A Process for Preparation of Mivacurium Chloride

Field of Invention

The present invention relates to a process for preparing the [R-[R*,R*- (E)]]-2,2'-(l,8-dioxo-4-octene-l,8-diyl) bis(oxy-3,l-propanediyl) bis(l,2,3,4- tetrahydro-6,7-dimethoxy-2-methyl-l-[(3,4,5-trimethoxyphenyl)- methyl]
isoquinolinium) dichloride, commonly known as mivacurium chloride, having the formula I:

Background of the Invention

Mivacurium chloride is a rapid, non-depolarising, neuromuscular blocking agent of short duration, used therefore as anaesthetic, to provide skeletal muscle relaxation in minor surgical operations, in emergency surgical procedures of short to intermediate duration and during intubation of the trachea.

As it is evident from the above formula, mivacurium chloride contains two chiral centres, at each centre, may therefore exist either the R or the S configuration. Moreover, the methyl substituent on each of the two quaternary nitrogen atoms may exist in either the R or the S configuration.

The compound having the R configuration at both chiral centres is known to be free from significant side effects at the normal dosages. In view of what explained above, this compound may exist in three distereoisomers: the trans- trans (1R, l'R; 2S, 2'S); the cis-trans (1R, l'R; 2R, 2'S), and the cis-cis distereoisomer (1R, l'R; 2R, 2'R). The trans-trans and the cis-trans distereoisomers have neuromuscular blocking potencies not significantly different from each other, whereas the cis-cis distereoisomer has been estimated to have approximately one tenth the neuromuscular blocking potency of the other two distereoisomers.

Mivacurium chloride has been disclosed for the first time in US patent 4,761,418. This patent describes a process for the preparation of mivacurium chloride by coupling of (E)-4-octene-l,8-dioic acid dichloride with N-3- hydroxypropyl-l-(R)-5'-methoxylaudanosinium chloride of formula (A), in warm 1,2-dichloroethane:

According to U.S. Pat. No. 4,761,418, once the coupling reaction is complete, the solvent is removed by distillation under vacuum and replaced by chloroform. The so obtained chloroform solution is then washed with diluted aqueous solutions of sodium chloride to eliminate the isochinolinic compound (A) in excess, and the organic solvent is removed by distillation under vacuum, thus obtaining an amorphous solid. This solid product is then purified from impurities by washings with warm 2-butanone, removing the residual organic solvent by distillation under vacuum. Finally, the amorphous solid product is dissolved in methanol, filtered and freeze-dried, thus yielding the mivacurium chloride.

A similar synthesis is disclosed in Current Medicinal Chemistry, vol. 9, Nov. 16, 2002 also.

The primary drawback of this process is that the raw product obtained contains a high amount of various impurities, mainly represented by the compound A used as starting material both as cis and trans diastereoisomer, and an "acid ester", both as cis and trans diastereoisomer represented by following formula:

Another patent US7,872,137 describes a process for preparation of mivacurium chloride by coupling of N-3-hydroxypropyI-l-(R)-5'- methoxylaudanosinium chloride with (E)-4-octene-l,8-dioic acid dichloride in MDC suitable organic solvent, to obtain raw mivacurium chloride, which is further extracted with water, treated with a suitable non-ionic polymeric adsorbent resin insoluble in water to recover pure mivacurium chloride. It is to be noted that US7,872,137 discloses only the final step coupling of N-3- hydroxypropyl-l-(R)-5'-methoxylaudanosinium chloride with (E)-4-octene-l,8- dioic acid dichloride, the preparation of N-3-hydroxypropyl-l-(R)-5'- methoxylaudanosinium chloride as disclosed in US4761418 involves coupling of R-(-)-5-methoxylaudanosine and 3-chloropropanol in presence of sodium iodide and passing through another resin preferably Dowex-resin. Thus to get mivacurium chloride prepared by this process finally two resins are needed one for the preparation of N-3-hydroxypropyl-l-(R)-5'-methoxylaudanosinium chloride and other for the purification of crude mivacurium chloride.

