FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A process for the preparation of N,N'-4,10-dioxa-3,ll-dioxotridecyIene-l,13-bis-tetrahydropapaverine and its conversion to Atracurium Besylate"

2. APPLICANT
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed

Technical Field of the Invention:
This invention relates to a process for the preparation of N,N'-4,iO-di'oxa-3,I 1-dioxotridecylene-l,13-bis-tetrahydropapaverine [CAS No: 64228-77-9] and its further reaction with methyl benzene sulfonate to yield Atracurium Besylate.
Background of the Invention and Prior Art:
In anesthesia, neuromuscular blocking agents are used to provide skeletal muscle relaxation during surgery. In general there are two types of neuromuscular blocking agents in use, non depolarizing (eg. Pancuronium Bromide, Vecuronium Bromide, Rocuronium Bromide and Atracurium Besylate) and depolarizing (eg. Succinylcholine chloride and Decamethonium Bromide)
Atracurium Besylate {CAS Name: 2,2'-[ 1,5-Pentanediylbis[oxy(3-oxo-3.1 -
propanediyl)]]bis[l-[(3,4-dimethoxyphenyl)methyl]-l,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate} of formula IV

(IV)
available under the brand name Tracrium, first became available for human surgical use in the UK in 1982 and a year later in the USA. For human surgical use Atracurium Besylate is employed as a mixture often optical and geometrical isomers (Eur. J. Med. Chem. 19, 1984, pages 441-450).

A prior art EP Publication No. 0219616 describes the synthesis of precursor of Atracurium and its conversion to Atracurium Besylate. Accordingly, N-(2-carboxyethyl)-l-(3,4-dimethoxybenzyl)-6,7-dimethoxy-I,2,3,4-tetrahydroisoquinoline [compound of formula (1)],

OMe (i) 1,5-pentanediol and p-ToIuenesulfonic acid are reacted under azeotropic removal of water in refluxing Toluene. The product, N,N'-4,10-dioxa-3,l I-dioxotridecylene-l,13-bis-tetrahydropapaverine {compound of formula (111)]

obtained, was isolated after prolonged reaction time as its oxalate, in poor yield and further converted into Atracurium Besylate.
The synthesis of Atracurium Besylate is disclosed in US Patent No. 4179507, wherein 1,5-pentanediol and acryloyl chloride are reacted to yield 1,5-pentamethylene diacrylate derivative, which on reaction with tetrahydropapaverine gave compound (III). Compound (III) was isolated as its oxalate, purified and converted into Atracurium Besylate.

The process for the preparation and isolation of Atracurium Besylate as described in WO Publication No. 97/30033 concerns reaction of compound (III), methyl benzene sulfonate (hereafter referred to as MBS) and catalytic amount of an insoluble base in a solvent. The isolation and purification of the product requires use of large volumes of solvents to get acceptable quality of (IV). so also residual methyl benzene sulfonate within acceptable limits.
Thus, there is major short coming of the existing prior art methods of producing N,N'-4,l0-dioxa-3,ll-dioxotridecylene-l,13-bis-tetrahydropapaverine (III), so also its reaction with MBS and isolation of pure Atracurium Besylate. Therefore, there is a continuous need for a method of producing N,N'-4,10-dioxa-3,l l-dioxotridecylene-l,]3-bis-tetrahydropapaverine (III) and Atracurium Besylate with acceptable purity in an efficient manner.
Objectives of the invention:
The primary object of the present invention is to provide a process for the preparation of pure N,N,-4,10-dioxa-3,ll-dioxotridecylene-lJ3-bis-tetrahydropapaverine of formula (III) via its oxalate salt.
Another object of the invention is to provide a process for the preparation of pure
Atracurium Besylate (IV) by bisquatemisation of pure compound (III) in absence of
solvent. This provides (IV) with an isomer ratio (cis-cis - 55-60%, cis-trans - 34.5-
38.5%, trans-trans - 5.0-6.5%) and levels of impurities within pharmaceutical acceptable
limits.
Yet another object of the present invention deals with selective extraction and isolation of
pwe AtTacurium Besy\ate, using reduced vo\umes of combination of soWents.
Summary of the invention:
The present invention discloses a process for the preparation of Atracurium Besylate which comprises the following steps:

1. Synthesis and purification of (III): Synthesis of pure N,N'-4,10-dioxa-3,ll-dioxotridecylene-l,13-bis-tetrahydropapaverine(lIl) by condensing N-(2-carboxy ethyl)-!-(3,4-dimethoxybenzyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoIine (I) with i,5-dihalopentanes (II) in presence of inorganic acid binder and inorganic iodide salt in suitable solvent. Compound (III) was isolated and purified via its oxalate salt.
2. Synthesis and purification of (IV): Preparation of pure Atracurium Besylate (IV) by bisquaternisation of pure compound (III), formed in step (1), by reaction with methyl benzene sulfonate (MBS) in presence of catalytic amount of inorganic base, in the absence of solvent. Further, selective extraction and isolation of pure Atracurium Besylate (IV) using reduced volumes of combination of solvents.
Detailed description of the invention:
1) Synthesis of compound (ill)*.

