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US 2011/0213168 A1Published application
Deuterated vitamin d compounds
AssigneeUniversidade De Santiago De Compostela
InventorsMiguel A. Maestro Saavedra, Antonio Mourino Mosquera, Daniel Nicoletti, Rita Sigueiro Ponte
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Abstract
The invention relates to deuterated vitamin D compounds and the process for preparing and synthesizing a class of vitamin D compounds which can be isotopically substituted. These compounds can be used as internal standards in methods for the quantification of vitamin D, its metabolites and analogues by mass spectrometry. These compounds are described by means of general formula I.
Claims9
A compound of formula I:
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R1, R2, R3 and R4 are independently selected from hydrogen, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- with the proviso that when N is hydrogen or methyl, then R2 is necessarily hydroxyl.
3 more elements
A process for preparing the compounds of formula I,
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R1, R2, R3 and R4 are independently selected from hydrogen, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- comprising
- a) a Wittig-Horner reaction between compounds II and III in the presence of a base
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R1, R2, R3 and R4 are independently selected from hydrogen, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups
- or
- b) coupling compounds IV and V in the presence of a catalyst,
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R3 is selected from hydrogen, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- X is indium bichloride (—InCl2), zinc bromide (—ZnBr) or dialkoxyboron [—B(OR)2], and
- Σ is an SiR3, SiR2R′, R and R′ being alkyl or aryl radicals, or a methoxymethyl group.
18 more elements
(canceled)
A compound selected from the group consisting of:
- (i) a compound of formula III,
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R3 is independently selected from the group consisting of hydrogen, hydroxyl or —OR, wherein R is selected from methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- with the exception of the following compound:
- wherein Σ is an SiR3, SiR2R′, R and R′ being alkyl or aryl radicals, or a methoxymethyl group;
- (ii) a compound of formula IV,
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R3 is independently selected from hydrogen, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- X is indium bichloride (—InCl2), zinc bromide (—ZnBr) or dialkoxyboron [—B(OR)2];
- (iii) a compound of formula VI,
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- N is a hydrogen, trideuteromethyl, methyl, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- R1 is a hydroxyl, trialkylsilyloxy or benzoate group,
- R2 is hydrogen, a hydroxyl group, a trialkylsilyloxy group;
- or R1 and R2 are both halomethylene,
- R3 is selected from hydrogen, hydroxyl or —OR, wherein R is selected from the group consisting of methoxymethyl, methoxyethyl, trimethylsilylethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyl, t-butyldiphenylsilyl, dimethylphenylsilyl, dimethylbenzylsilyl, benzoate, p-nitrobenzoate, pivalate, and acetate groups,
- with the exception of the following compound:
- wherein Σ is an SiR3 SiR2R′, R and R′ being alkyl or aryl radicals, or a methoxymethyl group;
- (iv) a compound of formula VII,
- wherein
- A is a single or double bond,
- M is a trideuteromethyl group,
- R1 is a hydroxyl, trialkylsilyloxy or benzoate group,
- R2 is hydrogen, or R1 and R2 can both be a halomethylene or carbonyl group;
- (v) a compound of formula VIII,
- wherein
- A is a single, double or triple bond,
- M is a trideuteromethyl group,
- Y is a hydroxyl, carbamate or diethylphosphate group,
- R1 is a hydroxyl, trialkylsilyloxy or benzoate group,
- R2 is hydrogen, or R1 and R2 can both be a halomethylene or carbonyl group;
- and
- (vi) a compound of formula IX, X or XI
- wherein
- Z is an oxygen or a dibromomethylene group,
- X is a hydrogen, a hydroxyl group or a trialkylsilyloxy group,
- Σ is an SiR3 SiR2R′, R and R′ being alkyl or aryl radicals, or a methoxymethyl group.
42 more elements
-12. (canceled)
Dependencies are inferred from the claim text.