Thus there is a need to develop a process for the preparation of Mivacurium chloride, which avoids the use of resin for the purification of final compound and is easy to handle on a commercial scale. The present inventors have developed a novel process for the preparation of Mivacurium chloride, which avoids the use of second resin to get a highly pure product.

Summary of the Invention

The principal aspect of the present invention is to provide a process for the preparation of [R-[R*,R*-(E)]]-2,2'-(l,8-dioxo-4-octene-l,8-diyl) bis(oxy- 3,1-propanediyl) bis(l,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-l-[(3,4,5- trimethoxyphenyl)- methyl]isoquinolinium)dichloride of formula I, which comprises:

a) condensation of (4E)-oct-4-enedioic acid chloride of formula (IV) with 3- chloropopanol in presence of a suitable organic solvent and a base to obtain bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III); and

b) coupling of bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III) with R-(-)-5-methoxylaudanosine of formula (II) in a suitable organic solvent, in presence of an alkali metal iodide, a base, and an ion exchange resin to obtain Mivacurium chloride of formula I.

The process of the present invention may be illustrated by the below scheme 1:

In another aspect, the present invention provides a novel compound bis(3- chloropropyl)(4E)-oct-4-enedioate of formula (III)

In another aspect, the present invention provides a process for the preparation of (R)-(-)-5'-methoxylaudanosine of formula (II) comprising:

a) condensation of 3,4-dimethoxyphenylethylamine of formula (X) and 3,4,5-trimethoxyphenyl acetic acid of formula (IX) in presence of an aromatic solvent and catalytic amount of boric acid at reflux temperature to form N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (VIIII);

b) reacting N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (Villi) with POCI3, NaOH and methyl iodide in presence of toluene to form 6-7-Dimethoxy-l-(3',4',5'-trimethoxybenzyl)-2-methyl- 3,4-dihydroisoquinolinium iodide of formula (VII);

c) reducing 6-7-Dimethoxy-1 -(3' ,4', 5' -trimethoxybenzyl)-2-methy 1-3,4- dihydroisoquinolinium iodide of formula (VII) with NaBHj in presence of an alcoholic solvent to form (R)-(±)-5'-methoxylaudanosine of formula (VI);

d) resolving (R)-(±)-5'-methoxylaudanosine using chiral acid to form (R)- (+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) and (S)- (-)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V') and

e) hydrolysing (R)-(+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) to obtain (R)-(-)-5'-methoxylaudanosine of formula (II).

The process of the present invention may be illustrated by the below scheme 2:

In yet another aspect, the present invention provides a process for the preparation of Mivacurium chloride of formula (I) comprising:

a) condensation of 3,4-dimethoxyphenylethylamine of formula (X) and 3,4,5-trimethoxyphenyl acetic acid of formula (IX) in presence of an aromatic solvent and catalytic amount of boric acid at reflux temperature to form N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (VIIII);

b) reacting N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (VIIII) with POCl3, NaOH and methyl iodide in presence of toluene to form 6-7-Dimethoxy-l-(3'4'5'-trimethoxybenzyl)-2-methyl- 3,4-dihydroisoquinolinium iodide of formula (VII);

c) reducing 6-7-Dimethoxy-1 -(3' ,4', 5' -trimethoxybenzyl)-2-methyl-3,4- dihydroisoquinolinium iodide of formula (VII) with NaBH4 in presence of an alcoholic solvent to form (R)-(±)-5'-methoxylaudanosine of formula (VI);

d) resolving (R)-(±)-5'-methoxylaudanosine using chiral acid to form (R)- (+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) and (S)-(-) -5'-methoxylaudanosinum dibenzoyltartarate of formula (V');

e) hydrolysing (R)-(+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) to obtain (R)-(-)-5'-methoxylaudanosine of formula (II);

f) condensation of (4E)-oct-4-enedioic acid chloride of formula (IV) with 3- chloropopanol in presence of a suitable organic solvent and a base to obtain bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III); and

g) coupling of bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III) with R-(-)-5-methoxylaudanosine of formula (II) in a suitable organic solvent, in presence of an alkali metal iodide, a base, and an ion exchange resin to obtain Mivacurium chloride of formula I.

