CA2156121C - Method of manufacturing the cycloheptimidazole derivatives - Google Patents
Method of manufacturing the cycloheptimidazole derivatives Download PDFInfo
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- CA2156121C CA2156121C CA002156121A CA2156121A CA2156121C CA 2156121 C CA2156121 C CA 2156121C CA 002156121 A CA002156121 A CA 002156121A CA 2156121 A CA2156121 A CA 2156121A CA 2156121 C CA2156121 C CA 2156121C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Disclosed is a method in which a compound of general formula (1) is reacted with a compound of general formula (2), followed by deprotection of protective group Z to give the cycloheptimidazole derivative (4) wherein R1 is hydrogen or isopropyl; R2 is a lower alkyl; A and A1 are each a substituent at the 4- or 8-position, Al is hydrogen or hydroxyl when A is a hydrogen or A and A1 together form an oxo group or =CHCOOR3 (R3 represents a lower alkyl); the dotted line means two double bonds or saturated single bonds; X is halogen atom or trifluoromethanesulfonate group; Y is B(OH)2 or -Sn(R5)3 (R5 represents a lower alkyl group). The cycloheptimidazole derivative (4) is useful as antihypertensive agent.
Description
21~~I~1 SPECIFICATTON
TITLE OF THE INVENTION
Method of Manufacturing the Cycloheptimidazole Derivatives.
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to a new method of synthesiz-ing cycloheptimidazole derivatives which are active angiotensin II receptor antagonists and are useful for treating hyper-tension and congestive heart failure.
TITLE OF THE INVENTION
Method of Manufacturing the Cycloheptimidazole Derivatives.
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to a new method of synthesiz-ing cycloheptimidazole derivatives which are active angiotensin II receptor antagonists and are useful for treating hyper-tension and congestive heart failure.
2. Description of the Prior Art We have synthesized a number of cycloheptimidazole derivatives in order to develop novel agents possessing potent antihypertensive activities. Recently we proposed a new class of cycloheptimidazole derivative compounds of the following general formula:
(wherein Rl is hydrogen or isopropyl; R2 represents a lower alkyl; R3 represents a carboxyl or tetrazoyl; A and Al are individually a substituent at the 4- or 8-position, Al is a hydrogen or hydroxy when A is a hydrogen or A and A1 may form an oxo group or =CHCOOR3 (R3 represents a lower alkyl); the 2~~sm~
dotted line is two double bonds or saturated single bonds);
and a method of their synthesis and their use as potent anti-hypertensive, anticongestive heart failure agents and intraocular pressure lowering agents (Japanese Unexamined Patent Publication No. 5-320139 (1993) and Japanese Patent Application No. 5-190153 (1993)).
In preparation of the above cycloheptimidazole derivatives, cycloheptimidazole compounds are reacted with halomethylbiphenyl compounds under the basic condition to give the cycloheptimidazole derivatives, and nitrile group (R4=CN) is then converted into carboxy group or tetrazol group (as shown below).
R,~~_~, >-Rz + XCf'~z --~~ ~Ni Ri ~.-,.
C/. , I \/ R2 R
A' z (wherein R4 is nitrite, X represents halogen atom), However, in the method we previously reported we must take two step synthetic reactions and further must use an expensive and hard to handle reagent such as SnN3 (Tin azide) and there are some difficulties in the process.
(wherein Rl is hydrogen or isopropyl; R2 represents a lower alkyl; R3 represents a carboxyl or tetrazoyl; A and Al are individually a substituent at the 4- or 8-position, Al is a hydrogen or hydroxy when A is a hydrogen or A and A1 may form an oxo group or =CHCOOR3 (R3 represents a lower alkyl); the 2~~sm~
dotted line is two double bonds or saturated single bonds);
and a method of their synthesis and their use as potent anti-hypertensive, anticongestive heart failure agents and intraocular pressure lowering agents (Japanese Unexamined Patent Publication No. 5-320139 (1993) and Japanese Patent Application No. 5-190153 (1993)).
In preparation of the above cycloheptimidazole derivatives, cycloheptimidazole compounds are reacted with halomethylbiphenyl compounds under the basic condition to give the cycloheptimidazole derivatives, and nitrile group (R4=CN) is then converted into carboxy group or tetrazol group (as shown below).
R,~~_~, >-Rz + XCf'~z --~~ ~Ni Ri ~.-,.
C/. , I \/ R2 R
A' z (wherein R4 is nitrite, X represents halogen atom), However, in the method we previously reported we must take two step synthetic reactions and further must use an expensive and hard to handle reagent such as SnN3 (Tin azide) and there are some difficulties in the process.
3. Object of the Invention A primary object of the present invention is to find an alternative process for the preparation of the cyclohept-21 i5~~~
imidazole derivatives, which method is simple, does not use toxic or expensive reagents and gives a good yield of the cycloheptimidazole derivatives.
SUMMARY OF THE INVENTION
The inventors have conducted intensive studies, and found a new simple and good yield synthetic method involving a palladium catalyzed cross-coupling reaction.
In accordance with the present invention, a compound of general formula ( 1 ) R~~~_.,~ N
Cc . I ~~R2 A/~~.,'~ N~ (1) X
(wherein Rl is hydrogen or isopropyl; R2 represents a lower alkyl; A and Al are each a substituent at the 4- or 8-position, and Al is hydrogen or hydroxy when A is hydrogen or A and A1 together form an oxo group or =CHCOOR3 (R3 represents a lower alkyl); the dotted line represents two double bonds or saturated single bonds; X is halogen atom or trifluoromethanesulfonate) is reacted with a compound of the following general formula (2):
Y N~N~ ;
J \,N
/ N~Z (2) 21:a 6121 (wherein Y is -B(OH)2 or -Sn(R5)3 (R5 represents a lower alkyl group; and Z is a protecting group for the tetraolyl group) to give the compound of following general formula ( 3 ) F
(3) (wherein the symbols are as defined above), then the compound (3) is deprotected to give the compound of general formula (4):
N
C, , I ~~-R2 I, A' C H
(4) (wherein the symbols are as defined above).
Preferably Z represents tert-butyl, trityl (-C(Ph)3), methoxymethyl, benzylmethyl, p-nitrophenyl group and R2 represents a Cl-C4 alkyl group.
The compounds of the general formulae (1) and (2) are also novel and are aspects of the present invention as well as their production processes.
21~6I21 DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
(A) A method for preparing a compound of general formula (1).
(I) A compound of general formula (1) (wherein A
and Al are each a substituent at the 4- or 8-position, and A1 is hydrogen or hydroxy when A is hydrogen or A and Ai may form an oxo group) may be prepared by the following reaction:
R~ ~.,, Ns Rt~~..~,, N
I ~?-R2 + XCHz ~ ~ X ----~ ~, I ~~""R2 / ' Nt H
Nt At ~H
At 2 X
imidazole derivatives, which method is simple, does not use toxic or expensive reagents and gives a good yield of the cycloheptimidazole derivatives.
SUMMARY OF THE INVENTION
The inventors have conducted intensive studies, and found a new simple and good yield synthetic method involving a palladium catalyzed cross-coupling reaction.
