HUGUET CLOTET JUAN (ES)
DALMASES BARJOAN PERE (ES)
| WO2009142771A2 | 2009-11-26 | |||
| WO2002050063A1 | 2002-06-27 | |||
| WO2002050063A1 | 2002-06-27 | |||
| WO1993021178A1 | 1993-10-28 |
| EP0592438B1 | 1997-08-27 | |||
| EP0776323A1 | 1997-06-04 |
| 1. Compound I Compound I wherein Boc is a ie f-butyloxycarbonyl protecting group and X is selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. 2. A compound I according to claim 1 , in crystalline form. 3. A crystalline compound I according to anyone of the preceding claims, wherein X is Br, having a DSC with an endothermic peak with an onset at approximately 172-175 °C and a maximum at approximately 182-185 °C. 4. A crystalline compound I according to anyone of the preceding claims, wherein X is Br, characterized in that it provides a DSC substantially in accordance to Figure 1. 5. A crystalline compound I according to anyone of the preceding claims, wherein X is Br, characterized in that it provides a TGA substantially in accordance to Figure 2. 6. A crystalline compound I according to any anyone of the preceding claims, wherein X is Br, characterized in that it provides an IR substantially in accordance to Figure 3. 7. A crystalline compound I according to anyone of the preceding claims characterized in that it shows substantially no color change over a storage period of 1 month under atmospheric conditions at room temperature. 8. A crystalline compound I according to anyone of the preceding claims, characterized in that it shows substantially no intake of water at a temperature of 30°C and 60% relative humidity. 9. A compound I according to claim 1 in amorphous form. 10. A compound I according to claim 1 to 2, in solvate form. A compound I according to claim 1 to 2, in hydrate form. A process for the preparation of a compound I according to any of the preceding claims, wherein compound A, is reacted with phenyl vinyl sulfone and a base in the presence of a cataly Compound A wherein Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable leaving group, selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. 13. A process according to claim 12, wherein the base used is selected from ammonia derivatives, metal orthophosphates and metal carbonates, preferably the base is ammonia derivatives. 14. A process according to claim 13, wherein the base used is triethylamine. 15. A process according to any of claims 12 to 14, wherein the reaction is carried out at a temperature from 50 °C to reflux. 16. A process according to claim 15, wherein the reaction is carried out at reflux temperature. 17. A process according to any of claims 12 to 16, wherein the molar ratio of Compound A to phenyl vinyl sulfone is from 1 :1 to 1 :5, wherein X is preferably CI and Br, most preferable, X is Br. 18. A process according to claim 17, wherein the molar ratio of Compound A to phenyl vinyl sulfone is from 1 :1 to 1 :2, preferably from 1 :1 to 1 :1.1 , wherein X is preferably CI and Br, most preferable, X is Br. 19. A process according to any of claims 12 to 18, wherein the molar ratio of Compound A to base is from 1 :1 to 1 :5, wherein X is preferably CI and Br, most preferable, X is Br. 20. A process according to claim 19, wherein the molar ratio of Compound A to base is from 1 :1 to 1 :2, preferably from 1 :1 to 1 :1 .5, wherein X is preferably CI and Br, most preferable, X is Br. 21 . A process according to any of claims 12 to 20, wherein the reaction is carried out in the presence of a solvent and wherein X of compound A is Br. 22. A process according to claim 21 , wherein the solvent is selected from 1 ,4-dioxane, Ν,Ν-dimethylformamide (DMF), tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof. 23. A process according to claim 22, wherein the solvent is selected from 1 ,4-dioxane, acetonitrile, ethanol and mixtures thereof. 24. Use of compound I according to any of the preceding claims for preparing eletriptan or pharmaceutically acceptable salts thereof, wherein X is preferably CI and Br, most preferable, X is Br. 25. An acid add Compound II wherein HA is an organic acid selected from (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous, (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate, (-)-0,0'-Dibenzoyl-D- tartaric acid anhydrous and (-)-0,0'-Dibenzoyl-D-tartaric acid monohydrate. 26. An acid addition salt of eletriptan according to claim 25, wherein the organic acid is (-)-0,0'-Dibenzoyl-L-tartaric acid. 27. An acid addition salt according to claim 26, wherein the organic acid is (-)-Ο,Ο'- Dibenzoyl-L-tartaric acid monohydrate. 28. An acid addition salt of eletriptan according to any of claims 25 to 27, in crystalline form. 29. An acid addition salt of eletriptan according to any of claims 25 to 28, in solvate form. 30. An acid addition salt of eletriptan, compound II according to claim 29 in hydrate form. 31 . An acid addition salt of eletriptan, compound II according to any of claims 25 to 27, in amorphous form. 32. A crystalline form of an acid addition salt of eletriptan, compound II, according to any of claims 25 to 28, wherein HA is (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate, having an X-ray powder diffraction pattern comprising the following main peaks at 2-theta values: 16.3, 18.1 , 19.2, 19.8, 21.6 and 26 ± 0.2° degrees two theta. 33. A crystalline form of an acid addition salt of eletriptan, compound II, according to claims 25 to 28 or 32, wherein HA is (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate, having a DSC thermogram showing an endothermic peak with an onset at approximately 150-153 °C, and a maximum at approximately 151 -154 °C. 34. A process for the preparation of acid addition salts of eletriptan, compound II, according to any of claims 25 to 33, wherein eletriptan is reacted with an acid, HA, to produce the novel acid addition salts of eletriptan, Compound II. 35. A process according to claim 34, wherein the acid, HA, is (-)-0,0'-Dibenzoyl-L- tartaric acid. 36. A process according to claim 35, wherein the acid, HA, is (-)-0,0'-Dibenzoyl-L- tartaric acid monohydrate. 37. A process according to any of claims 34 to 36, wherein the molar ratio of the acid, HA, to eletriptan is from 5: 1 to 1 : 1 . 38. A process according to any of claims 34 to 37, wherein the molar ratio of the acid HA to eletriptan is from 2: 1 to 1 : 1 , preferably is 1 :1. 39. A process according to according to any of claims 34 to 38, wherein the reaction is carried out in the presence of a solvent. 40. A process according to claim 39, wherein the solvent is selected from methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate and mixtures thereof, preferably the solvent is methanol. 41 . A process according to according to any of claims 34 to 40, wherein the reaction is carried out at a temperature from 0 °C to reflux. 42. A process according to according to any of claims 34 to 41 , wherein the reaction is carried out at a temperature from 25 °C to reflux, preferably the reaction is carried out at reflux temperature. 43. The use of an acid addition salt of eletriptan, compound II, according to any of claims 25 to 33, for preparing eletriptan or pharmaceutically acceptable salts thereof. 44. A process for preparing eletriptan or a pharmaceutically acceptable salt or co- crystal thereof from the acid addition salts of eletriptan, Compound II, according to any of claims 25 to 33, wherein the process comprises at least the following steps: a) Treating an acid addition salt of eletriptan, compound II, according to any of claims 25 to 33, with an aqueous base and in an organic solvent to yield eletriptan. b) Isolating the eletriptan obtained in step a), by means of conventional isolation techniques. c) Optionally, purifying the eletriptan of step b) by means of conventional purification techniques. d) Optionally, converting the eletriptan obtained in step b) or c) into a pharmaceutically acceptable salt or co-crystal thereof. 45. A process according to claim 44, wherein the aqueous base of step a) is selected from aqueous ammonia, diisopropylamine, diclyclohexylamine, triethylamine, metal hydroxides and metal carbonates 46. A process according to claim 45, wherein the aqueous base of step a) is aqueous ammonia. 47. A process according to any of claims 44 to 46, wherein the organic solvent of step a) is isopropylacetate. 48. A process according to any of claims 44 to 47, wherein the reaction of step a) is carried out at a temperature from 0 °C to reflux. 49. A process according to claim 48, wherein the reaction of step a) is carried out at a temperature from 0 °C to 50 °C, preferably at a temperature from 15 °C to 30 °C. 50. A process for the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof, wherein the process comprises at least the following steps: a) Treating a compound I according to claims 1 to 1 1 with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV. Compound I Compound IV wherein Boc is a ie f-butyloxycarbonyl protecting group and X is selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. Hydrogenating compound IV obtained in step a) to yield eletriptan. Compound IV Eletriptan c) Optionally, purifying eletriptan by the following steps: i. treating the eletriptan obtained in step b) with an acid, HA, to yield an acid addition salt Compound II wherein HA is an organic acid selected from (-)-0,0'-Di-p-toluoyl-L- tartaric acid (TLT), (-)-0,0'-Di-p-toluoyl-D-tartaric acid (TDT), (-)-Ο,Ο'- Dibenzoyl-D-tartaric acid (BDT) (anhydrous or monohydrate), (-)-Ο,Ο'- Dibenzoyl-L-tartaric acid (anhydrous or monohydrate) (BLT), benzenesulfonic acid (BSF) and gluconic acid (GLC). ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques. iii. Treating the compound II obtained in step ii) with a base to yield eletriptan. d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques. e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques. f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof. 51 . A process according to claim 50, wherein X of compound I is Br. 52. A process according to claim 50 or 51 , wherein the acid HB used in step a) is selected from the group consisting of hydrochloric acid, perchloric acid, hypochloric acid, chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, fluoroboric acid and mixtures thereof. 53. A process according to claim 52, wherein the acid HB used in step a) is selected from the group consisting of oxalic acid, malonic acid, fumaric acid, citric acid, including citric acid monohydrate, maleic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, succinic acid, acetyl salicylic acid, adipic acid, pivalic acid, benzoic acid, phenylacetic acid, p- methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, mandelic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and mixtures thereof. 54. A process according to any of claims 50 to 53, wherein the ratio of the acid to compound I is in the range of 2:1 to 15:1. 55. A process according to claim 54, wherein the ratio of the acid to compound I is in the range of 10:1 to 15:1 , preferably the ratio of the acid to compound I is 8:1 . 56. A process according to any of claims 50 to 55, which is carried out at a temperature in the range of 0 °C and 40 °C, preferably at a temperature in the range of 15 °C and 25 °C. 57. A process according to any of claims 50 to 56, which the reaction of step a) is carried out in the presence of an organic solvent as a reaction media. 58. A process according to claim 57, which the solvent used in the reaction of step a) is methylene chloride, tetrahydrofuran, dimethylformamide, ethyl acetate and mixtures thereof, preferably the solvent is methylene chloride. 59. A process according to any of claims 50 to 58, wherein the acid of step b) is methanesulfonic acid or sulfuric acid. 60. A process according to any of claims 50 to 59, wherein the solvent of step b) is a mixture of acetone and water. 61 . A process according to any of claims 50 to 60, wherein the acid HA of step i) is an organic acid selected from (-)-0,0'-Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0'-D\-p- toluoyl-D-tartaric acid (TDT), (-)-0,0'-Dibenzoyl-D-tartaric acid (BDT) (anhydrous or monohydrate) and (-)-0,0'-Dibenzoyl-L-tartaric acid (anhydrous or monohydrate) (BLT). 62. A process according to any of claims 50 to 61 , wherein the acid HA of step i) is (-)- 0,0'-Dibenzoyl-L-tartaric acid (anhydrous or monohydrate) (BLT). 63. A process according to any of claims 50 to 62, wherein the reaction of step i) is carried out at a temperature from 0 °C to reflux, preferably at a temperature from 25 °C to reflux, most preferably at reflux temperature. |
PHENYLSULFONYLETHYL)-1 H -INDOLE
FIELD OF THE INVENTION
The present invention provides an efficient and environmentally friendly process for the preparation of (R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonyl ethyl)- 1H- indole and pharmaceutically acceptable salts thereof, in good yield and high purity, which is also suitable for industrial scale applications.
