Indian Patents. 251644:A SUBSTITUTED IMIDAZOLE COMPOUND

Title of Invention	A SUBSTITUTED IMIDAZOLE COMPOUND
Abstract	The invention relates to a process for preparing substituted imidazole derivatives of formula (I) and acid addition salts thereof (I) in which formula Y is -CH2- or -CO-, Rl is H, halo or hydroxy, R2 is H or halo and R3 is H or lower alkyl, starting from a compound of formula (II) wherein Y, R1,R2 and R3 are as defined above. The invention also relates to intermediates and their preparation.

Full Text	PROCESS FOR PREPARING SUBSTITUTED IMIDAZOLE DERIVATIVES AND INTERMEDIATES USED IN THE PROCESS FIELD OF THE INVENTION The present invention relates to a new process for preparing substituted imidazole derivatives of formula (I) and acid addition salts thereof, N.,^NH (I) in which formula Y is -CH2- or -CO-, R1 is H, halogen or hydroxy, R2 is H or halogen and R3 is H or lower alkyl. The invention also relates to intermediates used in the process and to their preparation. BACKGROUND OF THE INVENTION The compounds of the above-mentioned formula (I) are highly selective and long-acting antagonists of a2-adrenoceptors and they have a good peroral bioavailability. The compounds are especially valuable in the treatment of cognitive disorders. Compounds of formula (I) have been described in patent publication EP 0 618 906 B1. Specific examples of such compounds are 4-{2-ethyl-5-fluoroindan-2-yl)-1 H-imidazole and 4-(5-fluoroindan-2-yl)-1 H-imidazole. The above-mentioned publication EP 0 618 906 B1 also discloses methods of preparing compounds of formula (I). Said methods relate to various ways of modifying the substituents in the benzene moiety of the indan ring system. There is no disclosure of a total synthesis, which would lead to the desired compounds in good yield. Publication EP 0 310 745 B1 discloses a process for preparing compounds of formula (i), wherein the last step of the process comprises the use of formamide for the formation of the imidazole ring. The use of formamide, however, requires severe reaction conditions, which should be avoided in connection with industrial production in large scale. wherein Y, R1, R2, R3 and R4 are as defined above, c) removing the mercapto group from the compound of formula (IV) to obtain a compound of formula (V) wherein Y, R1, R2, R3 and R4 are as defined above, d) removing the group R4 from the compound of formula (V) to obtain a compound of formula (I), and, if desired, e) converting the resulting compound of formula (I) into an acid addition salt thereof. Further the invention relates to a process for preparing a compound of formula (IV) wherein Y is -CH2- or -CO-, R1 is H, halogen or hydroxy, R2 is H or halogen and R3 is H or lower alkyl, comprising reacting a compound of formula (III) agent is Br2. The reaction is suitably carried out in a solvent, such as an alcohol, e.g. methanol, at room temperature or below. A suitable temperature is -8 °C to +25 oC, preferably -8 °C to -5 °C. In step b) the compound of formula (III) obtained in step a) is reacted with an amine of formula R4NH2 where R4 is a easily removable leaving group, and an alkali metal thiocyanate to obtain a mercapto compound of formula (IV). The reaction is suitably carried out in a solvent, such as as an alcohol, e.g. ethanol or butanol, at an elevated temperature, preferably at reflux temperature. The amine for the reaction may be one where R4 is aralkyi, preferably benzyl. A preferred alkali metal thiocyanat is potassium thiocyanate. In step c) the mercapto group is removed from the compound of formula (IV) obtained in step c) to obtain a compound of formula (V). The reaction is suitably carried out in the presence of a catalyst, e.g Raney-Nickel, at a temperature of 40 °C to 90 °C, preferably 40 °C to 60oC. In step d) the group R4 can be removed from the compound of formula (V) obtained in step c) by treating the compound of formula (V) with ammonium formate in the presence of a catalyst, such as Pd/C. Alternatively a catalyst, such as Raney-Nickel, may be used, or R4 may be removed by hydrogenation in the presence of Pd/C. The resulting compound of formula (1) may be converted into acid addition salts using methods known per se. Preferred acid addition salts are HCI and HBr. Preferred compounds of formulae (I) to (V) are