Indian Patents. 224370:"THE COMPOUNDS OF FORMULA (IV)"

Title of Invention	"THE COMPOUNDS OF FORMULA (IV)"
Abstract	The compounds of formula (IV): wherein, R represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms; and alk represents alkyl radical containing up to 4 carbon atoms.

Full Text	The present invention relates to the compounds of formula (IV). The present invention relates to a process for the preparation of 4-(3-pyridinyl)-IH-imidazole, of certain of its derivatives as well as the intermediate products used. A subject of the invention is a process for the preparation of compounds of formula (I] (Formula Removed) in which R represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms characterized in that a compound of formula (II) (Formula Removed) in which alk represents the remainder of an alkyl radical containing up to 4 carbon atoms is subjected to the action of a compound of formula (III) (Formula Removed) in which R retains its previous meaning, in order to obtain the compound of formula (IV) in which R retains its previous meaning which is subjected to a cyclization in order to obtain the sought product of formula (I). When R represents an alkyl radical, it is for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertbutyl radical Alk represents for example a methyl, ethyl or n-propyl radical. In a preferred embodiment, the reaction between the compounds (II) and (III) takes place in a mixture of alcohol and formamide. As alcohol there can be mentioned methanol, ethanol or propanol. The cyclization of the compound of formula (IV) takes place in formamide. A more particular subject of the invention is the preparation of the compound of formula (I) in which R is a hydrogen atom. A more particular subject of the invention is a process characterized in that alk represents a methyl radical. The cyclization preferably takes place by heating. 4-(3-pyridinyl)-1H imidazole is a known product described for example in J. Chem.-Soc.-753-5 1938 which can be used for preparing pharmaceutical products (cf. EP 680967). A subject of the invention is also a process characterized in that the product of formula (II) is prepared by the action of an alcohol and of an alkaline alcoholate, alkiOH/alk2OM/ alk: and alk2, identical or different, representing an alkyl radical containing up to 4 carbon atoms and M representing a sodium or potassium atom on a compound of formula (A) , OM representing a hydroxyl radical blocked, in the form of a good parting group in order to obtain 3- (2H-azirin-3-yl) pyridine which is subjected to the action of an acid in the presence of an alcohol alkOH, alk retaining the same meaning as previously in order to obtain the corresponding compound of formula (II) The oxime is protected for example in the form of mesylate or tosylate, the alcohol and the alkaline alccholate are for example methanol and sodium methylate, ethanol and sodium ethylate, butanol and sodium terbutylate. The acid used can be oxalic acid, formic acid or also hydrochloric or sulphuric acid. In a preferred embodiment: - M is a tosyl radical - methanol is used in the presence of sodium methylate - the acid is oxalic acid. A more particular subject of the invention is a process in which alk, alki and alk2 represent the same alkyl radical for example the methyl radical. A more particular subject of the invention is a process in which the intermediate product 3-(2H-azirin-3-yl)-pyridine is not isolated. A more particular subject of the invention is a process characterized in that 1-(3-pyridinyl)-ethanone 0-[ (4-methyl-phenyl) sulphonyl] oxime is subjected to the action of methanol and sodium methylate in order to obtain 3-(2H-azirin-3-yl)-pyridine which is subjected to the action of oxalic acid in order to obtain p, p-dimethoxy-2- (3-pyridinyl)ethyl]-amine which is subjected to the action of formamide in order to obtain N-(P,p-dimethoxy-2-(3-pyridinyl) ethyl]-formamide which is subjected to a cyclization in order to obtain the sought product. A quite particular subject of the invention is a process in which the intermediate products used are not isolated. The compounds of formula (II) with the exception of P,P~ diethoxy-3-pyridine ethanamine described in Org. Synth, (1986) 64, 1926 are new products and are in themselves a subject of the present invention. The compounds of formula (IV) are new and are in themselves a subject of the present invention. A more particular subject of the invention is the compounds of formula (II) and (IV) described in the experimental part namely: P,p-dimethoxy-3-pyridine ethanamine and N- [p,p-dimethoxy-2-(3-pyridinyl)ethyl]-formamide. The following examples illustrate the invention without however limiting it. Preparation: P,p-dimethoxy-3-pyridine ethanamine Stage A: 3-[2H-azirin-3-yl)-pyridine 100 g of 1-(3-pyridinyl)-ethanone 0-[(4- methylphenyl)sulphonyl]-oxime is introduced at 20°C under a nitrogen atmosphere into a solution containing 400 ml of anhydrous methanol and 23.45 g of sodium methylate. Agitation is carried out for 2 hours at 20-22°C and a suspension containing the sought product is obtained. Stage B: p,p-dimethoxy-3-pyridine ethanamine. The suspension obtained previously is cooled down to 0°C and 31.03 g of oxalic acid is added. Agitation is carried out for 15 minutes at 0°/+5°C. A suspension is obtained which is used as it is in Example 1. After isolation and purification, p, p-dimethoxy-3-pyridine ethanamine is obtained. NMR CDC13 ppm 1.03(broad m) assumed mobile NHZ I 3.02(s) -C-CH2-N I 3.22(s) 6H 2 OCH3 7.33(bdd, J=5 and 9) H5 7.80(dt, J=9 and 2} H4 8.59(dd, J-5 and 2) H6 8.73(dd, J=2 and 1) H2 EXAMPLE 1; 4-{3-pyridinyl)-IH-imidazole Stage Ai_: N- [P, p-dimethoxy-2- (3-pyridinyl) ethyl] -formamide 100 ml of formamide is added at 60°C to the suspension prepared above. In this way a suspension is obtained which is used as it is in the following stage. After separation and purification the sought product is obtained. Stage Ag: 4-(3-pyridinyl)-IHimidazole 7.2 g of P,p-dimethoxy-3-pyridineethanamine in 15 ml of formamide is heated for 5 hours at 80"C under nitrogen. The reaction mixture is maintained under agitation at 20°C for 16 hours. In this way the sought product is obtained. (Yield = 51 %). NMR CDC13 ppm 3.24 (s) 3.26(s) 6H 2 CH30 3.55(d, s after exch.) CH2-NHCO 3.75(d, s after exch.) CH2-NHCO 5.80(m) mobile H 8.21(m) mobile H 7.32(m) H5 7.64(d, s after exch.) NH-CHO 8.00(d, s after exch.) NH-CHO 7.75 to 7.82(m) H4 8.54 (dd)v 8.57 (dd) H6 8.68(m) 8.70(dd) H2 Stage B: 4-(3-pyridinyl)-IH-imidazole The suspension obtained in Stage A is heated at 125°C while distilling the methanol. The reaction medium is maintained under agitation for 16 hours. A suspension is obtained which is cooled down to 80°C and 400 ml of demineralized water is added. 130.3 g of oxalic acid is added at 80°C. After cooling down to 60°C, agitation is carried out for 1 hour at 60°C, followed by cooling down to 20 °C, agitating for 1 hour at 20°C, cooling down to 0°C, agitating for 16 hours at OeC, separating and washing. In this way the oxalate of the sought product is obtained. 4-(3-pyridinyl)-H-imidazole is obtained by the action of a solution of potash. NMR CDC13 ppm 7.38 (dd, J=5 and 8) H5 7.78(bs) 7.80(bs) H2' H5' 8.12(bd, J=8) H4 8.41(dd,J=2 and 5) H6 9.03(bs) H2 12.36(broad m) mobile H WE CLAIM: 1. The compounds of formula (IV): (Formula Removed) wherein, R represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms; and alk represents alkyl radical containing up to 4 carbon atoms. 2. The compounds as claimed in claim 1, wherein the said compound is N-[ ß , ß - dimethoxy -2-(3-pyridinyl)ethyl]-formamide.