In accordance with the present invention, a compound of general formula ( 1 ) R~~~_.,~ N
Cc . I ~~R2 A/~~.,'~ N~ (1) X
(wherein Rl is hydrogen or isopropyl; R2 represents a lower alkyl; A and Al are each a substituent at the 4- or 8-position, and Al is hydrogen or hydroxy when A is hydrogen or A and A1 together form an oxo group or =CHCOOR3 (R3 represents a lower alkyl); the dotted line represents two double bonds or saturated single bonds; X is halogen atom or trifluoromethanesulfonate) is reacted with a compound of the following general formula (2):
Y N~N~ ;
J \,N
/ N~Z (2) 21:a 6121 (wherein Y is -B(OH)2 or -Sn(R5)3 (R5 represents a lower alkyl group; and Z is a protecting group for the tetraolyl group) to give the compound of following general formula ( 3 ) F
(3) (wherein the symbols are as defined above), then the compound (3) is deprotected to give the compound of general formula (4):
N
C, , I ~~-R2 I, A' C H
(4) (wherein the symbols are as defined above).
Preferably Z represents tert-butyl, trityl (-C(Ph)3), methoxymethyl, benzylmethyl, p-nitrophenyl group and R2 represents a Cl-C4 alkyl group.
The compounds of the general formulae (1) and (2) are also novel and are aspects of the present invention as well as their production processes.
21~6I21 DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
(A) A method for preparing a compound of general formula (1).
(I) A compound of general formula (1) (wherein A
and Al are each a substituent at the 4- or 8-position, and A1 is hydrogen or hydroxy when A is hydrogen or A and Ai may form an oxo group) may be prepared by the following reaction:
R~ ~.,, Ns Rt~~..~,, N
I ~?-R2 + XCHz ~ ~ X ----~ ~, I ~~""R2 / ' Nt H
Nt At ~H
At 2 X
(5) (6) (1) (wherein Rl, A, Al, R2, X are the same as mentioned above).
The reaction of cycloheptimidazole (5) and halogeno-benzylhalogene compound (6) can be generally carried out in the presence of a base. A base is used in this reaction such as sodium hydride, sodium hydroxide and potassium carbonate.
As a solvent used in this reaction, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetone and dioxane may be employed. Furthermore a phase transfer catalyst such as tetra - n - butylammonium hydrogensulfate is applicable in this reaction and H2G and benzene are used as a solvent. Cycloheptimidazole (5) (the above described) may be prepared by a method described in Japanese Unexamined Patent Publication No. 5-320139 (1993).
(i) The cycloheptimidazole (5) in which A and Al together form an oxo group and the dotted line represents two double bonds, i.e., compounds of general formula (9), are prepared by the following reaction:
Ry O + HN R dil NaOH _ R1 ~ ~ N~ 2 R
/ OTs H2N- 2 ~ N
H
c~
( (wherein Rl is hydrogen or isopropyl; R2 represents a lower alkyl). Tosyl tropolone (7) is reacted with amidine (8) in the presence of a base to yield oxoimidazole (9) (C. A. 74,53785u, Japanese Examined Patent Publication JP-B-45-31,171).
(ii) The cycloheptimidazole (5) in which A and Al are each hydrogen and the dotted line represents single bonds, i.e., compounds of the general formula (12), are prepared by the following reaction:
O (8) EtONa R1~ ~R
+ / N z (10) (11) N
(H) N
H
(12) z~~s~2~
(wherein Rl, R2 are the same as mentioned above).
Methyl tropolone (10) is reacted with amidine (8) in the presence of EtONa to give cycloheptimidazole (11), and (11) is hydrogenated over Pt02 etc, to 1, 4, 5, 6, 7, 8-hexahydro-cycloheptimidazole (12).
(iii) The cycloheptimidazoles (5) in which A and Al together form an oxo group and the dotted line represents single bonds, i.e., compoundsof the general formula (13), are prepared by the following reaction:
N (H) N
'~2 'N N
O H O H
(9) (13) (wherein Rl, R2 are the same as mentioned above).
The oxocycloheptimidazole compound (9) is hydrogenated over Pd/c or Pt02 etc. to give the compound (13).
(iv) The cycloheptimidazole compound (5) in which A
is hydrogen and Al is hydroxyl is obtained from the compound (13) by using a reducing agent such as sodium borohydride and lithium aluminum hydride.
(II) The compounds of general formula (1) (Wherein A
or Al =CHCOOR3 and R3 represents a lower alkyl) are prepared by the following reactions:
_ 7 _ 2~5~1~~
N x_CH2 / \ X R
R y ( \/ R2 N
O H
(13) LiCH2COOR3 (C2H50)2P(O)COOR3 SOCIZ/pyridine (wherein R1, R2, R3, X are the same as mentioned above).
The compound (13) is reacted with p-halogenobenzyl-halogen compound (6) in the presence of a base and a phase transfer catalyst such as tetra - n - butylammonium hydrogen-sulfate to give the compound (14). The obtained compound (14) is reacted witr~ LiCH2COOR3 to give the compound (15), and then followed by the dehydration with SOC12/pyridine to give the compound (16). Also the reaction of the compound (14) with (C2H5O)2P(O)CH2COOR3 in the presence of base gives the compound (16 ) .
(B) A method for preparing a compound of general formula (2) .
(I) Boronic acids of general formula (2) are _ g -prepared by the following reaction:
N~N~ HO~ OOH
I N B N-N
\ N\Z 1) n-BuLi or Mg \ r ~N
N\Z
/ 2) B(OCH3)3 /
3) HZS04 (17) (2a) (wherein X is halogen atom, Z represents protecting group).
The compound of (17) is reacted with n-BuLi or Mg and then added B(OCH3)3 followed by hydrolysis with dilute H2S04 to give the boronic acid (2a). ~(Jikken Kagakukouza (Experimental Chemistry) 24, Yuukigousei (Organic Synthesis) VI, Maruzen (KK), Japan, 1992, P. 61-90.) (II) Tin compounds of general formula (2) are prepared by the following reaction:
Sn(R5)s N
N' \ N~Z ~ ~ ~N
1 ) n-BuLi / N Z
2) Sn(R5)3Ci (17) (2b) (wherein X is halogen atom, Z represents protecting group, R5 represents a lower alkyl group).
The compound (17) is reacted with n-BuLi and then Sn(R5)3C1 to give the tin compound (2b).
21~612~.
(C) A method for preparing a compound of general formula (3).
In accordance with the present invention, the compound of general formula (1) is reacted with the compound of general formula (2) to give the compound of general formula (3).
(I) In the case of Y is -B(OH)2 in the compound of general formula (2), the compound of the general formula (1) is reacted with the compound of the general formula (2) in the presence of a base and a catalyst to give the compound of the general formula (3). (Suzuki; Synthetic Communication, 11(7), 513 (1981).) The catalyst used in this reaction may be a palladium catalyst, such as Pd(PPh3)4, PdCl2 and Pd/C. The base used in this reaction is for example sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
A solvent may be used in this reaction such as water, ethanol, methanol, benzene and toluene. The reaction is conducted preferably at room temperature or at a temperature at which the solvent refluxes.
(II) In the case of Y is -Sn(R5)3 (wherein R5 is a lower alkyl group) in the compound of general formula (2), the compound of the general formula (1) is reacted with the compound of the general formula (2) in the presence of a catalyst to give the compound of the general formula (3).
(Shille; Angew. Chem. Int. Ed. Engl, 25, 508-524 (1988).) The catalyst used in this reaction may be a palladium, copper or lithium catalyst such as Pd(PPh3)4, PdCl2, Pd/C, CuI and LiCl. A solvent may be used in this reaction such as tetra-2.~~6I~~
hydrofuran (THF), dimethoxyethane (DME) and dimethyl formamide (DMF). The reaction is conducted preferably at room temperature or at a temperature at which the solvent refluxes.
(D) Deprotection.
The compound of the general formula (3) is deprotected with a strong acid such as HC1 and CH3S03H in benzene or toluene at reflux to give the object compound (4).
For better understanding the present invention, the following working examples are presented. By no means, however, the present invention should not be considered to be restricted to these working examples.
Example 1:
5-[2-4-(2-Propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methylbiphenylyl)]tetrazole.
(a) 1-(4-Iodobenzyl)-2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
2-Propyl-8-oxo-4,5,6,7-tetrahydro-cycloheptimidazole (S.Og) was dissolved in toluene (150m1) and 30~ NaOH aqueous solution (60m1) was added. The mixture was stirred at room temperature for 30 min. 4-Iodobenzylbromide (9.2g) and tetra-n-butylammonium hydrogensulfate (2.Og) were then added and the reaction mixture was stirred at room temperature for 8hrs.
The solution was filtered, and the filtrate was extracted with ethyl acetate (50m1x2), and the organic layer was washed with water and brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography (Si02 120g). Elution was carried out with n-hexane/ethyl acetate (1/1). The object compound was obtained as a yellow color crystal (8.69g): mp (°C) 64-65; Mass (m/e):
M+=408, 217 (BP): IR (cm 1): 2926, 1632, 1464, 1428. 1H-NMR
(CDC13): 0.95 (3H, t, -CH2CH2CH3), 1.70 (2H, m, -CH2CH2CH3), 1.87 (2H, m, Cyclo), 1.92 (2H, m, Cyclo), 2.58 (2H, m, Cyclo), 2.65 (2H, m, Cyclo), 2.96 (2H, t, -CH2CH2CH3), 5.47 (2H, s, -CH2-C6H5), 6.71 (2H, d, aromatic), 7.62 (2H, d, aromatic).
(b) 2-tertrButyl-5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methylbiphenyl)]tetrazole.
A solution of the compound (150mg) which was obtained by the method as described above (a) in toluene (lOml) and ethanol (lml) was added to [2-(2-tert-butyl-2H-tetrazol-5-yl)-phenyl] boronic acid (96mg) (example 3), Pd(PPh3)4 (35mg) and 2M Na2C03 (0.7m1). The mixture was stirred at reflux for 3 hrs.
The solution was concentrated under vacuum. The resulting product was purified by silica gel column chromatography.
Elution was carried out with ethyl acetate/n-hexane (10:1).
The object compound was obtained as a yellow color oil. IR
(cm 1): 2926, 1632, 1464, 1428. Mass (m/e) . M+=482, 426,178 (BP). 1H-NMR (CDC13): 0.96 (3H, t, -CH2CH2CH3), 1.55 (9H, s, -(CH3)3), 1.75 (2H, m, -CH2CH2CH3), 1.802.00 (4H, m, Cyclo), 2.59 (2H, t, Cyclo), 2.68 (2H, m, Cyclo), 3.01 (2H, q, -CH2CH2CH3), 5.57 (2H, s, -CH2C6H5), 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)methylbiphenylyl)Jtetrazole.
A solution of the compound (100mg) which was obtained by the method as described above (b) in toluene lOml and methanesulfonic acid (200mg) was refluxed for 3hrs. The solution was concentrated under vacuum, and poured into ice water. The aqueous solution was adjusted pH8 with 10~ NaOH.
The resulting precipitate was collected by filtration, and was recrystallized with ethanol. The product was obtained as white crystal (77.4mg): mp (°C) 214-216; Mass (m/e):
M+=426, 383, 355, 178 (BP), 152. 1H-NMR (CDC13): 0.90 (3H, t, -CH2CH2CH3), 1.58 (2H, m, -CH2CH2CH3), 1.68~(2H, m, Cyclo), 1.75 (2H, m, Cyclo), 2.30 (2H, m, Cyclo), 2.47 (2H, m, Cyclo), 2.53 (2H, t, -CH2CH2CH3), 5.45 (2H, s, -CH2C6H5), 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)methylbiphenylyl)]tetrazole.
To a solution of 1-(4-iodobenzyl)-2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole (100mg) which was prepared in a similar manner as described in step (a) of Example land 2-(2-tert.-butyl-2H-tetrazol-5-yl)phenyl]tri-n-butylstanano (120mg) (Example 4) in THF 8m1, added were lithium chloride (31.15mg) and Pd(PPh3)4 l.4mg. The reaction mixture was refluxed for 48hrs. The reaction mixture was filtered, and filtrate was concentrated under vacuum. After the addition of ethyl acetate, the mixture was washed with brine, dried (Na2S04), filtered, and organic solvent was evaporated under vacuum. The resulting oil was purified by silica gel column chromatography eluting with ethyl acetate/n-2~ i6l~I
hexane (1/1), 2-tert.-butyl-5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methylbiphenylyl)]tetrazole was obtained as a yellow oil (45mg): Mass (m/e): M+=482, 426, 369, 178 (BP). IR (cm 1): 2926, 1632, 1464, 1428, 1389.
1H-NMR (CDC13): 0.96 (3H, t, -CH2CH2CH3), 1.55 (9H, s, -(CH3)3)' 1.74 (2H, m, -CH2CH2CH3), 1.802.00 (4H, m, Cyclo), 2.59 (2H, t, Cyclo), 2.68 (2H, m, Cyclo), 3.01 (2H, q' -CH2CH2CH3), 5.57 (2H, s, -CH2C6H5), 6.90 (2H, d, aromatic), 7.09 (2H, d, aromatic), 7.35-..7.60 (3H, m, aromatic), 7.89 (2H, d, aromatic).
According to the procedure described in Example 1, tert.-butyl group of 2-tert.-butyl-5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl]methylbiphenylyl)]-tetrazole was deprotected to give the target compound of 5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)-methylbiprenylyl)]tetrazole.
Example 3:
[2-(2-tert.-Butyl-2H-tetrazole-5-yl)phenyl] boronic acid.
To a cooled (-78°C) solution of 5-(2-brornophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (3.3g) in THF (20m1) was added 1.6M n-BuLi in hexane (7.80m1) and triisopropyl borate (2.30g) was added. The cooling bath was removed, and the mixture was stirred at room temperature for lh. HC1 (0.5N) was added, and the mixture was stirred vigorously for 30min.
The layers were separated, and the aqueous phase was extracted with ether. The combined organic phases were extracted with 1N KOH (3x10m1). The aqueous extracts were acidified (pHl) with 2N HC1 (20m1), and the precipitate was collected by 21~612~
filtration to give 1.878 of the boronic acid as a white solid:
mp=117-~~~122°C. 1H-NMR (CDC13): 1.72 (9H, s, -C(CH3)3), 7.46 (2H, m, aromatic), 7.90 (2H, m, aromatic).
Example 4:
[2-(2-tert.-Butyl-2H-tetrazole-5-yl)phenyl] tri-n-butylstanane.
