HK1060562A - New process - Google Patents

Description

New method

The present invention relates to an improved process for the preparation of an anti-migraine drug, commercially obtained as the hydrobromide salt of (R) -5- (2-benzenesulfonylethyl) -3-N-methylpyrrolidin-2-ylmethyl) -1H-indole (eletriptan):

and the intermediates and dimer-free products obtained therefrom.

European patent 0592438 describes a process for the preparation of eletriptan by catalytic reduction of (R) -5- (2-benzenesulfonylvinyl) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole, the above compound being prepared by: (i) reacting N-benzyloxycarbonyl-D-prolyl chloride with 5-bromoindole in the presence of a Grignard reagent; (ii) (ii) reducing the resulting (R) -3- (N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl) -5-bromo-1H-indole to give (R) -5-bromo-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole and (iii) reacting it with phenylvinylsulfone in the presence of a palladium catalyst, a triarylphosphine and a base.

The complete scheme can be expressed as follows:

when eletriptan of formula (I) is prepared in reasonable yields according to the following scheme, (R) -5- (2-benzenesulfonylvinyl) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole precursor is found to have a tendency to dimerize when attempting to recrystallize in an impure form and/or dry prior to catalytic reduction:

not only does the formation of this dimeric impurity reduce the yield of eletriptan, but, perhaps more importantly, it requires costly and time-consuming removal of the dimer to provide a hydrobromide salt of sufficient purity to meet the stringent standards required for regulatory approval.

Because of this difficulty, we have now developed an alternative route to eletriptan synthesis which avoids the use of precursors which tend to dimerise. In particular, the process of the invention comprises the preparation of eletriptan by hydrolysis of (R) -1-acetyl-5- (2-benzenesulfonylethyl) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole, said compound being conveniently prepared by: (i) n-acetylated (R) -5-bromo-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole; (ii) (ii) reacting the resulting (R) -1-acetyl-5-bromo-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole with phenylvinylsulfone in the presence of a palladium catalyst, a triarylphosphine and a base to give (R) -1-acetyl-5- (2-benzenesulfonylvinyl) -3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole and (iii) catalytically reducing the compound.

The complete scheme is represented as follows:

by using this method, the formation of undesired dimer can be avoided, resulting in high purity eletriptan in good yield without the need for subsequent expensive and time consuming purification steps required to remove the dimer impurity.

Thus, according to the present invention, there is provided a process for the preparation of a compound of formula (I) which comprises hydrolysis of a compound of formula (II), typically under basic conditions, more particularly potassium carbonate in methanol/water.

According to another aspect of the invention, the compound of formula (II) used in the present process may be obtained by catalytic reduction of a compound of formula (III), typically using hydrogen or a source of hydrogen in the presence of a suitable catalyst. The reduction is usually carried out using hydrogen at a pressure of 1 to 15 atmospheres, or using a source of hydrogen, such as ammonium formate or formic acid. Suitable catalysts include palladium on carbon, for example 5% w/w Pd/C, Raney nickel, platinum oxide, rhodium or ruthenium. The reduction is conveniently carried out in the presence of an acid, for example methanesulphonic acid, acetic acid or trifluoroacetic acid. The resulting compound of formula (II) is conveniently slurried with cold aqueous tetrahydrofuran prior to hydrolysis to the compound of formula (I).

The present invention specifically provides the compounds of formula (II) described above, which have not been described so far.

According to another aspect of the invention, the compound of formula (III) used in the process of the invention can be obtained by treating the compound of formula (IV) with phenyl vinyl sulfone in the presence of a palladium catalyst, a triarylphosphine and a base, according to the process described in example 57 of US patent 5607951.

In another aspect of the present invention, the compound of formula (IV) used in the process of the present invention can be obtained by N-acetylating (R) -5-bromo-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole, also according to the process described in example 57 of US patent 5607951.

Eletriptan obtained by the process of the present invention can be converted into a pharmaceutically acceptable acid addition salt by treatment with a suitable acid, conveniently in situ, without isolation of the compound of formula (I). A particularly preferred salt is the hydrobromide salt obtained by treatment with hydrobromic acid.

Thus, according to the present invention, it also provides dimer-free eletriptan and its pharmaceutically acceptable salts, especially the hydrobromide salt, and pharmaceutical compositions containing them.

Examples

The process of the present invention can be illustrated by the following example for the preparation of (R) -5- (2-benzenesulfonylethyl) -3-N-methylpyrrolidin-2-ylmethyl) -1H-indole (I) and its hydrobromide salt:

(a) preparation of (R) -1-acetyl-5- (2-benzenesulfonylethyl) -3- (N-methylpyrrolidin-2-ylmethyl Base) -1H-indole (II)

To a solution of compound of formula (III) (200g) prepared by the method described in example 57 of US5607951 above in acetone (2.0L) was added water (0.5L), methanesulfonic acid (43.2g, 0.95 eq) was added dropwise, the resulting solution stirred for 5 minutes, then 5% w/w Pd/C catalyst (89.0g, johnson mattey Type 58, 50% moisture) was added. The solution was hydrogenated at room temperature under 200psi of hydrogen for 18 hours.