Full Text

The present invention relates to the compounds of formula (IV).

The present invention relates to a process for the preparation of 4-(3-pyridinyl)-IH-imidazole, of certain of its derivatives as well as the intermediate products used.
A subject of the invention is a process for the preparation of compounds of formula (I]
(Formula Removed)
in which R represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms characterized in that a compound of formula (II)
(Formula Removed)
in which alk represents the remainder of an alkyl radical containing up to 4 carbon atoms is subjected to the action of a compound of formula (III)

(Formula Removed)
in which R retains its previous meaning, in order to obtain the compound of formula (IV)

in which R retains its previous meaning which is subjected to a cyclization in order to obtain the sought product of formula (I).
When R represents an alkyl radical, it is for example the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertbutyl radical
Alk represents for example a methyl, ethyl or n-propyl radical.
In a preferred embodiment, the reaction between the compounds (II) and (III) takes place in a mixture of alcohol and formamide. As alcohol there can be mentioned methanol, ethanol or propanol.
The cyclization of the compound of formula (IV) takes place in formamide.
A more particular subject of the invention is the preparation of the compound of formula (I) in which R is a hydrogen atom.
A more particular subject of the invention is a process characterized in that alk represents a methyl radical.
The cyclization preferably takes place by heating.
4-(3-pyridinyl)-1H imidazole is a known product described for example in J. Chem.-Soc.-753-5 1938 which can be used for preparing pharmaceutical products (cf. EP 680967).
A subject of the invention is also a process
characterized in that the product of formula (II) is prepared by the action of an alcohol and of an alkaline alcoholate, alkiOH/alk2OM/ alk: and alk2, identical or different, representing an alkyl radical containing up to 4 carbon atoms
and M representing a sodium or potassium atom on a compound of formula (A) ,

