FIELD OF THE INVENTION
The present invention relates to a process for the preparation of vitamin Kl having desired purity. Specifically, the invention relates to a process for preparing phytonadione (1) comprising reaction of l-acetoxy-4-hydroxy-2-methylnaphthalene with phytol in presence of a Lewis catalyst-acid complex to give l-acetoxy-4-hydroxy-2-methyl, 3-[(2E)-3,7,l 1,15-tetramethylhexadec-2-en-l-yl)naphthalene, followed by treatment with sodium methoxide to yield phytonadione (1).
BACKGROUND OF THE INVENTION
Vitamin K is the generic name for 2-methyl-l,4-naphthoquinone derivatives having activity on blood-coagulation and electron transport systems. Vitamin K was first identified in 1929 by Danish scientist Henrik Dam during his investigations regarding the role of cholesterol in metabolism of chicken. The identified substances were found to be essential for synthesizing prothrombin in the liver, which is a precursor of the enzyme thrombin causing blood coagulation reaction and were also known to prevent release of calcium from the bones.
Amongst these derivatives, Vitamin Kl, also known as phylloquinone, phytonadione or phytomenadione is known to be the active ingredient which exhibits the aforementioned activity. Vitamin Kl, chemically identified as 2-Methyl-3-[(2E,7R,l 1R)-3,7,11,15-tetramethyl-2-hexadecenyl]-l,4-naphthalenedione has two geometrical isomers (cis / trans or Z / E isomers) as well as two asymmetric centers at C7 and CI 1, each generating a pair of two enantiomers. Thus, there are total eight diastereomers for the molecule, out of which, 2'trans-7R,11R stereoisomer is the only active diastereomer.

Various synthetic methods for vitamin Kl have been disclosed in the prior art. US 2,325,681 discloses a process wherein acetyl phytol is condensed with 2-methyl-1,4-naphthohydroquinone in presence of zinc chloride to give monoacetylβ-phytyl-l,4-naphthohydroquinone, which after hydrolysis and oxidation yields vitamin Kl. Lengthy reaction sequence, formation of undesired side products in significant proportions and consequently, elaborate separation methods are the major disadvantages of this method.
US 2,348,037 discloses condensation of phytyl bromide with monosodium salt of 2-methyl-1,4-dihydroxy naphthalene, followed by air oxidation of the resultant l,4-dihydroxy-2-methyl 3- phytyl naphthalene to give vitamin Kl. At this stage, the final product is either isolated or further converted to diacetyl derivative, which is purified, hydrolyzed and oxidized to yield vitamin Kl.
US 2,417,919 discloses the reaction of 2-methyl-l,4-naphthohydroquinone with phytol in the temperature range of 70-180°C wherein oxalic acid and trichloroacetic acid are used as condensation agents and the reaction takes about twenty-four hours for completion. Further oxidation either using air or silver oxide yields the desired vitamin Kl.
US 4,229,356 discloses a process for producing hydro-precursors for vitamin Kl comprising reacting 2-methyl 1,4-hydronaphthoquinone with phytyl bromide in presence of phase transfer catalysts such as quaternary ammonium or tetraalkyl phosphonium salts.
US 2,683,176 discloses condensation reaction of 2-methyl-1,4-naphthohydroquinone with phytol using boron trifluoride-etherate. The process further comprises stirring the condensation product in petroleum ether using hydrogen in presence of palladium catalyst, followed by oxidation of resulting hydroquinone derivative with silver oxide to give vitamin Kl.
Although the disclosure purports certain advantages due to use of boron trifluoride, the process poses serious drawbacks especially for a commercial scale application. Use of expensive, high-boiling solvents such as dioxane, acetylglycol monomethyl ether and extremely hazardous, highly inflammable solvent like ether, requirement of treatment with gaseous hydrogen and low yields up to 37% are some of the shortcomings in the synthetic sequence. Further, vitamin