The catalyst was removed by filtration and the filtrate was stripped to give an acetone-free slurry. To this was added dropwise a 40% aqueous NaOH solution (300ml) and then water (1.5L). The resulting slurry was stirred for 20 minutes, and a 40% aqueous NaOH solution (20ml) was added thereto. After granulation for 2 hours with vigorous stirring, the suspension was filtered and suction dried for 30 minutes to give a beige wet solid which was:

(i) drying at 45 ℃ to give the desired product (193.0g, 95% yield) or

(ii) Dissolved in tetrahydrofuran (1.6L) and water was added thereto over 10 minutes (1.5L total). The resulting suspension was stirred vigorously for 18 hours, filtered and dried under suction for 30 minutes to give the desired product as an off-white wet solid (calibration weight 129.0g, yield 67%).

Each form of product can be used directly in step (b).

(b) Preparation of (R) -5- (2-benzenesulfonylethyl) -3-N-methylpyrrolidin-2-ylmethyl) 1H-indole (I)

To a solution of compound of formula (II) (95.9g) from step (a) (i) or (II) in acetone (1L) and methanol (0.1L) was added K₂CO₃(46.8g, 1.5 eq.) and the resulting mixture was stirred for 24 hours. Charcoal (50g) was added thereto, and after 1 hour, anhydrous MgSO was added₄(300g) In that respect The resulting suspension was stirred for 1 hour and filtered. The filtrate was stripped to give a wet solid which was dried under vacuum at 45 ℃ to give the desired product (79.3g, 91.8%).

In the case of conversion of a compound of formula (I) into a pharmaceutically acceptable acid addition salt, isolation of the compound of formula (I) can be avoided by hydrolysis of the resulting solution directly with a suitable acid, for example hydrobromic acid, to give the hydrobromic acid salt.

(c) Preparation of (R) -5- (2-benzenesulfonylethyl) -3-N-methylpyrrolidin-2-ylmethyl) -1H-indole (I) And in situ hydrobromation

To a solution of compound of formula (II) (95.9g) from step (a) (i) or (II) in acetone (1L) and methanol (0.1L) was added K₂CO₃(46.8g, 1.5 eq.) and the resulting mixture was stirred for 24 hours. Charcoal (50g) was added thereto, and after 1 hour, anhydrous MgSO was added₄(300g) In that respect The resulting suspension was stirred for 1 hour and filtered.

The filtrate was partially concentrated by azeotropic distillation to remove methanol and the volume was adjusted to 0.45L with acetone. A solution of 48% w/v HBr (33.2g, 0.95 eq) in acetone (50ml) was added dropwise and the resulting suspension was stirred for 72 h. Filtration, suction drying for 30 minutes, vacuum drying at 45 ℃ gave the desired product as pale beige crystals (71.8g, 68.5%).

In a preferred embodiment of the invention, certain steps may be 'shortened' to reduce handling and to speed up processing times. For example, by using a wet mass slurried in aqueous tetrahydrofuran in said step (a) (II), drying of the compound of formula (II) prior to hydrolysis may be avoided. Also, in said step (c), the isolation of the compound of formula (I) prior to conversion to a salt may be avoided by in situ salt formation.

Claims (23)

1. A process for preparing a compound of formula (I):

which comprises hydrolysing a compound of formula (II):

2. the process of claim 1, carried out under basic conditions.

3. The process of claim 2, wherein the hydrolysis is carried out using potassium carbonate in methanol/water.

4. A process according to any one of claims 1 to 3, wherein the compound of formula (II) is obtained by catalytic reduction of a compound of formula (III):

5. the process of claim 4, wherein the reduction is carried out using hydrogen or a source of hydrogen in the presence of a suitable catalyst.

6. The process of claim 5, wherein the reduction is carried out using hydrogen at a pressure of 1 to 15 atmospheres.

7. The process of claim 5, wherein the reduction is carried out using a source of hydrogen, which is ammonium formate or formic acid.

8. The process of any of claims 4-7, wherein the catalyst is palladium on carbon, Raney nickel, platinum oxide, rhodium, or ruthenium.

9. The method of claim 8, wherein the catalyst is 5% w/w palladium on carbon.

10. The process of any one of claims 4-9, wherein the catalytic reduction is carried out in the presence of an acid.

11. The method of claim 10, wherein the acid is methanesulfonic acid, acetic acid, or trifluoroacetic acid.

12. A process according to any one of claims 4 to 11, wherein the compound of formula (II) obtained by catalytic reduction is slurried with cold aqueous tetrahydrofuran prior to hydrolysis to the compound of formula (I).

13. The process of any one of claims 4-12, wherein the compound of formula (III) is obtained by treating a compound of formula (IV) below with a phenyl vinyl sulfone in the presence of a palladium catalyst, a triarylphosphine, and a base:

14. the process of claim 13 wherein the compound of formula (IV) is obtained by N-acetylating (R) -5-bromo-3- (N-methylpyrrolidin-2-ylmethyl) -1H-indole.

15. A process according to any one of claims 1 to 14, wherein the compound of formula (I) obtained is converted into a pharmaceutically acceptable acid addition salt by treatment with a suitable acid.

16. The process of claim 15, wherein the conversion process is carried out in situ without isolation of the compound of formula (I).

17. The process of claim 15 or 16, wherein the acid is hydrobromic acid and the resulting salt is the hydrobromic acid salt.

18. A compound of formula (II):

19. eletriptan, which is substantially free of the following compounds:

20. a pharmaceutically acceptable acid addition salt of eletriptan which is substantially free of:

21. a pharmaceutically acceptable acid addition salt of eletriptan according to claim 20, which is the hydrobromide salt.

22. A pharmaceutical composition comprising eletriptan, or a pharmaceutically acceptable acid addition salt thereof, substantially free of:

and a suitable carrier or excipient.

23. The composition of claim 22, wherein said pharmaceutically acceptable acid addition salt is a hydrobromide salt.