FIELD OF THE INVENTION

This invention relates to the synthesis of lawsone and its derivatives or analogues of lawsone, and more particularly, relates to a convenient and facile process to produce the same involving very simple and cost-effective process steps. More specifically the simple process steps involves a simple inexpensive catalyst and a base in alcohol for the transformation of naphthol or its derivatives to lawsone and its derivatives in a single step, in the presence of oxygen but without the requirement of any oxygen pressure.
The process is further simple directed to the production of lawsone and its derivatives or analogues of lawsone with no extraneous heating making it further energy efficient.

BACKGROUND ART

Quinones having hydroxyl groups directly attached to the quinine ring constitutes a very interesting class of quinoid compounds. A great number of hydroxyquinones are found in nature and the majority of the compounds exhibit unique biological activity. Natural hydroxy quinones vary in structural complexity which starts from the simple 2-hydroxynaphthalene-l, 4-dlone or 2-hydroxy-l, 4-naphthoquinone or lawsone and 5-hydroxynaphthalene-l, 4-dione (Juglone).

Additionally, Quinones having hydroxyl groups directly attached to the quinine ring or hydroxyquinones constituting a class of quinoid compounds have been proved to exhibit unique biological activity. Natural hydroxy quinones vary in structural complexity which starts from simple 2-hydroxynaphthalene-l, 4-dione, lawsone and 5-hydroxynaphthalene-l, 4-dione (Juglone).

The biological activity of lawsone compound is directed to its anti-bacterial, antispasmodic, corrosion inhibitory property. The said compound further encompasses the characteristic properties of dyeing as well as the UV absorption, wherein the dyeing property of henna leaves were further attributed to the presence of the same compound lawsone in henna leaves.

Hair dyeing method by natural extracts (ex. Henna comprising lawsone as the active ingredient) can be traced back to atleast 4000 years. The hair of Egyptian mummies was found to be dyed with Henna. The natural hair dyes derived from flora and fauna are believed to be sage because of their non-toxic, nor-carcinogenic and biodegradable nature. The current trend throughout the world is shifting towards the use of ecofriendly and biodegradable ingredients and the demand for natural dyes is increasing day by day (Bhuyan et al., Indian J Fibre & Textile Research, 2004, 29, 470). The plant, Lawsonia inermis Linn., commonly known as Henna is a shrub or small tree cultivated in India, Pakistan, Afghanistan and Iran. The powdered leaves of the plant are continuously in use as cosmetic staining of the hair, skin and nails.

Several methods exist in literature on the synthesis of Iawsone and its derivatives.

References are drawn to the art by Oliveros et al., in New J, Chem., 1990 14, 161-167 wherein singlet oxygen was used for the conversion of a series of naphthalene diols into the corresponding hydroxynaphthaquinone derivatives. Higher yields of the said hydroxynaphthaquinone derivatives were further obtained by M. De Min et. al. in Tetrahedron, 1986, 42 (18), 4953-62 and Tetrahedron, 1992, 48 (10), 1869-82 wherein heterogeneous oxidation of 1,5-dihydroxynapthoquinones was carried out by using solid KO2 that is essentially a solid-liquid reaction further carried out in an aprotic solvent proceeding in two steps. However the use of highly sensitive reagents for the said transformation is the drawbacks of the said processes.

Kasturi et. al. in Can. J Chem., 1966, 44, 1086 teaches the oxidation of 2, 6-naphthalenediol to 2, 6-dihydroxynaphthalene-l, 4-dione thereby setting a characteristic example whereby tetralone is effectively oxidized to hydroxynaphthoquinone by oxygen and Potassium t-butoxide in Dimethyl sulphoxide. Moreover, oxidation of tetralone in two steps proved to be a most effective approach to highly polymethoxylated hydroxynaphthoquinones. The reagent, SeOa oxidized the tetralone to the corresponding orthoqulnone and solid KO2 converted the latter to the desired hydroxynaphthoquinone. The said synthetic approach was used to synthesize 5, 7, 8-trimethoxy-l, 4-naphthoquinone (Bekaert et al., Tetrahedron Lett., 1997, 4219-4220).