OMe (|||) OMe
In an embodiment of the present invention compound (I), compound ((IT)-where X = Br, CI, I), an inorganic acid binder and iodide salt are combined to form a reaction mixture that is maintained for sufficient period of time.


0

(II)

The reaction is conducted in presence of solvent selected from a group comprising of acetone, acetonitrile, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; preferably dimethyl formamide.
Although any of the 1,5-dihalopentanes like 1,5-dichloro pentane, 1,5-dibromo pentane or 1,5- diiodo pentane can serve the purpose in the present invention, 1,5-dibromo pentane, because of its reactivity and commercial availability in pure form, is most preferred.
The molar ratio of compound (I) and compound (II) can vary between the range of 0.4 to 0.6; more preferably 0.45 moles of compound (II) per mole of compound (I), as it minimizes the mono ester impurity and gives better yield of compound (III).
Inorganic acid binders include, but are not limited to sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, preferably anhydrous potassium carbonate. The inorganic acid binder is added to the reaction mixture in a ratio of 1 to 5 motes per mo"ie b?^ compooni {\)\ prefeiabVy \ mo'ie.
The inorganic iodide salt used in the invention is selected from potassium iodide or sodium iodide, v/hich is added in catalytic amount to the reaction mixture of compound (I) and (II). This salt accelerates the reaction and therefore results in higher yield of compound (III).
Further, the reaction involves heating a mixture of compound (I), compound (II), inorganic carbonate and an inorganic iodide salt in a solvent as described above, at temperature ranging from 35°C to 100°C for a sufficient amount of time. The most

preferable temperature for the said reaction being 50°C and sufficient time means time required to give the best yields which may vary between 2 to 6 hours but 4 hours are preferable.
Jn one of embodiment of the present invention compound (III) is isolated from the reaction mixture after working up by methods well described in an art including dilution, extraction and washing.
Compound (III) being finally isolated as its stable oxalate salt with HPLC purity greater than 96%. The purity of compound (III) being extremely significant in determining the purity of the final product Atracurium Besylate (IV). Treatment of the above obtained oxalate salt of compound (III), with solvents including acetone and dichloromethane at 50°C, forms a part of this invention. This treatment yields dioxalate of compound (111) with HPLC purity greater than 98.5%.
The aqueous suspension of pure oxalate salt of compound III is basified with sodium bicarbonate, followed by extraction with dichloromethane and evaporation of solvent to give free base (III) as oil with HPLC purity greater than 99%.
2) Synthesis and purification of (IV):
In another embodiment of the present invention, the free base (III), was subjected to the quatemization reaction. In accordance with such a process the compound (III), methyl benzene sulfonate (MBS) and catalytic amount of an inorganic base are allowed to react for a period of time sufficient for the complete conversion of compound (111) to compound (IV).
The reaction mixture is then filtered to remove the insoluble inorganic base and Atracurium Besylate (IV) was isolated by precipitation.
In an embodiment of the present invention, compound (IV) obtained after the above mentioned reaction and filtration of the insoluble base as its solution in MBS, is diluted with solvent mixture comprising water and an aromatic hydrocarbon with or without a ketonic organic solvent.