The present invention also provides new acid addition salts of (R)-3-[(-1- methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)-1 /-/-indole, which are also suitable for preparing ( ?)-3-[(-1 -methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfonylethyl)- 1 /-/-indole and pharmaceutically acceptable salts thereof, in good yield and high purity.
BACKGROUND OF THE INVENTION
(R)-3-[(-1-methylpyrrolidin-2-yl)methyl]-5-(2-phenylsulfo nylethyl)-1 /-/-indole, also known as eletriptan, depicted below, is a 5-HT1 D and 5-HT1 B agonist, developed by Pfizer for the treatment of migraine. Eletriptan is commercialized as a hydrobromide salt and is marketed under the tradename Relpax® and Relert®.
Eletriptan
Eletriptan was first disclosed by European patent EP0592438B in the name of Pfizer, which describes a synthetic approach to the preparation of eletriptan by catalytic reduction of ( ?)-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylm ethyl)-1 H- indole. Compound ( ?)-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2- ylmethyl)-1 H-indole is prepared by reacting /V-benzyloxycarbonyl-D-proline acid chloride with 5-bromoindole in the presence of a Grignard reagent followed by reduction of the resulting (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo- 1 /-/-indole to give (R)-5-bromo-3-(/V-methylpyrrolidin-2-ylmethyl)-1 /-/-indole, which is further reacted with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base to obtain a compound that is hydrogenated to yield eletriptan. The complete route of synthesis sequence in EP 0592438B can be represented as follows.
The above process can be problematic because it can lead to undesirable dimerization as follows:
EP 0776323A discloses the bromide salt of eletriptan. Also disclosed are the a- polymorph and β-polymorph thereof.
The a-polymorph is further characterized by the following powder X-ray diffraction pattern obtained using copper radiation filtered with a graphite monochromator (λ = 0.15405 nm) which shows main peaks 9.7, 10.7, 15.9, 16.5, 17.8, 18.3, 19.3, 19.8, 20.1 , 21 .2, 24.4, 25.5, 25.8, 26.7, 27.6 and 29.4 degrees 2Θ.
The β-polymorph is characterized by the following X-ray diffraction pattern obtained using copper radiation filtered with a graphite monochromator (λ = 0.15405 nm) which shows main peaks at 1 1.0, 17.2, 19.2, 20.1 , 21.6, 22.6, 23.6 and 24.8 degrees 2Θ.
The following process disclosure is also provided in EP 0776323A.
Process disclosure (A), which involves treatment of a solution of 3-(N-methyl-2(R)- pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1 /-/-indole in a suitable solvent, preferably acetone, at room temperature, with an aqueous solution of hydrogen bromide, followed by crystallisation of the isolated crude oil from a suitable solvent, preferably 2-propanol, affords the a-form of the required hydrobromide salt. Process disclosure (B), which involves treatment of a solution of 3-(/V-methyl-2( ?)- pyrrolidinylmethyl)-5-(2-phenylsulphonylvinyl)-1 /-/-indole in a suitable solvent, preferably acetone or an ether solvent such as tetrahydrofuran or 1 ,2- dimethoxyethane, more preferably 1 ,2-dimethoxyethane, at a temperature from 0 °C to 10 °C, with an aqueous solution of hydrogen bromide, furnishes the β-form of the required hydrobromide salt.
Also as disclosed in EP 0776323A, crystallisation of the β-form from a suitable solvent, preferably aqueous acetone, followed by slurrying of the resulting mixture, gives the desired a-form.
Process disclosure (C), which involves treatment of a solution of 3-(/V-methyl-2( ?)- pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1 H-indole in a suitable solvent, preferably acetone, at from 0 °C to 5 °C with an aqueous solution of hydrogen bromide and then slurrying of the reaction mixture, optionally followed by heating under reflux, cooling and further slurrying, provides the required a-form.
Earlier process steps are not disclosed in EP 0776323A. WO 02/50063A1 discloses the preparation of eletriptan by the following steps: (a) N- acetylating ( ?)-5-bromo-3-(/V-methylpyrrolidin-2-ylmethyl)-1 /-/-indole, (b) reacting the resulting ( ?)-1-acetyl-5-bromo-3-(/V-methylpyrrolidin-2-ylmethyl)-1 /-/-indole with phenyl vinyl sulphone to give (R)-1 -acetyl-5-(2-benzenesulphonylethenyl)-3-(/V- methylpyrrolidin-2-ylmethyl)-1 /-/-indole, (c) catalytically reducing the obtaining compound and (d) hydrolyzing to yield eletriptan base. As disclosed, this process provides eletriptan substantially free of the undesirable dimer.
N-acetylation
There remains a need to provide a process of preparing eletriptan that is advantageous compared to the above prior art processes. BRIEF DESCRIPTION OF THE INVENTION
The first aspect of the present invention relates to a novel compound, ie f-butyl(/?,£)-3- ((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl )-1 /-/-indole-1 -carboxylate- HX, compound I:
Compound I wherein Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion. Thus, compo
The second aspect of the present invention relates to a process for the preparation of the novel compound I, of the first aspect of the present invention, comprising the steps of:
i) Reacting compound A with phenyl vinyl sulfone and a base in the presence of a catalyst to yield iert-butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate ■ HX, compound I.
Compound A Compound I ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
The third aspect of the present invention is the use of compound I of the first and second aspect of the present invention for preparing eletriptan or pharmaceutically acceptable salts thereof.
The fourth aspect of the present invention relates to novel acid addition salts of eletriptan, compound II:
Compound II wherein HA is an organic acid selected from (-)-0,0'-Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0 -Di-p-toluoyl-D-tartaric acid (TDT), (-)-0,0'-Dibenzoyl-D-tartaric acid (BDT) (anhydrous or monohydrate), (-)-0,0'-Dibenzoyl-L-tartaric acid (anhydrous or as a monohydrate) (BLT), benzenesulfonic acid (BSF) and gluconic acid (GLC).
The fifth aspect of the present invention relates to a process for the preparation of the novel acid addition salts of eletriptan, compound II, of the fourth aspect of the present invention, comprising the steps of:
i) Reacting eletriptan with an acid, HA, to produce the novel acid addition salts of eletriptan, compound II.
ii) Isolating the compound II obtained in step i), by means of conventional isolation techniques.
The sixth aspect of the present invention is the use of the novel acid addition salts of eletriptan, compound II, of the fourth and fifth aspect of the present invention for preparing eletriptan or pharmaceutically acceptable salts thereof.