Detail Description of the Invention

Accordingly in an embodiment of the invention the condensation of 3,4- dimethoxyphenylethylamine and 3,4,5-trimethoxyphenyl acetic acid is carried out in presence of an aromatic solvent selected from the group comprising benzene, toluene, xylene, preferably toluene and catalytic amount of boric acid at reflux temperature.

In another embodiment of the invention the reduction of 6-7-Dimethoxy- 1 -(3',4',5'-trimethoxybenzyl)-2-methyl-3,4-dihydroisoquinolinium iodide of formula (VII) is carried out using with NaBH4 in presence of an alcoholic solvent selected from methanol, ethanol etc., preferably methanol.

In another embodiment of the invention, the chiral acid for the resolution of (R)-(±)-5'-methoxylaudanosine is selected from camphor sulphonic acid, mandelic acid, (-)-Dibenzoyltartaric acid and (+)-Dibenzoyltartaric acid preferably (-)-Dibenzoyltartaric acid and (+)-Dibenzoyltartaric acid.

In yet another embodiment of the invention, the hydrolysis of R)-(+)-5'- methoxylaudanosinum dibenzoyltartarate is carried out in an alcoholic solvent selected from methanol, ethanol, propanol, etc. preferably methanol and in presence of a base selected from alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, preferably sodium hydroxide, potassium hydroxide, more preferably sodium hydroxide.

In still another embodiment of the invention, the condensation of (4E)- oct-4-enedioic acid chloride of formula (IV) with 3-chloropopanol is carried out in presence of a suitable organic solvent selected from an halogenated solvent, preferably methylene dichloride, ethylene dichloride, chloroform etc., more preferably ethylene dichloride and a base selected from alkali metal carbonates, alkali metal bicarbonates etc. preferably sodium bicarbonate, potassium bicarbonate more preferably sodium bicarbonate.

In yet another embodiment of the invention, bis(3-chloropropyl)(4E)-oct- 4-enedioate of formula (III) is coupled with R-(-)-5-methoxylaudanosine of formula (II) in a suitable organic solvent preferably ketonic solvent , more preferably 2-butanone, in presence of an alkali metal iodide such as sodium iodide, potassium iodide, preferably sodium iodide; a base preferably alkali metal carbonates more preferably sodium carbonate, potassium carbonate and most preferably sodium carbonate; and an ion exchange resin, preferably Dowex resin.

The present invention can be illustrated by the following non-limiting examples.

Example:

(a) Preparation of N-(3,4.5-trimethoxyphenvl acetyl) homoveratrylamine:

3,4-dimethoxyphenylethylamine (100 g) was treated with 3,4,5- trimethoxyphenyl acetic acid (135.2g) and toluene (500ml). Boric acid (1.3
g) was added to the above reaction mass, heated to 110-125°C for 22-24 hrs. Reaction mass was cooled to 0-5 °C for 1hr, solids were filtered, washed with DM water and suck dried.

Yield: 203 g.

(b) Preparation of 6-7-Dimethoxy-l-(3'.4’5'-trimethoxybenzyl)-2- methvl-3,4-dihvdroisoauinolinium iodide:

N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine(100 g) was reacted with POCI3 at 94-96°C for 2 hrs. Reaction mass was quenched to DM water, pH was adjusted to 8-9 using 50% NaOH solution, toluene (500 ml) was added, and heated to 35-40°C. Two layers were separated, to the aqueous layer toluene (100 ml) was added, stirred and heated to 35-40°C. To the combined toluene layer DM water was added, stirred and heated to 35-40°C. Two layers were separated, the toluene layer was distilled under vaccum to distil traces of water. Methyl iodide(100 ml) was added to the above distillate, heated to 85-90°C for 2 hrs. Solids were filtered, washed with 50ml of toluene and then suck dried.

Yield: 107 g.

(c) Preparation of (RH+/-)-5'-methoxylaudanosine :
6-7-Dimethoxy-1-(3 ',4',5 '-trimethoxybenzyl)-2-methyl-3,4- dihydroisoquinolinium iodide (100g) was treated with NaBH4 (9.5 g) and methanol(500 ml), heated to 40-42°C.After completion of reaction, methanol was distilled out completely, DM water (200 ml) and MDC (200 ml) was added. Two layers were separated, to the aqueous layer MDC (100 ml) was added, stirred and layers were separated. The collected MDC layer was dried over Anhydrous Sodium Sulphate and distilled.