The resulting aqueous solution of compound (IV) so obtained is further extracted with toluene (aromatic hydrocarbon) and subsequently with diethyl ether or diisopropyl ether. Further, the compound (IV) is selectively extracted in suitable solvent like dichloromethane and recovered as oil by evaporation of the solvent. The oil is then dissolved in a mixture of solvent comprising alcohol like isopropanol and dichloromethane and precipitated by dropwise addition to a solution comprising an acetate and an ether. Acetate includes but is not intended to be limited to ethyl acetate, isopropyl acetate and methyl acetate. Ether includes but is not intended to be limited to diethyl ether, diisopropyl ether.
In another aspect of the present invention, the reaction is preferably carried out in MBS, which by itself provides suitable stirrability to the reaction mass. Preferred ratio of MBS to moles of compound (III) is 5 to 25 moles, more preferably 3 to 15 moles and most preferably 12 moles. The advantage of using no solvent and instead MBS as the reaction medium provides faster reaction rates, lesser monoquaternised impurity and other degradation impurities. It was found that catalytic amounts of anhydrous inorganic base like sodium carbonate or potassium carbonate helped to accelerate the conversion of compound (III) to compound (IV).
The use of inorganic base is limited to 2.5 mg to 10.0 mg per gram of (III) oxalate, as more amounts of the said catalyst adversely affected the yield and quality of Atracurium Besylate. Another feature of the invention is to eliminate the inorganic base from the reaction mass by process of filtration essentially, prior to dilution of the retention mass with solvent mixture of water and aromatic hydrocarbon with or without ketonic organic solvents. This ensures that Atracurium Besylate formed remains stable during the entire isolation process of extraction and precipitation.
Yet another important aspect of the present invention pertains to the suitable temperature of the reaction. The reaction can be carried out over a temperature range of 5°C to 40°C; more preferably 15°-20°C.

Another aspect of the invention relates to the time period of reaction, sufficient for Atracurium Besylate formation. The required time varies from 3 to 72 hours; preferably the time required is about 24 hours, more preferably 17 hours.
In an important embodiment of the present invention, a method is provided for the removal of residual MBS from the desired product (IV). The aqueous solution of (IV) obtained after aqueous workup was extracted with water immiscible solvents comprising aromatic hydrocarbon like toluene or xylene, preferably toluene and further with diethyl ether or diisopropyl ether.
Yet another aspect of the invention relates to the selective extraction of (IV) from its aqueous solution in solvent preferably dichloromethane.
Yet another embodiment of the present invention utilizes precipitation of compound (IV). For that, compound (IV) obtained as oil is dissolved in a solvent mixture comprising an alcohol and dichloromethane. Alcohols, which can be used in the present invention includes without limitation methanol, ethanol and isopropanol, most preferably isopropanol. When the most preferred alcohol used is isopropanol, the ratio of the diluting solvent mixture to the initial quantity of compound (III) is 5.0 to 6.0 volumes and the ratio of isopropanol to dichloromethane is 2.7:1. This solution is subsequently slowly added to a mixture of solvent comprising an acetate and an ether to induce precipitation of compound (IV) as a well defined solid. The acetate included is methyl acetate, ethyl acetate or isopropyl acetate. The suitable ether is selected from diethyl ether or diisopropyl ether; preferably diethyl ether. When the preferred acetate used is ethyl acetate and the preferred ether is diethyl ether, the ratio of the precipitating solvent mixture to the initial amount of compound (IV) is about 80 volumes and the ratio of ethyl acetate to diethyl ether is 1.5:1. Atracurium Besylate (IV) is then isolated by filtration, washing with diethyl ether and drying under vacuum.
Another embodiment of the present invention deals with process of purification of the isolated Atracurium Besylate by reprecipitation. The reprecipitation may be carried out in a method similar to the initial precipitation, using a combination of isopropanol and

dichloromethane as dissolving solvent and a mixture of ethyl acetate and diethyl ether as the precipitating solvent.
If necessary, the reprecipitation may be repeated with variation in the ratio of diluting/dissolving solvent and the precipitating solvent so as to achieve the desired purity of Atracurium Besylate (IV) (greater than 98%) and MBS within acceptable limits (less than 100 ppm) with an isomer ratio (cis-cis - 55-60%, cis-trans -34.5-38.5%, trans-trans - 5.0-6.5%) The examples are illustrative of the various aspects of the present invention and are not limiting of the specification and the claims in any way.
The invention is summarized in the following reaction scheme.