The seventh aspect of the present invention provides a process for preparing eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel acid addition salts of eletriptan, compound II, wherein the process comprises at least the following steps: a) Treating the acid addition salt of eletriptan, compound II, with a base to yield eletriptan.
b) Isolating the eletriptan obtained in step a), by means of conventional isolation techniques.
c) Optionally, purifying the eletriptan of step b) by means of conventional purification techniques.
d) Optionally, converting the eletriptan obtained in step b) or c) into a pharmaceutically acceptable salt or co-crystal thereof.
The eighth aspect of the present invention provides a process for preparing eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein the process comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin- -yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I Compound IV wherein HX is as defined above,
b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
Compound IV Eletriptan c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, to yield an acid addition salt of eletriptan, compound II,
Compound II
wherein HA is an organic acid selected from (-)-0,0'-Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0'-Di-p-toluoyl-D-tartaric acid (TDT), (-)-0,0'-Dibenzoyl- D-tartaric acid (BDT) (anhydrous or monohydrate), (-)-0,0'-Dibenzoyl-L- tartaric acid (anhydrous or monohydrate) (BLT), benzenesulfonic acid (BSF) and gluconic acid (GLC).
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with a base to yield eletriptan. d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
DEFINITIONS
As used herein the term "organic solvent" refers to a substance containing carbon capable of at least partially dissolving another substance (i.e., the solute). Organic solvents may be liquids at room temperature. The organic solvent may be formed by the combination of two or more organic solvents.
The term "one-pot reaction" as used herein means two or more reactions that take place without isolating intermediate compounds, wherein all the reactants are added at the beginning of the first reaction or adding all reactants sequentially during the course of the reaction.
The term "solvate" refers to a molecular complex comprising a compound and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g. acetone). The term "hydrate" refers to a solvate wherein the solvent is water. The term acid "HA" as used herein refers to a substance that tends to donate protons or hydrogen ions and/or to accept electrons. Suitable acids, HA, are selected from (-)- 0,0 -Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0'-Di-p-toluoyl-D-tartaric acid (TDT), (-)- 0,0'-Dibenzoyl-D-tartaric acid (anhydrous or monohydrate) (BDT), (-)-0,0'-Dibenzoyl- L-tartaric acid (anhydrous or monohydrate) (BLT), benzenesulfonic acid (BSF) and gluconic acid (GLC).
The term acid "HB" as used herein refers to a substance that tends to donate protons or hydrogen ions and/or to accept electrons. Suitable acids, HB, can be an inorganic or an organic acid. Non-limiting examples of suitable inorganic acids that may be used for the present invention include hydrochloric acid, perchloric acid, hypochloric acid, chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (also known as ortho phosphoric acid), fluoroboric acid and mixtures thereof. Non-limiting examples of suitable organic acids that may be used for the present invention include oxalic acid, malonic acid, fumaric acid, citric acid, including citric acid monohydrate, maleic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, succinic acid, acetyl salicylic acid, adipic acid, pivalic acid, benzoic acid, phenylacetic acid, p-methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, mandelic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and mixtures thereof.
The term "conventional isolation techniques" as used herein refers to the process wherein an isolated product can be obtained, which can be carried out on an industrial scale such as solvent extraction, filtration, distillation, slurring, washing, phase separation, evaporation, centrifugation or crystallization.
As used herein, the term, "solvent extraction" refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent.
The term "filtration" refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression "filtrate" refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression "filter cake" refers to residual solid material remaining on a feed side of a filtration element.
The term "distillation" refers to the act of separating the component substances from a liquid mixture by selective evaporation and condensation. It may result in essentially complete separation (nearly pure components), or it may be a partial separation that increases the concentration of selected components of the mixture. In either case the process exploits differences in the volatility of mixture's components. As used herein, the term "slurrying" refers to any process which employs a solvent to wash, suspend or disperse a crude solid product.
As used herein, the term "washing" refers to the process of purifying a solid mass (e.g., crystals) by passing a liquid over and/or through the solid mass, as to remove undesirable soluble matter. The process includes passing a solvent, such as distilled water, over and/or through a precipitate obtained from filtering, decanting, or a combination thereof. For example, in one embodiment of the invention, washing includes contacting solids with solvent or solvent mixture, vigorously stirring (e.g., for two hours), and filtering. The solvent can be water, can be an aqueous solvent system, or can be an organic solvent system. Additionally, the washing can be carried out with the solvent having any suitable temperature. For example, the washing step can be carried out with a solvent having a temperature between about 0 °C and about 100 °C.
The term "phase separation" refers to a solution or mixture having at least two physically distinct regions.
The term "evaporation" refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.
The term "crystallization" refers to any method known to a person skilled in the art wherein products are obtained in crystal form such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent crystallization. The term "purification" as used herein refers to the process of rendering a drug substance clean of foreign elements whereby a purified drug substance can be obtained. The term "industrial purification" refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization.
BRIEF DESCRIPTION OF THE DRAWINGS
Examples of the present invention are illustrated with the following drawings:
Figure 1 shows the DSC analysis of Compound I, wherein X = Br.
Figure 2 shows the TGA analysis of Compound I, wherein X = Br.
Figure 3 shows the IR spectra of Compound I, wherein X = Br.
Figure 4 shows the TGA and DSC analysis of Compound II.
Figure 5 shows the XPRD analysis of Compound II.
DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the present invention relates to a novel compound, ie f-butyl(R,E)-3- ((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)vinyl )-1 H-indole-1 -carboxylate HX, compound I:
Compound I wherein Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion, selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. According to the first aspect, in a preferred embodiment wherein X is Br, the novel compound I is characterized by a DSC thermogram showing an endothermic peak with an onset at approximately 172-175 °C, and a maximum at approximately 182-185 °C. The term "approximately" means in this context of DSC measurements that the °C values can vary by 2 °C, preferably by 1 °C.
In a further embodiment, wherein X is Br, the invention provides a compound I characterized in that it provides a DSC substantially in accordance to figure 1.
In a further embodiment, wherein X is Br, the invention provides a compound I characterized in that it provides a TGA substantially in accordance to figure 2.
In a further embodiment, wherein X is Br, the invention provides a compound I characterized in that it provides an IR substantially in accordance to figure 3.
Advantageously, compound I is easily obtained and isolated, in good yield and high purity and it is stable. In addition, the compound I showed no change in color over a long period of time, preferably over a month, when left under atmospheric conditions at room temperature. The term "room temperature" in this context means that the temperature is between 15-30 °C. In addition, no water intake was produced, at a temperature of 30 °C and 60 % RH (relative humidity). Thus, it does not have to be stored in special packaging containers or under expensive inert gas conditions to prevent or minimize its degradation or water intake.
A second aspect of the present invention relates to a process for the preparation of the novel compound I, of the first aspect of the present invention, comprising the steps of: i) Reacting compound A with phenyl vinyl sulfone and a base in the presence of a catalyst to yield iert-butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate ■ HX, compound I.
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and in Compound A, X is suitably leaving group and in Compound I X is a suitable salt counter ion. In both compounds Compound A and Compound I, X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
The base used in step i) can be an organic or an inorganic base. Suitable bases include non-limiting examples, metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate, cesium carbonate and potassium bicarbonate; metal phosphates, such as sodium orthophosphate, cesium orthophosphate and potassium orthophosphate, metal acetates, such as sodium acetate and potassium acetate; linear or branched alkoxides of metals (metal alkoxides), ammonium (ammonium alkoxides), boron (boron alkoxides) and silicon (silicon alkoxides), such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert-butoxide, lithium methoxide, lithium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium sec-butoxide, and potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, magnesium ethoxide, barium methoxide, barium ethoxide, aluminum methoxide, aluminum ethoxide, titanium methoxide, titanium ethoxide, zirconium methoxide, zirconium ethoxide, ammonium methoxide, ammonium ethoxide, silicon methoxide, silicon ethoxide, boron methoxide, boron ethoxide; ammonia derivatives; such as triethylamine, Λ/,/V-dicyclohexylmethylamine, Λ/,/V-dicyclohexylamine, N,N- diisopropylethylamine and methanolic ammonia, and heterocyclic bases such as pyridine or mixtures thereof. Among them ammonia derivatives, metal orthophosphates and metal carbonates are preferred. More preferably, triethylamine as yield is improved. The catalyst is an organopalladium catalyst. Suitable organopalladium catalysts include non-limiting examples, tetrakis(triphenylphosphine)palladium(0), palladium chloride with a ligand of triphenylphosphine, palladium chloride with a ligand of PHOX, palladium(ll) acetate with a ligand of triphenylphosphine, palladium(ll) acetate with a ligand of PHOX, dichloro[1 ,1- bis(diphenylphosphino) ferrocene] palladium(ll)acetone adduct, bis(tri-tert- butylphosphine)palladium (0), Dichloro [1 ,1 'bis(di-tert-butylphosphino)] ferrocene palladium (II), 1 ,2,3,4,5-pentaphenyl-1 '-(di-tert-butylphosphino) ferrocene, dichlorobis(tri-ortho-tolylphosphine)palladium(ll) and dichlorobis(di- tert-butylphenylphosphine) palladium(ll).
