US 4,539,153 AGranted

Method of preparing 1 .alpha.-hydroxyvitamin D and 1 .alpha.-hydroxyprevitamin D compounds, and adducts of a previtamin D or tachysterol compound with a suitable dienophile

AssigneeDuphar International Research B.V.

InventorsMaurits Vandewalle, Luc J. Vanmaele, Pierre J. De Clercq, Sebastianus J. Halkes, Wilhelmus R. M. Overbeek

Life of this patent

Estimating the term…

Loading patent…

Abstract

The invention relates to a method of preparing 1 .alpha.-hydroxyvitamin D or 1 .alpha.-hydroxy-previtamin D compounds by hydroxylating the 1 .alpha.-position of an adduct of a previtamin D compound with a suitable dienophile, in which adduct optionally present hydroxy group or hydroxy groups is or are protected, if desired, and after removal of the protecting group or groups, isolating the 1 .alpha.-hydroxyvitamin D or 1 .alpha.-hydroxy-previtamin D compound. The invention also relates to 1 .alpha.-hydroxy-previtamin D compounds. The invention further relates to an adduct of a previtamin D or tachysterol compound with a dienophile of the general formula ##STR1## in which A' and B' are equal and represent methoxy groups or ethoxy groups, or in which A' and B' together constitute a phenylimino or o-phenylene group.

Claims34

Dependent claims

A method of preparing a 1.alpha.-hydroxyvitamin D or 1.alpha.-hydroxyprevitamin D compounds, characterized in that an adduct of a previtamin D compound and a dienophile, having the general formula:

##STR2## in which:
R.sub.2 is a side chain derived from a compound selected from the group consisting of a previtamin D compound selected from the group consisting of previtamin D.sub.3, 25-hydroxyprevitamin D.sub.3, and 24,25-dihydroxyprevitamin D.sub.3 ;
the esterification product of a previtamin D compound selected from said group of previtamin D compounds and an esterification agent selected from the group consisting of alkylchlorocarbonates having 2 to 5 carbon atoms, aromatic carboxylic acids, saturated aliphatic carboxylic acids having 1 to 4 carbon atoms, p-toluenesulphonic acid, methane sulphonic acid, trifluoroacetic acid, and derivatives of said acids suitable for the esterification reaction;
and the etherification product of a previtamin D compound selected from said group of previtamin D compounds and an etherification agent selected from the group consisting of triphenyl methyl halides, 2,3-dihydropyran, trialkylsilylhalides having 1 to 6 carbon atoms in the alkyl groups, and trialkylsilylethoxymethylhalides having 1 to 6 carbon atoms in the alkyl groups;
R is selected from the group consisting of hydrogen, hydroxy, hydroxy esterified with an esterification agent selected from said group of esterification agents, and hydroxy etherified with an etherification agent selected from said group of etherification agents;
and
A and B independently represent alkoxy having 1 to 4 carbon atoms or jointly constitute a substituent selected from the group consisting of phenylimino and o-phenylene;
is hydroxylated in the 1.alpha.-position by a reaction with an oxidant selected from the group consisting of chromic acid, pyridine dichromate, tert.-butylchromate, bis(tetrabutylammonium) dichromate, chromiumtrioxide-3,5-dimethylpyrazole complex, and selenium dioxides, followed by reduction with a reductant selected from the group consisting of metal hydrides and complex metal hydrides;
and subsequently, after removal of any protective ester or ether groups present, the 1.alpha.-hydroxyvitamin D or 1.alpha.-hydroxyprevitamin D compound is isolated.

6 more elements

A method of preparing a compound selected from the group consisting of 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyprevitamin D.sub.3, 1.alpha.,25-dihydroxyvitamin D.sub.3, 1.alpha.,25-dihydroxyprevitamin D.sub.3, 1.alpha.,24,25-trihydroxyvitamin D.sub.3 and 1.alpha.,24,25-trihydroxyprevitamin D.sub.3, characterized in that an adduct of a previtamin D compound and a dienophile, having the general formula:

##STR6## in which:
R.sub.1 is a side chain derived from a previtamin D compound selected from the group consisting of previtamin D.sub.3, 25-hydroxyprevitamin D.sub.3, 24,25-dihydroxyprevitamin D.sub.3, the etherification product of 25-hydroxyprevitamin D.sub.3 and an etherification agent selected from the group consisting of tert.-butyl dimethylsilylchloride and trimethylsilylchloride, and the etherification product of 24,25-dihydroxyprevitamin D.sub.3 and an agent selected from said group of etherification agents;
R.sub.1 ' is selected from the group consisting of tert.-butyl dimethylsilyl and trimethylsilyl;
and
A' and B' are the same and are selected from the group consisting of methoxy and ethoxy, or together constitute a substituent selected from the group consisting of phenylimino and o-phenylene;
is hydroxylated in the 1.alpha.-position by a reaction with an oxidant selected from the group consisting of chromic acid, pyridine dichromate and chromiumtrioxide-3,5-dimethylpyrazole, followed by reduction with the reaction product of lithium aluminum hydride and aluminum chloride;
and subsequently, after removal of the tert.-butyl dimethylsilyl group or the trimethylsilyl group by means of treatment with a fluorine-containing compound or a mineral acid, respectively, and after removal of the dienophile group by means of treatment with potassium hydroxide in a lower aliphatic alcohol, the 1.alpha.-hydroxyvitamin D or 1.alpha.-hydroxyprevitamin D compound is isolated.

