Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-10-21
2004-02-10
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06689885
ABSTRACT:
The invention relates to a process for preparing compounds of the formula I
where R
1
is
a linear or branched alkyl radical having from 1 to 10 carbon atoms, in which one or two CH
2
groups may be replaced by —CH═CH groups or
a cycloalkyl radical or cycloalkylalkylene radical having from 5 to 12 carbon atoms or
a phenyl radical or phenylmethyl radical
and said radicals are monosubstituted by —COOH, —COOA, —CONH
2
, —CONHA, —CON(A)
2
or —CN where A is an alkyl group having from 1 to 6 carbon atoms.
Compounds of the formula I constitute an effective starting point for the synthesis of medicaments,since the presence of the carbonyl group of pyrimidine makes it possible to attach various radicals, thereby paving the way for the synthesis of novel medicinal substances whose properties may be modified by varying the group to be attached.
Medicinal substances containing the heterocyclic system of compounds of the formula I are described, for example, in DE-198 190 23 A1. These compounds and the salts thereof show good tolerability and possess very valuable pharmacological properties. They show in particular a specific inhibition of cGMP phosphodiesterase (PDE V). Therefore the compounds are suitable for the treatment of diseases of the cardiovascular system, in particular heart failure, and for the treatment and/or therapy of impaired potency (erectile dysfunction).
For broad application of these medicinal substances it is necessary to be able to provide sufficient amounts of suitable starting compounds. The medicinal substances should be obtained in great purity because of the rigorous demands on their purity. Furthermore the reaction should result in a high yield in order to keep costs down and to avoid waste disposal problems.
Houben-Weyl, E9b/2, page 29 to 30 describes the preparation of 2-substituted quinazolin-4(3H)-ones. In this process anthranilic acid or anthranilic esters are reacted with nitrites.
In J. Heterocyclic Chem. 17, 1497 (1980) K. G. Dave et al. describe a process for preparing condensed pyrimidines. The synthesis of benzothieno[3,2-d]pyrimidines and of substituted 4-ethoxy-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidines is described inter alia.
The object of the invention is to provide a process for preparing compounds of the formula I which is simple to carry out and provides the compounds of the formula I in good yields and high purity.
This object is achieved by a process for preparing compounds of the formula I wherein a 2-aminobenzothiophene-3-carboxylic ester of the formula II
where R
2
is a linear or branched alkyl group having from 1 to 6 carbon atoms, in particular methyl, and a nitrile of the formula III
N≡C—R
1
III
where R
1
has the above meaning in solution or suspension in a solvent is reacted in the presence of an acid.
Preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl is used as radical R
2
of the carboxylic ester of the formula II. For the radical R
1
of the nitrile of the formula III linear or branched alkyl radicals having from 1 to 10 carbon atoms may be used, in which one or two CH
2
groups may be replaced by —CH═CH— groups. The alkyl radical used is preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-3-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, linear or branched heptyl, octyl, nonyl or decyl. Furthermore R
1
may be but-2-enyl or hex-3-enyl.
Cycloalkyl radicals or cycloalkylalkylene radicals having from 5 to 12 carbon atoms which may be used are cyclopentylmethylene, cyclohexylmethylene, cyclohexylethylene, cyclohexylpropylene or cyclohexylbutylene. The cycloalkyl radicals preferably comprise from 5 to 7 carbon atoms. Examples are cyclopentyl, cyclohexyl or cycloheptyl groups. Furthermore R
1
may be a phenyl or phenylmethyl radical.
Each of said radicals is mono-substituted by —COOH, —COOA, —CONH
2
, —CONHA, —CON(A)
2
or —CN. A is in this case alkyl having from 1 to 6 carbon atoms. Examples of suitable groups are methyl, ethyl or propyl, and isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, neopentyl, isopentyl or hexyl.
In the process according to the invention the compounds of the formula I are obtained as salts. These precipitate in general from the reaction solution as a crystalline precipitate and may be obtained in sufficient purity by simple filtering off.
The synthesis of the compound of the formula I is in general carried out by initially introducing the carboxylic ester of the formula II and the nitrile of the formula III into a suitable solvent and then adding the acid, for example by passing it into the solution as a gas.
However, it is possible to significantly increase the reaction yield and the purity of the reaction product of the formula I and further to shorten the reaction time if initially an excess of acid is dissolved in the solvent, preferably the solvent is saturated with the acid, and subsequently the 2-aminobenzothiophene-3-carboxylic ester of the formula II and the nitrile of the formula III are added.
An excess of acid is an amount of acid so large that after quantitative reaction of the compounds of the formulae I and II and subsequent precipitation as salt unbound acid still remains in the solution. This amount of acid is to be already present in the reaction mixture at the start of the reaction.
The reaction may proceed such that first a, preferably saturated, solution of the acid in the solvent is prepared and separately therefrom a solution which contains the compounds of the formula I and the formula II. It is possible either for the two solutions then to be introduced simultaneously into a reaction vessel for the reaction or for the acid solution to be initially charged and the solution of the compounds of the formula I and the formula II to be added. It is, however, also possible to initially charge the solution of the compounds of the formula I and the formula II and to add the acid solution. However, in this case the acid solution should be added very rapidly to the solution of the compounds of the formula I and the formula II.
It has proved to be appropriate for the solvent to be selected from the group consisting of ethers, alcohols, esters, water, formamides, amines, carboxylic acids, chlorinated hydrocarbons and mixtures thereof. A particularly suitable solvent is dioxane.
Suitable ethers are, for example, diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane. Suitable alcohols are, for example, methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol. Also suitable are glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methylglycol or ethylglycol), diethylene glycol dimethyl ether (diglyme). Suitable amides are, for example, acetamide, dimethylacetamide, N-methylpyrrolidone or dimethylformamide. A suitable carboxylic acid is, for example, glacial acetic acid. An ester which may be used is, for example, ethyl acetate. Suitable chlorinated hydrocarbons are, for example, trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane. It is also possible to employ mixtures of the solvents mentioned.
The acids are suitably selected from the group consisting of Brönsted acids and Lewis acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, aluminium trichloride and boron trifluoride. Particularly suitable are gaseous acids, in particular hydrogen chloride.
The reaction is suitably carried out at a temperature of from −10° C. to 100° C., preferably 0° C. to 60° C., in particular 10° C. to 50° C.
In a particularly preferred
Juraszyk Horst
Wendel Peter
Woissyk Markus
Ford John M.
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
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