According to a preferred embodiment, the process of the invention is carried out in the presence of a ligand, being said ligand preferably phosphines when PdCI 2 , Pd(AcO) 2 and Pd 2 (dba) 3 are used. Many phosphines may be found in the art. The election of the most suitable phosphine is a matter of routine experimentation for the skilled person and finetunes parameters of the reaction such as the yield, the speed or the turnover of the catalyst. According to a preferred embodiment, the reaction is carried out in the presence of triphenylphosphine, tri-ortotolylphosphine (P(oTol) 3 ) or tri-tert-butylphosphine.
The reaction may be carried out at a temperature from 0 °C to reflux. Preferably, the temperature is from 30 °C to reflux. Most preferably, the temperature is from 50 °C to reflux. The obtained mixture can also be stirred to easy the formation of the novel compound I, as a precipitate. Afterwards, the obtained compound I may be isolated by means of conventional isolation techniques. Preferably, the compound I is isolated by filtration. Optionally, compound I obtained is purified or dried or both.
In a particular embodiment of the present aspect, the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :5, 1 mol of compound A per 1 mol of phenyl vinyl sulfone to 1 mol of compound A per 5 mol of phenyl vinyl sulfone. More preferably, the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2. Most preferably, the molar ratio is about 1 :1 .1 as the purity is improved.
In a particular embodiment of the present aspect, the molar ratio of the compound A to base may be from 1 :1 to 1 :5, 1 mol of compound A per 1 mol of base to 1 mol of compound A per 5 mol of base. More preferably, the molar ratio of the compound A to base may be from 1 :1 to 1 :2. Most preferably, the molar ratio is about 1 :1.5. Optionally, the reaction may proceed in the presence of an organic solvent as a reaction media. Examples of organic solvents that may be used for the present aspect of the invention include, but are not limited to: hydrocarbon solvents (e.g. n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cyclopentanone, 2-pentanone etc.), ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, methyltetrahydrofuran, 1 ,4-dioxane, etc.), carbon disulfide, nitrobenzene, /V,/V-dimethylformamide (DMF), Λ/,/V-dimethylacetamide, dimethyl sulfoxide (DMSO), /V-methyl-2-pyrrolidone, acetonitrile, silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones), 1 ,2-dimethoxyethane. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents. Preferably, the organic solvent is selected from 1 ,4- dioxane, /V,/V-dimethylformamide (DMF), tetrahydrofuran, 2- methyltetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone or mixtures thereof. Most preferably, 1 ,4-dioxane, acetonitrile or ethanol or mixtures thereof. ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques. particular embodiment of the second aspect of the present invention the processhe preparation of compound I comprise at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and a base in the presence of a catalyst to yield iert-butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate ■ HX, compound I,
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. wherein the base is selected from ammonia derivatives, metal orthophosphates and metal carbonates,
ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more particular embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and triethylamine in the presence of a catalyst to yield fe/t-butyl (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole-1 -carboxylate ■ HX, compound
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Wherein the reaction proceeds in the presence of an organic solvent as a reaction media at a temperature from 50 °C to reflux,
ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more particular embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and triethylamine in the presence of a catalyst to yield fe/t-butyl (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole-1 -carboxylate ■ HX, compound I.
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Wherein the reaction proceeds in the presence of an organic solvent as a reaction media at a temperature from 50 °C to reflux, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2. ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more particular embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and triethylamine in the presence of a catalyst to yield fe/t-butyl (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole-1 -carboxylate ■ HX, compound
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. wherein the reaction proceeds in the presence of an organic solvent selected from 1 ,4-dioxane, acetonitrile or ethanol or mixtures thereof, as a reaction media at a temperature from 50 °C to reflux, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2. ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more particular embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and triethylamine in the presence of a Pd(OAc) 2 in the presence of tri-ortotolylphosphine as a catalyst to yield ie/f-butyl (R,£)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate ■ HX, compound I.
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Wherein the reaction proceeds in the presence of acetonitrile as a reaction media at reflux temperature, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2.
ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more particular embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and triethylamine in the presence of a Pd(OAc) 2 in the presence of tri-ortotolylphosphine as a catalyst to yield ie/f-butyl (R,£)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate ■ HX, compound I.
Compound A Compound I wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Wherein the reaction proceeds in the presence of acetonitrile as a reaction media at reflux temperature, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :1.1.
ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more particular embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: i) Reacting compound A with phenyl vinyl sulfone and triethylamine in the presence of a Pd(OAc) 2 in the presence of tri-ortotolylphosphine as a catalyst to yield ie/f-butyl (R,£)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate ■ HX, compound I.
Compound A Compound I
wherein Boc is a fe/t-butyloxycarbonyl protecting group and X may be selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (also known as triflate), nonafluorobutanesulfonat.es (also known as nonaflates), tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br;
wherein the reaction proceeds in the presence of acetonitrile as a reaction media at reflux temperature, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :1 .1. In addition, the molar ratio of the compound A to base is about 1 :1 .5.
ii) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and a base in the presence of a catalyst to yield ie/f-butyl (R,£)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate hydrobromide, compound I,
Compound I
wherein the base is selected from ammonia derivatives, metal orthophosphates and metal carbonates.
iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and triethylamine in the presence of a catalyst to yield iert-butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate hydrobromide, compound I.
Compound I
wherein the reaction proceeds in the presence of an organic solvent as a reaction media at a temperature from 50 °C to reflux,
iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and triethylamine in the presence of a catalyst to yield iert-butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate hydrobromide, compound I.
Compound I wherein the reaction proceeds in the presence of an organic solvent as a reaction media at a temperature from 50 °C to reflux, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2. iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and triethylamine in the presence of a catalyst to yield iert-butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-
(phenylsulfonyl)vinyl)-1 /-/-indole-1-carboxylate hydrobromide, compound I.
Compound I
wherein the reaction proceeds in the presence of an organic solvent selected from 1 ,4-dioxane, acetonitrile or ethanol or mixtures thereof, as a reaction media at a temperature from 50 °C to reflux, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2. iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps:
iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and triethylamine in the presence of a Pd(OAc) 2 in the presence of tri-ortotolylphosphine as a catalyst to yield tert- butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfo nyl)vinyl)-1 H- i
Compound I
wherein the reaction proceeds in the presence of acetonitrile as a reaction media at reflux temperature, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :2.
iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and triethylamine in the presence of a Pd(OAc) 2 in the presence of tri-ortotolylphosphine as a catalyst to yield tert- butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfo nyl)vinyl)-1 H- indole-1 -carboxylate hydrobromide, compound I.
Compound I wherein the reaction proceeds in the presence of acetonitrile as a reaction media at reflux temperature, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :1.1.
iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the second aspect of the present invention the process for the preparation of compound I comprises at least the following steps: iii) Reacting ie f-butyl(/?)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole-1- carboxylate with phenyl vinyl sulfone and triethylamine in the presence of a Pd(OAc) 2 in the presence of tri-ortotolylphosphine as a catalyst to yield tert- butyl (R,£)-3-((1-methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfo nyl)vinyl)-1 H- indole-1 -carboxylate hydrobromide, compound I.
Compound I
wherein the reaction proceeds in the presence of acetonitrile as a reaction media at reflux temperature, and the molar ratio of the compound A to phenyl vinyl sulfone may be from 1 :1 to 1 :1 .1. In addition, the molar ratio of the compound A to base is about 1 :1 .5.
iv) Isolating the compound I obtained in step i), by means of conventional isolation techniques.
Novel compound I is obtained in good yield and high purity. The purity exceeds of 98 %.
Compound A may be prepared as disclosed in Preparation 51 , page 1 1 1 of the international application W093/21 178A. Further, a third aspect of the present invention relates to the use the novel compound I for the preparation of eletriptan and pharmaceutical acceptable salts or co-crystals thereof. The inventors have found that the novel compound I can be also used for preparing eletriptan or pharmaceutically acceptable salts or co-crystals thereof in good yield and high purity. Advantageously, the use of compound I avoids the formation of undesirable dimeric by-products generated during the process for the preparation of eletriptan or pharmaceutically acceptable salts thereof that are highly difficult to eliminate. The dimeric by-products usually found in the impurity profile of eletriptan are depicted in scheme 1 . The eletriptan obtained from the compound I has a purity not less than 99,8 % and free of the dimeric by-products depicted in scheme 1 .