those where Y is CH2, Ri is F, R2 is H and R3 is ethyl. The process according to the present invention makes it possible to prepare compounds of formula (I) in good yield and in a simple way, e.g. by using lower reaction temperatures, that also are suitable for large-scale production. The known methods result in poor yields and require severe reaction conditions, e.g. high temperatures, which makes large-scale production difficult. For instance, compared to the process using formamide (EP 0 310 745 B1), the process of the present invention using lower temperatures does not create separation or isolation problems relating to great amounts of various impurities that are typically formed in the known formamide process The following examples illustrate the invention, but are not intended to restrict the scope of the invention. minutes and the reaction mixture was refiuxed for 2 hours. The reaction mixture was evaporated to dryness before 150 mi ethyl acetate was added and the solution was washed with water. The organic phase was dried over Na2SO4, filtered and evaporated providing 1,13 g of 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole-2-thiol (yield 31 %). The analytical sample was purified using TLC-plates. The purity was measured by HPLC: 62 %. Normally the crude product was used in the following step. 1H NMR (200 MHz. CDCI3, ppm): 0.75 (t. CH2CH3), 1.80 (q, CH2CH3), 2.81-3.30 (m, the indan ring H2-I and H2-3), 5.18 (s. N-CHg-Ar), 6.24 (s, -SH), 6.77-7.09 (m, Ar-H. im-H). 7.23-7.36 (m, Ar-H-CHa-N). HPLC-MS: 353 (100, M+). 221 (29), 187 (12). Example 3 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole 7,5 ml of Raney-Nickel prepared according to Vogel, Practical Organic Chemistry, 5th Edition, 1999, Longman, U.K. p. 450-451, was mixed with 20 ml of ethanol under nitrogen atmosphere in a round-bottomed flask equipped with a thermometer and a stirring bar. 500 mg of 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole-2-thiol was dissolved in 10 ml of ethanol and added to the mixture. The reaction mixture was stirred at 40 °C for about 10 hours and then the temperature was raised to 60 oC for 2 hours followed by cooling to room temperature. The mixture was filtered and the filter (Celite™) was washed with ethanol. The ethanol solution was evaporated to dryness to obtain 151 mg of a crude product. After chromatographic purification using methylene chloride, methylene chloride:methanol (10:1) and methylene chloride:methanol (1:1) as eluents 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole was obtained. The purity was measured by HPLC: 83 %. 1H NMR (200 MHz, MeOD, ppm): 0.70 (3H, t, CH2CH3). 1.82 (2H, q, CH2CH3), 2.90-3.01 (2 H, dd, the indan ring H2-I or H2-3), 3.13-3.25 (2 H, dd, the indan ring H2-I or H2-3), 5.10 (2H, s. N-CH2-Ar), 6.72-6.87 (3H, m, Ar-H, im-H), 7.05- 7.18 (3H, m, Ar-H, Ar-H-CH2-N), 7.29-7.32 (3H, m, Ar-H-CH2-N), 7.56 (1H, s, im-H). HPLC-MS: 321 (100, M+). Example 6 4-(2-ethyl-5-fluoro-indan-2-yl)-1H-imidazole-hydrochloride A HCI/methanol reagent was prepared by bubbling HCI-gas through methanol. 100 mg of 4-(2-ethyl-5-fluoro-indan-2-yl)-1 H-imidazole was dissolved in 2 ml methanol in a round-bottomed flask. 2 ml of HCI/methanol reagent (3 M) was added slowly to the solution while stirring. During the addition the internal temperature of the mixture was kept below 29°C by cooling. The resulting mixture was evaporated at a temperature between 35°C and 40°C to viscous colourless oil whereupon it was dissolved in 2 ml of acetone at the same temperature. The solution was cooled to a temperature between 10°C and 15°C at which temperature the mixture started to crystallize. The crystalline material was filtered, washed with cooled acetone and dried in a vacuum oven at 35°C overnight. A second crop was isolated from the mother liquid followed by cooling, filtering and drying as described above. The yield of 4-(2-ethyl-5-fluoro-indan-2-yl)-1H-imidazole-hydrochloride was altogether 87% of the theoretical, m.p. 171 - 173°C. We claim: 1. A compound of formula (IV) wherein Y is -CH2 or -CO-, R1 is halogen or hydroxy, R2 is H or halogen, R3 is H or lower alkyl and R4 is an easily removable leaving group. 2. A compound as claimed in claim 1, wherein Y is -CH2-, Ri is F, R2 is H, R3 is ethyl and R4 is benzyl.

