycloheptimidazole derivatives and the used intermediates - Google Patents

Description

According to the invention, a compound of formula (I) wherein R _q , R ₂ , A, A ·, and the dashed line are as defined above, while X is a halogen or trifluoromethanesulfonate group, is prepared according to the invention. ) in which Y is -B (OH) ₂ or -Sn (R ₅ ) ₃ (in which R ₅ is lower alkyl) and Z is a protecting group, then a compound of formula 3 is obtained. - the protecting group R ₁ , R ₂ , A, A ·, and the dashed line and Z are as defined above are removed.

HU 226 806 Β1

The length of the description is 12 pages (including 5 pages)

HU 226 806 Β1

The present invention relates to a novel process for the preparation of cycloheptimidazole derivatives which are potent angiotensin (II) receptor antagonists and thus useful in the treatment of hypertension and congestive heart failure.

A number of different cycloheptimidazole derivatives have been synthesized to develop new effective antihypertensive agents. Recently, novel cycloheptimidazole derivatives of formula (I) have been described which are effective in treating hypertension, in treating congestive heart failure and in reducing intraocular pressure. Said novel compounds are disclosed in Japanese Patent Laid-open Publication Nos. 5-320139 and 5-190153, published in 1993. In the general formula (I)

R ₁ is hydrogen or isopropyl;

R ₂ is lower alkyl;

R ₄ is carboxyl or tetrazolyl;

A and A ₁ are independently located in the 4 or 8 position, and A a hydrogen atom or a hydroxy group when A is hydrogen or A and A ₁ together form an oxo group or a group -CHCOOR ₃ (where R ₃ is lower alkyl); and the dashed line represents two double bonds or saturated single bonds.

In the preparation of the aforementioned cycloheptimidazole derivatives of formula (I), a corresponding cycloheptimidazole was reacted with a halomethyl biphenyl derivative under basic conditions, and the resulting compound containing R _{4 as} cyano was converted to the corresponding carboxy or tetrazole derivative according to Scheme A. (wherein R _{4 in} this case is a nitrile group and X is a halogen atom). However, this method requires a two-step synthesis and involves the use of expensive and difficult to handle reagents such as tin azide (SnN ₃ ), which has various difficulties.

It is an object of the present invention to provide a process for the preparation of the aforementioned cycloheptimidazole derivatives in good yield without the use of simple, toxic or costly reagents.

In order to accomplish this goal, extensive, intensive research into new types of these compounds has been conducted, and they have been discovered to be readily prepared in good yields by palladium-catalyzed cross-coupling reactions. According to the invention there is provided a compound of formula (I): wherein

R 1 is hydrogen or isopropyl;

R ₂ is lower alkyl;

A and A ₁ are independently at the 4 or 8 position and A 1 is is hydrogen or hydroxy, when A is H, or A and A ₁ together form = O or = CHCOOR ₃ group of formula (where R is ₃ represents a lower alkyl group);

the dashed line represents 2 double bonds or saturated single bonds; and

X is halogen or trifluoromethanesulfonate with a compound of formula 2 wherein Y is -B (OH) ₂ or -Sn (R ₅ ) ₃ (in which R ₅ is lower alkyl) and Z is reacting a protecting group to form a compound of formula (3) wherein R ₁ is hydrogen or isopropyl;

R ₂ is lower alkyl;

A and A ₁ are independently at the 4 or 8 position and A ₁ is hydrogen or hydroxy when A is hydrogen or A and A ₁ are hydrogen. together are oxo or = CHCOOR ₃ (in which R ₃ is lower alkyl);

the dashed line represents 2 double bonds or saturated single bonds; and

Z is deprotected to give a compound of formula 4 wherein R ₁ is hydrogen or isopropyl;

R ₂ is lower alkyl;

A and A- | are independently at the 4 or 8 position and A ₁ is hydrogen or hydroxy when A is hydrogen or A and A ₁ are hydrogen; together are oxo or = CHCOOR ₃ (in which R ₃ is lower alkyl);

the dashed line represents 2 double bonds or saturated single bonds.

In the compounds of formula (3), Z as a protecting group is suitably t-butyl, trityl, methoxymethyl, benzylmethyl or p-nitrophenyl.

In each of the above formulas, R ₂ or R _{3 is} lower alkyl having from 1 to 4 carbon atoms.

The compounds of formula (I) used as starting materials in the process of the present invention can be prepared by a variety of methods. These methods are described below.

(I) Compounds of formula (I) wherein A and A; are independently at the 4 or 8 position and A- | is hydrogen or hydroxy, when A is H, or A and A ₁ together represent oxo, may be prepared as shown in Scheme 1. In this scheme, R 1, A, A ₂ , R ₂ and X are as previously defined.

Thus, the cycloheptimidazole compound (5) is reacted with a halobenzyl halide (6), usually in the presence of a base. Examples of suitable bases include sodium hydride, sodium hydroxide and potassium carbonate. Suitable solvents for the reaction include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetone and dioxane. Further, a phase transfer catalyst, ex2, may be used in the reaction

For example, tetra-n-butylammonium bisulfate can be used, whereby a mixture of water and benzene can be used as a solvent. The cycloheptimidazole compounds of formula (5) may be prepared by the method described in Japanese Patent Publication No. 5-320139.

(i) If A and A- | together represent an oxo group, and the compound contains 2 double bonds, the corresponding compounds of formula (9) may be prepared as shown in Scheme 2. In this scheme, R ₁ is hydrogen or isopropyl and R ₂ is lower alkyl.

Thus, the reaction comprises reacting a tosyltropolone of formula (7) with an amidine of formula (8) in the presence of a base as described in Chemical Abstracts, 74, 53785a, Japanese Patent 7,031,171, in the presence of a base of formula (9). The oxo-imidazole derivative of formula (II) is obtained.

(ii) When A and A _{1 are} hydrogen and the corresponding compound contains single bonds, compounds of formula (12) are prepared as shown in Scheme 3. In this scheme, R ₁ and R ₂ are as previously defined.

Thus, the reaction scheme involves reacting a methyl tropolone derivative (10) with an amidine (8) in the presence of sodium ethylate and hydrogenating the resulting cycloheptimidazole compound (11) over platinum oxide (12). 1,4,5,6,7,8-hexahydrocycloheptimidazole.

(iii) When A and A ₁ together represent an oxo group and the compound contains single bonds, the corresponding compounds of formula (13) may be prepared as shown in Scheme 4. In this scheme, R. | and R ₂ is as previously defined.

Thus, an oxocycloheptimidazole compound of formula (9) is hydrogenated over palladium on carbon or platinum oxide to give the corresponding compound of formula (13).

(iv) Suitable compounds containing A as hydrogen and A _{1 as} hydroxy can be prepared from compounds of Formula 13 using a reducing agent such as sodium borohydride or lithium aluminum hydride.

(II) Starting compounds of formula (I) wherein A and A; together = CHCOOR ₃ (where R ₃ is lower alkyl) may be prepared as shown in Scheme 5. In this scheme, R _h, R ₂ , R ₃ and X are as previously defined.

Thus, in the reaction scheme, a compound of Formula 13 is reacted with a p-halobenzyl halide derivative of Formula 6 in the presence of a base and a phase transfer catalyst such as tetra-n-butylammonium hydrogen sulfate, followed by The compound of formula (14) thus obtained is reacted with a reagent of LiCH ₂ COOR ₃ and the resulting compound of formula (15) is dehydrated with a mixture of thionyl chloride and pyridine to give the corresponding compound of formula (16). The latter may also be prepared by reacting a compound of formula (14) with a reagent of formula (C ₂ H ₅ O) ₂ P (O) CH ₂ COOR ₃ in the presence of a base.

(B) Compounds of formula (2) used as another starting material in the process of the present invention can be prepared by the following methods.

(I) The corresponding boron derivatives of formula (2a) can be prepared as shown in Scheme 6. In this scheme, X is halogen and Z is protecting group.

According to the reaction scheme or as described in Zikken Kagakukouza 24, Yuukigousei VI, Maruzen (KK) 80 (1992), a compound of formula (17) is reacted with n-butyllithium or magnesium, followed by trimethoxyborane. followed by hydrolysis with dilute sulfuric acid.

