5-Hydroxy-2-adamantanone

Idramantone is an immune agonist

5-Hydroxy-2-adamantanone is used in the hydrosilylation of hydroxyketones. Also used in the preparation of adamantane substituted guanylhydrazones as inhibitors of butyrylcholinesterase, natural enzymes affecting succinic acid regulation.

Idramantone is a member of adamantanones.

Step (i): Preparation of compound of formula (11)Adamantanone (50 grams, 333 mmol) was added with stirring to nitric acid (98percent, 440 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 hours and then heated at 60 °C, for 2 hours until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling. The reaction mixture was diluted with water (200 mL) and concentrated sulphuric acid (75 mL). The resultant clear yellow solution was heated on the steam bath in a hood for 1 hour. The reaction mixture was neutralized with 30percent aqueous sodiumhydroxide solution, and while warm, extracted with chloroform. The extracts were combined, washed with brine solution and concentrated in vacuum. The crude product was dissolved in dichloromethane ( 15 mL) and hexane was added until no more precipitate was formed. The solid material was isolated by filtration and dried under vacuum to obtain compound of formula (11) (40.9 grams). Yield: 74 percent. Melting Range: 278.8-300 °C; -NMR (CDCI3): δ 2.69 (bs, 2H), 2.36-2.32 (m, 2H), 2.12-2.02 (m, 2H), 2.02-1 :88 (m, 6H), 1.80- 1.68 (m, 1H).IR: 3410, 2929, 2855, 2645, 1725, 1539, 1452, 1351, 1288, 1 1 16, 1055, 927, 900, 797;Mass (m/z): 167 [Μ+ΗAdamantanone (12 g, 80 mmol) was added under stirring to nitric acid (98percent, 100 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 h and then heated to 60 °C, for 2 h until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling (NOStep (i): Preparation of compound of formula (11)Adamantanone (50 grams, 333 mmol) was added with stirring to nitric acid (98%, 440 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 hours and then heated at 60 C, for 2 hours until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling. The reaction mixture was diluted with water (200 mL) and concentrated sulphuric acid (75 mL). The resultant clear yellow solution was heated on the steam bath in a hood for 1 hour. The reaction mixture was neutralized with 30% aqueous sodiumhydroxide solution, and while warm, extracted with chloroform. The extracts were combined, washed with brine solution and concentrated in vacuum. The crude product was dissolved in dichloromethane ( 15 mL) and hexane was added until no more precipitate was formed. The solid material was isolated by filtration and dried under vacuum to obtain compound of formula (11) (40.9 grams). Yield: 74 %. Melting Range: 278.8-300 C; -NMR (CDCI3): delta 2.69 (bs, 2H), 2.36-2.32 (m, 2H), 2.12-2.02 (m, 2H), 2.02-1 :88 (m, 6H), 1.80- 1.68 (m, 1H).IR: 3410, 2929, 2855, 2645, 1725, 1539, 1452, 1351, 1288, 1 1 16, 1055, 927, 900, 797;Mass (m/z): 167 [Mu+Eta+].Adamantanone (12 g, 80 mmol) was added under stirring to nitric acid (98%, 100 mL) at ice bath temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 72 h and then heated to 60 C, for 2 h until most of the nitrogen dioxide evaporated. Excess nitric acid was distilled off under reduced pressure. The light yellow oil solidified upon cooling (NO3 adduct of the hydroxyketone). Water (40 mL) and cone. H2SO4 (98%, 15 mL) were added. The resulting clear yellow solution was heated on the steam bath in a hood (nitrous fumes) for 1 h. The solution was then cooled and extracted with a 2:1 mixture of n-hexane and diethylether to remove unreacted adamantanone (1.0 g). The acid layer was neutralized with 30% aq. NaOH solution, and while warm, extracted with chloroform. The extracts were combined, washed with brine solution, and concentrated in vacuum. The crude product was dissolved in CH2Cl2 (15 mL) and hexane was added until no more precipitate was formed. The solid material was isolated by filtration and dried to get (a) Synthesis of 5-Hydroxyadamantan-2-one (40) Into a single neck 500 mL round bottom flask equipped with a magnetic stirrer and water bath, 75 parts of acetic acid containing 5 parts acetic anhydride was added. Twenty five parts of chromium trioxide was added in portions in 40 minutes while the temperature was maintained at 15-20 C. with water bath. Five parts of Adamantan-2-one was added in portions over a period of 15 minutes. Stirring was continued for one hour. The viscous reaction mixture was poured into cold 250 mL of aqueous 20% sodium hydroxide solution. The aqueous layer was extracted with 3*250 mL of ethyl acetate and washed with 2*250 mL of water and dried over sodium sulfate. Solvent was evaporated under reduced pressure and chromatographed on silica gel column using 75% ethyl acetate/hexane. The desired fractions were collected and solvent was evaporated to give a solid, yield 2.6 parts, single spot on silica gel TLC plate. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:(a) Synthesis of 5-Hydroxyadamantan-2-one (40) Into a single neck 500 mL round bottom flask equipped with a magnetic stirrer and water bath, 75 parts of acetic acid containing 5 parts acetic anhydride was added. Twenty five parts of chromium trioxide was added in portions in 40 minutes while the temperature was maintained at 15-20 C. with water bath. Five parts of Adamantan-2-one was added in portions over a period of 15 minutes. Stirring was continued for one hour. The viscous reaction mixture was poured into cold 250 mL of aqueous 20% sodium hydroxide solution. The aqueous layer was extracted with 3*250 mL of ethyl acetate and washed with 2*250 mL of water and dried over sodium sulfate. Solvent was evaporated under reduced pressure and chromatographed on silica gel column using 75% ethyl acetate/hexane. The desired fractions were collected and solvent was evaporated to give a solid, yield 2.6 parts, single spot on silica gel TLC plate. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:(a) Synthesis of 5-Hydroxyadamantan-2-one (40). Into a single neck 500 mL round bottom flask equipped with a magnetic stirrer and water bath, 75 parts of acetic acid containing 5 parts acetic anhydride was added. Twenty five parts of chromium trioxide was added in portions in 40 minutes while the temperature was maintained at 15-20 C. with water bath. Five parts of Adamantan-2-one was added in portions over a period of 15 minutes. Stirring was continued for one hour. The viscous reaction mixture was poured into cold 250 mL of aqueous 20% sodium hydroxide solution. The aqueous layer was extracted with 3*250 mL of ethyl acetate and washed with 2*250 mL of water and dried over sodium sulfate. Solvent was evaporated under reduced pressure and chromatographed on silica gel column using 75% ethyl acetate/hexane. The desired fractions were collected and solvent was evaporated to give a solid, yield 2.6 parts, single spot on silica gel TLC plate. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:Example II This example illustrates the preparation of [4-(2-methoxy(D3))-4-(3-phosphoryloxy-4-chlorophenyl)] spiro [1, 2-dioxetane-3, 2'-(5-chloroadamantane)], disodium salt (28). (a). Synthesis of 5-Hydroxyadamantan-2-one (23), (a starting intermediate ketone).; Into a single neck 500mL round bottom flask equipped with a magnetic stirrer and water bath, 75 parts of acetic acid containing 5 parts acetic anhydride was added. Twenty-five parts of chromium trioxide was added in portions in 40 minutes while the temperature was maintained at 15-20 C with water bath. Five parts of adamantan-2-one (22) was added in portions over a period of 15 minutes. Stirring was continued for one hour. The viscous reaction mixture was poured into cold 250mL of aqueous 20% sodium hydroxide solution. The aqueous layer was extracted with 3x 250mL of ethyl acetate and washed with 2 x 250mL of water and dried over sodium sulfate. Solvent was evaporated under reduced pressure and chromatographed on silica gel column using 75% ethyl acetate / hexane. The desired fractions were collected and solvent was evaporated to give a solid, yield 2.6 parts, single spot on silica gel TLC plate. The structure was confirmed on the basis of 1H NMR. The reaction proceeded as follows:General procedure: The reaction mixture (50ml) contained cells of the transformed E. coli strain (15g dry cell weight (DCW)/l), 2-adamantanone (20mM), dimethylsulfoxide (DMSO) (10%, v/v), and potassium phosphate buffer (200mM, pH 7.5) containing glycerol (10%, v/v). The reaction mixture was supplemented with glucose (50mM) when required. Fifteen grams of DCW corresponded to 50g of wet cell weight. The reactions were performed at 30C with rotary shaking at a speed of 120rpm.(b). Synthesis of 5-chloroadamantan-2-one (24), (a coupling ketone).; In a round bottom flask 20 parts of 5-hydroxyadamantan-2-one was dissolved in 120mL of thionylchloride and boiled under refluxed for two hours. The excess thionyl chloride was evaporated. The residue was dissolved in 100mL of methylene chloride and washed with 0.5N sodium hydroxide and then 10% aqueous sodium chloride solution. The organic layer was dried on sodium sulfate and the solvent evaporated under reduced pressure to give a white solid, yield 16.9g. The reaction proceed as follows:Example 54 N-[(E)-5-(Aminosulfonyl)-2-adamantyll-2-(4-chlorophenoxyV2-methylpropanamideExample 54A1 -Bromoadaman-4-one; 5-Hydroxy-2-adamantanone (5.00 g, 30.1 mmol) was mixed with 48% hydrobromic acid (50 mL) and heated at 1000C for 48 hours (H. W. Geluk, J. L. M. A. Schlatmann, Tetrahedron 24: 5369-5377, 1968). Reaction diluted with water and extracted twice with ether. Combined extracts dried (Na2SO4), decanted, and evaporated under reduced pressure. The residue was purified on normal phase HPLC (silica gel, 5-10% ethyl acetate in hexane) to provide the title compound (4.19 g, 61%).

anthelmintic

Molecular Weight:166.22
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:166.099379685
Monoisotopic Mass:166.099379685
Topological Polar Surface Area:37.3
Heavy Atom Count:12
Complexity:228
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes