Vitamin K

To a dichloromethane solution (20ml) of 2-methyl-1,4-naphthoquinone (172mg, 1.0mmol) BF₃^.Et₂O (3.0mmol) was added under N₂ at -78 C. After that phytyltrimethyltin was (532mg, 1.2mmol) was added, and the temperature of the resulting solution was gradually elevated within 1h. Then, ether and aqueous saturated NaCl solution were added to the reaction mixture. The organic layer and the combined ether extract were dried over anhydrous magnesium sulfate. Subsequent oxidation with excess silver oxide gave crude vitamin K₁ after solvent was evaporated in vacuo. The resulting crude product was purified by preparative TLC on silica gel; affording vitamin K₁(176mg) (Ref. 0009)
[Table 0006] (Ref. 0008).

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with methylbutenol (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with linalool (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with nerolidol (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with geranyllinalool (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with farnesyllinalool (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with farnesylnerolidol (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with farnesylgeranyllinalool (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Condensation of 2-methyl-1,4-naphthohydroquinone (I) with farnesylfarnesyllinalool (II). I (27.5g) is dissolved in 65 ml of dry dioxane, 1.5 g of zinc chloride, and 3.5 ml of borontrifluoride etherate are added with stirring, and the mixture is heated to 50. A solution of 0.87 mole of II per mole of I in 25 ml of dry dioxane is added, and the reaction mixture is stirred for 20 min longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of petroleum ether, the solution cooled to -50. The precipitate centrifuged. The precipitate dissolved in 100 ml of ether, 20 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed. (Ref. 0017)

Seven grams of 2-methyl-1,4-naphthohydroquinone (I) is dissolved in 50 ml of dry dioxane, 0.5 g of zinc chloride and 1 ml of boron trifluoride etherate in 65 ml of dry dioxane, 1.5 g of zinc chloride of borontrifluoride etherate are added with stirring, and the mixture is heated to 55 - 60 under nitrogen. A solution of 7.5 g of solanesol in 30 ml of dry dioxane is added, and the reaction mixture is stirred for 1 hour longer. After cooling water and ether are added, the layers were separated and the etheral layer is washed. The ether solution is evaporated. The residue is dissolved in 200 ml of ether, 10 g of dry silver oxide is added and the mixture shaken for 30 min.
After filtration the etheral solution is evaporated in vacuo, the residue dissolved in petroleum ether and chramatogphed through a colum of aluminum oxide. Yield : 120 mg. m.p. 56-57. (Ref. 0017)

Menaquinone-10 (Ref. 0011) is prepared in analogy to menaquinone-9 (Ref. 0010) from 7g of farnesylfarnesylgeranyllinalool, 7 g of 2-methyl-1,4-naphthohydroquinone (I) is dissolved in 50 ml of dry dioxane, 0.5 g of zinc chloride and 1 ml of boron trifluoride etherate in 65 ml of dry dioxane, 1.5 g of zinc chloride of borontrifluoride etherate are added with stirring, and the mixture is heated to 55 - 60 under nitrogen. The crude product, m.p. 56., is chromatographed on Hostalen, yielding pure menaquinone-10 as fine yellow crystals, melting at 62. (Ref. 0017)

By heating, 187.5 g of stannous chloride are dissolved in 800 cm³ of concentrated hydrochloric acid (d=1.19). To the hot solution a suspension of 60 g of the monoxime of 2-methyl-1,4-naphthoquinone in 250 cm³ of warm concentrated hydrochloric acid is added. The desired hydrochloride separates out and the reaction mixture stirred for about 5 minutes. When the temperature has fallen to 50C the substance is filtered rapidly (Schott G3 glass filter) and washed three times with 125 cm3 of 4n hydrochloric acid. The crude compound is dissolved in a solution of 30 g of potassium metabisulphite in 750 cm³ of water, and after treating with charcoal, the pure hydrochloride is precipitated by means of 600 cm³ of concentrated hydrochloric acid to which 6 g of potassium metabisulphite have been added. The substance is filtrated by suction (glass filter), washed three times with 100 cm³ of 4n hydrochloric acid, then with 60 cm³ of alcohol and dried in vacuo over potassium hydroxide. Yield 50 g (75%).(Ref. 0041)

A suspension of 40 g of 1-amino-2-methyl-4-p-sulphophenylazo-naphthalenee in 200 cm³ of concentrated hydrochloric acid (d=1.19) is added to a hot solution of 75 g of stannous chloride in 400 cm3 of hydrochloric acid (d=1.19). The mixture is boiled until it has become colorless, with the occasional addition of a piece of spongy tin. After adding 500 cm³ of hydrochloric acid (d=1.19) and cooling, the white crystalline material filtered by suction and washed three times with 100 cm³ of hydrochloric acid (d=1.19). The substance is dissolved in a solution of 3 g of K₂S₂O₅ in 300 cm³ of water, decolorlized with charcoal, and after filtration the pure dihydrochloride precipitated by adding 300 cm³ of hydrochloric acid (d=1.19). After cooling to 0C the compound is filtered by suction, washed three times with 50 cm³ of 4n hydrochloric acid, then with 150cm³ of alcohol and dried in vacua over potassium hydroxide. Yield 20g. (70%).(Ref. 0041)

3-Methyl-1-naphthol (4 g) was treated with solution prepared by diazotizing 5.3 g of sulfanilic acid, the azo derivative was reduced with 16 g of sodium dithionite and the precipitated aminonaphtol, purified by recrystallization from hydrochloric acid containing stannous chloride, yielded 3.4 g of pure 1-amino-2-methyl -4-naphthol hydrochloride (charred at 270). (Ref. 0016)