(II) The tin compounds of formula (2b) may be prepared as shown in Scheme 7. In this scheme, X is halogen, Z is protecting group, and R ₅ is lower alkyl.

Thus, according to the reaction scheme, a compound of formula (17) is reacted first with n-butyllithium and then with a tin reagent of the formula -Sn (R ₅ ) ₃ Cl.

(C) The reaction of the compounds of formula (1) and (2) according to the invention is carried out as follows.

(I) When Y is -B (OH) _{2 in the} compound of formula (2), a compound of the formula (1) is reacted with a compound of the formula (2) in the presence of a base and a catalyst by Suzuki in Synthetic Communication, 11 (7), 513 (1981), to give a corresponding compound of formula (3). The catalysts used for this reaction include, for example, Pd (PPh ₃ ) ₄ , PdCl ₂ and Pd / C. Suitable bases for the reaction are, for example, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide. Suitable solvents are, for example, water, ethanol, methanol, benzene or toluene. The reaction is carried out at room temperature or under reflux.

(II) When Y is -Sn (R ₅ ) ₃ , wherein R ₅ is lower alkyl, a compound of formula (1) with a compound of formula (2) is prepared by Shille by Angew. Chem. Inst. Ed. Engl., 25, 508-524 (1988), in the presence of a catalyst. For this purpose, one of the following catalysts may be used: Pd (PPh ₃ ) ₄ , PdCl ₂ , Pd / C, Cul and LiCl. Tetrahydrofuran, dimethoxyethane or dimethylformamide may be used as the solvent for this reaction.

EN 226 806 Β1 for example. The reaction is carried out at room temperature or under reflux.

(D) For the conversion of the compounds of formula (3) to the target compounds of formula (4), the deprotection may be effected, for example, by refluxing with hydrogen chloride or methanesulfonic acid in the presence of benzene or toluene.

The following examples are intended to illustrate the invention.

Example 1

5- [2- (4- (2-Propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) cycloheptimidazolyl) methylhyphenyl)] - tetrazole (a) 1- (4-Iodine) benzyl) -2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cikloheptimidazol

2-Propyl-8-oxo-4,5,6,7-tetrahydrocycloheptimidazole (5.0 g) in toluene (150 mL) was added followed by the addition of 30% aqueous sodium hydroxide (60 mL). After stirring at room temperature for 30 minutes, 9.2 g of iodobenzyl bromide and 2.0 g of tetra-n-butylammonium hydrogen sulfate are added. After stirring at room temperature for 8 hours, the reaction mixture was filtered and the filtrate was extracted twice with 50 ml of ethyl acetate each time. The combined extracts were washed with water followed by brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography on silica (120 g), eluting with 1: 1 n-hexane: ethyl acetate. 8.69 g of the title compound are obtained in the form of yellow crystals, m.p. 64-65 ° C.

Mass Spectrum (m / e): M ⁺ = 408, 217 (BP).

IR (cm ^-1 ): 2926.1632, 1464, 1428.

¹ H-NMR (CDCl ₃ ) δ 0.95 (3H, t, -CH ₂ CH ₂ CH ₃ ), 1.70 (2H, m, -CH ₂ CH ₂ CH ₃ ), 1.87 (2H, m , cyclohexyl), 1.92 (2H, m, cyclopropyl), 2.58 (2H, m, cyclopropyl), 2.65 (2H, m, cyclopropyl), 2.96 (2H, t, _{-CH2 CH2} CH ₃ ), 5.47 (2H, s, -CH ₂ -C ₆ H ₅ ), 6.71 (2H, d, aromatic), 7.62 (2H, d, aromatic).

(b) 2- (tert-Butyl) -5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole))] - tetrazole

To a solution of 150 mg of the compound prepared in (a) above in a mixture of 10 ml of toluene and 1 ml of ethanol is added 96 mg of [2- (2-tert-butyl-2H-tetrazole-5-one) prepared as in Example 3. yl) phenyl] boronic acid, 35 mg Pd (PPh ₃ ) ₄ and 0.7 ml 2 M sodium carbonate solution. The resulting mixture was stirred at reflux for 3 hours and then concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel using a 10: 1 by volume mixture of ethyl acetate and n-hexane as eluent. The title compound was obtained as a yellow oil.