Further Baillie et al., in J. Chem. Soc, Sect C: Organic 1966, 23, 2184-86 reported a method for the preparation of lawsone from tetralone by autoxidation of the said tetralone in the presence of tert-BuOK. The Intermediate compounds such as 1, 2-dihydroxynaphthalenes formed during the process were simultaneously and rapidly auto-oxidized to 2-hydroxy-l, 4-naphthoqulnones or lawsone. The usage of expensive and low commercially available starting materials like a, β-tetralones is the major drawback of this method.

Sartori et.al., in J. Org. Chem., 1993, 58, 840 reveals that substituted hydroxyquinones can be obtained via., a Friedel-Crafts cyclization process involving the reaction of Oxalyl chloride with an aromatic a-ketoester, in the presence of Aluminium chloride to yield the corresponding 3-hydroxy-l, 4-naphthoquinone-4-carboxylate. The latter was hydrolyzed and decarboxylated to the desired 2-hydroxy-1, 4-naphthoquinone derivative. Expensive starting materials and the use of sensitive reagents remains the main setback of the method.

References are drawn to Catalysis Communications, 2004, 5 (8), 387-390 by Y. Van et al., wherein Naphthol is selectively converted into 2-hydroxy-l, 4-naphthoquinone by clean oxidant of molecular oxygen under air pressure at 45 "C in an alkaline solution over iron porphyrin catalysts; Synthetic Communications 2002, 32 (10), 1501-1515 by D. Villemin et. al. wherein supported metalated pthalocyanlne on KIO or on lamellar zirconium phosphate catalyzes the oxidation of hydroquinones into quinones thereby obtaining juglone, lawone etc.; Journal of Porphyrins and phthalocyanines 2003, 7 (9 and 10), 645-650 by M. Kawasaki et. al. wherein effect of pH and organic co-solvent on the oxidation of naphthalene with peroxosulfate catalyzed by iron (III) tetrakis (p-sulfonatophenyl) phenyl were established; Chinese Journal of Chemistry, 2004, 22 (5), 487-491 by Y. Yan et al., relates to the catalytic conversion of 2-napthol to 2-hydroxy-l, 4-naphthoquinone or lawsone by a milder reaction pathway wherein catalalytic oxidation of napthol was carried out in by molecular oxygen in alkaline methanolic solution in the presence of tetra(4-methoxy-phenyl) porphyrinate catalyst, wherein all the above discussed process suffer from the drawback of the involvement of costly catalyst.

Reference yet again is drawn to PL 167265 B1 by Rutkowska et al. that is directed to a process of synthesis of lawsone, useful as a UV-resistant dye for hair and skin, by oxidizing l-annino-2-naphthol-4-suiphonic acid with HNO2, followed by desulfonating rearrangement resulting in 1, 2-naphthoquinone 4-sulphonic acid that was further treated with H2SO4 at 10-40 ˚C involving further alkali and acid treatment steps to yield the final abovesaid compound of interest.

JP11035517A by A. Sonobe et al. relates to the synthesis of Lawsone from 1, 4-naphthaquinone via. epoxidation, hydrolysis and esterification followed by neutralization with mineral acids; JP 10218829 A by J. Sonobe et. al is directed to the preparation of lawsone by the reaction of epoxy-2, 3-dihydro-l, 4 napthoqulnone with alkaline compounds In the presence of water insoluble inert organic solvents and alcohols thereby leading to the fact that such multistep processes suffer from use of expensive reagents that are not desirable to make the process industrially acceptable.

Inspite of the huge number of teachings flowing from the background art, such above said processes for the synthesis of lawsone are summarized to suffer from either one or many of the drawbacks which include:

a) low yielding and thus less efficient;
b) involvement of harsh reaction conditions;
c) toxic and lachrymatic nature of the reagents;
d) moisture sensitive reagent and difficulty in handling;
e) involvement of thermal energy;
f) expensive nature of the reagents and low commercial availability.