To a cooled (-78°C) solution of 5-(2-bromophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (1.23g) in THF 8m1 was added to 1.6M n-BuLi in hexane (3.27m1). After lh., tri-n-butyltin chloride (1.71g) was added, and stirring was continued for 3hr at -78°C. The mixture was warmed to room temperature and stirred for 18h. Water was added, and the mixture was extracted with ether (30m1x2). The combined extracts were washed with water and brine, dried, and concentrated. The resulting oil was purified by silica gel column chromatography eluting with n-hexane, the butylstanane was obtained as a yellow oil (l.Og). 1H-NMR (CDC13): 0.78 (9H, t, -(CH3)3), 0.93 (6H, t, - (CH2-) 3 ) , 1. 21 (6H, m, - (CH2-) 3) , 1. 43 (6H, m, - (CH2-) 3) ' 1.80 (9H, s, (CH3)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-ethoxycarbonylmethylidene-1-[(2'-1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole.
(a) 1-(4-Bromobenzyl)-2-ethyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
2-Ethyl-8-oxo-4,5,6,7-tetrahydro-cycloheptimidazole (2.5g) was dissolved in toluene (50m1) and 30~ NaOH aqueous solution (30m1) was added. The mixture was stirred at room temperature for 30min. 4-Bromobenzylbromide (3.6g) and tetra-n-butylammonium hydrogensulfate (0.5g) were then added and the reaction mixture was stirred at room temperature for 8hrs.
The solution was filtered, and filtrate was extracted with ethyl acetate (20m1x2), and the organic layer was washed with water and brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography (Si02 100g). Elution was carried out witr. n-hexane/ethyl acetate (1/1). The object compound was obtained as a yellow color oil (4.Og). Mass (m/e): M+=347, 319, 169 (BP). IR (cm 1): 2950, 1640, 1480, 1400, 1330.
1H-NMR (CDC13): 1.27 (3H, t, -CH2CH3), 1.85 1.87 (2H, m, Cyclo), 1.91~1.94 (2H, m, Cyclo), 2.602.65 (4H, m, Cyclo), 3.01 (2H, q, CH2CH3), 5.48 (2H, s, -CH2C6H4), 6.86 (2H, d, aromatic), 7.41 (2H, d, aromatic).
(b) 1-(4-Bromobenzyl)-2-ethyl-8-ethoxycarbonylmethyl-8-hydroxy-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
To a solution of (Me3Si)2NLi (2.88m1) in THF (5m1) was added dry ethyl acetate (0.25m1) at -78°C, and the mixture was stirred for l5min. Then compound (0.5g) which was prepared by Example 5 (a) in dry THF was dropwised. The reaction mixture was stirred at -78°C for lh, and treated with 6N HC1 to adjust the pH5Ø The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography. Elution was carried out with chloroform/-~~~s12~
methanol (20/1). The object compound was obtained as a yellow oil (388mg). Mass (m/e): M+=435, 348, 169 (BP), 90. IR (cm 1):
3300, 2900, 1720, 1170, 1000. 1H-NMR (CDC13): 1.28 (3H, t, -CH2CH3), 1.33 (3H, t, -CH2CH3), 1.80 ~2.20 (6H, m, Cyclo), 2.71 (2H, m, -CH2COOEt), 2.78 (2H, q, -CH2CH3), 2.97 (2H, m, Cyclo), 4.57 (2H, q, -CH2CH3), 5.81 (2H, s, -CH2C6H5), 7.20 "~
7.40 (4H, m, aromatic).
(c) 1-(4-Bromobenzyl)-2-ethyl-8-ethoxycarbonyl-methylidene-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
(1) 1-(4-Bromobenzyl)-2-ethyl-8-ethoxycarbonyl-methyl-8-hydroxy-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole (0.38g) which was prepared in step (b) of Example 5 was dissolved in pyridine (2m1), and SOC12 (0.32g) was added thereto, and the mixture was stirred at room temperature for lh. The reaction mixture was poured into 10~ HC1 (20m1) at 0°C, and extracted with ethyl acetate, and ethyl acetate layer was washed with brine and dried (Na2S04 ) , filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography. Elution was carried out with chloroform/-methanol (20/1). The object compound was obtained as a yellow oil (280mg).
(2) KH (0.08g) was dissolved in THF 5m1, and then diethyl phosphonoacetate (0.37g) was added at 5°C. After the mixture was stirred at 10°C for lOmin, 1-(4-bromobenzyl)-2-ethyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole (0.5g) in THF lml which was prepared in step (a) of Example 5 was added. The mixture was stirred at 40°C for 5hrs. The reaction mixture was poured into ice water (20m1), and extracted ~~~s~
with ethyl acetate. The organic layer was washed with water and then brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography. Elution was carried out with chloroform/methanol (20/1). The object compound was obtained as a yellow color oil (60mg). Mass (m/e): M++1=418, 371, 343, 171 (BP), 90. IR (cm 1): 2900, 1710, 1230, 1170, 1000.
1H-NMR (CDC13): 1.26 (3H, t, -CH2CH3), 1.26 (3H, t, -CH2CH3), 1.85 (2H, m, Cyclo), 1.90 (2H, m, Cyclo), 2.91 (2H, q, CH2CH3), 2.92 (2H, q, CH2CH3), 4.054.20 (4H, m, Cyclo), 5.28 (2H, s, -CH2C6H5), 5.68 (1H, s, =CHCOOC2H5), 6.80 (2H, d, aromatic), 7.55 (2H, d, aromatic).
(d) 2-tert.-Butyl-5-[2-(4-(2-ethyl-8-ethoxycarbonyl-methylidene-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methyl-biphenylyl)]tetrazole.
To a solution of the compound (280mg) which was prepared by Example 5 (c) in toluene (5m1) and ethanol (O.lml), added were [2-(2-tert.-butyl-2H-tetrazole-5-yl)phenyl] boronic acid (175.5mg), Pd(PPh3)4 (26.8mg) and 2M Na2C03 (1.6m1). The mixture was stirred at reflux for 4.5hrs. The reaction mixture was poured into water (30m1), and extracted with toluene (20m1x3) , and toluene layer was washed with brine and dried (Na2S04)' filtered, and concentrated under vacuum. The resulting product was purified with silica gel column chromatography. Elution was carried out with ethyl acetate/n-hexane (1/1). The object compound was obtained as a yellow oil (230mg). Mass (m/e):
M++1=539, 451, 253, 178 (BP). IR (cm 1): 3420, 3000, 1230, 2950, 1720. 1H-NMR (CDC13): 1.25 (3H, s, t-Bu), 1.82 (2H, m, ~~~6121 Cyclo), 1.89 (2H, m, Cyclo), 2.55 (2H, q,'-CH2CH3), 2.80-2.83 (2H, m, Cyclo), 3.04~~3.07 (2H, m, Cyclo), 4.12 (2H, q, -CH2CH3), 5.17 (2H, s, -CH2C6H5), 5.56 (1H, s, =CHCOOC2H5), 6.82 (2H, d, aromatic), 7.14 (2H, d, aromatic), 7.39-~-7.88 (4H, m, aromatic).
(e) 2-Ethyl-8-carboxymethylidene-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole.