A mixture of compound (I) (lOOgm), 1,5-dibromopentane (II) (25gm) in dimethyl formamide (450 ml) and anhydrous potassium carbonate (33.25 gm) is heated at 50°C in presence of potassium iodide (0.4gm) for 4 hrs. Solid is filtered out and filtrate is quenched in cold mixture of water (2.8 L) and methylenedichloride (500 ml). After layer separation, aqueous phase is extracted 3 times with methylenedichloride (250ml). Combined organic phase is washed twice with aq. saturated sodium bicarbonate solution (100ml), followed by saturated brine (100ml). Organic phase is evaporated to yield oily product.
Example 2:
Purification of compound (III):
a) Oily product obtained in example 1 is taken in acetone (600 ml), decolorized and a
solution of oxalic acid dihydrate in 50% aqueous acetone (30gm in 200ml) is added at
reflux. The reaction mixture is cooled, filtered and dried under vacuum to give crude
oxalate derivative of compound (III) with HPLC purity greater than 96%.
b) The crude compound obtained in step (a) is stirred with a mixture of acetone and methylenedichloride (1:1) (600ml) at 50°C for 1 hr. After cooling and filtering, the solid is washed with acetone followed by n-hexane and dried under vacuum to yield 79 gm of pure oxalate derivative of compound (III) with HPLC purity greater than 98.5%.
c) The crude compound obtained in step (b) is dissolved in water and treated with saturated sodium bicarbonate solution for 0.5 hr. The product is isolated by extracting in dichloromethane and concentrated to yield compound (III) as oil with HPLC purity greater than 99%.
Example 3:
Preparation of Atracurium Besylate (IV)
A reaction mixture of compound (III) (100gm); MBS (417 ml) and anhydrous sodium
carbonate (0.259gm) is stirred at temperature of 15-20°C. After a period of 17 hours, the
filtered reaction mixture is diluted with solvent mixture comprising distilled water
(1500ml), toluene (1000 ml) and acetone (100ml). The separated aqueous layer is
extracted with three equal portions of toluene each 750 ml and further with diethyl ether
(2 x 375ml).Subsequently Atracurium Besylate (IV) formed is extracted into
dichloromethane The exhaustive extraction required about four extracts each of 400 ml of

dichloromethane. Crude Atracurium is recovered as oil by evaporating dichloromethane solution.
Example 4:
Purification of Atracurium Besylate (IV)
Crude (IV) obtained in example 3 is dissolved in a mixture of dichloromethane (150ml) and isopropanol (440 ml). Pure (IV) was isolated by dropwise addition of this solution to a mixture of ethyl acetate (4800 ml) and diethyl ether (3200 ml). The filtered solid is washed with diethyl ether and dried under vacuum. The reprecipitation if necessary is repeated using same solvent ratios used above to yield 60.5 gm of compound (IV) as a white free flowing powder. Purity (HPLC) = >98%

We claim,
1) A novel process for preparation of N,N'-4.10-dioxa-3,l l-dioxotridecylene-1,13-bis-tetrahydropapaverine of formula (III),



OMe

comprising condensation of a compound of formula (I)


MeO MeO
MeO
OMe (I) and 1,5-dihalopentane in presence of inorganic acid binders and iodide salt in a
solvent.
2) The process as claimed in claim j, wherein 1,5-dihalopentane is selected from a group comprising of 1,5-dichIoropentane, 1,5-dibromopentane, 1,5-diiodopentane; preferably 1,5-dibromopentane.
3) The process as claimed in claim 1, wherein 1,5-dihalopentane is added in mole ratio of 0.4 - 0.6 with respect to compound (1); preferably in a ratio of 0.45.
4) The process as claimed in claim 1, wherein an inorganic acid binder is selected from a group comprising of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; preferably anhydrous potassium carbonate.
5) The process as claimed in claim 1, wherein an inorganic iodide salt is selected from a group comprising of sodium iodide, potassium iodide; preferably potassium iodide.

6) The process as claimed in claim 1, wherein a solvent is selected from a group comprising of acetone, acetonitrile, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide; preferably dimethyl formamide.
7) The process as claimed in claim 1, wherein the reaction is carried between the temperature ranging from 35°C to 100°C. more specifically about 50°C.
8) The process as claimed in claim 1, wherein the reaction is carried out for 2 - 6 hours; preferably for 4 hours.
9) The process as claimed in claim 1 comprises purification of compound (III) via its oxalate salt to obtain purity greater than 99%.
10) A process for preparation of Atracurium besylate of formula (IV),

MeO
OMe

OMe

(IV)
comprising bisquaternisation of compound (III)

MeO
OMe

(ill)

OMe

using methyl benzene sulfonate and inorganic base in the absence of solvent.
11) The process as claimed in claim 10 comprising purification of formula IV using mixture of solvents, which comprises
a) dissolving compound (IV) in a solvent mixture comprising an alcohol and dichloromethane: and

b) adding the solution of step (1) to a mixture of solvent comprising an acetate and an ether to induce precipitation of compound (IV).
12)The process as claimed in claim 11, wherein the alcohol used is selected from methanol, ethanol and isopropanol, most preferably isopropanol; acetate used is selected from methyl acetate, ethyl acetate or isopropy! acetate, preferably ethyl acetate; and the suitable ether is selected from diethyl ether or diisopropyl ether; oreferablv diethyl ether.