Yield: 75.0 g.

(d) Preparation of (R)-(+)5'-methoxvlaudanosinum dibenzoyltartarate :
(R)-(+/-)-5'-methoxylaudanosine(66 g) was treated with dibenzoyl-L- tartaric acid(64 g) and methanol (330 ml), heated to reflux for 10 mins, cooled for 8-10 hrs at 0-5°C , obtained solids were filtered and washed with chilled methanol. The filtrate obtained was concentrated under vaccum, water (4 volumes) and MDC (3 volumes) was added. pH was adjusted to 10-10.5 using 50% lye , stirred and two layers were separated. Aqueous layer was again extracted with MDC. The combined organic layer was concentrated, methanol(5 volume) was added, dibenzoyl-D-tartaric acid(40.6g) was added, heated to reflux for 10 mins, cooled for 8hrs. Solids were filtered, washed with chilled methanol, suck dried and recrystallised using methanol.

Yield: 42.5 g.

(e) Preparation of (R)-(-)-5'-methoxylaudanosine :
(R)-(+)-5'-methoxylaudanosinum dibenzoyltartarate was treated with methanol(520 ml) and pH was adjusted using 50% lye solution. Methanol was distilled, DM water and MDC (80 ml) were added, stirred for 15 mins. Two layers were separated, aqueous layer was again extracted with MDC, the combined organic layer was concentrated to form residue under vaccum.

Yield: 20.6 g.

(f) Preparation of 1.8-octene dioic acid chloropropionate :
4-octene-l,8-octene dioic acid(3.0 g) was treated with thionyl chloride(15 ml) and EDC (30 ml), heated to 70-75°C for 3 hrs. Excess of thionyl chloride was distilled, cooled to 25-30°C. 3- chloropropanol was added slowly with stirring for 3 hrs. 5% NaHCC>3 solution was added, stirred for 10 mins. Two layers were separated, organic layer was washed with DM water. The combined organic layer was distilled under vaccum.

Yield: 1.72 g.

(g) Preparation of mivacurium chloride :
(R)-(-)-5'-methoxylaudanosine was treated with 1,8-octene dioic acid chloropropionate (1.7 g), 2-butanone(28.9 ml) and DMF (5.1 ml). Na2C03(0.14 g) and Nal (3.1 g) were added and heated to 60-65°C for 24 hrs.

Reaction mass was filtered, washed with 2-butanone, distilled under vacuum below 60°C. DM water was added, two layers were separated, aqueous layer was again extracted with MDC, and the combined organic layer was distilled under vacuum. The residue was diluted with methanol and Dowex-resin (34.4 g) was added to the above Reaction mass, stirred for 15 mins. Resin was filtered, washed with methanol and methanol was distilled. MDC and water were added, stirred and two layers were separated. To the aqueous layer NaCl (10g) and MDC(50 ml) were added, stirred and layers were separated and MDC layer was distilled.

Yield: 3.9 g.

We claim:

1. A process for the preparation of [R-[R*,R*-(E)]]-2,2'-(l,8-dioxo-4- octene-l,8-diyl) bis(oxy-3,1-propanediyl) bis(l ,2,3,4-tetrahydro-6,7- dimethoxy-2-methyl-l-[(3,4,5-trimethoxyphenyl)-methyl]isoquinolinium) dichloride of formula I, which comprises:

a) condensation of (4E)-oct-4-enedioic acid chloride of formula (IV)

with 3-chloropopanol in presence of a suitable organic solvent and a base to obtain bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III); and

b) coupling of bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III)

with R-(-)-5-methoxylaudanosine of formula (II)

in a suitable organic solvent, in presence of an alkali metal iodide, a base, and an ion exchange resin to obtain Mivacurium chloride of formula I.