Due to the everlasting demand for development of a convenient and industrially advantageous process for producing 2-hydroxy 1, 4-naphthoquinone or lawsone and its derivatives or analogues of lawsone possessing hair coloring property, it is thus a need in the art to tame down the process for the synthesis of lawsone to thereby increase its industrial viability in involving fewer reaction steps, operative under mild
conditions such as room temperature conditions, involving simple and cost effective reagents and high yield.

OBJECTS OF THE INVENTION
It is thus the basic object of the present invention to provide for a process for the manufacture of lawsone and its derivatives or analogues of lawsone in an industrial scale that would enable an efficient, economic and importantly also high yielding process with high purity of product.

Another object of the invention is to provide for a clean process for a large scale manufacture of lawsone and its derivatives or analogues of lawsone.

Yet another object of the invention is to provide for a process for manufacturing lawsone and its derivatives or analogues of lawsone that would be economically viable, energy efficient for large scale production of said lawsone.

Yet further object of the present invention is directed to the manufacture of lawsone and its derivatives or analogues of lawsone involving inexpensive and easily available starting materials, and simple inexpensive catalysts.

A further object of the invention is to provide for a process for the manufacture of lawsone and its derivatives or analogues of lawsone that would be simple and easy to operate that would not involve harsh reaction conditions.

Yet another object of the invention is to provide for a process for the manufacture of lawsone and its derivatives or analogues of lawsone which would be energy efficient with no requirement for any external heating.

Still another object of the invention is to provide for a process for the manufacture of lawsone and its derivatives or analogues of lawsone in high yields that would results in highly pure product specifications.

SUMMARY OF THE INVENTION

Thus according to the basic aspect of the invention there is provided a process for the preparation of lawsone and its derivatives or analogues of lawsone comprising of (a) reacting a naphthaiene substrate with a base in the presence of catalyst such as urea-hydrogenperoxide (UHP) in an organic solvent (b) obtaining therefrom the said lawsone or its derivatives.

In another preferred aspect of the invention there is provided a process wherein the said step of obtaining the lawsone and its derivatives or analogues of lawsone by reacting the naphthalene substrate with a base in organic solvent preferably organic protic solvent comprises of (1) dissolving the base in the said organic protic solvent to obtain a solution (li) saturating the said solution with oxygen (iii) adding the naphthalene substrate and the catalyst such as urea-hydrogenperoxide (UHP) to the said solution obtained in step (i) above in the presence of oxygen (iv) cooling the reaction mixture to about 0°C and quenching with HCI to result in an aqueous phase and further adding water immiscible solvent (v) extracting the product in water immiscible solvent layer, washing and concentrating in vacuo to thereby obtain the said lawsone or its derivatives.

In yet another preferred aspect of the invention there is provided a process wherein the said step of obtaining lawsone and its derivatives or analogues of lawsone by the reaction of naphthalene substrate with a base in organic solvent preferably organic protic solvent comprises of (i) dissolving the base preferably potassium tert-butoxide in the said organic protic solvent preferably tert-butanol to obtain a solution (ii) saturating the said solution with oxygen (iii) adding the naphthalene substrate and the catalyst urea-hydrogenperoxide (UHP) to the said solution of potassium tert-butoxide in tert-butanol obtained in step (i) above in the presence of oxygen (iv) cooling the reaction mixture to about CC thereby quenching with HCI preferably with IM HCI to result in an aqueous phase and further adding water immiscible solvent preferably chloroform (v) extracting the product in said chloroform layer and further washing the chloroform layer with NaOH preferably IM NaOH and concentrating in vacuo to thereby obtain the said lawsone or its derivatives.

In yet another preferred aspect of the process of the invention the said lawsone and its derivatives or analogues of lawsone are the substituted or unsubstituted 2-hydroxy-1, 4-naphthoquinones.