The quinone (2gm) is dissolved in 35cc of ether by warming and the solution is poured into a separatory funnel and shaken with a fresh solution of 4 gm of sodium hydrosulfite in 30 cc of water. After the mixture is shaken for a few minutes, the solution passes through a brown phase (quinhydrone) and becomes pale yellow. After removal of the aqueous layer the ethereal solution shaken with a mixture of 25 cc of saturated sodium chloride solution and 1 to 2 cc of saturated hydrosufite solution to remove the bulk of the water and filtered by gravity through a paper moistened with ether and about one-third filled with an hydrous magnesium (or sodium ) sulfate. The filtrate is evaporated until nearly all of the ether has been removed, cooled, and treated with petroleum ether (b.p. 20-40). The hydroquinone separating as a white or grayish powder is washed with petroleum ether and air-dried ; yield, 1.9 gm (94 per cent).(Ref. 0038)

A solution of 0.3 g of the hydroquinone in 0.8 cc of pyridine was added by drops with ice cooling to a suspension prepared by addling 0.5 cc of phosphorous oxychloride with cooling to 1 cc of pyridine. At the end the mixture was allowed to warm up until the exohthermic reaction was over. The white suspension was then treated with 6 cc of water, added cautiously at first with ice cooling and later heating to dissolve the product. Sodium carbonate was added until alkaline litmus and the pyridine layer which separated was removed. The solution of sodium salts was stirred with absolute alcohol and the solvent decanted, leaving an aqueous solution of greatly diminshed volume. The remainder of the water can be removed by stirring either with fresh portions of alcohol or with smaller portions of pyridine , leaving the sodium salt as a gum.(Ref. 0036)

A mixture of 0.5 g of 2-methyl-1,4-naphthohyrdroquinone with a cooled suspension from 1 cc of pyridine, 10 cc of carbon tetrachloride and 0.5 cc of chlorosulfonic acid was heated for ten minutes on the steam-bath, cooled, and the solvent decanted from the oily yellow pyridine salt. This was treated with a slight excess of 10 N alkalin the mixture was extracted with ether, and the residual red oil taken up in a little hot water. Alcohol added in portions precipitated first inorganic material which was removed, and then the ester salt as tan crystals (0.58 g, 0.27 g more from the mother liquor). Crystallization from water gave 0.4 g of colorless product free from inorganic salts, and this was further purified by dissolving it in water and adding alcohol. The air dried material proved to be a dihydrate.(Ref. 0036)

To a solution of 10.0 g (70.3 mmol) of 2-methylnaphthalene and 349 mg (1.40 mmol) of methyltrioxorhenium in 150 ml of acetic acid was added drop wise at room temperature 14.3 ml (0.49 mol) of 85% H₂ O₂. The reaction mixture was allowed to stir at 40 C for 4 h under a N₂ atmosphere, before 100 ml of water was added. The mixture was extracted with CH₂ Cl₂2 (3 x 200 ml). The combined organic phases were washed with 150 ml of water, dried over Na₂SO₄ and concentrated at 20-40C/10-20 Torr. The quinone products were separated from the starting material by column chromatography. Recrystallization of the chromatographed product from ethanol afforded the quinone in more than 98% purity (NMR) and in 58% yield (5.65 g).(Ref. 0035)

The addition of sodium bisulfite to 2-methyl-1,4-naphthoquinone was carried out. The purified colorless crystalline salt obtained from aqueous solution gave analyses indicating approximately four molecules of water of crystallization. The spectrum determined for this material agreed nicely well with the spectrum determined on another specimen which was purified by washing with 95% ethyl alcohol, followed by several recrystallizations from the same solvent; the colorless, nicely crystalline product from 95% alcohol showed the composition of a dihydrate.(Ref. 0040)

Five grams of 6-Acetoxy-2-(b-carbomethoxyethyl)-3,4-dihydro-2,5-dimethyl-2H-naphtho-[1,2-b]- pyran(Ref. 0008) is dissolved in 75ml of dioxan, a mixture of 5 ml of water and 5 ml of concentrated sulfuric acid is added, and the solution is reflexed for 3 hours under nitrogen. After cooling, the mixture is diluted with water and worked up as usual to give 4.2 g of red-brown viscous oil. To a solution of this material in 100 ml of methanol are added dropwise with stirring within 10 minutes at room temperature, 110 ml of a solution of 22.5 g of FeCl₃^. 6H₂O in 85 ml of water and 85 ml of methanol. The mixture is stirred longer for 2 hours at room temperatue and the the main part of the methanol is evaporated in vacuo. After saturation with ammonium chloride the mixture is worked up as usual to yield 3.8 g (89%) of a red-brown oil which crystallizes slowly. Recrysatllization from benzene-petroleum ether gives 2.9 g (70%) of the metabolite as yellow crystals.(Ref. 0008)

Treatment of farnesol (1) with phosphorous tribromide followed by reaction of the bromide product with ethyl [3-¹⁴C] acetoacetate (3) gave [3-¹⁴C] farnesylacetone (4). Witting reaction of (4) with triethyl phosphonoacetate (5) gave the farnesylcrotonic derivative (6) which was reduced with lithium aluminum hydride to [3-¹⁴C] geranylgeraniol (7). Condensation of (7) with menadiol monoacetate (8) followed by hydrolysis and oxidation with silver oxide gave a cis-trans mixture of [3'-¹⁴C] menaquinone-4 (11). The mixture was purified by chromatography on silica gel then recrystallization from acetone at -60C to give all trans [3'-¹⁴C] menaquinone-4 (tans isomer : more than 96%). The overall radiochemical yield of this synthesis was 12% from (3)
[Table 0001]. (Ref. 0033)