Full Text

PROCESS FOR PREPARING SUBSTITUTED IMIDAZOLE DERIVATIVES AND INTERMEDIATES USED IN THE PROCESS
FIELD OF THE INVENTION
The present invention relates to a new process for preparing substituted imidazole derivatives of formula (I) and acid addition salts thereof,

N.,^NH

(I)

in which formula Y is -CH2- or -CO-, R1 is H, halogen or hydroxy, R2 is H or halogen and R3 is H or lower alkyl.
The invention also relates to intermediates used in the process and to their preparation.
BACKGROUND OF THE INVENTION
The compounds of the above-mentioned formula (I) are highly selective and long-acting antagonists of a2-adrenoceptors and they have a good peroral bioavailability. The compounds are especially valuable in the treatment of cognitive disorders. Compounds of formula (I) have been described in patent publication EP 0 618 906 B1. Specific examples of such compounds are 4-{2-ethyl-5-fluoroindan-2-yl)-1 H-imidazole and 4-(5-fluoroindan-2-yl)-1 H-imidazole.
The above-mentioned publication EP 0 618 906 B1 also discloses methods of preparing compounds of formula (I). Said methods relate to various ways of modifying the substituents in the benzene moiety of the indan ring system. There is no disclosure of a total synthesis, which would lead to the desired compounds in good yield.
Publication EP 0 310 745 B1 discloses a process for preparing compounds of formula (i), wherein the last step of the process comprises the use of formamide for the formation of the imidazole ring. The use of formamide, however, requires severe reaction conditions, which should be avoided in connection with industrial production in large scale.

wherein Y, R1, R2, R3 and R4 are as defined above,
c) removing the mercapto group from the compound of formula (IV) to obtain a
compound of formula (V)

wherein Y, R1, R2, R3 and R4 are as defined above,
d) removing the group R4 from the compound of formula (V) to obtain a
compound of formula (I), and, if desired,
e) converting the resulting compound of formula (I) into an acid addition salt
thereof.
Further the invention relates to a process for preparing a compound of formula (IV)

wherein Y is -CH2- or -CO-, R1 is H, halogen or hydroxy, R2 is H or halogen and R3 is H or lower alkyl, comprising reacting a compound of formula (III)

agent is Br2. The reaction is suitably carried out in a solvent, such as an alcohol, e.g. methanol, at room temperature or below. A suitable temperature is -8 °C to +25 oC, preferably -8 °C to -5 °C.
In step b) the compound of formula (III) obtained in step a) is reacted with an amine of formula R4NH2 where R4 is a easily removable leaving group, and an alkali metal thiocyanate to obtain a mercapto compound of formula (IV). The reaction is suitably carried out in a solvent, such as as an alcohol, e.g. ethanol or butanol, at an elevated temperature, preferably at reflux temperature. The amine for the reaction may be one where R4 is aralkyi, preferably benzyl. A preferred alkali metal thiocyanat is potassium thiocyanate.
In step c) the mercapto group is removed from the compound of formula (IV) obtained in step c) to obtain a compound of formula (V). The reaction is suitably carried out in the presence of a catalyst, e.g Raney-Nickel, at a temperature of 40 °C to 90 °C, preferably 40 °C to 60oC.
In step d) the group R4 can be removed from the compound of formula (V) obtained in step c) by treating the compound of formula (V) with ammonium formate in the presence of a catalyst, such as Pd/C. Alternatively a catalyst, such as Raney-Nickel, may be used, or R4 may be removed by hydrogenation in the presence of Pd/C.
The resulting compound of formula (1) may be converted into acid addition salts using methods known per se. Preferred acid addition salts are HCI and HBr.
Preferred compounds of formulae (I) to (V) are those where Y is CH2, Ri is F, R2 is H and R3 is ethyl.
The process according to the present invention makes it possible to prepare compounds of formula (I) in good yield and in a simple way, e.g. by using lower reaction temperatures, that also are suitable for large-scale production. The known methods result in poor yields and require severe reaction conditions, e.g. high temperatures, which makes large-scale production difficult. For instance, compared to the process using formamide (EP 0 310 745 B1), the process of the present invention using lower temperatures does not create separation or isolation problems relating to great amounts of various impurities that are typically formed in the known formamide process
The following examples illustrate the invention, but are not intended to restrict the scope of the invention.