IR (cm ^-1 ): 2926.1632, 1464, 1428. Mass spectrum (m / e): M ⁺ = 482, 178 (BP).

¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t, -CH ₂ CH ₂ CH ₃ ),

1.55 [9H, s, - (CH ₃ ) ₃ ], 1.75 (2H, m, -CH ₂ CH ₂ CH ₃ ),

1.80-2.00 (4H, m, cyclopropyl), 2.59 (2H, t, cyclo), 2.68 (2H, m, cyclopropyl), 3.01 (2H, q, -CH ₂ CH ₂ CH ₃ ), 5.57 (2H, s, -CH ₂ C ₆ H ₅ ), 6.90 (2H, d, aromatic), 7.09 (2H, d, aromatic), 7.35-7.60 (3H, m, aromatic), 7.89 (2H, d, aromatic).

(c) 5- [2- (4- (2-Propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) -methyl-biphenyl)] -tetrazole

A solution of 100 mg of the compound prepared in (b) above in 10 ml of toluene containing 200 mg of methanesulfonic acid is refluxed for 3 hours, then concentrated in vacuo and the residue is poured into ice water. The resulting aqueous solution was then adjusted to pH 8 with 10% aqueous sodium hydroxide. The resulting precipitate was filtered off and recrystallized from ethanol to give 77.4 mg of the title compound as white crystals, m.p. 214-216 ° C.

Mass spectrum (m / e): M ⁺ = 426, 383, 355, 178 (BP). ¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, -CH ₂ CH ₂ CH ₃ ),

1.58 (2H, m, -CH ₂ CH ₂ CH _3), 1.68 (2H, m, cyclopropyl), 1.75 (2H, m, cyclopropyl), 2.30 (2H, m, cyclopropyl); 2.47 (2H, m, cyclo), 2.53 (2H, t, -CH ₂ CH ₂ CH ₃ ), 5.45 (2H, s, -CH ₂ C ₆ H ₅ ), 6.75 (2H , d, aromatic), 7.00 (2H, d, aromatic), 7.42 (2H, d, aromatic), 7.52 (2H, d, aromatic), 7.60 (2H, d, aromatic), 7.85 (2H, d, aromatic).

Example 2

5- [2- (4- (2-Propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazolyl) -methyl-biphenyl)] -tetrazole (a) 1- (4-Iodo-benzyl) ) -2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cikloheptimidazol

100 mg of 1- (4-iodobenzyl) -2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole, prepared in a manner similar to that described in Example 1, and 120 mg of To a solution of 2- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] -trin-n-butyl-stannane prepared as described in Example 1b, is added 31.15 mg of lithium chloride and 1.4 g of lithium chloride. mg Pd (PPh ₃ ) ₄ -t. The reaction mixture was refluxed for 48 hours, then filtered and the filtrate evaporated in vacuo. Ethyl acetate was added to the residue, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and the organic solvent was evaporated in vacuo. The residual oil was purified by column chromatography on silica gel using a 1: 1 by volume mixture of ethyl acetate and n-hexane as eluent. Thus 45 mg of 2- (tert-butyl) -5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole) methyl] -2-tert-butyl is obtained as a yellow oil. biphenyl)] - tetrazole is obtained.

Mass Spectrum (m / e): M ⁺ = 482, 426, 369, 178 (BP). IR (cm ^-1 ) 2926, 1632, 1464, 1428, 1389.

HU 226 806 Β1 ¹ H-NMR (CDCl ₃ ) δ 0.96 (3H, t, -CH ₂ CH ₂ CH ₃ ),

1.55 [9H, s, - (CH3) _3], 1.74 (2H, m, -CH ₂ CH ₂ CH _3), l, 80-2.00 (4H, m, cyclopropyl) 2, 59 (2H, t, cyclo), 2.68 (2H, m, cyclo), 3.01 (2H, q, -CH ₂ CH ₂ CH ₃ ), 5.57 (2H, s, -CH ₂ C _6). H ₅ ), 6.90 (2H, d, aromatic), 7.09 (2H, d, aromatic), 7.35-7.60 (3H, m, aromatic), 7.89 (2H, d, aromatic) ).

2- (tert-Butyl) -5- [2- (4- (2-propyl-8-oxo-4,5,6,7-tetrahydro-1 (4H)) was prepared as described in Reference Example 1 above. ) -cycloheptimidazole) -methyl-biphenylyl] -tetrazole is cleaved to give the title compound of the example.

Example 3 [2- (2-tert-Butyl-2H-tetrazol-5-yl) -phenylboronic acid

To a solution of 3.3 g of 5- (2-bromophenyl) -2- (1,1-dimethylethyl) -2H-tetrazole in 20 ml of tetrahydrofuran was added 7.80 ml of hexane, cooled to -78 ° C. 1.6 molar solution of n-butyllithium and 2.30 g of triisopropyl borate. The cooling bath was removed and the reaction mixture was stirred at room temperature for one hour. Hydrochloric acid (0.5 N) was added and the mixture was stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were extracted three times with 10 ml of 1 N potassium hydroxide solution and the pH of the combined aqueous extracts was adjusted to 1 with 20 ml of 2N hydrochloric acid. The resulting precipitate was filtered off to give the title compound (1.87 g) as a white solid, m.p. 117-122 ° C.

¹ H-NMR (CDCl 3) δ 1.72 [9H, s, -C (CH ₃ ) ₃ ], 7.46 (2H, m, aromatic), 7.90 (2H, m, aromatic).

Example 4 [2- (2-tert-Butyl-2H-tetrazol-5-yl) -phenyl] -tri-n-butylstannate

To a solution of 5- (2-bromophenyl) -2- (1,1-dimethylethyl) -2H-tetrazole (1.23 g) in tetrahydrofuran (8 ml) cooled to -78 ° C was added 3.27 ml of hexane. 1.6 M n-butyl lithium solution and after one hour 1.71 g tri-n-butyl tin chloride. The resulting reaction mixture was stirred at -78 ° C for an additional 3 hours, then warmed to room temperature and stirred at this temperature for 18 hours. Water was added and the reaction mixture was extracted twice with 30 ml of diethyl ether. The combined extracts were washed with water followed by brine, dried and evaporated. The resulting oil was purified by column chromatography over silica gel using n-hexane as the eluent. 1.0 g of the title compound is obtained as a yellow oil.

¹ H-NMR (CDCl 3) δ: 0.78 [9H, t, - (--CH ₃ ) ₃ ], 0.93 [6H, t

- (CH ₂ -) ₃ ], 1.21 [6H, m, - (CH ₂ -) ₃ ], 1.43 [6H, m,

- (CH ₂ -) ₃ ], 1.80 [9 H, s, (CH ₃ ) ₃ ], 7.43 (1H, d, aromatic), 7.45 (1H, d, aromatic), 7.60 ( 1H, m, aromatic), 8.00 (1H, m, aromatic).

Example 5

2-Ethyl-8- (ethoxycarbonylmethylene) 1 - [(2'-1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -4,5,6,7-tetrahydro-cycloheptimidazole (a) 1 - (4-Bromo-benzyl) -2-etil8-oxo-4,5,6,7-tetrahydro-1 (4H) cikloheptimidazol

To a solution of 2.5 g of 2-ethyl-8-oxo-4,5,6,7-tetrahydrocycloheptimidazole in 50 ml of toluene was added 30 ml of 30% aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 30 minutes. . Thereafter, 3.6 g of 4-bromobenzyl bromide and 0.5 g of tetra-n-butylammonium hydrogen sulfate are added, and the reaction mixture is stirred at room temperature for 8 hours. Filtration is carried out and the filtrate is extracted twice with 20 ml of ethyl acetate each time. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography on silica (100 g), eluting with a 1: 1 mixture of n-hexane and ethyl acetate. This gave 4.0 g of the title compound as a yellow oil.