OM representing a hydroxyl radical blocked, in the form of a good parting group in order to obtain 3- (2H-azirin-3-yl) pyridine

which is subjected to the action of an acid in the presence of an alcohol alkOH, alk retaining the same meaning as previously in order to obtain the corresponding compound of formula (II)
The oxime is protected for example in the form of mesylate or tosylate, the alcohol and the alkaline alccholate are for example methanol and sodium methylate, ethanol and sodium ethylate, butanol and sodium terbutylate.
The acid used can be oxalic acid, formic acid or also hydrochloric or sulphuric acid.
In a preferred embodiment: - M is a tosyl radical
- methanol is used in the presence of sodium methylate
- the acid is oxalic acid.
A more particular subject of the invention is a process in which alk, alki and alk2 represent the same alkyl radical for example the methyl radical.
A more particular subject of the invention is a process in which the intermediate product 3-(2H-azirin-3-yl)-pyridine is not isolated.
A more particular subject of the invention is a process characterized in that 1-(3-pyridinyl)-ethanone 0-[ (4-methyl-phenyl) sulphonyl] oxime is subjected to the action of methanol and sodium methylate in order to obtain 3-(2H-azirin-3-yl)-pyridine which is subjected to the action of
oxalic acid in order to obtain p, p-dimethoxy-2- (3-pyridinyl)ethyl]-amine which is subjected to the action of
formamide in order to obtain N-(P,p-dimethoxy-2-(3-pyridinyl) ethyl]-formamide which is subjected to a cyclization in order to obtain the sought product.
A quite particular subject of the invention is a process in which the intermediate products used are not isolated.
The compounds of formula (II) with the exception of P,P~ diethoxy-3-pyridine ethanamine described in Org. Synth, (1986) 64, 1926 are new products and are in themselves a subject of the present invention.
The compounds of formula (IV) are new and are in themselves a subject of the present invention.
A more particular subject of the invention is the compounds of formula (II) and (IV) described in the experimental part namely:
P,p-dimethoxy-3-pyridine ethanamine and N- [p,p-dimethoxy-2-(3-pyridinyl)ethyl]-formamide.
The following examples illustrate the invention without however limiting it.
Preparation: P,p-dimethoxy-3-pyridine ethanamine Stage A: 3-[2H-azirin-3-yl)-pyridine
100 g of 1-(3-pyridinyl)-ethanone 0-[(4-
methylphenyl)sulphonyl]-oxime is introduced at 20°C under a nitrogen atmosphere into a solution containing 400 ml of anhydrous methanol and 23.45 g of sodium methylate. Agitation is carried out for 2 hours at 20-22°C and a suspension containing the sought product is obtained. Stage B: p,p-dimethoxy-3-pyridine ethanamine.
The suspension obtained previously is cooled down to 0°C and 31.03 g of oxalic acid is added. Agitation is carried out for 15 minutes at 0°/+5°C. A suspension is obtained which is used as it is in Example 1. After isolation and purification, p, p-dimethoxy-3-pyridine ethanamine is obtained. NMR CDC13 ppm 1.03(broad m) assumed mobile NHZ
I 3.02(s) -C-CH2-N
I
3.22(s) 6H 2 OCH3 7.33(bdd, J=5 and 9) H5 7.80(dt, J=9 and 2} H4 8.59(dd, J-5 and 2) H6 8.73(dd, J=2 and 1) H2 EXAMPLE 1; 4-{3-pyridinyl)-IH-imidazole
Stage Ai_: N- [P, p-dimethoxy-2- (3-pyridinyl) ethyl] -formamide
100 ml of formamide is added at 60°C to the suspension prepared above. In this way a suspension is obtained which is used as it is in the following stage. After separation and purification the sought product is obtained. Stage Ag: 4-(3-pyridinyl)-IHimidazole
7.2 g of P,p-dimethoxy-3-pyridineethanamine in 15 ml of formamide is heated for 5 hours at 80"C under nitrogen. The reaction mixture is maintained under agitation at 20°C for 16 hours. In this way the sought product is obtained. (Yield = 51 %). NMR CDC13 ppm
3.24 (s) 3.26(s) 6H 2 CH30
3.55(d, s after exch.) CH2-NHCO
3.75(d, s after exch.) CH2-NHCO
5.80(m) mobile H
8.21(m) mobile H
7.32(m) H5
7.64(d, s after exch.) NH-CHO
8.00(d, s after exch.) NH-CHO
7.75 to 7.82(m) H4
8.54 (dd)v 8.57 (dd) H6
8.68(m) 8.70(dd) H2
Stage B: 4-(3-pyridinyl)-IH-imidazole
The suspension obtained in Stage A is heated at 125°C while distilling the methanol. The reaction medium is maintained under agitation for 16 hours. A suspension is obtained which is cooled down to 80°C and 400 ml of demineralized water is added. 130.3 g of oxalic acid is added at 80°C. After cooling down to 60°C, agitation is carried out for 1 hour at 60°C, followed by cooling down to 20 °C, agitating for 1 hour at 20°C, cooling down to 0°C, agitating for 16 hours at OeC, separating and washing. In this way the oxalate of the sought product is obtained. 4-(3-pyridinyl)-H-imidazole is obtained by the action of a solution of potash. NMR CDC13 ppm 7.38 (dd, J=5 and 8) H5 7.78(bs) 7.80(bs) H2' H5' 8.12(bd, J=8) H4 8.41(dd,J=2 and 5) H6 9.03(bs) H2 12.36(broad m) mobile H

