Chloro-8-hydroxy-1,2-methylene-3 -7-from

Prepare under argon a solution of 8 g of 4-dimethylaminopyridine in 250 ml of dry methylene chloride. Cool on an ice bath and add to the stirred solution 6.0 ml of 2-furoyl chloride. Remove from the ice bath, allow the temperature to rise to room temperature and then add 11.5 g of the 21-chloro-9p,lip-epoxy-17a-hydroxy-16a-methyl-l,4-pregnadiene-3,20-dione. After 24 hours add 500 ml of ethyl acetate saturated with water. Filter off the precipitate and then evaporate off the solvent to give the crude 21-chloro-9p,lip-epoxy-17a-hydroxy-16a-methyl-l,4-pregnadiene-3,20-dione 17-(2 -furoate). 

The 3-chloro-l-(4-indolyloxy)-2-propanol is dissolved in 50 ml of toluene and 50 ml of isopropylamine and heated to the boil for 45 h. Evaporation to dryness is effected in a vacuum, the residue is shaken out thrice between ethyl acetate and a 1 N tartaric acid solution and a 5 N sodium hydroxide solution is then added to the combined tartaric acid phases until an alkaline reaction is obtained. The alkaline solution is shaken out thrice with 50 ml of methylene chloride, the extracts are dried over magnesium sulfate and the solvent evaporated in vacuum. The residue is crystallized from ethyl acetate/ether to give the 4-(2-hydroxy-3-isopropylaminopropoxy)indole. 

Androstenolone, 1, can be transformed microbiologically to the 7a,15a-dihy-droxy derivative 2 by the action of Colletotrichium Uni. During formation of the acetal (3), inversion takes place on C-7. Acidic cleavage of 3 results in the triol, 4, which can also be produced by direct acidic catalysis from 2 [12,13]. After selective protection to the 3/l,15a-dipivalate (5), the 15/1,16/1-methylene compound, 6, can be synthetized, and then stereoselectively transformed to the 5/ ,6/ -epoxide, 7. This reacts with triphenylphosphine and tetrachloromethane in pyridine to produce the 7a-chloro derivative, 8. On treatment with zinc and acetic acid, 8 can be converted to the key compound 9, which has a 5/i-hydroxy-6-ene structure. Compound 9 can then be methylenated stereoselectively in the 6/1,7/1 position by the Simmons-Smith method. The last three steps - 10 —> 11 —> 12 — drospirenone -include the build-up of the spironolactone ring, after which water is lost from the molecule and oxidation affords drospirenone. 

ZT-1 is a Schiff base derivative from natural HA, and its chemical name is [51 -(5a,9p,ll )]-5- [(5-chloro-2-hydroxy-3-methoxyphenyl)methylene]amino -ll-ethylidene-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta[b]pyridin-2(lH)-one. ZT-1 is a prodrug and is transformed nonenzymatically into the active compound HA. In aqueous solution, ZT-1 is rapidly degraded into HA and 5-Cl-o-vanillin by hydrolysis. Now, ZT-1 is being developed as a drug candidate for the treatment of AD by Debiopharm S.A. of Switzerland. 

Hydrolysis of 2-amino-3-hydroxy-l-methylpyrazinium toluenesulfonate (87) with aqueous sodium hydroxide at 95° afforded 3-hydroxy-l-methyl-2-oxo-l, 2-dihydropyrazine which was also prepared in poor yield from the action of nitrous acid on 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (832) and hydrolysis of 6-chloro-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine with boiling methanolic sodium methoxide (followed by acidification) gave 6-hydroxy-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine (873). 1,3,6-Trimethyl-2-oxo-1,2-dihydropyrazine methiodide has been converted through l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahy dropy razine and 3-benzoylmethylene-1,4,6-trimethyl-2-oxo-1,2,3,4-tetra-hydropyrazine (in water) to 1,4,6-trimethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazine (1129). 

Mukaiyama cyclization promoted with 2-chloro-l-pyridinium iodide in boiling methylene dichloride <87JOC5296,92JOM(43i)335> was used for the formation of seven-membered alkynic lactones with the triple bond stabilized by complex formation from respective alkynic hydroxy acids (Equation (8)). 

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