Kl so obtained, contains various impurities above regulated limits which necessitates extensive
purification methods to get the desired purity for final compound.
In general, the processes disclosed in the prior art have serious limitations such as low yields,
requirement of chromatographic purifications at intermediate stages in synthesis, use of
hazardous reagents etc. making them inapplicable on industrial scale.
Thus, there still exists a need for an industrially viable process for synthesis of vitamin Kl (1)
which avoids use of hazardous, inflammable solvents like diethyl ether, eliminates need for
derivatization of phytol and yet yields vitamin Kl in a convenient manner, in substantially pure
form as well as in good yield.
The present inventors have developed a novel process for synthesis of vitamin Kl (1) comprising condensation of 1- acetoxy-4-hydroxy 2-methylnaphthalene (4) with phytol (5) in presence of a Lewis catalyst-acid complex such as boron trifluoride-acetic acid to give phytol-substituted naphthohydroquinone derivative (6), further treatment with sodium methoxide and isolation to give vitamin Kl in substantially pure form.
OBJECT OF THE INVENTION
An objective of the present invention is to provide vitamin Kl of formula (1) having desired purity by a robust and commercially applicable process which does not involve flammable solvents and cumbersome separation procedures at intermediate stages.
Another object of the present invention is to provide an efficient process for preparation of vitamin Kl (1), comprising use of boron trifluoride-acetic acid complex for condensation of acetoxy naphthohydroquinone and phytol, and further treatment of the condensation product With sodium methoxide to give substantially pure vitamin Kl with a significant improvement in the overall yield.
SUMMARY OF THE INVENTION
The present invention relates to a novel method for synthesis of vitamin Kl of formula (1) in substantially pure form.

An aspect of the invention relates to a process for preparation of vitamin Kl (1) comprising reaction of l-acetoxy-4-hydroxy-2-methylnaphthalene (4) with phytol (5) in presence of boron trifluoride-acetic acid complex to give 1 -acetoxy-4-hydroxy-2-methyl-3-[(2E)-3,7,11,15-tetramethylhexadec-2-en-l-yl) naphthalene (6), which on further treatment with sodium methoxide yields vitamin Kl (1).
The objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Vitamin K analogues, originally recognized as a factor required for normal blood coagulation, are now receiving more attention in relation to their role in bone metabolism and various other biological activities.
Hence, the present inventors aimed at designing a commercially applicable, robust process, which would be applicable to different analogues in the vitamin K family, especially keeping in view the most active compound, vitamin KL The synthetic strategy would avoid hazardous, inflammable solvents like diethyl ether, and also elaborate synthetic processes such as derivatization of the reactants or extensive chromatographic purifications at intermediate stages.
While designing the synthetic strategy and carrying out the requisite experimentation for same, the present inventors surprisingly found that use of boron trifluoride-acetic acid complex during condensation reaction of naphthohydroquinone derivative with phytol resulted in a very facile'and convenient, industrially applicable reaction. The complex containing gaseous boron trifluoride and acetic acid was a cost-effective, commercially available reagent, which could be easily handled and gave the desired condensation product in substantially higher yield as compared to prior art methods.
With the use of BF3-acetic acid complex, need for hazardous, highly inflammable solvent like diethyl ether was eliminated making the process easily applicable on industrial scale. The reaction took place with reduced side reactions, thus resulting in control on formation of

impurities. As a consequence, the desired product, l-acetoxy-4-hydroxy-2-methyl-3-(3,7,11,15-tetramethyl hexadec-2-en-l-yl) naphthalene (6) was obtained in higher yield and possessed improved impurity profile in comparison with prior art methods,
Compound (6) was further treated with sodium methoxide and the hydrolyzed product was treated with Silica gel to obtain crude Phytonadione or 2-methyl, 3-((2E)-3,7,11,15-tetramethylhexadec-2-en-1 -yl) 1,4-dihydronaphthalene-1,4-dione.
Crude phytonadione, thus obtained was subjected to chromatographic separation using n-heptane and acetone, followed by preparative chromatography using acetonitrile and methanol to get the desired diastereomer, vitamin Kl (1).

0 • acetyl chloride zinc dust OCOCH3 methanolic ammonia OCOCH3



ethyl acetate 50 -70°C
\^ k^ ethyl acetate 10-30°C \^s N^
u OCOCH3 OH
2-methyl 1,4-naphthaquinone 1-acetoxy-4-hydroxy
(2) 1,4-diacetoxy 2-methyl naphthalene (4)
2-methyl naphthalene (3)
+ H0^/^
3,7,11,15 tetramethyl hexadec-2-en-l-ol (5)
OCOCH3
BF3-acetic acid comple X
dichloromethane


k.^/^^^/^^V^^^^
15-45»C iH
1-acetoxy-4-hydroxy2-methyl,3-{3,7,11,15 tetramethyl hexadec-2-en-1-yl)naphthalene (6)
0
sodium methoxide, toluene z^^/^/
hydrochloric acid silica gel, n-heptane ^^