Mass Spectrum (m / e): M ⁺ = 347, 319, 169 (BP). IR (cm ^-1 ): 2950, 1640, 1480, 1400, 1330. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, -CH ₂ CH ₃ ), 1.85-1.87 (2H, m, cyclo), 1.91-1.94 (2H, m, cyclo), 2.60-2.65 (4H, m, cyclo), 3.01 (2H, q, CH ₂ CH ₃ ), 5.48 (2H, s,

-CH ₂ C ₆ H ₄ ), 6.86 (2H, d, aromatic), 7.41 (2H, d, aromatic).

(b) 1- (4-Bromobenzyl) -2-ethyl-8- (ethoxycarbonyl) -8-hydroxy-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole

To a solution of 2.88 ml (Me ₃ Si) ₂ NLi in 5 ml of tetrahydrofuran at -78 ° C is added 0.25 ml of anhydrous ethyl acetate and the resulting mixture is stirred for 15 minutes. Then, 0.5 g of a solution of the compound prepared in step (a) above in anhydrous tetrahydrofuran is added dropwise. The resulting reaction mixture was stirred at -78 ° C for 1 hour and then adjusted to pH 5.0 with 6N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography over silica gel using chloroform / methanol (20: 1, v / v) as the eluent. 388 mg of the title compound are obtained in the form of a yellow oil.

Mass Spectrum (m / e): M ⁺ = 435, 348, 169 (BP), 90. IR Spectrum (crrr ¹ ): 3300, 2900, 1720, 1170, 1000. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, -CH ₂ CH ₃ ), 1.33 (3H, t,

-CH ₂ CH ₃ ), 1.80-2.20 (6H, m, cycle), 2.71 (2H, m,

-CH ₂ COOEt), 2.78 (2H, q, -CH ₂ CH ₃ ), 2.97 (2H, m, cyclo), 4.57 (2H, m, cyclo), 4.57 (2H, q) , CH ₂ CH ₃ ), 5.81 (2H, s, -CH ₂ C ₆ H ₅ ), 7.20-7.40 (4H, m, aromatic).

EN 226 806 Β1 (c) 1- (4-Bromobenzyl) -2-ethyl-8- (ethoxycarbonylmethylidene) -4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole (1) 0.38 g, 1- (4-bromobenzyl) -2-ethyl-8- (ethoxycarbonyl) -8-hydroxy-4,5,6,7-tetrahydro-1 (4H) - prepared as described in step (b) above. To a solution of cycloheptimidazole in pyridine (2 mL) was added thionyl chloride (0.32 g), and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was then poured into 20 ml of 10% hydrochloric acid at 0 ° C and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography over silica gel using chloroform / methanol (20: 1, v / v) as the eluent. 280 mg of the target compound are obtained.

(2) To a solution of 0.08 g of potassium hydride in 5 ml of tetrahydrofuran is added 0.37 g of diethyl phosphonoacetate at 5 ° C, and after stirring at 10 ° C for 10 minutes, 0.5 g of the above compound is added. A solution of 1- (4-bromobenzyl) -2-ethyl-8-oxo-4,5,6,7-tetrahydro-1 (4H) -cycloheptimidazole prepared in step a) in 1 ml of tetrahydrofuran. The resulting mixture was stirred at 40 ° C for 5 hours and then poured into ice water (20 ml). After extraction with ethyl acetate, the resulting organic layer was washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography over silica gel using a 20: 1 by volume mixture of chloroform and methanol as eluent. This gave 60 mg of the title compound as a yellow oil.

Mass Spectrum (m / e): M ⁺ = 418, 371, 343, 171 (BP),

90th

IR (cm ^-1 ): 2900.1710, 1230, 1170, 1000. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, -CH ₂ CH ₃ ), 1.26 (3H, t,

-CH ₂ CH ₃ ), 1.85 (2H, m, cyclo), 1.90 (2H, m, cyclo),

2.91 (2H, q, CH ₂ CH ₃ ), 2.92 (2H, q, CH ₂ CH ₃ ),

4.05-4.20 (4H, m, cyclopropyl), 5.28 (2H, s, -CH ₂ C ₆ H _5);

5.68 (1H, s, = CHCOOC ₂ H _5), 6.80 (d, 2H, aromatic),

7.55 (2H, d, aromatic).