minutes and the reaction mixture was refiuxed for 2 hours. The reaction mixture was evaporated to dryness before 150 mi ethyl acetate was added and the solution was washed with water. The organic phase was dried over Na2SO4, filtered and evaporated providing 1,13 g of 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole-2-thiol (yield 31 %). The analytical sample was purified using TLC-plates. The purity was measured by HPLC: 62 %. Normally the crude product was used in the following step.
1H NMR (200 MHz. CDCI3, ppm): 0.75 (t. CH2CH3), 1.80 (q, CH2CH3), 2.81-3.30 (m, the indan ring H2-I and H2-3), 5.18 (s. N-CHg-Ar), 6.24 (s, -SH), 6.77-7.09 (m, Ar-H. im-H). 7.23-7.36 (m, Ar-H-CHa-N). HPLC-MS: 353 (100, M+). 221 (29), 187 (12).
Example 3
1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole
7,5 ml of Raney-Nickel prepared according to Vogel, Practical Organic Chemistry, 5th Edition, 1999, Longman, U.K. p. 450-451, was mixed with 20 ml of ethanol under nitrogen atmosphere in a round-bottomed flask equipped with a thermometer and a stirring bar. 500 mg of 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole-2-thiol was dissolved in 10 ml of ethanol and added to the mixture. The reaction mixture was stirred at 40 °C for about 10 hours and then the temperature was raised to 60 oC for 2 hours followed by cooling to room temperature. The mixture was filtered and the filter (Celite™) was washed with ethanol. The ethanol solution was evaporated to dryness to obtain 151 mg of a crude product. After chromatographic purification using methylene chloride, methylene chloride:methanol (10:1) and methylene chloride:methanol (1:1) as eluents 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole was obtained. The purity was measured by HPLC: 83 %.
1H NMR (200 MHz, MeOD, ppm): 0.70 (3H, t, CH2CH3). 1.82 (2H, q, CH2CH3),
2.90-3.01 (2 H, dd, the indan ring H2-I or H2-3), 3.13-3.25 (2 H, dd, the indan
ring H2-I or H2-3), 5.10 (2H, s. N-CH2-Ar), 6.72-6.87 (3H, m, Ar-H, im-H), 7.05-
7.18 (3H, m, Ar-H, Ar-H-CH2-N), 7.29-7.32 (3H, m, Ar-H-CH2-N), 7.56 (1H, s,
im-H).
HPLC-MS: 321 (100, M+).

Example 6
4-(2-ethyl-5-fluoro-indan-2-yl)-1H-imidazole-hydrochloride
A HCI/methanol reagent was prepared by bubbling HCI-gas through methanol. 100 mg of 4-(2-ethyl-5-fluoro-indan-2-yl)-1 H-imidazole was dissolved in 2 ml methanol in a round-bottomed flask. 2 ml of HCI/methanol reagent (3 M) was added slowly to the solution while stirring. During the addition the internal temperature of the mixture was kept below 29°C by cooling. The resulting mixture was evaporated at a temperature between 35°C and 40°C to viscous colourless oil whereupon it was dissolved in 2 ml of acetone at the same temperature. The solution was cooled to a temperature between 10°C and 15°C at which temperature the mixture started to crystallize. The crystalline material was filtered, washed with cooled acetone and dried in a vacuum oven at 35°C overnight. A second crop was isolated from the mother liquid followed by cooling, filtering and drying as described above. The yield of 4-(2-ethyl-5-fluoro-indan-2-yl)-1H-imidazole-hydrochloride was altogether 87% of the theoretical, m.p. 171 - 173°C.

We claim:
1. A compound of formula (IV)

wherein Y is -CH2 or -CO-, R1 is halogen or hydroxy, R2 is H or halogen, R3 is H or lower alkyl and R4 is an easily removable leaving group.
2. A compound as claimed in claim 1, wherein Y is -CH2-, Ri is F, R2 is H, R3 is
ethyl and R4 is benzyl.

Documents:

1893-chenp-2007 amended pages of specification 06-05-2011.pdf

1893-chenp-2007 amended claims 06-05-2011.pdf

1893-chenp-2007 form-1 06-05-2011.pdf

1893-chenp-2007 form-3 06-05-2011.pdf

1893-chenp-2007 power of attorney 06-05-2011.pdf

1893-CHENP-2007 CORRESPONDENCE OTHERS 28-01-2011.pdf

1893-chenp-2007 examination report reply received 06-05-2011.pdf

1893-chenp-2007-abstract.pdf

1893-chenp-2007-claims.pdf

1893-chenp-2007-correspondnece-others.pdf

1893-chenp-2007-description(complete).pdf

1893-chenp-2007-form 1.pdf

1893-chenp-2007-form 3.pdf

1893-chenp-2007-form 5.pdf

« Previous Patent

Next Patent »

Patent Number

251644

Indian Patent Application Number

1893/CHENP/2007

PG Journal Number

13/2012

Publication Date

30-Mar-2012

Grant Date

27-Mar-2012

Date of Filing

03-May-2007

Name of Patentee

OY JUVANTIA PHARMA LTD

Applicant Address

LEMMINKAISENKATU 5 FIN-20520 TURKU

Inventors:

#	Inventor's Name	Inventor's Address
1	JUUJARVI, PAIVI	ANSAKATU 10 B 8 FIN-20660 LITTOINEN
2	PARHI, SEPPO	SINKKIVALKKEENTIE 3 FIN-90240 OULU
3	KARJALAINEN, JAANA,	MAKITUVANTIE 2 A 1 FIN-90650 OULU

PCT International Classification Number

C07D 471/04

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	20030026	2003-01-08	Finland