4 more elements

##STR7## in which:
R.sub.1 is a side chain derived from a previtamin D compound selected from the group consisting of previtamin D.sub.3, 25-hydroxyprevitamin D.sub.3, 24,25-dihydroxyprevitamin D.sub.3, the etherification product of 25-hydroxyprevitamin D.sub.3 and an etherification agent selected from the group consisting of tert.-butyl dimethylsilylchloride and trimethylsilylchloride, and the etherification product of 24,25-dihydroxyprevitamin D.sub.3 and an agent selected from said group of etherification agents;
R.sub.1 ' is selected from the group consisting of tert.-butyl dimethylsilyl and trimethylsilyl;
and
A' and B' are the same and are selected from the group consisting of methoxy and ethoxy, or together constitute a substituent selected from the group consisting of phenylimino and o-phenylene;
is hydroxylated in the 1.alpha.-position by a reaction with a brominating agent selected from the group consisting of N-bromosuccinimide, N,N'-dibromodimethylhydantoin and N-bromophthalimide, followed by hydrolysis;
and subsequently, after removal of the tert.-butyl dimethylsilyl group or the trimethylsilyl group by means of treatment with a fluorine-containing compound or a mineral acid, respectively, and after removal of the dienophile group by means of treatment with potassium hydroxide in a lower aliphatic alcohol, the 1.alpha.-hydroxyvitamin D or 1.alpha.-hydroxyprevitamin D compound is isolated.

4 more elements

##STR8## in which:
R.sub.1 is a side chain derived from a previtamin D compound selected from the group consisting of previtamin D.sub.3, 25-hydroxyprevitamin D.sub.3, 24,25-dihydroxyprevitamin D.sub.3, the etherification product of 25-hydroxyprevitamin D.sub.3 and an etherification agent selected from the group consisting of tert.-butyl dimethylsilylchloride and trimethylsilylchloride, and the etherification product of 24,25-dihydroxyprevitamin D.sub.3 and an agent selected from said group of etherification agents;
R.sub.1 ' is selected from the group consisting of tert.-butyl dimethylsilyl and trimethylsilyl;
and
A' and B' are the same and are selected from the group consisting of methoxy and ethoxy, or together constitute a substituent selected from the group consisting of phenylimino and o-phenylene;
is hydroxylated in the 1.alpha.-position by a reaction with an brominating agent selected from the group consisting of N-bromosuccinimide, N,N'-dibromodimethylhydantoin and N-bromophthalimide, followed by oxidation with an oxidant selected from the group consisting of pyridine-dichromate and bis(tetrabutylammonium)dichromate and stereospecific reduction with the reaction product of lithium aluminum hydride and aluminum chloride;
and subsequently, after removal of the tert.-butyl dimethylsilyl group or the trimethylsilyl grou by means of treatment with a fluorine-containing compound or a mineral acid, respectively, and after removal of the dienophile group by means of treatment with potassium hydroxide in a lower aliphatic alcohol, the 1.alpha.-hydroxyvitamin D or 1.alpha.-hydroxyprevitamin D compound is isolated.

4 more elements

##STR9## in which:
R.sub.1 is a side chain derived from a previtamin D compound selected from the group consisting of previtamin D.sub.3, 25-hydroxyprevitamin D.sub.3, 24,25-dihydroxyprevitamin D.sub.3, the etherification product of 25-hydroxyprevitamin D.sub.3 and an etherification agent selected from the group consisting of tert.-butyl dimethylsilylchloride and trimethylsilylchloride, and the etherification product of 24,25-dihydroxyprevitamin D.sub.3 and an agent selected from said group of etherification agents;
R.sub.1 ' is selected from the group consisting of tert.-butyl dimethylsilyl and trimethylsilyl;
and
A' and B' are the same and are selected from the group consisting of methoxy and ethoxy, or together constitute a substituent selected from the group consisting of phenylimino and o-phenylene;
is hydroxylated in the 1.alpha.-position by an oxidation reaction with an oxidant selected from the group consisting of chromic acid, pyridine dichromate and manganese dioxide, followed by reduction with the reaction product of lithium aluminum hydride and aluminum chloride, said adduct having been hydroxylated in the 1.alpha.-position prior to the oxidation reaction by reaction with a brominating agent selected from the group consisting of N-bromosuccinimide, N,N'-dibromodimethylhydantoin and N-bromophthalimide followed by hydrolysis;
and subsequently, after removal of the tert.-butyl dimethylsilyl group or the trimethylsilyl group by means of treatment with a fluorine-containing compound or a mineral acid, respectively, and after removal of the dienophile group by means of treatment with potassium hydroxide in a lower aliphatic alcohol, the 1.alpha.-hydroxyvitamin D or 1.alpha.-hydroxyprevitamin D compound is isolated.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/636,782Filed 31 Jul 1984 · continuation
Priority: NL 810339317 Jul 1981
Granted: 3 Sep 1985
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 3/02
Drugs for disorders of the metabolism: nutrients, e.g. vitamins, minerals
A61P 3/14
For electrolyte homeostasis: for calcium homeostasis
C07D 237/26
Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings: condensed with carbocyclic rings or ring systems