(d) 2- (tert-Butyl) -5- [2- (4- (2-ethyl-8-ethoxycarbonylmethylidene-4,5,6,7-tetrahydro-1 (4H) cycloheptimidazolyl) methyl) - biphenylyl] tetrazole

To a solution of 280 mg of the compound prepared in step (c) above in a mixture of 5 ml of toluene and 0.1 ml of ethanol is added 175.5 mg of [2- (2-tert-butyl-2H-tetrazol-5-yl) -phenyl] ] -Boronic acid, 26.8 mg Pd (PPh ₃ ) ₄ and 1.6 ml of 2 M sodium carbonate solution are added and the resulting mixture is stirred at reflux for 4.5 hours. The reaction mixture was poured into water (30 mL) and extracted with toluene (3 x 20 mL). The toluene layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting product was purified by column chromatography on silica gel using ethyl acetate / n-hexane (1: 1 v / v) as the eluent. This gave 230 mg of the title compound as a yellow oil.

Mass Spectrum (m / e): M ⁺ = 539, 451.253, 178 (BP). IR (cm ^-1 ): 3420, 3000, 1230, 2950, 1720. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, s, t-Bu), 1.82 (2H, m, cyclo), 1.89 (2H, m, cyclo), 2.55 (2H , q, -CH ₂ CH ₃ ), 2.80-2.83 (2H, m, cyclo), 3.04-3.07 (2H, m, cyclo), 4.12 (2H, q, -CH) ₂ CH ₃ ), 5.17 (2H, s, -CH ₂ C ₆ H ₅ ), 5.56 (1H, s, = CHCOOC ₂ H ₅ ), 6.82 (2H, d, aromatic), 7, 14 (2H, d, aromatic), 7.39-7.88 (4H, m, aromatic).

(e) 2-Ethyl-8-carboxymethylene-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -4,5,6,7-tetrahydro-cycloheptimidazole

A solution of 200 mg of the compound prepared in (d) above in toluene (20 ml) containing methanesulfonic acid (400 mg) is refluxed for 3 hours, then concentrated in vacuo and the concentrate is poured into ice water. The resulting aqueous mixture was adjusted to pH 4 with 10% sodium hydroxide solution, and the resulting precipitate was filtered off and then recrystallized from methanol (2 mL) to give 120 mg of the title compound of this step. ° C in the form of white crystals.

Mass Spectrum (m / e): M ⁺ = 408 (M ⁺ -COOH), 367, 192 (BP), 134.

IR (cm ^-1 ): 2914, 1692, 1611, 1452, 1362, 1197.

¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, -CH ₂ CH ₃ ), 1.94 (4H, bs, cyclo), 2.65-3.03 (6H, m, -CH ₂ CH ₃ + cyclo), 5.43 (2H, s, -CH ₂ C ₆ H ₅ ), 5.92 (1H, s, = CHCOOH), 6.80-7.70 (8H, m, aromatic). , 7.96 (1H, s, -NH).

Claims (3)

PATENT CLAIMS A process for the preparation of a compound of formula (4): wherein R 1 is hydrogen or isopropyl, R ₂ is lower alkyl; A and A! independently a substituent at the 4- or 8-position and A 1 is hydrogen or hydroxy when A is hydrogen or A and A ₁ together are oxo or -CHCOOR ₃ and in the latter R ₃ is lower alkyl; and the dashed line represents 2 double bonds or saturated single bonds, characterized in that a compound of formula (I) wherein R _{1 is;} R ₂ , A, A ·, and the dashed line are as defined herein, while X is halogen or trifluoromethanesulfonate with a compound of formula (2) wherein Y is -B (OH) ₂ or -Sn (R _{5) 3} (the latter _R5 represents lower alkyl) and Z is a protecting group HU 226 806 Β1 reacting and deprotecting a compound of formula (3) thus obtained, wherein R 1, R ₂ , A, A 1 and the dashed line are within the scope and Z is the representative moiety. Compounds of formula (1) according to claim 1. Compounds of formula (2) according to claim 1.