Process for preparing...

Details Process for preparing... Process for preparing...

1999-12-15

2001-01-30

Ramsuer, Robert W. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S360000, C546S193000, C546S212000, C546S232000, C546S338000, C564S256000

Reexamination Certificate

active

06180787

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel process for preparing O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of the formula (I) wherein
R
1
is phenyl, pyridyl or thienyl or substituted phenyl, wherein the one or more substituent(s) may be halo and/or haloalkyl and/or nitro,
X is halo,
R
2
and R
3
are independently from each other straight or branched lower alkyl or
R
2
and R
3
together with the nitrogen connecting thereto form a saturated 5 to 7-membered heterocyclic group which may contain additional hetero atom and may be substituted.
The invention also relates to a process for preparing the acid addition salts and optically active forms of the above compounds.
BACKGROUND ART
O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of the general formula (I) are well known as active substances in the treatment of pathological changes in the vascular system connected with diabetes mellitus, especially with diabetic angiopathy. These compounds are particularly described e.g. WO-A-90/04584.
O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides of the general formula (I) can be prepared in many different ways some of them being also described in the WO-A-90/04584.
Although the known synthesis routes for manufacture are suitable allow the preparation of the compounds of formula (I), they are not sufficient for the preparation of the said compounds in industrial scale. The disadvantage thereof is that they need reagents which are difficult to handle or prepare or comprise unfavourable reactions with non-satisfactory yields due to the possibility of side reactions. The urging need for the compounds of formula (I) requires a novel process which is secure, has a satisfactory yield and can be carried out under industrial conditions.
DISCLOSURE OF INVENTION
The present invention aims to provide a process for preparing O-(3-amino-2-hydroxy-propyl)-hydroxymic acid halides in industrial scale.
The present invention provides an industrially applicable process for preparing the compounds of the formula (I) by
i) reacting an amidoxime compound of the formula (II) with a 3-hydroxy-azetidinium salt of the formula (III) wherein
R
2
and R
3
have the meaning as specified above and
Y
−
is a salt forming anion in a basic-alcoholic medium,
ii) neutralizing the mixture and removing the organic solvent,
iii) reacting the residue with sodium nitrite in aqueous medium in the presence of hydrochloric acid
iv) decomposing the diazonium salt thus obtained and
v) isolating the crude product of the formula (I) from the mixture.
Reactions of amidoxime compounds of the formula II and suitably substituted 3-amino-2-hydroxy-propane derivates (usually 1-halo- or 1,2-epoxy derivates) are described e.g. in GB Patent No. 1.582.029. However, the 3-hydroxy azetidinium salts of the formula (III) are more suitable reagents than the 1-halo- or 1,2-epoxi derivates used in the known reactions. Namely, compounds of the formula (III) are solid materials which can easily be prepared, isolated and stored unlike the reagents materials. The use thereof became known from WO-A-90/08131, but in the process described therein neither these nor the other two reagents are directly reacted with the compounds of the formula (II), but with an amidoxime complex prepared therefrom with alkali hydroxide or alkali and dimethyl formamide alcoholate or 1,3-dimethyl-2-imidazolidinone in a medium containing dimethyl formamide. Thus, O-substituted amidoxime derivatives were isolated which, however appear only as non-isolated intermediates in the reaction sequence according to the present invention.
Based on our observations efforts were made to eliminate the technologically difficult complex forming from the process and to avoid the use of dimethyl formamide as solvent. Dimethyl formamide is hazardous for health as it causes cancer, furthermore it is difficult to regenerate and purify and extremely difficult to make water-free. This is especially important as dimethyl formamide impurity must be minimized as pointed out in WO-A-90/08131. Moreover, it is preferable that the solvent contains only very small quantity of water, practically less than 1% to achieve a proper yield. An additional disadvantage of the use of dimethyl formamide is that it decomposes when exposed to light thus becoming contaminated by the toxic compounds envolved. It has been found that the reaction can safely and easily be carried out by redacting the compounds of the formulae (II) and (III) directly in a basic alcoholic medium which may also contain water. In respect of the outcome of the synthesis it is very useful that the O-substituted carboxamide oxime intermediate is not isolated from the reaction mixture, but directly reacted further after neutralizing the mixture and removing the organic solvent. It has also been found that the side products formed during the contracted steps can all be removed by one suitable isolation step and thus, the synthesis is appropriate for manufacturing the product in the desired purity.
Based on these observations, the invention provides a process for preparing compounds of the formula (I), wherein
R
1
is phenyl, pyridyl or thienyl or substituted phenyl, wherein the one or more
X is halo,
R
2
and R
3
are independently from each other straight or branched lower alkyl or
R
2
and R
3
together with the nitrogen connecting thereto form a 5 to 7-membered saturated heterocyclic group which may contain additional hetero atom and may be substituted,
and the acid addition salts and optically active forms thereof by reacting a carboxamide oxime of the formula (II) wherein the meaning of R
1
is as specified above with a reactive 3-amino-2-hydroxy-propane derivate, diazotizing the resulting O-substituted carboxamide oxime with sodium nitrite in the presence of hydrohalide, decomposing the diazonium salt, isolating the product obtained and, if desired, separating the optically acive enantiomers and/or reacting the resulting base with an organic or mineral acid; which comprises reacting the carboxamide oxime of the formula (II) with a 3-hydroxy acetidinium salt of the formula (III) wherein R
2
and R
3
have the meaning as specified above and Y
−
is a salt forming anion in a C
1-4
alcoholic preferably ethanolic medium made alkaline with an alkali hydroxide, the said medium optionally containing water while neutralizing the reaction mixture and removing the organic solvent therefrom before diazotizing the resulting O-substituted carboxamide oxime intermediate.
BEST MODE FOR CARRYING OUT THE INVENTION
A preferred mode of carrying out the process according to the invention is as follows:
The carboxamid oxime of the formula (II) and the 3-hydroxy azetid nium salt of the formula (III) are reacted at stoichiometric ratio, however, it may be advantageous to apply the compound of the formula (III) in a slight excess. The reaction can be carried out with any order of addition of the reagents, preferably the compound of the formula (II) is added to the basic-alcoholic solution of the compound of the formula (III). As solvent preferably a C
1-4
alkanol, preferably ethanol is used and the reaction is carried out preferably with heating, most preferably at the boiling point of the solvent. After termination of the reaction, the mixture is cooled and neutralized with a mineral pressure. After removing the solvent the reaction mixture is diluted with water, the concentrated hydrochloric acid necessary for diazotizing is added, cooled to the diazotizing temperature and is diazotized by the addition of the sodium nitrite under cooling at a temperature of 0 to +5° C. The diazonium salt decomposes in situ into the corresponding hydroximoyl-halide derivative. To isolate the crude product, the reaction mixture is made alkaline with an inorganic alkali compound, extracted with an organic solvent non-miscible with water, preferably ethyl acetate, the extract is dried and concentrated, or directly an acid addition salt is formed from the product by adding a suitable acid to the mixture and separating the acid addition salt by

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