In another preferred aspect of the process of the Invention the said water immiscible solvent is selected from CHCI3, dichloromethane, diethyl ether, ethyl acetate, and the like more preferably CHCI3.

Yet another preferred aspect of the process of the invention the product lawsone and its derivatives or analogues of lawsone are obtained in yield% of 80-95 % and purity of >90%.

The details of the invention, its objects and advantages are explained here under in greater detail in relation to non-limiting exemplary illustrations as per the following examples and the following examples are given by way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As already disclosed herein before, the present invention comprises of a simple and cost-effective process for the manufacture of lawsone and its derivatives or analogues of lawsone in high yields. The process is convenient and facile that involves cost effective and single process step with no difficulty in reagent handling which leads to the production of the said lawsone or its derivatives without the requirement of any external heating making the process further energy efficient.

The simple process steps involves the reaction of naphthol or its derivatives with simple base such as KOBut in t-butanol in the presence of an inexpensive catalyst such as urea hydrogen peroxide and oxygen to yield for the transformation of naphthol or its derivatives to lawsone and its derivatives in a single step, In the presence of oxygen to yield lawsone or its derivatives in high yield.

EXAMPLE 1; Preparation of Urea-Hydroaenperoxlde (UHP) catalyst

A mixture of urea (0.1 mol) and hydrogenperoxide (50 ml) was placed in a 500 ml
bolt-head flask provided with magnetic stirrer. The mixture was stirred for 2h at
room temperature. The stirrer was removed and the homogeneous mixture was kept
in the refrigerator overnight. The formed solid product was collected on a Buckner
funnel.
The general schematic for the preparation of lawsone or its derivatives are illustrated
below in Scheme 1:

Oxygen was passed through a solution of KO tBu (33.6 g) in HO ^Bu (250 ml) for 45 minutes. a-Naphthol (14.4 g) and urea-hydrogenperoxide (UHP) catalyst (2 g) were then added, and oxygen continued to bubble through the reaction mixture for 24h. The reaction mixture was cooled to O'C, quenched with IM HCI (250 ml) and extracted with CHCI3. The chloroform layer was extracted with aqueous IM NaOH. The aqueous layer was acidified with concentrated HCI and extracted with CHCI3. The organic layer was dried and concentrated in vacuo to yield an orange solid, mp: 191-93°C (Yield 80%). The abovesald process is schematically represented in Scheme 2 below.

UV λmax (methanol): 280, 290 (nm)

IR (KBr): 3268 (OH), 3071, 3011 (Aromatic), 2922, 2851, 1688 (C=0), 1602 (C=C), 1292, 1029, 933, 708, 667 and 552 cm-1

1H NMR (300 MHz, DMSO-dg): 813.11 (broad singlet, IH) 8.02 - 7.49 (m, 5H, Aromatic protons).

13C NMR (75 MHz, DMSO-d6): 5182.0 (C-4), 178.2 (C-1), 159.4 (C-2), 114.1 (C-3) 131.5 - 135.3 (Other aromatic Carbons)

Oxygen was passed through a solution of KO ^Bu (33.6 g) in HO ^Bu (250 ml) for 45 min. 1, 5-Dihydroxynaphthalene (24 g) and urea-hydrogenperoxide (UHP) catalyst (3 g) were added, and oxygen continued to bubble through the reaction mixture for 28h. The reaction mixture was cooled to 0°C, quenched with IM HCI (250 ml) and extracted with CHCI3. The chloroform layer was extracted with aqueous IM NaOH. The aqueous layer was acidified with concentrated HCI and extracted with CHCI3. The combined organic layer were dried and concentrated in vacuo to get the product (Yield: 90%, mp: 160-164''C). The abovesaid process is schematically outlined in Scheme 3 below.

UVλmax (methanol): 287, 308, 380nm.
IR(KBr): 3203(OH), 3027, 3084(Aromatic), 2923, 2852 1646 (C=0), 1588 (C=C),
1333, 1023, 981, 702, 618 cm-1

1H NMR (500 MHz, DMSO-dg) : 8 5.98 (S, IH), 7.92-7.23 (m, 3H, hydroxyl protons exchanged with solvent).

