FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"IMPROVED PROCESS FOR PREPARATION OF METHOXSALEN"
2. APPLICANT:
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: B-Wing, 10th Floor, BSEL Tech Park, Sector 30 A, Plot No.39/5
& 39/5A, Opp. Vashi Railway Station, Navi- Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of Invention:
The present invention relates to a process for preparation of Methoxsalen substantially free of chlorine degradation products by using sodium acetate as chlorine scavenger.
Background of Invention:
Methoxsalen is a drug used to treat psoriasis, eczemλ vitiligo, and some cutaneous Lymphomas in conjunction with exposing the skin to sunlight. Methoxsalen is extracted from Ammimajus, a plant of the family Umbelliferae. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up tHe disease. The dosage comes in l0mg tablets, which are taken in the amount of 30mg 75 minutes before a PUVA light treatment. The substance is also present in bergamot oil which is used in many perfumes and aromatherapy oils.
Methoxsalen was first disclosed in US2889337 assigned to Secretary of Agriculture, US Government. The said patent discloses a physical process for separation of coumarins like methoxsalen and fluorocoumerins from citrus oil using solid phase chromatography. The yield of Metoxsalen therein is about 65% and purity is verylow
A process for manufacturing Methoxsalen is disclosed in USRE30376 (US '376), the process as disclosed herein does not eliminate the impurities, thereby resulting in impure form of Methoxsalen. US '376, also, does not teach or suggest a method for reducing chlorine degradation products of Methoxsalen which hamPer the purity of Methoxsalen.
Still other techniques are known in art which are generally used to reduce the content of impurities specifically the chlorine derivatives of Metho salen such as manipulating the molar ratio of dimethyl dicyano benzoquinone (DDQ) and/or volume of methyl chlorobenzene, maintaining reaction temperature etc.
Chlorine is generated as by-product of'degradation of dimethyl dicyano benzoquinoneto monochlorodicyanohydroxy-p-benzoquinone' in presence of moisture and alkaline pH. The released chlorine degrades Methoxsalen to form impurities of Formula A and

Formula B, as described below. These two impurities (Formula A and Formula B) are formed in range of 0.1 to 6.0% during the reaction of 9-Methoxy-2,3-dihydrofuro[3,2-g]coumarin with dimethyl dicyano benzoquinone.
The concentration of impurities was reduced to 0.1 - 1% by crystallization methods using various solvents or solvent groups such as, C1 to C5 alcohol and their mixture; aliphatic and aromatic Hydrocarbons and their mixture; mixture of C1-C5 alcohol and aliphatic and aromatic Hydrocarbons; ketones and water and their mixture; MDC, DMF, ether and ester and their mixtures.
Manipulation of reaction conditions and post-reaction solvent purification were also the options which were used, but the purity obtained was 0.15% which is not acceptable. Further, this process was not found to be commercially feasible.
The above processes did not result in Methoxsalen which is substantially free of impurities, particularly chlorine degradation products of Methoxsalen. Consequently, the present invention provides a process for obtaining a Methoxsalen substantially free of impurities particularly chlorine degradation product.
Summary of Invention:
The present invention provides an improved process for manufacturing Methoxsalen comprising use of sodium acetate as chlorine scavenger during reaction of 9-Methoxy-2,3-dihydrofuro[3,2-g)coumarin with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) to obtain Methoxsalen substantially free of impurities.
In an aspect of invention, the process of manufacturing of Methoxsalen consists of following steps:
(a) Heating pyrogallol, monochloroacetic acid and phosphorous oxychloride together to obtain trihydroxychloroacetophenone;
(b) refluxing isopropyl alcohol, trihydroxychloroacetophenone of step (a) and sodium acetate to obtain dihydroxycoumaranone;
(c) hydrogenating dihydroxycoumaranone of step (b) in presence of Pd/C catalyst to obtain dihydroxanthotoxal;

(d) refluxing dihydroxanthotoxal of step (c) with acetone, potassium carbonate, dimethyl sulphate to yield dihydroxanthotoxin and
(e) dehydrogenatingdihydroxanthotoxin of step (d) with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone to yield Methoxsalenin presence of sodium acetate as chlorine scavenger.
Detailed Description of Invention:
The invention will now be described in details in conjunction with preferred and optional embodiments to establish the scope and extent of invention clearly.

Formula A
For the purpose of this invention, the phrase "substantially free of impurities" implies that the Methoxsalen obtained according to the process of invention have less than 0.1% impurities, particularly of formula A and B mentioned below.

Formula B
The invention describes a process for preparation of Methoxsalen comprising use of sodium acetate as chlorine scavenger during dehydrogenation stage.