Dimer 3H Dimer 3
Scheme 1
The fourth aspect of the present invention relates to novel acid addition salts of eletriptan, compound II:
Compound II wherein HA is an organic acid selected from (-)-0,0'-Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0 -Di-p-toluoyl-D-tartaric acid (TDT), (-)-0,0'-Dibenzoyl-D-tartaric acid (BDT) (anhydrous or monohydrate), (-)-0,0'-Dibenzoyl-L-tartaric acid (anhydrous or monohydrate) (BLT), benzenesulfonic acid (BSF), gluconic acid (GLC). Preferably, the organic acid is (-)-0,0'-Di-p-toluoyl-L-tartaric acid, (-)-0,0'-Di-p-toluoyl-D-tartaric acid or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate. More preferably, the organic acid (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
The new acid addition salts of eletriptan may exist in crystalline form or non-crystalline form or as a mixture thereof. For the compounds of the invention that are in crystalline form, the skill in the art will appreciate that solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethyl acetate, acetone, dichloromethane, tetrahydrofuran, acetonitrile, dimethylsulfoxide, dimethylformamide, toluene, ethanol or they may involve water. Solvates wherein water is the solvate that is incorporated into the crystal lattice are typically referred as to hydrates. The new crystalline acid addition salts may also exist as an anhydride material. It is also understood by the skilled in the art that the term anhydrous when used in reference to novel acid addition salts describes novel acid addition salts which are substantially free of water. These novel acid addition salts are easily obtained and isolated, in good yield, having good solubility, stability and high purity.
The inventors have found that these acid addition salts of the present invention showed no change in color over a long period of time, preferably over a month, when left under atmospheric conditions at room temperature. The term "room temperature" in this context means that the temperature is between 15 °C and 30 °C. In addition, no water intake was produced, at a temperature of 30 °C and 60 % RH (relative humidity). Thus, they do not have to be stored in special packaging containers or under expensive inert gas conditions to prevent or minimize their degradation or water intake.
According to the fourth aspect, the present invention provides the crystalline novel compound II, wherein the HA is (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate, which is characterized by at least one of the following:
(i) a powder X-ray diffraction (PXRD) pattern having characteristics peaks at approximately 16.3, 18.1 , 19.2, 19.8, 21.6 and 26.0 ± 0.2° degrees two theta (i.e. Bragg's angle); or
(ii) a DSC thermogram showing an endothermic peak with an onset at approximately 150-153 °C, and a maximum at approximately 151 -154 °C.
The term "approximately" means in the context X-ray diffraction measurements that there is an uncertainty in the measurements of the degrees 2-theta of ± 0.2 (expressed in degrees 2-theta). The term "approximately" means in this context of DSC measurements that the °C values can vary by 2 °C, preferably by 1 °C.
In a particular embodiment, the crystalline novel compound II, wherein the HA is (-)- 0,0'-Dibenzoyl-L-tartaric acid monohydrate, is further characterized in that the pattern further X-ray powder diffraction further comprises the following peaks at approximately: 14.2 17.2, 18.4 and 21 .8 ± 0.2° degrees 2-theta.
In a further embodiment, the invention provides the crystalline novel compound II, wherein the HA is (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values shown below:
13,5 6,56
13,8 6,39
14,0 6,32
14,2 6,22
14,7 6,03
15,1 5,87
15,6 5,67
16,3 5,44
16,7 5,31
17,2 5,16
18,1 4,90
18,4 4,81
19,2 4,62
19,8 4,49
20,4 4,36
20,8 4,28
21 ,6 4,12
21 ,8 4,07
22,8 3,90
23,0 3,87
24,0 3,71
24,7 3,60
25,2 3,54
25,6 3,48
26,0 3,43
27,2 3,28
27,9 3,19
28,3 3,15
29,3 3,05
29,8 3,00
30,6 2,92
34,4 2,61
In a particular embodiment, the invention provides the crystalline novel compound II, wherein the HA is (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate, characterized in that it provides an X-ray diffraction pattern, characterized by the interplanar distance values and relative intensity (in percentage) at approximately the values shown below:
Angle 2Θ d-Value (A) Relative Intensity %
5,6 15,63 64,1
6,9 12,71 37,5
8,3 10,66 27
9,6 9,16 28,2
1 1 ,4 7,75 56,6
12,0 7,34 47,4
12,4 7,15 34,2
12,9 6,88 29,9
13,5 6,56 26,5
13,8 6,39 54,5
14,0 6,32 54,9
14,2 6,22 86,4
14,7 6,03 38,1
15,1 5,87 40
15,6 5,67 37,2
16,3 5,44 90,3
16,7 5,31 23,7
17,2 5,16 65,4
18,1 4,90 195,7
18,4 4,81 69,4
19,2 4,62 94,6
19,8 4,49 106,2
20,4 4,36 30,4
20,8 4,28 59,6
21 ,6 4,12 100
21 ,8 4,07 80,7
22,8 3,90 38,8
23,0 3,87 44,8
24,0 3,71 61 ,2
24,7 3,60 35,7
25,2 3,54 64,4
25,6 3,48 37,1
26,0 3,43 92,8
27,2 3,28 38,9
27,9 3,19 30,9
28,3 3,15 31 ,8
29,3 3,05 32,4
29,8 3,00 20,8
The term "approximately" means in this context of XRD intensity measurements that there is an uncertainty in the measurements of the relative intensities. It is known to the person skilled in the art that the uncertainty of the relative intensities depends strongly on the measurement conditions. The relative intensity values can e.g. vary by 30 %.
In a further embodiment, the invention provides a crystalline novel compound II characterized in that it provides a TGA and a DSC substantially in accordance to figure 4.
In a further embodiment, the invention provides a crystalline novel compound II characterized in that it provides an XPRD substantially in accordance to figure 5.
A fifth aspect of the present invention relates to a process for the preparation of the novel acid addition salts of eletriptan, compound II, of the fourth aspect of the present invention, comprising the steps of: i) Reacting eletriptan with an acid, HA, to produce the novel acid addition salts of eletriptan, compound II.
Suitable acids, HA, are selected from (-)-0,0'-Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0'-Di-p-toluoyl-D-tartaric acid (TDT), (-)-0,0'-Dibenzoyl-D-tartaric acid (anhydrous or monohydrate) (BDT), (-)-0,0'-Dibenzoyl-L-tartaric acid (anhydrous or monohydrate) (BLT), benzenesulfonic acid (BSF), gluconic acid (GLC). Preferably, the organic acid is (-)-0,0'-Di-p-toluoyl-L-tartaric acid, (-)- Ο,Ο'-Di-p-toluoyl-D-tartaric acid or (-)-0,0'-Dibenzoyl-L-tartaric acid (anhydrous or monohydrate). More preferably, the organic acid (-)-Ο,Ο'- Dibenzoyl-L-tartaric acid monohydrate.
The reaction may be carried out at a temperature from 0 °C to reflux. Preferably, the temperature is from 25 °C to reflux. Most preferably, the temperature is the reflux temperature. The obtained suspension can also be stirred to easy the formation of the novel acid addition salts of eletriptan, as a precipitate. Afterwards, the obtained acid addition salt of eletriptan is isolated by means of conventional isolation techniques. Preferably, the acid addition salt of eletriptan is isolated by filtration. Optionally, the acid addition salt of eletriptan obtained is purified or dried or both.
In a particular embodiment of the present aspect, the ratio of the acid to eletriptan may be from 1 :1 (mol/mol) to 5:1 (mol/mol), 1 mol of acid per 1 mols of eletriptan to 5 mol of acid per mol of eletriptan, more preferably from 1 :1 (mol/mol) to 2:1 (mol/mol). Most preferably, the ratio is about 1 :1 (mol/mol).
Optionally, the reaction can be carried out in the presence of an organic solvent as a reaction media. Examples of organic solvents that may be used for the present invention include, but are not limited to: hydrocarbon solvents (e.g., n- pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone, etc.), ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, 1 ,4-dioxane, etc.), carbon disulfide, nitrobenzene, /V,/V-dimethylformamide (DMF), Ν,Ν,- dimethylacetamide, dimethyl sulfoxide (DMSO), /V-methyl-2-pyrrolidone, acetonitrile, silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents and with water. In a preferred embodiment, the organic solvent is a polar solvent and it is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone or mixtures thereof. More preferably, methanol, ethanol, acetone, tetrahydrofuran or ethyl acetate or mixtures thereof or mixtures with water. Most preferably, the solvent is methanol as yield and purity is improved. Isolating the compound II obtained in step i), by means of conventional isolation techniques. In a preferred embodiment of the fifth aspect of the present invention the process for the preparation of the novel acid addition salts of eletriptan, compound II, comprises at least the following steps i) Reacting eletriptan with an acid, HA, to produce the novel acid addition salts of eletriptan, compound II.
Wherein HA is selected from (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous monohydrate in a ratio of the acid to eletriptan from 1 :1 (mol/mol) to 2:1 (mol/mol) and in the presence of an organic solvent as a reaction media. ii) Isolating the compound II obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the fifth aspect of the present invention the process for the preparation of the novel acid addition salts of eletriptan, compound II, comprises at least the following steps i) Reacting eletriptan with an acid, HA, to produce the novel acid addition salts of eletriptan, compound II.
Wherein HA is selected from (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous monohydrate in a ratio of the acid to eletriptan about 1 :1 and in the presence of an organic solvent as a reaction media. ii) Isolating the compound II obtained in step i), by means of conventional isolation techniques.
