Notes- 9(11)-Dehydro Cortical Steroids. Synthesis of 9(11)-Anhydro-17α-hydroxycorticosterone Acetate and 9(11)-Anhydrocorticosterone Acetate

Chamberlin, E. M.; Tristam, E; Utne, Torleif; Chemerda, J. M.

doi:10.1021/jo01072a628

Cited by 14 publications

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“…It has been well understood that the problem in the elimination step was associated with the configuration of carbon C-11. With an 11β-OH, − the base-catalyzed anti E 2 elimination provided the Δ 9,11 double bond in greater than 90% yield. Obviously, with the 11α-OH, the leaving group cannot be anti-coplanar with the H-9 to form the Δ 9,11 double bond exclusively.…”

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confidence: 99%

Process Improvements in the Synthesis of Corticosteroid 9,11β-Epoxides

Fu¹,

Tann²,

Thiruvengadam³

2001

Org. Process Res. Dev.

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Corticosteroid 9,11β-epoxides are key intermediates in the preparation of pharmaceutically important compounds such as betamethasone, mometasone, beclomethasone, and dexamethasone. A new process for the 9,11β-epoxide was developed using a PCl 5 -mediated regioselective dehydration of 11r-hydroxysteroid to form the corresponding ∆ 9,11 double bond. The olefin is then converted into 9r,11β-bromoformate by treatment with 1,3-dibromo-5, 5-dimethyl hydantoin (DBH) in DMF and subsequently cyclized to produce the desired 9,11β-epoxide upon treatment with NaOH. Major process-related impurities such as 21-OH-∆ 9,11 -triene, 21-OH-∆ 11,12 -triene, 21-Cl-∆ 9,11 -triene, and β-epoxide-21-cathylate as well as 11β-Cl are all eliminated or minimized. This new process has been implemented in our manufacturing facility in full-scale production and proved to raise the overall yield and the quality of the product dramatically compared to the existing process.

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mentioning

confidence: 99%

Process Improvements in the Synthesis of Corticosteroid 9,11β-Epoxides

Fu¹,

Tann²,

Thiruvengadam³

2001

Org. Process Res. Dev.

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Methyl chlorosulfite

Ho¹,

Fieser²,

Fieser³

2006

Fieser and Fieser's Reagents for Organic Synthesis

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2,6‐Dimethyl Semibullvalene‐2,6‐dicarboxylates

et al. 1992

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The enolized p-0x0 ester 9 is reduced by NaB(CN)H, in weakly acidic methanol solution to afford an almost quantitative yield of a mixture of diastereomeric P-hydroxy esters 10. On treatment with phosphorus oxychloride in pyridine, 10 is converted into a mixture of the P-chloro esters exo-11, endo-11, exo-12, endo-12, and 13 which is separated in part by chromatography. Sodium methoxide in methanol eliminates hydrogen chloride from the crude mixture of P-chloro esters producing the a$-unsaturated ester ?a in 84% yield based on 9. -Acid-catalysed equilibration of the known vinyl sulphides C2-and Cs-15 is carried out on large scale furnishing a 7 3~2 7 ratio of C2-and Cs-15. This mixture is oxidized to the sulphones C2-and Cs-16 which are allowed to react with sodium cyanide supported on aluminium oxide affording the u,punsaturated dinitrile 17 which is isolated by chromatography. Thus, 17 is now available on a 30-g scale. Methanolysis of l?by a prolonged treatment with hydrogen chloride in methanol followed by hydrolysis of the Pinner salt leads to ?b. -Both a$-unsaturated esters 7 a and b are readily brominated at the allylic positions by N-bromosuccinimide to yield the y,y'-dibromo esters 19a and b. Zinc-copper couple in tetrahydrofuran converts 19a and b into the semibullvalenedicarboxylates 2 a and b. While 2 a is persistent only in dilute solutions, thus frustrating all attempts at its isolation, 2b exhibits considerable stability in solution and forms lemon-coloured crystals.The semibullvalenedicarboxylates 2 a and b undergo a very rapid degenerate Cope rearrangement in solution. In addition, 2 b exhibits reversible thermochromism in both solution and solid state. The structures of the new compounds are based on spectroscopic evidence, including mass, IR, and NMR spectra. The configurations of exo-11, exo-l2,19a and bare established by X-ray diffraction analyses.The predicted accelerating effect of n-acceptor substituents on the degenerate Cope rearrangement of bridged homotropilidenes, e.g. bullvalenes, barbaralanes, and semibullvalenes[21, was demonstrated for the first time in the barbaralane series, with 2,6-dicyanobarbaralane as the andi id ate^^,^]. Shortly afterwards, the 2,6-dicyanosemibullvalene 1 b has been which not only corroborated this resultr6] but also stimulated new interest by exhibiting exceptional properties, such as being yellow in the absence of a chromophor, showing reversible thermochromism ['], and, in the solid state, a rapid non-degenerate Cope rearrangement between valence tautomers non-equivalent only by virtue of their environment in the crystal lattice"'. The interesting colour and thermochromism of 1 b are shared by the 1,5-bridged semibullvalene-2,6-dicarbonitrile 1 c[lo,lll but not by the 3,7-dicyanosemibullvalene 4a['2-141 nor the corresponding dimethyl 3,7-dicarboxylate 4 b"2,151. Grohmann's series of tetramethyl semibullvalenetetracarboxylates 3 seems to exhibit properties similar to those of the dinitriles 1. Unfortunately, an investigation of the thermochromism of 3 is s...

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Notes- 9(11)-Dehydro Cortical Steroids. Synthesis of 9(11)-Anhydro-17α-hydroxycorticosterone Acetate and 9(11)-Anhydrocorticosterone Acetate

Cited by 14 publications

References 1 publication

Process Improvements in the Synthesis of Corticosteroid 9,11β-Epoxides

Process Improvements in the Synthesis of Corticosteroid 9,11β-Epoxides

Methyl chlorosulfite

2,6‐Dimethyl Semibullvalene‐2,6‐dicarboxylates

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