C NMR (125MHz, DMSO-dg) :5 183.7 (C-1), 181.6 (C-4), 163.0 (C-2), 160.8 (C-5), 110.1 (C-3), 117.7-137.1 (other aromatic carbons).

Thus the examples clearly illustrate an overall simple and efficient process for the manufacture of lawsone or its derivatives.

It is also noteworthy that the process is very economical for the Inexpensive nature and easy commercial availability of the reagents employed.

Advantageously the process provided in this invention is favorable with respect to easy handling of the reagents that does not require inert atmosphere techniques.

The advantage associated with the above said single step process is the easy work up to lead to the final product of lawsone or its derivatives and is also energy efficient since no external heating is required.

It is thus possible by way of the present invention to provide for a process for the manufacture of lawsone and its derivatives or analogues of lawsone which is efficient in terms of energy needed for activation for the formation of products from reactants, cost-effective in terms of the simple and inexpensive catalyst required for the process and highly pure isolated yields of the product. The mild reaction conditions employed and the harmless by product obtained further add to the advantage obtained from the process of the invention.

We Claim:
1. A process for the preparation of lawsone and its derivatives or analogues of lawsone comprising of (a) reacting a napthalene substrate with a base in the presence of catalyst such as urea-hydrogenperoxide (UHP) in an organic solvent (b) obtaining therefrom the said lawsone or its derivatives.

2. A process as claimed in claim 1 wherein said step of obtaining the said lawsone and its derivatives or analogues of lawsone by reacting the naphthalene substrate with a base in organic solvent preferably organic protic solvent comprises of (i) dissolving the base in the said organic protic solvent to obtain a solution (ii) saturating the said solution with oxygen (ill) adding the naphthalene substrate and the catalyst such as urea-hydrogenperoxide (UHP) to the said solution obtained in step (i) above in the presence of oxygen (iv) cooling the reaction mixture to about 0°C and quenching with HCI to result In an aqueous phase and further adding water immiscible solvent (v) extracting the product in water immiscible solvent layer, washing and concentrating in vacuo to thereby obtain the said lawsone or its derivatives.

3. A process as claimed in claim 1 wherein the said step of obtaining lawsone and its derivatives or analogues of lawsone by the reaction of naphthalene substrate with a base in organic solvent preferably organic protic solvent comprises of (i) dissolving the base preferably potassium tert-butoxide in the said organic protic solvent preferably tert-butanol to obtain a solution (ii) saturating the said solution with oxygen (iii) adding the naphthalene substrate and the catalyst urea-hydrogenperoxide (UHP) to the said solution of potassium tert-butoxide in tert-butanol obtained In step (i) above in the presence of oxygen (iv) cooling the reaction mixture to about 0°C thereby quenching with HCI preferably with 1M HCI to result in an aqueous phase and further adding water immiscible solvent preferably chloroform (v) extracting the product in said chloroform layer and further washing the chloroform layer with NaOH preferably 1M NaOH and concentrating in vacuo to thereby obtain the said lawsone or its derivatives.

4. A process as claimed in 1 wherein the naphthalene substrate is hydroxy naphthalene or substituted or unsubstituted œ- or β-naphthols.

5. A process as claimed in claim 1 wherein the said lawsone and its derivatives or analogues of lawsone are the substituted or unsubstituted 2-hydroxy-1, 4- naphthoquinone.

6. A process as claimed in claim 2 wherein the said water immiscible solvent is selected from chloroform, dichloromethane, diethyl ether, ethyl acetate and the like more preferably chloroform.

7. A process as claimed in claim 1 wherein the product obtained comprise a yield% of 80-95 % and purity of >90%.

8. A process for the preparation of lawsone or its derivatives substantially as herein described and illustrated with reference to the accompanying examples.