In a more preferred embodiment of the fifth aspect of the present invention the process for the preparation of the novel acid addition salts of eletriptan, compound II, comprises at least the following steps i) Reacting eletriptan with an acid, HA, to produce the novel acid addition salts of eletriptan, compound II. Wherein HA is (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous monohydrate in a ratio of the acid to eletriptan about 1 :1 and in the presence of an organic solvent selected from methanol, ethanol, acetone, tetrahydrofuran or ethyl acetate as a reaction media. ii) Isolating the compound II obtained in step i), by means of conventional isolation techniques.
Advantageously, the process is easily reproducible at an industrial scale with low energy and costs. In addition, the product is obtained in high yields and high purity.
Novel acid addition salts of eletriptan, compound II, are obtained in good yield and high purity. The purity is as high as 99 %. Moreover, the novel acid addition salts of eletriptan, compound II, are stable in atmospheric conditions (25 °C, 60 % RH) for at least 1 month.
The sixth aspect of the present invention is the use of the novel acid addition salts of eletriptan, compound II, of the fourth and fifth aspect of the present invention for preparing eletriptan or pharmaceutically acceptable salts or co-crystals thereof.
As the novel acid addition salts of the present invention are obtained in high yield and purity, the inventors have found that these acid addition salts of eletriptan can be also used as intermediates for the preparation of eletriptan and pharmaceutically acceptable salts thereof in good yield and purity as it is disclosed in the fourth aspect of the present invention.
The seventh aspect of the present invention provides a process for preparing eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel acid addition salts of eletriptan, compound II, wherein the process comprises at least the following steps: a) Treating the acid addition salt of eletriptan, compound II, with an aqueous base to yield eletriptan. The acid addition salt of eletriptan, compound II is mixed with an aqueous base to yield eletriptan. Suitable bases that may be used for this step include, but are not limited to: metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate and potassium bicarbonate; metal acetates, such as sodium acetate and potassium acetate; ammonia derivatives; such as triethylamine, dicyclohexylamine, Λ/,/V-diisopropyl-ethylamine and aqueous ammonia or mixtures thereof. Among them triethylamine, aqueous ammonia, metal hydroxides and metal carbonates are preferred, most preferred in aqueous solution. More preferably, aqueous ammonia.
Optionally, the reaction can be carried out in the presence of an organic solvent as a reaction media. Examples of organic solvents that may be used for this step include, but are not limited to toluene, tetrahydrofuran, methyltetrahydrofuran, xylene, n-heptane, octane, isooctane, cyclohexane, pentane, 1 ,4-dioxane, isopropylacetate, ethyl acetate. Preferably, the organic solvent is isopropylacetate.
The reaction may be carried out at a temperature from 0 °C to reflux. Preferably, the temperature is from 0 °C to 50 °C. Most preferably, the reaction is carried out at room temperature. The term "room temperature" in this context means that the temperature is between 15 0 and 30 °C. The obtained mixture can also be stirred to easy the formation of the eletriptan. b) Isolating the eletriptan obtained in step a), by means of conventional isolation techniques.
c) Optionally, purifying the eletriptan of step b) by means of conventional purification techniques.
d) Optionally, converting the eletriptan obtained in step b) or c) into a pharmaceutically acceptable salt or co-crystal thereof. Salts or co-crystals of eletriptan, can be prepared by contacting eletriptan with a pharmaceutical acceptable acid at temperature between -10 °C and 100 °C. a preferred embodiment of the seventh aspect of the present invention the processr the preparation of eletriptan, comprises at least the following steps a) Treating the acid addition salt of eletriptan, compound II, with aqueous ammonia at room temperature in an isopropylacetate to yield eletriptan. b) Isolating the eletriptan obtained in step a), by means of conventional isolation techniques.
c) Optionally, purifying the eletriptan of step b) by means of conventional purification techniques.
d) Optionally, converting the eletriptan obtained in step b) or c) into a pharmaceutically acceptable salt or co-crystal thereof. Salts or co-crystals of eletriptan, can be prepared by contacting eletriptan with a pharmaceutical acceptable acid at temperature between -10 °C and 100 °C.
In a preferred embodiment, eletriptan is converted to eletriptan hydrobromide following the steps: Contacting eletriptan with an aqueous solution of 48 % hydrobromic acid to obtain eletriptan hydrobromide monohydrate. Refluxing the former product in a mixture of ethanol and acetone at 55 °C and filtering and oven drying to yield anhydrous eletriptan hydrobromide. As these novel acid addition salts of eletriptan, compound II, are obtained in high purity and yields, the inventors have found that these acid addition salts can be also used as intermediates for the preparation of eletriptan and eletriptan derivates in high purity and yields. The eletriptan obtained from the novel acid addition salts has a purity not less than 98 % and essentially free of dimeric by-products depicted in scheme 1.
The eighth aspect of the present invention provides a process for preparing eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein the process comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I Compound IV wherein Boc is a fe/t-butyloxycarbonyl protecting group and X is a suitable salt selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with an acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV.
The acid used in step a) can be an inorganic or an organic acid. Non-limiting examples of suitable inorganic acids that may be used for the present invention include hydrochloric acid, perchloric acid, hypochloric acid, chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (also known as ortho phosphoric acid), fluoroboric acid and mixtures thereof. Non-limiting examples of suitable organic acids that may be used for the present invention include oxalic acid, malonic acid, fumaric acid, citric acid, including citric acid monohydrate, maleic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid, succinic acid, acetyl salicylic acid, adipic acid, pivalic acid, benzoic acid, phenylacetic acid, p-methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid, glycolic acid, mandelic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and mixtures thereof.
The ratio of the acid to compound I may be comprised between 1 :1 (mol/mol) and 20:1 (mol/mol), thus from 1 mol of acid per mol of compound I to 20 mol of acid per mol of compound I may be used. Preferably, the ratio is from 2:1 (mol/mol) to 15:1 (mol/mol). Most preferably, the ratio is from 10:1 to 15:1 , most preferably 8:1 , yielding compound IV in higher yields and purity.
The reaction is carried out over a range of temperatures from 0 °C to 100 °C. Preferably, the reaction temperature range is from 0 °C to 40 °C. Most preferably, between 15 °C and 25 °C.
The acid of step a) may constitute the reaction media. Optionally, the reaction can also be carried out in the presence of an organic solvent as a reaction media. Suitable organic solvents for the present invention include, but are not limited to: from hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils; aromatic hydrocarbon solvents, such as benzene, toluene, o-xylene, m-xylene, and p-xylene; halogenated hydrocarbon solvents, such as carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate; ketone solvents, such as acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone; ether solvents, such as diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, 1 ,4-dioxane; nitrobenzene, N,N- dimethylformamide, Λ/,/V-dimethylacetamide, dimethyl sulfoxide, /V-methyl-2- pyrrolidone, acetonitrile; silicone solvents, such as silicone oils, polysiloxanes, cyclosilicones. In an embodiment of the present invention the organic solvent is a polar organic solvent and preferably, the organic solvent is selected from the group consisting of Λ/,/V-dimethylformamide, C 1 -C4 alkyl alcohols, CrC 4 -alkyl acetates and mixtures thereof. In a more preferred embodiment the organic solvent is selected from the group consisting of methylene chloride, tetrahydrofuran, /V,/V-dimethylformamide, ethyl acetate and mixtures thereof. More preferably, the organic solvent is methylene chloride. In a particular embodiment, the organic solvent may be formed by the combination of two or more organic solvents. The use of an organic solvent, as a reaction media, facilitates the reaction and also the precipitation of the compound IV.
Hydrogenating compound IV obtained in step a) to yield eletriptan.
Compound IV Eletriptan
The hydrogenation of step b) may be carried out by adding a 5 % Pd/C catalyst to a suspension of compound IV in a solvent and an acid and hydrogenating at 30 °C at a pressure of 3 bar for 6 hours.
Suitable acids that may be used for this step include, but are not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, fumaric acid, acetic acid, trifluoroacetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, succinic acid, malic acid. Preferred acid is methanesulfonic acid or sulfuric acid. Suitable solvents that may be used for this step include, but are not limited to: acetone, acetonitrile, ethanol, methanol, isopropanol, toluene, tetrahydrofuran, methyltetrahydrofuran, xylene, n-heptane, octane, isooctane, cyclohexane, pentane, 1 ,4-dioxane, isopropylacetate, ethylacetate and mixtures in water thereof. Preferably, the solvent is mixture of acetone and water as yield is improved. Optionally, purifying eletriptan by the following steps:
i. treating the eletriptan obtained in step b) with an acid, HA, to yield an acid addition salts
Compound II wherein HA is an organic acid selected from (-)-0,0'-Di-p-toluoyl-L-tartaric acid (TLT), (-)-0,0'-Di-p-toluoyl-D-tartaric acid (TDT), (-)-0,0'-Dibenzoyl- D-tartaric acid (BDT) (anhydrous or monohydrate), (-)-0,0'-Dibenzoyl-L- tartaric acid (anhydrous or monohydrate) (BLT), benzenesulfonic acid (BSF) and gluconic acid (GLC).
