Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2003-05-23
2004-03-23
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06710178
ABSTRACT:
DESCRIPTION
The present invention relates to a novel process for the preparation of compounds of the general formula
in which R, R
2
, R
3
and R
4
have the meaning below.
Compounds of the formula I are important intermediates for the preparation of pharmaceutically active compounds, for example of HMG-Co A reductase inhibitors. Japanese Patent publication JP-A 06 256318, and Watanabe M. et al.,
Bioorg. Med. Chem.
1997, Vol. 5, No. 2, 437-444 describe processes for the preparation of compounds of the formula I.
The process described in JP-A 06 256316 has the disadvantage that three stages are needed in order to prepare 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylic acid.
A process for the preparation of ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate has been described by Watanabe M. et al.,
Bioorg. Med. Chem.
1997, Vol. 5, No. 2, 437-444. In this process, in the first stage p-fluorobenzaldehyde is converted using ethyl iso-butyrylacetate into an unsaturated ketoester, which is then cyclocondensed in the second stage with S-methylisothiourea hydrogensulphate and subsequently dehydrated in the third stage to give the corresponding pyrimidine. In the fourth stage, this is then oxidized using m-chloroperbenzoic acid to give the corresponding sulphonylpyrimidine, which is then reacted in the fifth stage with methylamine and subsequent treatment with methanesulphonyl-chloride to give ethyl 4-(4-fluoro-phenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methyl-amino)pyrimidine-5-carboxylate.
It is disadvantageous in this process, on the one hand, that many reaction stages are necessary and, on the other hand, that the desired product is only formed in moderate yield.
The object of the invention was to make available an economical, industrially feasible process for the preparation of compounds of the formula I.
The object is achieved by the novel process according to Patent Claim
1
.
According to the invention, compounds of the general formula
in which
R is hydrogen or a group of the formula —SO
2
R
1
;
R
1
is C
1-6
-alkyl;
R
2
is hydrogen or C
1-6
-alkyl;
R
3
is C
1-6
-alkyl;
R
4
is C
1-6
-alkyl,
are prepared in that, in a first stage, a compound of the general formula
in which R
3
and R
4
have the abovementioned meaning, is reacted in the presence of a Lewis acid with 4-fluorobenzonitrile to give a compound of the general formula
in which R
3
and R
4
have the abovementioned meaning, and in a second stage the compound of the formula III obtained is reacted with a compound of the general formula
in which R and R
2
have the abovementioned meaning, to give the final product of the formula I.
“C
1-6
-alkyl” is understood here and below as meaning linear and branched alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, sec-butyl, pentyl and its isomers and hexyl and its isomers.
The compounds of the formula II can be prepared according to
Chem. Berichte
1958, 91, 759 or are commercially available organic synthetic chemicals. 4-Fluorobenzonitrile is a commercially available organic synthetic chemical.
The Lewis acid employed in the first stage is expediently an aprotic Lewis acid such as, for example, tin tetrachloride, titanium tetrachloride or aluminium chloride.Tin tetrachloride is preferably employed.
The first stage is expediently carried out in the presence of an organic solvent. The organic solvents employed can be, for example, aromatic hydrocarbons, chlorinated aromatic and aliphatic hydrocarbons. Aromatic hydrocarbons employed are preferably toluene, benzene or xylene. The chlorinated aromatic hydrocarbon employed is preferably chlorobenzene; the chlorinated aliphatic hydrocarbon employed is preferably 1,2-dichloroethane. Toluene and 1,2-dichloroethane are particularly preferably employed.
The reaction in the first stage is expediently carried out at a temperature from −5 to 140° C., advantageously at 60 to 100° C.
After a reaction time of 30 min to 6 h and subsequent hydrolysis, the compounds of the formula III can be isolated by known methods such as, for example, by extraction or can be employed directly, without isolation, for the second stage. The intermediate (formula III) is preferably isolated.
Compounds of the formula III include cis and trans isomers.
In a second stage, a compound of the formula III is reacted with a compound of the formula IV to give the final product of the formula I.
The invention comprises, on the one hand, compounds of the formula I in which R and R
2
are hydrogen. These compounds are prepared by reaction of compounds of the formula III with cyanamide.
The reaction with cyanamide is expediently carried out in the presence of an organic solvent, a mixture of water with an organic solvent or in water. Water is particularly preferably employed. Organic solvents employed are advantageously toluene or ethyl acetate. Organic solvents employed as a mixture with water are advantageously alcohols such as, for example, methanol, ethers such as, for example, dioxane or aromatic hydrocarbons such as, for example, toluene or N,N-dimethylacetamide.
The reaction with cyanamide is expediently carried out at a temperature of 10 to 120° C., advantageously at 40 to 100° C. The pH is expediently in a range from 3 to 9, advantageously in a range from 4 to 7. After a reaction time of, in total, 1 to 20 h, the compounds of the general formula I are obtained, which can be worked up according to known methods.
In a particular embodiment, 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylic acid esters of the general formula
in which R
3
has the meaning indicated in formula I are prepared in that, in a first stage, an alkyl isobutyrylacetate of the general formula
in which R
3
has the meaning mentioned is reacted in the presence of a Lewis acid with 4-fluorobenzonitrile to give a 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoic acid ester of the general formula
and in a second stage the compound of the formula IIIa is reacted with cyanamide of the formula
in which R and R
2
are hydrogen, to give the final product of the formula Ia.
The radical R
3
is preferably methyl.
The compounds of the formula III are novel and also a subject of the invention.
The invention comprises, on the other hand, compounds of the formula I in which R is a group of the formula —SO
2
R
1
and R
1
and R
2
are C
1-6
-alkyl. These 4-(4-fluorophenyl)-6-alkyl-2-(N-alkanesulphonyl-N-alkylamino)pyrimidine-5-carboxylic acid esters of the general formula
in which R
1
, R
2
, R
3
and R
4
are identical or different and are a C
1-6
-alkyl group, can be prepared in that 2-[1-amino-1-(4-fluorophenyl)methylene]-4-alkyl-3-oxo-alkanoic acid esters of the general formula
in which R
3
and R
4
have the abovementioned meaning, are reacted with N-cyano-N-alkylalkanesulphonamides, optionally isolated or prepared in situ, of the general formula
in which R
1
and R
2
are a C
1-6
-alkyl group.
The reaction can be carried out either in the presence of a base or in the presence of a Lewis acid.
Bases which can be employed are alkali metal compounds such as, for example, alkali metal hydrides, alkali metal carbonates, alkali metal alkoxides or alkali metal silazanes. Alkali metal carbonates which can be used are lithium, sodium or potassium carbonate. The alkali metal hydride employed can be potassium, lithium or sodium hydride; sodium hydride is preferably employed. The alkali metal alkoxide employed can be sodium or potassium tert-pentoxide or sodium or potassium tert-butoxide, preferably sodium tert-pentoxide or sodium tert-butoxide. The alkali metal silazane used can be sodium hexamethyldisilazane or potassium hexamethyldisilazane. The base preferably employed is an alkali metal hydride or an alkali metal alkoxide.
The reaction is expediently carried out in the presence of a base in a polar organic solvent. The polar solvent used can be, for example, N,N-dimethylacetamide, isopropanol, tert-butanol, toluen
Ford John M.
Lonza AG
LandOfFree
Preparation of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Preparation of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3270225