A solution of the compound (200mg) which was obtained by the Example 5 (d) as described above in toluene 20m1 and methanesulfonic acid (400mg) was refluxed for 3hrs.
The solution was concentrated under vacuum, and poured into ice water. The aqueous solution was adjusted pH4 with 10$
NaOH. The resulting precipitate was collected by filtration, and was recrystallized with methanol (2m1). The product was obtained as white crystal (120mg). mp: 191~193°C. Mass (m/e): M+=408 (M+-COOH), 367, 192 (BP), 134. IR (cm 1):
2914, 1692, 1611, 1452, 1362, 1197. 1H-NMR (CD30D): 1.30 (3H, t, -CH2CH3), 1.94 (4H, bs, Cyclo), 2.65-3.03 (6H, m, -CH2CH3+Cyclo), 5.43 (2H, s, -CH2C6H5), 5.92 (1H, s, =CHCOOH), 6.80~J7.70 (8H, m, aromatic), 7.96 (1H, s, -NH).
The reaction of cycloheptimidazole (5) and halogeno-benzylhalogene compound (6) can be generally carried out in the presence of a base. A base is used in this reaction such as sodium hydride, sodium hydroxide and potassium carbonate.
As a solvent used in this reaction, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetone and dioxane may be employed. Furthermore a phase transfer catalyst such as tetra - n - butylammonium hydrogensulfate is applicable in this reaction and H2G and benzene are used as a solvent. Cycloheptimidazole (5) (the above described) may be prepared by a method described in Japanese Unexamined Patent Publication No. 5-320139 (1993).
(i) The cycloheptimidazole (5) in which A and Al together form an oxo group and the dotted line represents two double bonds, i.e., compounds of general formula (9), are prepared by the following reaction:
Ry O + HN R dil NaOH _ R1 ~ ~ N~ 2 R
/ OTs H2N- 2 ~ N
H
c~
( (wherein Rl is hydrogen or isopropyl; R2 represents a lower alkyl). Tosyl tropolone (7) is reacted with amidine (8) in the presence of a base to yield oxoimidazole (9) (C. A. 74,53785u, Japanese Examined Patent Publication JP-B-45-31,171).
(ii) The cycloheptimidazole (5) in which A and Al are each hydrogen and the dotted line represents single bonds, i.e., compounds of the general formula (12), are prepared by the following reaction:
O (8) EtONa R1~ ~R
+ / N z (10) (11) N
(H) N
H
(12) z~~s~2~
(wherein Rl, R2 are the same as mentioned above).
Methyl tropolone (10) is reacted with amidine (8) in the presence of EtONa to give cycloheptimidazole (11), and (11) is hydrogenated over Pt02 etc, to 1, 4, 5, 6, 7, 8-hexahydro-cycloheptimidazole (12).
(iii) The cycloheptimidazoles (5) in which A and Al together form an oxo group and the dotted line represents single bonds, i.e., compoundsof the general formula (13), are prepared by the following reaction:
N (H) N
'~2 'N N
O H O H
(9) (13) (wherein Rl, R2 are the same as mentioned above).
The oxocycloheptimidazole compound (9) is hydrogenated over Pd/c or Pt02 etc. to give the compound (13).
(iv) The cycloheptimidazole compound (5) in which A
is hydrogen and Al is hydroxyl is obtained from the compound (13) by using a reducing agent such as sodium borohydride and lithium aluminum hydride.
(II) The compounds of general formula (1) (Wherein A
or Al =CHCOOR3 and R3 represents a lower alkyl) are prepared by the following reactions:
_ 7 _ 2~5~1~~
N x_CH2 / \ X R
R y ( \/ R2 N
O H
(13) LiCH2COOR3 (C2H50)2P(O)COOR3 SOCIZ/pyridine (wherein R1, R2, R3, X are the same as mentioned above).
The compound (13) is reacted with p-halogenobenzyl-halogen compound (6) in the presence of a base and a phase transfer catalyst such as tetra - n - butylammonium hydrogen-sulfate to give the compound (14). The obtained compound (14) is reacted witr~ LiCH2COOR3 to give the compound (15), and then followed by the dehydration with SOC12/pyridine to give the compound (16). Also the reaction of the compound (14) with (C2H5O)2P(O)CH2COOR3 in the presence of base gives the compound (16 ) .
(B) A method for preparing a compound of general formula (2) .
(I) Boronic acids of general formula (2) are _ g -prepared by the following reaction:
N~N~ HO~ OOH
I N B N-N
\ N\Z 1) n-BuLi or Mg \ r ~N
N\Z
/ 2) B(OCH3)3 /
3) HZS04 (17) (2a) (wherein X is halogen atom, Z represents protecting group).
The compound of (17) is reacted with n-BuLi or Mg and then added B(OCH3)3 followed by hydrolysis with dilute H2S04 to give the boronic acid (2a). ~(Jikken Kagakukouza (Experimental Chemistry) 24, Yuukigousei (Organic Synthesis) VI, Maruzen (KK), Japan, 1992, P. 61-90.) (II) Tin compounds of general formula (2) are prepared by the following reaction:
Sn(R5)s N
N' \ N~Z ~ ~ ~N
1 ) n-BuLi / N Z
2) Sn(R5)3Ci (17) (2b) (wherein X is halogen atom, Z represents protecting group, R5 represents a lower alkyl group).
The compound (17) is reacted with n-BuLi and then Sn(R5)3C1 to give the tin compound (2b).
21~612~.
(C) A method for preparing a compound of general formula (3).
In accordance with the present invention, the compound of general formula (1) is reacted with the compound of general formula (2) to give the compound of general formula (3).
(I) In the case of Y is -B(OH)2 in the compound of general formula (2), the compound of the general formula (1) is reacted with the compound of the general formula (2) in the presence of a base and a catalyst to give the compound of the general formula (3). (Suzuki; Synthetic Communication, 11(7), 513 (1981).) The catalyst used in this reaction may be a palladium catalyst, such as Pd(PPh3)4, PdCl2 and Pd/C. The base used in this reaction is for example sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.
A solvent may be used in this reaction such as water, ethanol, methanol, benzene and toluene. The reaction is conducted preferably at room temperature or at a temperature at which the solvent refluxes.
(II) In the case of Y is -Sn(R5)3 (wherein R5 is a lower alkyl group) in the compound of general formula (2), the compound of the general formula (1) is reacted with the compound of the general formula (2) in the presence of a catalyst to give the compound of the general formula (3).
(Shille; Angew. Chem. Int. Ed. Engl, 25, 508-524 (1988).) The catalyst used in this reaction may be a palladium, copper or lithium catalyst such as Pd(PPh3)4, PdCl2, Pd/C, CuI and LiCl. A solvent may be used in this reaction such as tetra-2.~~6I~~
hydrofuran (THF), dimethoxyethane (DME) and dimethyl formamide (DMF). The reaction is conducted preferably at room temperature or at a temperature at which the solvent refluxes.
(D) Deprotection.
The compound of the general formula (3) is deprotected with a strong acid such as HC1 and CH3S03H in benzene or toluene at reflux to give the object compound (4).
For better understanding the present invention, the following working examples are presented. By no means, however, the present invention should not be considered to be restricted to these working examples.
Example 1:
5-[2-4-(2-Propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methylbiphenylyl)]tetrazole.
(a) 1-(4-Iodobenzyl)-2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
2-Propyl-8-oxo-4,5,6,7-tetrahydro-cycloheptimidazole (S.Og) was dissolved in toluene (150m1) and 30~ NaOH aqueous solution (60m1) was added. The mixture was stirred at room temperature for 30 min. 4-Iodobenzylbromide (9.2g) and tetra-n-butylammonium hydrogensulfate (2.Og) were then added and the reaction mixture was stirred at room temperature for 8hrs.
The solution was filtered, and the filtrate was extracted with ethyl acetate (50m1x2), and the organic layer was washed with water and brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography (Si02 120g). Elution was carried out with n-hexane/ethyl acetate (1/1). The object compound was obtained as a yellow color crystal (8.69g): mp (°C) 64-65; Mass (m/e):
M+=408, 217 (BP): IR (cm 1): 2926, 1632, 1464, 1428. 1H-NMR
(CDC13): 0.95 (3H, t, -CH2CH2CH3), 1.70 (2H, m, -CH2CH2CH3), 1.87 (2H, m, Cyclo), 1.92 (2H, m, Cyclo), 2.58 (2H, m, Cyclo), 2.65 (2H, m, Cyclo), 2.96 (2H, t, -CH2CH2CH3), 5.47 (2H, s, -CH2-C6H5), 6.71 (2H, d, aromatic), 7.62 (2H, d, aromatic).
(b) 2-tertrButyl-5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methylbiphenyl)]tetrazole.
A solution of the compound (150mg) which was obtained by the method as described above (a) in toluene (lOml) and ethanol (lml) was added to [2-(2-tert-butyl-2H-tetrazol-5-yl)-phenyl] boronic acid (96mg) (example 3), Pd(PPh3)4 (35mg) and 2M Na2C03 (0.7m1). The mixture was stirred at reflux for 3 hrs.
The solution was concentrated under vacuum. The resulting product was purified by silica gel column chromatography.
Elution was carried out with ethyl acetate/n-hexane (10:1).
The object compound was obtained as a yellow color oil. IR
(cm 1): 2926, 1632, 1464, 1428. Mass (m/e) . M+=482, 426,178 (BP). 1H-NMR (CDC13): 0.96 (3H, t, -CH2CH2CH3), 1.55 (9H, s, -(CH3)3), 1.75 (2H, m, -CH2CH2CH3), 1.802.00 (4H, m, Cyclo), 2.59 (2H, t, Cyclo), 2.68 (2H, m, Cyclo), 3.01 (2H, q, -CH2CH2CH3), 5.57 (2H, s, -CH2C6H5), 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)methylbiphenylyl)Jtetrazole.
A solution of the compound (100mg) which was obtained by the method as described above (b) in toluene lOml and methanesulfonic acid (200mg) was refluxed for 3hrs. The solution was concentrated under vacuum, and poured into ice water. The aqueous solution was adjusted pH8 with 10~ NaOH.
The resulting precipitate was collected by filtration, and was recrystallized with ethanol. The product was obtained as white crystal (77.4mg): mp (°C) 214-216; Mass (m/e):
M+=426, 383, 355, 178 (BP), 152. 1H-NMR (CDC13): 0.90 (3H, t, -CH2CH2CH3), 1.58 (2H, m, -CH2CH2CH3), 1.68~(2H, m, Cyclo), 1.75 (2H, m, Cyclo), 2.30 (2H, m, Cyclo), 2.47 (2H, m, Cyclo), 2.53 (2H, t, -CH2CH2CH3), 5.45 (2H, s, -CH2C6H5), 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)methylbiphenylyl)]tetrazole.
To a solution of 1-(4-iodobenzyl)-2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole (100mg) which was prepared in a similar manner as described in step (a) of Example land 2-(2-tert.-butyl-2H-tetrazol-5-yl)phenyl]tri-n-butylstanano (120mg) (Example 4) in THF 8m1, added were lithium chloride (31.15mg) and Pd(PPh3)4 l.4mg. The reaction mixture was refluxed for 48hrs. The reaction mixture was filtered, and filtrate was concentrated under vacuum. After the addition of ethyl acetate, the mixture was washed with brine, dried (Na2S04), filtered, and organic solvent was evaporated under vacuum. The resulting oil was purified by silica gel column chromatography eluting with ethyl acetate/n-2~ i6l~I
hexane (1/1), 2-tert.-butyl-5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methylbiphenylyl)]tetrazole was obtained as a yellow oil (45mg): Mass (m/e): M+=482, 426, 369, 178 (BP). IR (cm 1): 2926, 1632, 1464, 1428, 1389.
1H-NMR (CDC13): 0.96 (3H, t, -CH2CH2CH3), 1.55 (9H, s, -(CH3)3)' 1.74 (2H, m, -CH2CH2CH3), 1.802.00 (4H, m, Cyclo), 2.59 (2H, t, Cyclo), 2.68 (2H, m, Cyclo), 3.01 (2H, q' -CH2CH2CH3), 5.57 (2H, s, -CH2C6H5), 6.90 (2H, d, aromatic), 7.09 (2H, d, aromatic), 7.35-..7.60 (3H, m, aromatic), 7.89 (2H, d, aromatic).
According to the procedure described in Example 1, tert.-butyl group of 2-tert.-butyl-5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl]methylbiphenylyl)]-tetrazole was deprotected to give the target compound of 5-[2-(4-(2-propyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)-methylbiprenylyl)]tetrazole.
Example 3:
[2-(2-tert.-Butyl-2H-tetrazole-5-yl)phenyl] boronic acid.
To a cooled (-78°C) solution of 5-(2-brornophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (3.3g) in THF (20m1) was added 1.6M n-BuLi in hexane (7.80m1) and triisopropyl borate (2.30g) was added. The cooling bath was removed, and the mixture was stirred at room temperature for lh. HC1 (0.5N) was added, and the mixture was stirred vigorously for 30min.
The layers were separated, and the aqueous phase was extracted with ether. The combined organic phases were extracted with 1N KOH (3x10m1). The aqueous extracts were acidified (pHl) with 2N HC1 (20m1), and the precipitate was collected by 21~612~
filtration to give 1.878 of the boronic acid as a white solid:
mp=117-~~~122°C. 1H-NMR (CDC13): 1.72 (9H, s, -C(CH3)3), 7.46 (2H, m, aromatic), 7.90 (2H, m, aromatic).
Example 4:
[2-(2-tert.-Butyl-2H-tetrazole-5-yl)phenyl] tri-n-butylstanane.
To a cooled (-78°C) solution of 5-(2-bromophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (1.23g) in THF 8m1 was added to 1.6M n-BuLi in hexane (3.27m1). After lh., tri-n-butyltin chloride (1.71g) was added, and stirring was continued for 3hr at -78°C. The mixture was warmed to room temperature and stirred for 18h. Water was added, and the mixture was extracted with ether (30m1x2). The combined extracts were washed with water and brine, dried, and concentrated. The resulting oil was purified by silica gel column chromatography eluting with n-hexane, the butylstanane was obtained as a yellow oil (l.Og). 1H-NMR (CDC13): 0.78 (9H, t, -(CH3)3), 0.93 (6H, t, - (CH2-) 3 ) , 1. 21 (6H, m, - (CH2-) 3) , 1. 43 (6H, m, - (CH2-) 3) ' 1.80 (9H, s, (CH3)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-ethoxycarbonylmethylidene-1-[(2'-1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole.