The reaction may be carried out at a temperature from 0 °C to reflux. Preferably, the temperature is from 25 °C to reflux. Most preferably, the temperature is the reflux temperature. The obtained suspension can also be stirred to easy the formation of the novel acid addition salts of eletriptan, as a precipitate. Afterwards, the obtained acid addition salt of eletriptan is isolated by means of conventional isolation techniques. Preferably, the acid addition salt of eletriptan is isolated by filtration. Optionally, the acid addition salt of eletriptan obtained is purified or dried or both.
In a particular embodiment of the present aspect, the ratio of the acid to eletriptan may be from 1 :1 (mol/mol) to 5:1 (mol/mol), 1 mol of acid per 1 mols of eletriptan to 5 mol of acid per mol of eletriptan, more preferably from 1 :1 (mol/mol) to 2:1 (mol/mol). Most preferably, the ratio is about 1 :1 (mol/mol). Optionally, the reaction can be carried out in the presence of an organic solvent as a reaction media. Examples of organic solvents that may be used for the present invention include, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone, etc.), ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, 1 ,4-dioxane, etc.), carbon disulfide, nitrobenzene, Ν,Ν-dimethylformamide (DMF), N,N,-dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, acetonitrile, silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents and with water. In a preferred embodiment, the organic solvent is a polar solvent and it is preferably selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone or mixtures thereof. More preferably, methanol, ethanol, acetone, tetrahydrofuran or ethyl acetate or mixtures thereof or mixtures with water. Most preferably, the solvent is methanol as yield and purity is improved.
Isolating the compound II obtained in step i) by means of conventional isolation techniques.
Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
The acid addition salt of eletriptan, compound II is preferably mixed with an aqueous base in an organic solvent to yield eletriptan.
Suitable organic solvents that may be used for this step include, but are not limited to: toluene, tetrahydrofuran, methyltetrahydrofuran, xylene, n- heptane, octane, isooctane, cyclohexane, pentane, 1 ,4-dioxane, isopropylacetate, ethylacetate. Preferably, the organic solvent is isopropylacetate. Suitable bases that may be used for this step include, but are not limited to: metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate and potassium bicarbonate; metal acetates, such as sodium acetate and potassium acetate; ammonia derivatives; such as triethylamine, dicyclohexylamine, Λ/,/V-diisopropyl- ethylamine and aqueous ammonia or mixtures thereof. Among them triethylamine, aqueous ammonia, metal hydroxides and metal carbonates are preferred, most preferred in aqueous solution. More preferably, aqueous ammonia. The reaction may be carried out at a temperature from 0 °C to reflux.
Preferably, the temperature is from 0 °C to 50 °C. Most preferably, the reaction is carried out at room temperature. The term "room temperature" in this context means that the temperature is between 15 °C and 30 °C. The obtained mixture can also be stirred to easy the formation of the eletriptan. d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
Preferably the eletriptan is isolated by precipitation and filtration, or also removing the solvent by distillation. e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques. Eletriptan is obtained in very high purity and yields. Yields of the reaction are as good as 65 %, and the purity is always very high, being as good as 99.8 %. f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
Salts or co-crystals of eletriptan, can be prepared by contacting eletriptan with a pharmaceutical acceptable acid at temperature between -10 °C and 100 °C. In a preferred embodiment, eletriptan is converted to eletriptan hydrobromide following the steps: Contacting eletriptan with an aqueous solution of 48 % hydrobromic acid to obtain eletriptan hydrobromide monohydrate. Refluxing the former product in a mixture of ethanol and acetone at 55 °C and filtering and oven drying to yield anhydrous eletriptan hydrobromide.
Advantageously, the process of the present invention avoids the undesirable dimer byproducts depicted in scheme 1 and is easily reproducible at an industrial scale. In addition, this process provides eletriptan in good yields and high purity.
In a particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Wherein in compound I, Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with an acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-Ο,Ο'- Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-/--tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques. iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
The acid addition salt of eletriptan, compound II is mixed with an aqueous base in an organic solvent to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Wherein in compound I, Boc is a fe/t-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate (, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with trifluoroacetic acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in a solvent to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L- tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques. iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof. In a more particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1 -methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Wherein in compound I, Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with trifluoroacetic acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. treating the eletriptan obtained in step b) with an acid, HA, in methanol to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)- 0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-/--tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan. d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV. Wherein in compound I, Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with trifluoroacetic acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperatureto yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques. e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Wherein in compound I, Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br. Compound I is treated with trifluoroacetic acid in methylene chloride to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperature to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques,
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan wherein the base is ammonia.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques. f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Wherein in compound I, Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with trifluoroacetic acid in methylene chloride at a temperature between 15 °C and 25 °C to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV.
b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperature to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-/--tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base in a solvent to yield eletriptan wherein the base is ammonia.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof. In a more particular embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Wherein in compound I, Boc is a ie f-butyloxycarbonyl protecting group and X is a suitable salt counter ion selected from halogens, selected from CI, Br or I; pseudohalogens, selected from aryldiazonium salts and iodonium salts, trifluoromethanesulfonate, nonafluorobutanesulfonat.es, tosylates, mesylates, sulfonyl chlorides, acid chlorides, phosphates and sulfoxides. Preferably X is CI and Br. Most preferable, X is Br.
Compound I is treated with trifluoroacetic acid in methylene chloride at a temperature between 15 °C and 25 °C to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperature to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base in methanol to yield eletriptan wherein the base is ammonia. d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof. In a preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I is treated with an acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-Ο,Ο'-
Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-/--tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
The acid addition salt of eletriptan, compound II is mixed with an aqueous base in an organic solvent to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield ( ?,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV. Compound I is treated with trifluoroacetic acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in a solvent to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L- tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I is treated with trifluoroacetic acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L- tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I is treated with trifluoroacetic acid to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperatureto yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques. e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I is treated with trifluoroacetic acid in methylene chloride to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperatureto yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base to yield eletriptan wherein the base is ammonia.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield (R,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I is treated with trifluoroacetic acid in methylene chloride at a temperature between 15 °C and 25 °C to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperature to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-/--tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-/--tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques,
iii. Treating the compound II obtained in step ii) with an aqueous base in a solvent to yield eletriptan wherein the base is ammonia.
d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In a more preferred embodiment of the eighth aspect of the present invention the preparation of eletriptan or a pharmaceutically acceptable salt or co-crystal thereof from the novel compound I, wherein X is Br, comprises at least the following steps: a) Treating the compound I with an acid, HB, to yield ( ?,£)-3-((1-methylpyrrolidin-2- yl)methyl)-5-(2-(phenylsulfonyl)vinyl)-1 /-/-indole monohydrate, compound IV.
Compound I is treated with trifluoroacetic acid in methylene chloride at a temperature between 15 °C and 25 °C to eliminate the Boc protecting group yielding the compound IV. The mixture can also be stirred to ease the formation of the compound IV. b) Hydrogenating compound IV obtained in step a) to yield eletriptan.
c) Optionally, purifying eletriptan by the following steps:
i. Treating the eletriptan obtained in step b) with an acid, HA, in methanol at reflux temperature to yield an acid addition salts of eletriptan, compound II, wherein HA is (-)-0,0'-Dibenzoyl-L-tartaric acid anhydrous or (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate.
ii. Isolating the compound II obtained in step i) by means of conventional isolation techniques.
iii. Treating the compound II obtained in step ii) with an aqueous base in methanol to yield eletriptan wherein the base is ammonia. d) Isolating the eletriptan obtained in step b) or step c), by means of conventional isolation techniques.
e) Optionally, purifying the eletriptan of step d) by means of conventional purification techniques.
f) Optionally, converting the eletriptan obtained in step b) or c) or d) or e) into a pharmaceutically acceptable salt or co-crystal thereof.
In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius.
EXPERIMENTAL
The compounds of the present invention were characterized by common analytical techniques such as Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Thermogravimety (TGA) using the following methods:
Powder diffraction patterns were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using CuKal -radiation (1.54056 A) in transmission geometry. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller. Programs used: Data collection with DI FFRAC plus XRD Commander V.2.5.1 and evaluation with EVA V.12.0. In order to acquire a powder diffraction pattern of the obtained solid, approximately 15 mg of the non- manipulated samples were prepared in standard sample holders using two foils of polyacetate. Each sample was measured in a 1 hour scan in a range from 4° to 40° in 2Θ.
DSC analyses were recorded in a Mettler Toledo DSC822e calorimeter. Experimental conditions: 40 μΙ_ aluminum crucibles; atmosphere of dry nitrogen at 50 mL/min flow rate; heating rate of 10°C/min between 30 and 300°C. Data collection and evaluation was done with software STARe.
Thermogravimetric analyses were recorded in a Mettler Toledo SDTA851 e thermobalance. Experimental conditions: 40 μΙ_ aluminium crucibles; atmosphere of dry nitrogen at 80 mL/min flow rate; heating rate of 10°C/min between 30 and 300°C. Data collection and evaluation was done with software STARe.