WE CLAIM:
1. The compounds of formula (IV):

(Formula Removed)
wherein, R represents a hydrogen atom or an alkyl radical containing up to
8 carbon atoms; and
alk represents alkyl radical containing up to 4 carbon atoms.
2. The compounds as claimed in claim 1, wherein the said compound is N-[ ß , ß - dimethoxy -2-(3-pyridinyl)ethyl]-formamide.

Documents:

3081-DELNP-2005-Abstract-(20-09-2008).pdf

3081-DELNP-2005-Abstract-06-12-2007.pdf

3081-delnp-2005-abstract.pdf

3081-DELNP-2005-Claims-(20-09-2008).pdf

3081-DELNP-2005-Claims-06-12-2007.pdf

3081-delnp-2005-claims.pdf

3081-delnp-2005-complete specification (granded).pdf

3081-DELNP-2005-Correspondence-Others-06-12-2007.pdf

3081-delnp-2005-correspondence-others.pdf

3081-DELNP-2005-Description (Complete)-(20-09-2008).pdf

3081-delnp-2005-description (complete)-20-09-2008.pdf

3081-delnp-2005-description (complete).pdf

3081-DELNP-2005-Description (Complete)06-12-2007.pdf

3081-DELNP-2005-Form-1-(20-09-2008).pdf

3081-DELNP-2005-Form-1-06-12-2007.pdf

3081-delnp-2005-form-1.pdf

3081-delnp-2005-form-18.pdf

3081-DELNP-2005-Form-2-(20-09-2008).pdf

3081-DELNP-2005-Form-2-06-12-2007.pdf

3081-delnp-2005-form-2.pdf

3081-DELNP-2005-Form-3-06-12-2007.pdf

3081-delnp-2005-form-3.pdf

3081-delnp-2005-form-5.pdf

3081-DELNP-2005-GPA-06-12-2007.pdf

3081-delnp-2005-gpa.pdf

3081-DELNP-2005-Petition-137-06-12-2007.pdf

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Patent Number

224370

Indian Patent Application Number

3081/DELNP/2005

PG Journal Number

44/2008

Publication Date

31-Oct-2008

Grant Date

13-Oct-2008

Date of Filing

23-Dec-2005

Name of Patentee

AVENTIS PHARMA S.A.

Applicant Address

20 AVENUE RAYMOND-ARON, F-92160 ANTONY, FRANCE.

Inventors:

#	Inventor's Name	Inventor's Address
1	JACQUES LAGOUARDAT	21 CLOS DES CASCADES, F-93160 NOISY LE GRAND, FRANCE.
2	JACQUES SCHOLL	22, BOULEVARD DE LA BOISSIERE, F-93230 ROMAINVILLE, FRANCE.
3	RAPHAEL BOUCHET	1, ALLEE QUIZET, APPT, 21, F-93310 LE PRE SAINT GERVAIS, FRANCE.

PCT International Classification Number

C07D233/54

PCT International Application Number

PCT/FR 99/01649

PCT International Filing date

1999-07-08

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	98/08796	1998-07-09	France