2. A process for the preparation of (R)-(-)-5'-methoxylaudanosine of formula (II) comprising:

a) condensation of 3,4-dimethoxyphenylethylamine of formula (X)

and 3,4,5-trimethoxyphenyl acetic acid of formula (IX)

in presence of an aromatic solvent and catalytic amount of boric acid at reflux temperature to form N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (VIIII);

b) reacting N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (VIIII) with POCI3, NaOH and methyl iodide in presence of a solvent to form 6-7-Dimethoxy-l-(3',4',5'-trimethoxybenzyl)-2-methyl- 3,4-dihydroisoquinolinium iodide of formula (VII);

c) reducing 6-7-Dimethoxy-1 -(3',4',5'-trimethoxybenzyl)-2-methyl-3,4- dihydroisoquinolinium iodide of formula (VII) with NaBH4 in presence of an alcoholic solvent to form (R)-(±)-5'-methoxylaudanosine of formula (VI);

d) resolving (R)-(±)-5'-methoxylaudanosine using chiral acid to form (R)- (+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) and (S)-(-)- 5'-methoxylaudanosinum dibenzoyltartarate of formula (V'); and

e) hydrolysing (R)-(+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) to obtain (R)-(-)-5'-methoxylaudanosine of formula (II).

3. A process for the preparation of Mivacurium chloride of formula (I) comprising:

a) condensation of 3,4-dimethoxyphenylethylamine of formula (X) and 3,4,5-trimethoxyphenyl acetic acid of formula (IX) in presence of an aromatic solvent and catalytic amount of boric acid at reflux temperature to form N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (VIIII);

b) reacting N-(3,4,5-trimethoxyphenyl acetyl) homoveratrylamine of formula (Villi) with POCI3, NaOH and methyl iodide in presence of a solvent to form 6-7-Dimethoxy-l-(3',4',5'-trimethoxybenzyl)-2-methyl- 3,4-dihydroisoquinolinium iodide of formula (VII);
c) reducing 6-7-Dimethoxy-1 -(3' ,4', 5' -trimethoxybenzyl)-2-methyl-3,4- dihydroisoquinolinium iodide of formula (VII) with NaBtLi in presence of an alcoholic solvent to form (R)-(±)-5'-methoxylaudanosine of formula (VI);

d) resolving (R)-(±)-5'-methoxylaudanosine using chiral acid to form (R)- (+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) and (S)- (-)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V');

e) hydrolysing (R)-(+)-5'-methoxylaudanosinum dibenzoyltartarate of formula (V) to obtain (R)-(-)-5'-methoxylaudanosine of formula (II);

f) condensation of (4E)-oct-4-enedioic acid chloride of formula (IV) with 3-chloropopanol in presence of a suitable organic solvent and a base to obtain bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III); and

g) coupling of bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III) with R-(-)-5-methoxylaudanosine in a suitable organic solvent, in presence of an alkali metal iodide, a base, and an ion exchange resin to obtain Mivacurium chloride of formula I.

4. A compound bis(3-chloropropyl)(4E)-oct-4-enedioate of formula (III).

5. A process according to claim 1 or 3 wherein, the condensation of (4E)- oct-4-enedioic acid chloride of formula (IV) with 3-chloropopanol is carried out in presence of ethylenedichloride and a sodium bicarbonate.

6. A process according to claim 1 or 3 wherein, the coupling of bis(3- chloropropyl)(4E)-oct-4-enedioate of formula (III) with R-(-)-5- methoxylaudanosine is carried out in 2-butanone, in presence of sodium iodide, a sodium carbonate and Dowex resin.

7. A process according to claim 2 or 3 wherein, condensation of 3,4- dimethoxyphenylethylamine of formula (X) and 3,4,5-trimethoxyphenyl acetic acid of formula (IX) is carried out in toluene at reflux temperature.

8. A process according to claim 2 or 3 wherein the chiral acids for resolution of (R)-(±)-5'-methoxylaudanosine are (-)-Dibenzoyltartaric acid and (+)- Dibenzoyltartaric acid.

9. A process according to claim 2 or 3 wherein, hydrolysis of (R)-(+)-5'- methoxylaudanosinum dibenzoyltartarate of formula (V) is carried out using an alcoholic solvent and a base.

10. A process according to claim 8 wherein, the alcoholic solvent is methanol and the base is sodium hydroxide.