Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1998-12-09
2001-01-23
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C514S621000, C540S200000, C546S226000, C548S539000, C548S966000, C564S134000, C564S138000, C564S148000
Reexamination Certificate
active
06177594
ABSTRACT:
The invention relates to benzamides of the formula I:
wherein
R
1
and R
2
independently of one another are each alkyl having 1-6 C atoms, or
R
1
and R
2
together are alkylene, and their salts.
The object of the invention was to find novel compounds which can be used especially as intermediates in the synthesis of drugs, but which can also be used directly for the preparation of drugs.
It has been found that the compounds of the formula I and their salts are important intermediates for the preparation of drugs.
The invention provides the benzamide derivatives of the formula I and their salts.
Above and below, the radicals R
1
and R
2
are as defined in the formulae I to III, unless expressly indicated otherwise.
In the above formulae, alkyl is preferably unbranched and has 1, 2, 3, 4, 5 or 6 C atoms, preferably 1, 2, 3, 4 or 5 C atoms; it is preferably methyl, ethyl or propyl, other preferences being isopropyl, butyl, isobutyl, sec-butyl or tert-butyl as well as n-pentyl, neopentyl or isopentyl.
Alkylene is preferably, ethylene, propylene, butylene or pentylene.
The invention also provides a process for the preparation of benzamides of the formula I according to claim
1
and their salts, characterized in that a compound of the formula II:
wherein
L is Cl, Br, OH or a reactive esterified OH group, is reacted with a compound of the formula III:
HNR
1
R
2
III
or one of its salts,
wherein R
1
and R
2
are defined as indicated, and/or
in that a base of the formula I is converted to one of its salts by treatment with an acid.
Incidentally, the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, such as those described in the literature (e.g. in the standard works like Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart), under reaction conditions which are known and suitable for said reactions. It is also possible here to make use of variants known per se, which are not mentioned in greater detail in this specification.
If desired, the starting materials can also be formed in situ so that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I.
In the compounds of the formulae II, the radical L is preferably Cl or Br; however, it can also be I, OH or a reactively modified OH group such as alkylsulphonyloxy having 1-6 C atoms (preferably methylsulphonyloxy) or arylsulphonyloxy having 6-10 C atoms (preferably phenylsulphonyloxy, p-tolylsulphonyloxy or 1- or 2-naphthalenesulphonyloxy).
The methods used for reacting the compounds of the formulae II with compounds of the formulae III are those known from the literature for the acylation of amines. The components can also be melted together, optionally in a sealed tube or in an autoclave, without the presence of a solvent.
The compounds of the formula III can also be used in the form of their salts, as described for example by Davidson et al., Synthetic Commun. 20, 727-732 (1990).
However, the compounds can also be reacted in the presence of an inert solvent.
Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether (methyl glycol or ethyl glycol) or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulphoxides such as dimethyl sulphoxide (DMSO); carbon disulphide; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; and optionally also mixtures of said solvents with one another or mixtures with water.
It may be favourable to add an acid-binding agent, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another alkali metal or alkaline earth metal salt of a weak acid, preferably the potassium, sodium or calcium salt of a weak acid, or to add an organic base such as triethylamine, dimethylamine, pyridine or quinoline or an excess of the amine component. The reaction time is between a few minutes and 14 days, depending on the conditions applied; the reaction temperature is between −20 and 1000, normally between −10 and 40°.
A base of the formula I can be converted with an acid to the corresponding acid addition salt, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol, and then evaporating the solution. Acids which are particularly suitable for this reaction are those which produce biocompatible salts. Thus it is possible to use inorganic acids, e.g. sulphuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, or sulphamic acid, and organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulphonic or sulphuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethyl-acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulphonic or ethanesulphonic acid, ethanedisulphonic acid, 2-hydroxy-ethanesulphonic acid, benzenesulphonic acid, p-toluene-sulphonic acid, naphthalenemonosulphonic and naphthalene-disulphonic acids or laurylsulphuric acid. Salts with non-biocompatible acids, e.g. picrates, can be used to isolate and/or purify the compounds of the formula I.
On the other hand, compounds of the formula I can be converted with bases (e.g. sodium or potassium hydroxide or carbonate) to the corresponding metal salts, especially alkali metal or alkaline earth metal salts, or to the corresponding ammonium salts.
The invention also provides the use of the compounds of the formula I as intermediates for the synthesis of drugs.
The invention also provides the use of the compounds of the formula I according to claim
1
in reduction reactions, characterized in that the reaction of the compounds of the formula I is carried out with complex metal hydrides.
The reduction of the ketoamides according to the invention can be carried out e.g. with lithium aluminium hydride, analogously to the method of Deslongchamps et al., Can. J. Chem., 53, 3613-3619 (1975).
Examples of other reducing agents which can be used are NaBH
4
or NaAl(OCH
2
CH
2
OCH
3
)
2
H
2
, as well as diborane, if desired with the addition of catalysts such as BF
3
, AlCl
3
or LiBr. Examples of suitable solvents are the inert solvents mentioned above.
Above and below, all temperatures are given in ° C. “Conventional working-up” has the following meaning in the Examples below: Water is added, if necessary, the pH is adjusted to between 2 and 10, if necessary, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulphate and evaporated and the residue is purified by chromatography on silica gel and/or by crystallization. Rf values on silica gel.
REFERENCES:
patent: 5454974 (1995-10-01), Boller et al.
EP331933-English Abstract, 1989.
Reiffenrath Volker
Stern Margit
W{umlaut over (a)}chtler Andreas
Kumar Shailendra
Merck Patent Gesellschaft mit beschrankter Haftung
Millen White Zelano & Branigan P.C.
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