WO2007104383A1 - Hémimaléate de tégasérode et procédé de synthèse - Google Patents

Hémimaléate de tégasérode et procédé de synthèse Download PDF

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Publication number
WO2007104383A1
WO2007104383A1 PCT/EP2007/000748 EP2007000748W WO2007104383A1 WO 2007104383 A1 WO2007104383 A1 WO 2007104383A1 EP 2007000748 W EP2007000748 W EP 2007000748W WO 2007104383 A1 WO2007104383 A1 WO 2007104383A1
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Prior art keywords
compound
mixture
temperature
stirred
added
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PCT/EP2007/000748
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English (en)
Inventor
Pascale Hoehn
Peter Fünfschilling
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Novartis Ag
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Publication of WO2007104383A1 publication Critical patent/WO2007104383A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention relates to a new salt of 3-(5-methoxy-1 H-indol-3-yl-methylene)- N-pentylcarbazimidamide (tegaserod).
  • the present invention also relates to a process for the manufacture of tegaserod and its maleate salts, for example tegaserod maleate.
  • the present invention relates to an improved process for the manufacture of tegaserod hydrogen maleate.
  • the invention further relates to the use of tegaserod maleate in the manufacture of a medicament for the treatment of conditions for which a partial 5-HT4 receptor is required.
  • the compound 3-(5-methoxy-1 H-indol-3-yl-methylene)-N-pentylcarbazimidamide may also be referred to herein as tegaserod. Accordingly, salts, solvates and other derivatives of 3-(5-methoxy-1 H-indol-3-yl-methylene)-N-pentylcarbazimidamide may be referred to herein with the prefix tegaserod.
  • Thiosemicarbazide (A) is mixed with 1-bromododecane in the presence of anhydrous ethanol and heated to 68-70 0 C and maintained at this temperature for 15-20 hours. The mixture is cooled to 38-42 0 C and gradually further cooled to approximately -10 0 C. The reaction solution is stirred at -1 O 0 C for at least 2 hours, the mixture is filtered and the filter cake is washed with cold anhydrous ethanol and dried at a temperature not exceeding 50 0 C under reduced pressure to form compound (I).
  • Step 1 Preparation of N-PENTYL-HYDRAZINECARBOXIMIDAMIDE HYDROBROMIDE (II)
  • Compound (I) is mixed with 1-pentylamine in the presence of anhydrous ethanol.
  • the reaction mixture is heated to 60-64 0 C and stirred for at least 6 hours.
  • the reaction mixture is cooled to approximately room temperature.
  • Compound (II) is not isolated at this stage nor is it in any way purified e.g. by crystallisation or extraction.
  • Compound(ll) is used tel quel in the preparation of compound (III).
  • the also formed 1-dodecanethiol is carried through to the next step.
  • the reaction mixture of Step 1 is stirred at room temperature. Hydrogen chloride gas is added to the mixture to obtain a pH range of between 1 and 4. Then, 5-methoxy-3-indolaldehyde (III) is added to the mixture in several portions. The mixture is diluted with anhydrous ethanol and stirred for about 1 hour. The mixture is heated to 38-42 0 C and extensively diluted with tert- butyl methyl ether. The reaction mixture is cooled to 0-5 0 C and stirred for about 1.5 hours. The reaction mixture is filtered and washed with sufficient amounts of a cold mixture of tert-butyl methyl ether and anhydrous ethanol in a ratio of 3:1. The compound (IV) was dried in a temperature not exceeding 6O 0 C under reduced pressure.
  • Step 3 Preparation of 3-(5-METHOXY-I H-INDOL-3-YL-METHYLENE) -N-PENTYLCARBAZIMIDAMIDE (V)
  • Compound (IV) is suspended in a mixture of isopropyl acetate and methanol, the mixture is cooled to 15-2O 0 C and sodium hydroxide (30%) is added in such a manner so as to maintain a temperature of 15-20 0 C.
  • the resulting two-phase mixture is separated and the aqueous phase discarded.
  • the organic phase is concentrated under reduced pressure and cooled to 25-30 0 C and further cooled to 0-2 0 C and stirred for at least one hour.
  • the resulting mixture is filtered and the filter cake washed with sufficient amounts of cold isopropyl acetate.
  • the filter cake is finally washed with water and dried at a temperature not exceeding 7O 0 C under reduced pressure.
  • Step 4 Preparation of the HYDROG EN-MALEATE SALT 3-(5-METHOXY-I H- INDOL-3-YL- METHYLENE)-N-PENTYLCARBAZIMIDAMIDE (Vl)
  • Compound (V) is dissolved in ethyl acetate saturated with water and stirred at 60-65 0 C. Activated carbon is added to the solution and the solution is filtered. A solution of maleic acid in water is added at 50-55 0 C for over a period of 20-30 minutes to form a suspension. The suspension is stirred for a further 15-30 minutes at 50-55 0 C and then for 2 hours at 68-70 0 C. The mixture is cooled to 20-25 0 C and compound salt (Vl) is isolated by filtration and washed with ethyl acetate.
  • Step 5 Further steps, such as micronisation of compound (Vl), may be carried out. Such further steps will be known to the person skilled in the art, and reference may be made to publications describing processes for making tegaserod, for example WO2005/014544 and EP 505322.
  • Step 1 i.e. the formation of compound (II)
  • the products from this reaction include, amongst other things, the product compound (II) and 1-dodecanethiol. Therefore, it is the crude product of compound (II) that is used for the subsequent condensation reaction of step 2.
  • 5-methoxy-3-indolaldehyde (III) is added to crude compound (II). The result of the use of this crude material means that the yield may only reach up to only 73%.