The reactions involved in process of present invention are as per below scheme:

(i) Chiercice:k idi. POCI:; (ii;ScdhKi i-fii'e; i'ii:;H;-?d C; :.r.-> Malic icid, iuiphuri; i-::i; (V: Diviurhyl iuiphatr.^CO:;
In an embodiment, pyrogallol(l)is heated with monochloroacetic acid and phosphorous oxychloride(i). The reaction mass is chilled and demineralized water is added. The reaction massis stirred and centrifuged.The wet cake thus obtained is washed with water and dried under vacuum to obtain trihydroxychloroacetophenone (2).
The trihydroxychloroacetophenone(2) formed is refluxed with isopropyl alcohol and sodium acetate(ii). Isopropyl alcohol is distilled under vacuum, water is further added and half the water is distilled. The reaction mass is cooled and demineralized water is added to form dihydroxycoumaranone(3). Dihydroxycoumaranone(3) thus formed is dried and filtered.
Dihydroxycoumaranone(3)obtained,is further hydrogenated in presence of ethyl acetate, acetic acid mixture with Pd/C catalyst(iii). The reaction mass is cooled and catalyst is filtered. The solvent is distilled under vacuum. Acetic acid is stripped using toluene followed by cooling reaction mass ((4) intermediate). To the cooled mass, methylene dichloride is added. The MDC layer thus formed is separated, which is added into the solution of sulphuric acid and malic acid (iii) and heated. The reaction mass is quenched

with chilled water. Further, the layers are allowed to settle and the methylene di-cbloride layer is washed with water. All the organic layers thus formed are combined and washed with demineralized water and carbon treated. The methylene di-chloride layer dried over sodium sulphate. The organic layer is distilled / concentrated till a thick stirrable mass is obtained. Hexane is added to the reaction mass, distilled and cooled. The reaction mass is washed with hexane and dried under vacuum to obtain dihydroxanthotoxal(5).
The dihydroxanthotoxal(5) thus obtained is refluxed with acetone, potassium carbonate and dimethyl sulphate(iv). The reaction mass is filtered and the filtrate obtained is collected. The residueis further washed with hot acetone and again filtered and acetone filtrate is collected. The said filtrate and acetone filtrate are combined and distilled till thick stirrable reaction mass is obtained. The reaction mass is stirred with chilled sodium hydroxide and dried under vacuum to obtain crude dihydroxanthotoxin(6). Dihydroxanthotoxin(6) thus obtained is crystallized with ethyl acetate.
The crystallized dihydroxanthotoxin(6) is reacted with 2.3-dichloro-5,6-dicyano-l,4-benzoquinone in presence of monochlorobenzene (MCB), anhydrous sodium sulphate and sodium acetateat elevated temperature. The reaction mass is cooled and hydroquinone is filtered. The filtrate so obtained is washed with 5% sodium carbonate solution followed by 5% sodium bicarbonate solution. The organic layer is dried with 1 mole anhydrous sodium sulphate and distilled under vacuum. Hexane is added slowly to the reaction mass and stirred and filtered to obtain a solid residue. The residueobtained is washed with hexane and dried under vacuum to obtain methoxsalen substantially free of impurities of Formula A and Formula B. The reactions of this stage proceed according to below mentioned reaction scheme;


The use of sodium acetate at this stage eliminates and free Chlorine formed during this reaction thereby reducing substantially reducing the content of impurities of Formula A and Pormula B.
EXAMPLES Example 1:
Preparation of trihydroxychloroacetophenone(2):
1.0 mol of Pyrogallol(l), 1.2 mol of monochloroactic acid and 2.5 mol of Phosphorous oxychloride were heated to 65°C and maintained for 3.5 hrs. The reaction mass was cooled to 40 - 45°C and 800 ml of chilled demineralized water wasadded. The reaction mass wasstirred for 12 hours at 0 - 5°C. The product was centrifuged and the wet cake was washedwith 100 ml of chilled (0-5°C) water. The cake thus obtained was dried under vacuum at 70°C.
Yield of trihydroxychloroacetophenone(2)is 55.4%.
Example 2:
Preparation of dihydroxvcoumaranone(3):
7.5 volumes of Isopropyl alcohol, 1.0 mole of example 1 and 3.0 moles of sodium acetate were heated to reflux and maintained for 12 hours. Isopropyl alcohol was distilled off under vacuum at 70°C. 2 volumes of water were added and 50% of waterwas distilled off.

Reaction mass was cooled to 45°C and 5 volumes of demineralized water were added. The reaction mass was cooled to 0°C and maintained for 2 hours. The product was filtered and washed with chilled 1.0 moie of Isopropyl alcohol. The product thereby obtained was dried in a VTD at 70°C for 12 hrs. Yield of Dihydroxycoumaranone(3) is 85%.
Example 3:
Preparation of dihydroxanthotoxal(5):
Example 2 was hydrogenated in presence of mixture of 17 volumes of Ethyl acetate and 3.5 volumes of acetic acid with 33% Pd/C at pressure 7.0 Kg/cm3 and temperature of 50°C ± 2°C for 15 hours. The reaction mass was cooled to room temperature and the Pd/C catalyst was filtered. Solvent was distilled off under vacuum at 70°C. The reaction mass was stripped of acetic acid with help of toluene (3x3.5 volumes). The reaction mass ((4) intermediate)was cooled to room temperature and 10 volumes of methylene dichloride (MDC)were added. TheMDC layer was addedinto a solution of 15 volumes of sulphuric acidand 1.1 mol of malic acid. The reaction mass was heatedto 40°C and maintained for 3.0 hour. The reaction mass was quenchedwith 50 volumes of chilled water below 40°C. The reaction mass was stirred for 30 min at 40°C, the layer were settled and separated. MDC layer was washed with 3x10 volumes of water.All organic layers were combined and washed with 10 volumes of demineralizedwater followed by carbon treatment. MDC layer was dried with sodium sulphate. The organic layer was distilled offat 45°C, atmospherically till thick stirrable reaction mass was obtained. 4 volumes of hexanewere added to reaction mass and 2 volumes were distilled offat 70°C. The reaction mass was cooled to 0-5°C and maintained for 30 min. The reaction mass was filteredand washed with hexane. The product thereby obtained was driedunder vacuum at 45°C.
Yield % of Dihydroxanthotoxal(5) 40%.
Example 4:
Part A:
Preparation of Dihydroxanthotoxin(6):