(a) 1-(4-Bromobenzyl)-2-ethyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
2-Ethyl-8-oxo-4,5,6,7-tetrahydro-cycloheptimidazole (2.5g) was dissolved in toluene (50m1) and 30~ NaOH aqueous solution (30m1) was added. The mixture was stirred at room temperature for 30min. 4-Bromobenzylbromide (3.6g) and tetra-n-butylammonium hydrogensulfate (0.5g) were then added and the reaction mixture was stirred at room temperature for 8hrs.
The solution was filtered, and filtrate was extracted with ethyl acetate (20m1x2), and the organic layer was washed with water and brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography (Si02 100g). Elution was carried out witr. n-hexane/ethyl acetate (1/1). The object compound was obtained as a yellow color oil (4.Og). Mass (m/e): M+=347, 319, 169 (BP). IR (cm 1): 2950, 1640, 1480, 1400, 1330.
1H-NMR (CDC13): 1.27 (3H, t, -CH2CH3), 1.85 1.87 (2H, m, Cyclo), 1.91~1.94 (2H, m, Cyclo), 2.602.65 (4H, m, Cyclo), 3.01 (2H, q, CH2CH3), 5.48 (2H, s, -CH2C6H4), 6.86 (2H, d, aromatic), 7.41 (2H, d, aromatic).
(b) 1-(4-Bromobenzyl)-2-ethyl-8-ethoxycarbonylmethyl-8-hydroxy-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
To a solution of (Me3Si)2NLi (2.88m1) in THF (5m1) was added dry ethyl acetate (0.25m1) at -78°C, and the mixture was stirred for l5min. Then compound (0.5g) which was prepared by Example 5 (a) in dry THF was dropwised. The reaction mixture was stirred at -78°C for lh, and treated with 6N HC1 to adjust the pH5Ø The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography. Elution was carried out with chloroform/-~~~s12~
methanol (20/1). The object compound was obtained as a yellow oil (388mg). Mass (m/e): M+=435, 348, 169 (BP), 90. IR (cm 1):
3300, 2900, 1720, 1170, 1000. 1H-NMR (CDC13): 1.28 (3H, t, -CH2CH3), 1.33 (3H, t, -CH2CH3), 1.80 ~2.20 (6H, m, Cyclo), 2.71 (2H, m, -CH2COOEt), 2.78 (2H, q, -CH2CH3), 2.97 (2H, m, Cyclo), 4.57 (2H, q, -CH2CH3), 5.81 (2H, s, -CH2C6H5), 7.20 "~
7.40 (4H, m, aromatic).
(c) 1-(4-Bromobenzyl)-2-ethyl-8-ethoxycarbonyl-methylidene-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole.
(1) 1-(4-Bromobenzyl)-2-ethyl-8-ethoxycarbonyl-methyl-8-hydroxy-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole (0.38g) which was prepared in step (b) of Example 5 was dissolved in pyridine (2m1), and SOC12 (0.32g) was added thereto, and the mixture was stirred at room temperature for lh. The reaction mixture was poured into 10~ HC1 (20m1) at 0°C, and extracted with ethyl acetate, and ethyl acetate layer was washed with brine and dried (Na2S04 ) , filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography. Elution was carried out with chloroform/-methanol (20/1). The object compound was obtained as a yellow oil (280mg).
(2) KH (0.08g) was dissolved in THF 5m1, and then diethyl phosphonoacetate (0.37g) was added at 5°C. After the mixture was stirred at 10°C for lOmin, 1-(4-bromobenzyl)-2-ethyl-8-oxo-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazole (0.5g) in THF lml which was prepared in step (a) of Example 5 was added. The mixture was stirred at 40°C for 5hrs. The reaction mixture was poured into ice water (20m1), and extracted ~~~s~
with ethyl acetate. The organic layer was washed with water and then brine and dried (Na2S04), filtered, and concentrated under vacuum. The resulting product was purified by silica gel column chromatography. Elution was carried out with chloroform/methanol (20/1). The object compound was obtained as a yellow color oil (60mg). Mass (m/e): M++1=418, 371, 343, 171 (BP), 90. IR (cm 1): 2900, 1710, 1230, 1170, 1000.
1H-NMR (CDC13): 1.26 (3H, t, -CH2CH3), 1.26 (3H, t, -CH2CH3), 1.85 (2H, m, Cyclo), 1.90 (2H, m, Cyclo), 2.91 (2H, q, CH2CH3), 2.92 (2H, q, CH2CH3), 4.054.20 (4H, m, Cyclo), 5.28 (2H, s, -CH2C6H5), 5.68 (1H, s, =CHCOOC2H5), 6.80 (2H, d, aromatic), 7.55 (2H, d, aromatic).
(d) 2-tert.-Butyl-5-[2-(4-(2-ethyl-8-ethoxycarbonyl-methylidene-4,5,6,7-tetrahydro-1(4H)-cycloheptimidazolyl)methyl-biphenylyl)]tetrazole.
To a solution of the compound (280mg) which was prepared by Example 5 (c) in toluene (5m1) and ethanol (O.lml), added were [2-(2-tert.-butyl-2H-tetrazole-5-yl)phenyl] boronic acid (175.5mg), Pd(PPh3)4 (26.8mg) and 2M Na2C03 (1.6m1). The mixture was stirred at reflux for 4.5hrs. The reaction mixture was poured into water (30m1), and extracted with toluene (20m1x3) , and toluene layer was washed with brine and dried (Na2S04)' filtered, and concentrated under vacuum. The resulting product was purified with silica gel column chromatography. Elution was carried out with ethyl acetate/n-hexane (1/1). The object compound was obtained as a yellow oil (230mg). Mass (m/e):
M++1=539, 451, 253, 178 (BP). IR (cm 1): 3420, 3000, 1230, 2950, 1720. 1H-NMR (CDC13): 1.25 (3H, s, t-Bu), 1.82 (2H, m, ~~~6121 Cyclo), 1.89 (2H, m, Cyclo), 2.55 (2H, q,'-CH2CH3), 2.80-2.83 (2H, m, Cyclo), 3.04~~3.07 (2H, m, Cyclo), 4.12 (2H, q, -CH2CH3), 5.17 (2H, s, -CH2C6H5), 5.56 (1H, s, =CHCOOC2H5), 6.82 (2H, d, aromatic), 7.14 (2H, d, aromatic), 7.39-~-7.88 (4H, m, aromatic).
(e) 2-Ethyl-8-carboxymethylidene-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole.
A solution of the compound (200mg) which was obtained by the Example 5 (d) as described above in toluene 20m1 and methanesulfonic acid (400mg) was refluxed for 3hrs.
The solution was concentrated under vacuum, and poured into ice water. The aqueous solution was adjusted pH4 with 10$
NaOH. The resulting precipitate was collected by filtration, and was recrystallized with methanol (2m1). The product was obtained as white crystal (120mg). mp: 191~193°C. Mass (m/e): M+=408 (M+-COOH), 367, 192 (BP), 134. IR (cm 1):
2914, 1692, 1611, 1452, 1362, 1197. 1H-NMR (CD30D): 1.30 (3H, t, -CH2CH3), 1.94 (4H, bs, Cyclo), 2.65-3.03 (6H, m, -CH2CH3+Cyclo), 5.43 (2H, s, -CH2C6H5), 5.92 (1H, s, =CHCOOH), 6.80~J7.70 (8H, m, aromatic), 7.96 (1H, s, -NH).
