Abstract |
In Niemann-Pick disease, type C1, increased amounts of 3beta,7beta-dihydroxy-5-cholenoic acid are reported to be present in urinary bile acids. The compound occurs as a tri-conjugate, sulfated at C-3, N-acetylglucosamidated at C-7, and N-acylamidated with taurine or glycine at C-24. For sensitive LC-MS/MS analysis of this bile acid, a suitable internal standard is needed. We report here the synthesis of a satisfactory internal standard, 3beta-sulfooxy-7beta-hydroxy-24-nor-5-cholenoic acid (as the disodium salt). The key reactions involved were (1) the so-called "second order" Beckmann rearrangement (one- carbon degradation at C-24) of hyodeoxycholic acid (HDCA) 3,6-diformate with sodium nitrite in a mixture of trifluoroacetic anhydride and trifluoroacetic acid, (2) simultaneous inversion at C-3 and elimination at C-6 of the ditosylate derivatives of the resulting 3alpha,6alpha-dihydroxy-24-nor-5beta-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3beta,7beta-dihydroxy-24-nor-Delta(5) derivative using sulfur trioxide- trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.
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Authors | Genta Kakiyama, Akina Muto, Miki Shimada, Nariyasu Mano, Junichi Goto, Alan F Hofmann, Takashi Iida |
Journal | Steroids
(Steroids)
Vol. 74
Issue 9
Pg. 766-72
(Sep 2009)
ISSN: 1878-5867 [Electronic] United States |
PMID | 19394355
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 3-sulfooxy-7-hydroxy-24-nor-5-cholenoic acid
- Bile Acids and Salts
- Norsteroids
- Sulfuric Acid Esters
- Cholic Acid
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Topics |
- Bile Acids and Salts
(chemistry, urine)
- Cholic Acid
(chemical synthesis, chemistry, urine)
- Chromatography, High Pressure Liquid
- Chromatography, Liquid
- Humans
- Mass Spectrometry
(standards)
- Niemann-Pick Diseases
(urine)
- Norsteroids
(chemical synthesis, chemistry, urine)
- Reference Standards
- Sensitivity and Specificity
- Sulfuric Acid Esters
(chemical synthesis, chemistry, urine)
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