10 volumes of Aacetone, 3.0 mol of potassium carbonate, 1.2 mol of di-methyl sulfide and 1.0 mol of example 3 were heated to reflux and maintained for 8 hours. Solid inorganic mass was filtered to-at 60°C and the filtrate was collected. Solid inorganic mass was washedtwice with hot 2.0 volumes of Acetone. The filtrate and acetone filtrate thereby obtained were combinedand distiltedat 70°C till thick stirrable reaction mass was obtained. To the reaction mass 10 volumes of chilled 1% sodium hydroxide solution were added and mainta in stirred at 10°C for 2.0 hour. The product was filteredand washed with 2x2 volumes of water. The product is driedunder vacuum at 65°C for 12 hrs.
Yield % of crude Dihydroxanthotoxin(6)is 80.21%.
Part B:
The crude Dihydroxanthotoxin(6)was crystallized with ethyl acetate.
Over all yield of Dihydroxanthotoxin(6) is 60% having HPLC purity more than 99.5%.
Example 5:
Preparation of Methoxsalen:
1 mole of Example 4, 5-70 volumes of monochlorobenzene, 0.5-10 mole of anhydrous sodium sulphate, 0.1 - 5.0 moles of sodium acetate and 1.0 to 5.0 moles of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone were heated to 80-135°C and maintained for 2-25 hours. The reaction mass was cooled to room temperature and hydroquinone was filtered. The filtrate was washed with 3x400 ml 5% sodium carbonate solution followed by 400ml 5% sodium bicarbonate solution. The organic layer thereby obtained was dried with 1 mole anhyd. Sodium sulphate, organic layer was distilled off/concentrated under vacuum at 70-130°C till 80%. 2 volumes of hexane were added at 70-80°C slowly and stirred for 30 min. The product thereby obtained was filtered and washed with 2 volumes of hexane. The product is dried under vacuum at 40- 80°C for 5 - 15.0 hrs.
Yield: 75.0% of Methoxsalen substantially free of impurities of Formula A and Formula B.

We Claim,
1. An improved process for preparation of Methoxsalen characterized in that dehydrogenation of dihydroxanthotoxin with 2,3-dichloro-5.6-dicyano-l,4-benzoquinone in presence of sodium acetate as chlorine scavenger to reduce the molar concentration of impurities of formula A and formula B to less than 0.1%.
2. The process for preparation of Methoxsalen according to claim 1, wherein the process comprises:

(a) Heating pyrogalloi, monochloroacetic acid and phosphorous oxychloride together to obtain trihydroxychloroacetophenone;
(b) refluxing isopropyl alcohol, trihydroxychloroacetophenone of step (a) and sodium acetate to obtain dihydroxycoumaranone;
(c) hydrogenating dihydroxycoumaranone of step (b) in presence of Pd/C catalyst to obtain dihydroxanthotoxal; .
(d) refluxing dihydroxanthotoxal of step (c) with acetone, potassium carbonate, dimethyl sulphate to yield dihydroxanthotoxin and
(e) crystalizing dihydroxanthotoxin obtained in step (d) and
(f) dehydrogenatingdihydroxanthotoxin of step (e) with 2.3-dichloro-5,6-dicyano-l,4-benzoquinonein presence of sodium acetate to yield Methoxsalensubstantially free of impurities of Formula A and Formula B.
(g) Example 6 reaction condition
(i) Volume of MCB is 5-70 vol
(ii) Temperature of reaction mass 80 -140°C
(Hi) Sodium acetate is 0.5 to 5 mol
(iv) Anhy. Sodium sulphate 0.5 to 10 mol
(v) Reaction maintaining 2-25 hrs
(vi) pH of Formula 6 is in range of 6.5 to 7.5
(vii) Reaction mass moisture will in range of 0.1 to 2.0%
(viii) The said acetate of all salt of acetate C1 to C5 e.g. ammonium
acetate, potassium acetate, isopropyl acetate etc
(ix) Distillation of MCB under vacuum at 70-130°C upto 60 - 80%.

(x) Said vacuum 650 to 760 mm Hg (xi) Reaction mixture of hexane and MCB