Claims (8)
1. A process which comprises:
reacting a compound of the general formula (1):
(wherein R1 is hydrogen or isopropyl; R2 is a lower alkyl; A and A1 are each a substituent at the 4- or 8-position, and A1 is hydrogen or hydroxyl when A is hydrogen, or A and A1 together form an oxo group or =CHCOOR3 (in which R3 is a lower alkyl); the dotted line represents two double bonds or saturated single bonds; and X is halogen atom or trifluoro-methanesulfonate) with a compound of the general formula (2):
(wherein Y is -B(OH)2 or -Sn(R5)3(in which R5 is a lower alkyl); and Z is a protecting group), to give a compound of the general formula (3):
(wherein R1, R2, A, A1, the dotted line and Z are as defined above), and then deprotecting the compound (3) to give a compound of the general formula (4):
(wherein R1, R2, A, A1 and the dotted line are as defined above).
reacting a compound of the general formula (1):
(wherein R1 is hydrogen or isopropyl; R2 is a lower alkyl; A and A1 are each a substituent at the 4- or 8-position, and A1 is hydrogen or hydroxyl when A is hydrogen, or A and A1 together form an oxo group or =CHCOOR3 (in which R3 is a lower alkyl); the dotted line represents two double bonds or saturated single bonds; and X is halogen atom or trifluoro-methanesulfonate) with a compound of the general formula (2):
(wherein Y is -B(OH)2 or -Sn(R5)3(in which R5 is a lower alkyl); and Z is a protecting group), to give a compound of the general formula (3):
(wherein R1, R2, A, A1, the dotted line and Z are as defined above), and then deprotecting the compound (3) to give a compound of the general formula (4):
(wherein R1, R2, A, A1 and the dotted line are as defined above).
2. The process according to claim 1, wherein the portion of the formulae (1) and (3) is
3. The process according to claim 1 or 2, wherein Y in the formula (2) is -B(OH)2; and the reaction of the compound (1) with the compound (2) is carried out in the presence of a base and a catalyst selected from the group consisting of Pd(PPh3)4, PdCl2 and Pd/C.
4. The process according to claim 1 or 2, wherein Y in the formula is -Sn(R5)3 in which R5 is a lower alkyl group;
and the reaction of the compound (1) with the compound (2) is carried out in the presence of a catalyst selected from the group consisting of Pd(PPh3)4, PdCl2, Pd/C, CuI and LiCl.
and the reaction of the compound (1) with the compound (2) is carried out in the presence of a catalyst selected from the group consisting of Pd(PPh3)4, PdCl2, Pd/C, CuI and LiCl.
5. The process according to claim 1, 2, 3 or 4, wherein the protective group Z is a member selected from the group consisting of tert-butyl, trityl, methoxymethyl and p-nitrophenyl; and the protective group is removed from the compound (3) by treating the compound (3) with HCl or CH3SO3H
in benzene or toluene at a reflux temperature.
in benzene or toluene at a reflux temperature.
6. A compound of the general formula (1):
(wherein R1 is hydrogen or isopropyl; R2 is a lower alkyl; A and A1 are each a substituent at the 4- or 8-position, and A1 is hydrogen or hydroxyl when A is hydrogen, or A and A1 together form an oxo group or =CHCOOR3 (in which R3 is a lower alkyl); the dotted line represents two double bonds or saturated single bonds; and X is halogen atom or trifluoro-methanesulfonate).
(wherein R1 is hydrogen or isopropyl; R2 is a lower alkyl; A and A1 are each a substituent at the 4- or 8-position, and A1 is hydrogen or hydroxyl when A is hydrogen, or A and A1 together form an oxo group or =CHCOOR3 (in which R3 is a lower alkyl); the dotted line represents two double bonds or saturated single bonds; and X is halogen atom or trifluoro-methanesulfonate).
7. The compound according to claim 6, wherein the portion of the formula (1) is
8. A process for producing a compound of the general formula (1) as defined in claim 6. which comprises:
reacting a compound of the general formula (5):
(wherein R1, R2, A, A1 and the dotted line are as defined in claim 6) with a halogenobenzylhalogene of the formula (6) in the presence of a base.
reacting a compound of the general formula (5):
(wherein R1, R2, A, A1 and the dotted line are as defined in claim 6) with a halogenobenzylhalogene of the formula (6) in the presence of a base.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP210867/94 | 1994-09-05 | ||
| JP21086794A JP4316686B2 (en) | 1994-09-05 | 1994-09-05 | Cycloheptimidazole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2156121A1 CA2156121A1 (en) | 1996-03-06 |
| CA2156121C true CA2156121C (en) | 2006-03-28 |
Family
ID=16596423
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002156121A Expired - Fee Related CA2156121C (en) | 1994-09-05 | 1995-08-15 | Method of manufacturing the cycloheptimidazole derivatives |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JP4316686B2 (en) |
| CN (1) | CN1061655C (en) |
| CA (1) | CA2156121C (en) |
| CH (1) | CH689511A5 (en) |
| HU (1) | HU226806B1 (en) |
| NO (1) | NO308358B1 (en) |
| TW (1) | TW408113B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6638937B2 (en) | 1998-07-06 | 2003-10-28 | Bristol-Myers Squibb Co. | Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists |
| CN115093372B (en) * | 2022-06-16 | 2023-05-30 | 安徽工程大学 | Synthesis method of imidazole derivative |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2707390B2 (en) * | 1992-05-22 | 1998-01-28 | 壽製薬株式会社 | Cycloheptoimidazole derivative, method for producing the same, and drug containing the same |
-
1994
- 1994-09-05 JP JP21086794A patent/JP4316686B2/en not_active Expired - Fee Related
-
1995
- 1995-06-17 TW TW084106287A patent/TW408113B/en not_active IP Right Cessation
- 1995-07-19 HU HU9502172A patent/HU226806B1/en not_active IP Right Cessation
- 1995-08-15 CA CA002156121A patent/CA2156121C/en not_active Expired - Fee Related
- 1995-08-29 CH CH02449/95A patent/CH689511A5/en not_active IP Right Cessation
- 1995-09-04 NO NO953459A patent/NO308358B1/en not_active IP Right Cessation
- 1995-09-05 CN CN95115611A patent/CN1061655C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0873454A (en) | 1996-03-19 |
| NO953459L (en) | 1996-03-06 |
| HU226806B1 (en) | 2009-10-28 |
| CA2156121A1 (en) | 1996-03-06 |
| NO953459D0 (en) | 1995-09-04 |
| JP4316686B2 (en) | 2009-08-19 |
| CN1061655C (en) | 2001-02-07 |
| CN1127752A (en) | 1996-07-31 |
| CH689511A5 (en) | 1999-05-31 |
| TW408113B (en) | 2000-10-11 |
| NO308358B1 (en) | 2000-09-04 |
| HUT73184A (en) | 1996-06-28 |
| HU9502172D0 (en) | 1995-09-28 |
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