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US 5,684,156 AGranted
Process for preparation of clonidine derivatives
OwnerDavid R. Pierce, William D. Dean +1inventors
InventorsDavid R. Pierce, William D. Dean, Michael E. Deason
Life of this patent
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Abstract
A novel process for preparing clonidine derivatives has been discovered which is shorter, less expensive and safer than previously known methods. A new thiourea complex has also been discovered which can be directly cyclized to produce the corresponding heterocyclic product.
Claims23
A process for preparing a compound of formula:
- ##STR10## by reacting a complex of formula (I):
- ##STR11## in a solvent at reflux, wherein:
- Ar is a phenyl or naphthyl, and unsubstituted or substituted with one or more moieties selected from the group consisting of:
- Cl, F, Br, I, C.sub.1 to C.sub.4 alkyl, phenyl, naphthyl, C.sub.1 to C.sub.4 alkoxy, phenylalkoxy and naphthylalkoxy;
- NO.sub.2 is in the para or ortho position;
- and
- n is 1 to 4.
4 more elements
A process for preparing a compound of formula:
- ##STR12## by reacting a compound of formula:
- ##STR13## wherein:
- Ar is a phenyl or naphthyl, and unsubstituted or substituted with one or more moieties selected from the group consisting of:
- Cl, F, Br, I, C.sub.1 to C.sub.4 alkyl, phenyl, naphthyl, C.sub.1 to C.sub.4 alkoxy, phenylalkoxy and naphthylalkoxy;
- NO.sub.2 is in the para or ortho position;
- and
- n is 1 to 4;
- with a base selected from the group consisting of:
- diaminoalkanes, imidazoles, metal hydroxides, metal alkoxides in a solvent or metal carbonates, at elevated temperatures.
6 more elements
A process for preparing amino clonidine derivatives, comprising the steps of:
- (a) converting a substituted or unsubstituted o- or p- nitroaniline to the corresponding nitrophenylisothiocyanate by addition of thiophosgene to the nitroaniline in an aliphatic or aromatic hydrocarbon solvent, adding dimethylformamide or a metal carbonate, and heating the mixture to reflux;
- (b) converting the nitrophenylisothiocyanate from step (a) to the corresponding complex, .omega.-aminoalkylnitrophenylthiourea, alkyl-.alpha., .omega.-diamine solvate, by slowly adding the nitrophenylisothiocyanate to an alkyl-.alpha., .omega.-diamine in an aliphatic or aromatic solvent at room temperature or lower;
- (c) direct cyclization of the .omega.-aminoalkylnitrophenylthiourea, alkyl-.alpha.,.omega.-diamine solvate to the corresponding heterocyclic product by heating the complex in a solvent to reflux;
- and
- (d) converting the nitrophenyl product of step (c) to the corresponding aminophenyl dihydrochloride by reaction with hydrogen and a Raney nickel catalyst in an alcoholic solvent, followed by HCl treatment.
2 more elements
A process for preparing 4-aminoclonidine, comprising the steps of:
- (a) converting 2,6-dichloro-4-nitroaniline to 2,6-dichloro-4-nitrophenylisothiocyanate by addition of thiophosgene to the nitroaniline in an aliphatic or aromatic solvent, adding dimethylformamide, and heating the mixture to reflux;
- (b) converting the nitrophenylisothiocyanate from step (a) to 1,(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)thiourea, ethylenediamine solvate by slowly adding the nitrophenylisothiocyanate to ethylenediamine in a non-hydroxylic solvent at or below room temperature;
- (c) direct cyclization of the 1 (2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)thiourea, ethylenediamine solvate to 2-(2,6-dichloro-4-nitrophenyl)imino!imidazolidine by heating the complex in a solvent at reflux;
- (d) converting the nitrophenyl product of step (c) to 2-(2,6-dichloro-4-aminophenyl)imino!imidazolidine dihydrochloride by reaction with Raney nickel in methanol, followed by treatment with hydrogen chloride;
- and
- (e) converting the dihydrochloride to the monohydrochloride.
3 more elements
A process for preparing amino clonidine derivatives, comprising the steps of:
- (a) converting a substituted or unsubstituted o- or p- nitroaniline to the corresponding nitrophenylisothiocyanate by addition of thiophosgene to the nitroaniline in an aliphatic or aromatic hydrocarbon solvent, adding dimethylformamide or a metal carbonate, and heating the mixture to reflux;
- (b) converting the nitrophenylisothiocyanate from step (a) to the corresponding complex, .omega.-aminoalkylnitrophenylthiourea, alkyl-.alpha.,.omega.-diamine solvate, by slowly adding the nitrophenylisothiocyanate to an alkyl-.alpha.,.omega.-diamine in an aliphatic or aromatic solvent at room temperature or lower;
- (c) converting the .omega.-aminoalkylnitrophenylthiourea, alkyl-.alpha.,.omega.-diamine solvate to the corresponding .omega.-aminoalkylnitrophenylthiourea hydrochloride by adding HCl gas to methanol containing the .omega.-aminoalkylnitrophenylthiourea, alkyl-.alpha., .omega.-diamine solvate until the mixture reaches a pH of about 1-2 and filtering the aminoalkylnitrophenylthiourea hydrochloride from the methanol;
- (d) direct cyclization of the .omega.-aminoalkylnitrophenylthiourea hydrochloride to the corresponding heterocycle by heating the .omega.-aminoalkylnitrophenylthiourea hydrochloride in water containing sodium hydroxide at reflux;
- and
- (e) converting the nitrophenyl product of step (d) to the corresponding aminophenyl dihydrochloride by reaction with hydrogen and a Raney nickel catalyst in an alcoholic solvent, followed by HCl treatment.
3 more elements
A process for preparing 4-aminoclonidine, comprising the steps of:
- (a) converting 2,6-dichloro-4-nitroaniline to 2,6-dichloro-4-nitrophenylisothiocyanate by addition of thiophosgene to the nitroaniline in an aliphatic or aromatic solvent, adding dimethylformamide, and heating the mixture to reflux;
- (b) converting the nitrophenylisothiocyanate from step (a) to 1,(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)thiourea, ethylenediamine solvate by slowly adding the nitrophenylisothiocyanate to ethylenediamine in a non-hydroxylic solvent at or below room temperature;
- (c) converting 1,(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl) thiourea, ethylenediamine solvate to 1,(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl) thiourea hydrochloride by adding HCl gas to methanol containing the nitrophenylthiourea, ethylenediamine solvate until the mixture reaches a pH of about 1-2 and filtering the 1,(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)thiourea hydrochloride from the methanol;
- (d) direct cyclization of the 1,(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)thiourea hydrochloride to 2-(2,6-dichloro-4-nitrophenyl)imino!imidazolidine by heating the nitrophenylthiourea hydrochloride in water containing sodium hydroxide at reflux;
- (e) converting the nitrophenyl product of step (d) to 2-(2,6-dichloro-4-aminophenyl)imino!imidazolidine dihydrochloride by reaction with Raney nickel in methanol, followed by treatment with hydrogen chloride;
- and
- (f) converting the dihydrochloride to the monohydrochloride.
4 more elements
Dependencies are inferred from the claim text.