X-ray Crystal Structures were determined (SCXRD) as follows:
Data collection: The measured crystals were prepared under inert conditions immersed in perfluoropolyether as protecting oil for manipulation. Crystal structure determinations were carried out using a Apex DUO Kappa 4-axis goniometer equipped with an APPEX 2 4K CCD area detector, a Microfocus Source E025 luS using MoKa radiation (0.71073 A), Quazar MX multilayer Optics as monochromator and a Oxford Cryosystems low temperature device Cryostream 700 plus (7 = -173 °C). Full-sphere data collection was used with ω and φ scans. Programs used: Data collection APEX-21 , data reduction Bruker Saint2 V/.60A and absorption correction TWINABS3. Structure Solution and Refinement: Crystal structure solution was achieved using direct methods as implemented in SHELXTL4 and visualized using the program XP. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL. All non-hydrogen atoms were refined including anisotropic displacement parameters.
In addition, Compound I of the present invention was analyzed by infrared spectrometry in a Perkin Elmer FTIR Spectrum One appliance using a Perkin Elmer ATR accessory.
EXAMPLES
Example 1 : Preparation of tert-butyl (R,E)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)vinyl)-1 H-indole-1 -carboxylate hydrobromide (Compound I)
To a solution of (R)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 /-/-indole (25 g, 85.3 mmol) in acetonitrile (75 mL) was added DMAP (0.52 g, 4.3 mmol). To the resulting suspension was added a solution of Boc 2 0 (21.4 g, 98.0 mmol) in 50 mL of acetonitrile. The reaction was stirred at room temperature for 2 h to yield the tert-butyl-( ?)-5-bromo- 3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole-1 -carboxylate.
This mixture was added to a suspension of Pd(OAc) 2 (0.96 g, 4.3 mmol), P(oTol) 3 (2.6 g, 8.5 mmol), phenylvinylsulfone (15.8g, 93.8 mmol) and triethylamine (17.8mL, 127.9 mmol) in 50 mL of acetonitrile. The solution was heated under nitrogen to reflux for 15h. The reaction mixture was cooled to 45 °C and 1 .25 g of neutral charcoal was added. The suspension was stirred for 1 h and filtered. The solvent was completely distilled off and fresh isopropanol (250 mL) was charged. The resulting slurry was heated to reflux, cooled to room temperature, stirred for 12 h and filtered washing with toluene to provide 31.1 g of the title compound as a light brown solid.
Yield 65 % (from tert-butyl-(R)-5-bromo-3-((1-methylpyrrolidin-2-yl)methyl)-1 H-indole-1- carboxylate)
Purity by HPLC higher than 98 %. 1 H-RMN (200 MHz, CDCI 3 ): 1 .62 (s, 9H); 1 .87-2.01 (m, 4H); 2.73 (s, 3H); 3.10-3.18 (m, 4H); 3.63 (m, 1 H); 6.96 (d, J = 14.0 Hz, 1 H); 7.38-7.58 (m, 4H); 7.71 (d, J = 2.0 Hz, 1 H); 7.80 (s, 1 H); 7.93 (dd, J, = 2.0 Hz, J 2 = 8.0 Hz, 1 H); 8.12 (d, J = 8.0 Hz, 1 H) ppm. Example 2: Preparation of (R,E)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)vinyl)-1 H-indole monohydrate (compound IV)
To a solution of the compound I of the example 1 (26 g, 46.3 mmol) in methylene chloride (125 mL) was added trifluoroacetic acid (32.6 ml_, 426.3 mmol). The reaction was stirred at room temperature for 4 h, water (75 mL) was added and neutralized with 20 % w/w solution of sodium hydroxide (75 mL). The aqueous phase was re-extracted with methylene chloride and the combined organic phases were washed with water. The organic layer was treated with 0.75 g of neutral charcoal at room temperature for 30 min and filtered. The solvent was concentrated under vacuum and the crude product precipitated from a mixture of acetonitrile-water affording 13.6 g of compound IV as a yellowish solid.
Yield 74 % (from compound I of example 1 )
Purity by HPLC 99.6 %
1 H-RMN (200 MHz, CDCI 3 ): 1 .59-1.77 (m, 4H); 2.22 (m, 1 H); 2.46 (s, 3H); 2.55-2.67 (m, 2H); 3.1 1 -3.20 (m, 2H); 6.78 (d, J = 16.0 Hz, 1 H); 7.1 1 (d, J = 2.0 Hz); 7.32 (m, 2H); 7.53-7.58 (m, 3 H); 7.72 (s, 1 H); 7.84 (d, J = 16.0 Hz, 1 H); 7.95-7.99 (m, 2 H); 8.52 (bs, 1 H) ppm.
Example 3: Preparation of (R)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)ethyl)-1 H-indole BLT (acid addition salt of eletriptan)
To a solution of compound IV (10 g, 25.1 mmol) in acetone (90 mL) and water (10 mL), methanesulfonic acid (3.2 mL, 50.2 mmol) was added dropwise and the resulting solution stirred for 5 min before adding 5 % w/w Pd/C catalyst (3.5 g, Johnson Matthey Type 58, 50 % wet). The suspension was hydrogenated at 30 °C at 3 bar for 6 h. The catalyst was removed by filtration and the filtrate stripped to give an acetone-free slurry. To this was added isopropyl acetate (50 mL) and a 20 % w/w aqueous solution of K 2 C0 3 (30 mL). The aqueous phase was re-extracted with isopropyl acetate and the combined organic phases were washed with water. The solvent was concentrated under vacuum and the crude eletriptan was dissolved in methanol (120 mL). The solution was heated to reflux and (-)-0,0'-Dibenzoyl-L-tartaric acid monohydrate (9.4 g, 25.1 mmol) was added. The solution was stirred at this temperature for 30 min and cooled down to room temperature, affording a suspension. The solid was isolated by filtration yielding (R)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2-(phenylsulfonyl)ethyl)- 1 H-indole BLT. The obtained acid addition salt of eletriptan was further purified in 70 mL of fresh methanol to reflux. The obtained solid was dried yielding 15.8 g of the titled compound. Yield 85 %
Purity by HPLC exceeds 99 %
1 H NMR (400 MHz, d4-methanol) δ: 8.12 (d, J = 8.2 Hz, 4H), 7.93 (d, J = 8.1 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1 H), 7.59 (q, J = 7.6 Hz, 4H), 7.45 (t, J = 8 Hz, 4H), 7.35 (s, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 7.13 (s, 1 H), 6.91 (d, J = 8.3 Hz, 1 H), 5.94 (s, 2H), 3.80 - 3.44 (m, 4H), 3.24 (dd, J = 14.3, 5.7 Hz, 1 H), 3.1 1 - 2.92 (m, 4H), 2.79 (s, 3H), 2.20 - 1 .74 (m, 4H).
DSC (10°C/min): Endothermic peak with an onset at 96°C coinciding with the weight loss observed in the TGA. Endothermic peak corresponding to the melting point with an onset at 151°C followed by an exothermic peak at 154°C as Figure 1.
PXRD peaks (2Θ values (±0.2), (CuKal 1 .54056 A)): 5.6, 1 1.4, 1 1.3, 14.0, 14.2, 16.3, 17.2, 18.1 , 18.4, 19.2, 19.8, 20.8, 21.6, 21.8, 24.0, 25.2 and 26.0.
Example 4: Preparation of (R)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)ethyl)-1 H-indole (eletriptan base)
The solid of compound obtained in example 3 ((R)-3-((1-methylpyrrolidin-2-yl)methyl)- 5-(2-(phenylsulfonyl)ethyl)-1 H-indole BLT) is mixed with isopropyl acetate (60 mL), water (50 mL) and a 25 % aqueous solution of NH 4 OH (15 mL). The aqueous phase was re-extracted with isopropyl acetate and the combined organic phases containing eletriptan base were washed with water, so any remaining (-)-0,0'-Dibenzoyl-L-tartaric acid is eliminated. The solvent was removed under reduced pressure, obtaining crude eletriptan. Yield 100 %
Purity HPLC exceeds 99 % Example 5: Preparation of (R)-3-((1 -methylpyrrolidin-2-yl)methyl)-5-(2- (phenylsulfonyl)ethyl)-1 H-indole hydrobromide (eletriptan hydrobromide) This crude eletriptan obtained in example 4, was dissolved in ethanol (20 mL) and 3.4 g of an aqueous solution of 48 % hydrobromic acid was added. The suspension thus obtained was stirred for 6 h at room temperature and filtered, affording eletriptan hydrobromide monohydrate. This compound was refluxed in a mixture of ethanol and acetone at 55 °C, followed by filtering and oven drying at 45 °C yielding 7.5 g of eletriptan hydrobromide as a white-off solid.
Yield 65 % from Compound IV
Purity by HPLC≥ 99.80 % 1 H-RMN (200 MHz, CDCI 3 ): 1 .59-1.77 (m, 4H); 2.22 (m, 1 H); 2.46 (s, 3H); 2.55-2.67 (m, 2H); 3.1 1 -3.20 (m, 2H); 6.78 (d, J = 16.0 Hz, 1 H); 7.1 1 (d, J = 2.0 Hz, 1 H); 7.32 (m, 2H); 7.53-7.58 (m, 3 H); 7.72 (s, 1 H); 7.84 (d, J = 16.0 Hz, 1 H); 7.95-7.99 (m, 2 H); 8.52 (bs, 1 H) ppm.