  • the present invention relates to a new salt of the compound 3-(5- methoxy-1 H-indol-3-yl-methylene)-N-pentylcarbazimidamide: 3-(5-methoxy-1 H-indol- 3-yl-methylene)-N-pentylcarbazimidamide Maleate referred to herein as tegaserod Maleate (X):
  • the present invention relates to the use of 3-(5-methoxy-1 H-indol- 3-yl-methylene)-N-pentylcarbazimidamide maleate in the manufacture of a medicament for treating conditions for which a partial agonist of 5-HT 4 receptors is required.
  • the present invention relates to the use of 3-(5-methoxy-1 H-indol- 3-yl-methylene)-N-pentylcarbazimidamide maleate as a new intermediate in the manufacture of a medicament for treating conditions for which a partial agonist of 5- HT 4 receptors is required.
  • Gl disorders gastrointestinal disorders
  • Such Gl disorders may be but are not limited to, heartburn, bloating, postoperative ileus, abdominal pain and discomfort, early satiety, epigastric pain, nausea, vomiting, burbulence, regurgitation, intestinal pseudoobstruction, anal incontinence, irritable bowel syndrome (IBS), gastro-esophageal reflux disease (GERD), functional dyspepsia, chronic constipation or diarrhea, gastroparesis, e.g. diabetic gastroparesis, ulcerative colitis, Crohn's disease, ulcers, gastrointestinal hyperactivity, and relaxing effect on intestinal smooth muscle cells and the visceral pain associated therewith.
  • IBS irritable bowel syndrome
  • GFD gastro-esophageal reflux disease
  • functional dyspepsia chronic constipation or diarrhea
  • gastroparesis e.g. diabetic gastroparesis, ulcerative colitis, Crohn's disease, ulcers, gastrointestinal hyperactivity, and relaxing effect on intestinal smooth muscle cells
  • the 3-(5-methoxy-1 H-indol-3-yl- methylene)-N-pentylcarbazimidamide maleate is new intermediate in the manufacture of the partial 5-HT 4 receptor 3-(5-methoxy-1 H-indol-3-yl-methylene)-N- pentylcarbazimidamide hydrogen maleate.
  • the present invention provides a route that overcomes the problems associated with the current processes, such as the one hereinbefore described.
  • the present invention provides a route for the large-scale production of tegaserod.
  • R is a C 5- Ci 5 alkane, for example C 8 to Ci3, typically Ci 2 , dodecane.
  • R is dodecane
  • the inorganic acid, HX is preferably HBr.
  • salts are hydrogen bromide salts where an inorganic acid salt is formed.
  • the value, m is preferably a value from 1 to 3, for example 1.5 to 2.5, typically 2.
  • the salt formed by C 4 H 4 O 4 is a maleate salt.
  • the compound C 4 H 4 O 4 is maleic acid.
  • the compounds of the disclosure can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the disclosure includes all variant forms of the compounds.
  • a particular example of synthesis incorporating the present invention is shown below in Scheme 4:
  • This step relates to the formation of compound (I) as hereinbefore described.
  • thiosemicarbazide (A) is added to ethanol e.g. absolute ethanol to form e.g. a suspension and heated at a temperature of, for example, 55-75 0 C, typically 60-70 0 C, more preferably 60 0 C.
  • The, e.g. suspension may be stirred.
  • 1- Bromododecane is added to the reaction mixture and the reaction mixture may be stirred at a temperature of, for example, 60-80 0 C, typically 70 0 C for a period of, for example, 15-20 hours, typically 16 hours.
  • the reaction mixture may be cooled to ambient temperature, for example, room temperature (20-25 0 C, typically 22°C).
  • the reaction mixture is further cooled to a temperature below O 0 C for example, -20 to - 1O 0 C, typically -10 0 C, where the reaction mixture may form crystals.
  • the resulting, e.g. crystalline, product is isolated, e.g. by filtration.
  • step A in order to achieve complete conversion of compound (A) to compound (I), an excess of at least 0.15 mole equivalent of 1- bromododecane is preferably added, for example 0.2 mole equivalents.
  • This step relates to the formation of N-pentyl-hydrazinecarboximidamide (II).
  • a mixture e.g. suspension
  • of compound (I) in ethanol e.g. absolute ethanol
  • 1-pentylamine may be added.
  • the 1-pentylamine may be added in one portion or portionwise over a period of time, for example, 15-60 minutes, typically 20 minutes.
  • the 1-pentylamine may be added at an ambient temperature, for example, room temperature, typically 20-25 0 C 1 for example, 22 0 C.
  • the reaction mixture may be heated to a temperature of 55- 7O 0 C, typically 60-65 0 C, e.g.
  • the ethanol and any excess of 1- pentylamine may be removed, for example, by distillation, to leave a residue.
  • the residue may be diluted with, e.g. water, and washed with an alkane, for example, an alkane having up to 10 carbon atoms, typically, heptane.
  • the compound (II) remains in the aqueous phase.
  • 1-pentylamine should be added drop-wise at a temperature between 4O 0 C and 6O 0 C.
  • the inert atmosphere prevents the reaction of 1-dodecanethiol with oxygen leading to dodecyldisulphide, which may precipitate out.
  • the washing with heptane is preferably done at least twice, for example three times. However, in certain embodiments of the present invention the third wash of heptane may be omitted.
  • compound (II) if stored, is stored in salt form.
  • Compound (II) remains stable in an aqueous environment. Therefore, the reaction may be terminated at this stage and compound (II) may be stored as an aqueous solution.
  • such an aqueous solution is stored at a temperature of between 5 0 C and O 0 C, typically in a refrigerator. Under these conditions, compound (II) may be stored for many weeks.
  • the mixture in the final step i.e. where the compound (II) in aqueous solution is washed with an alkane, is preferably two-phase.
  • the phase separation and repeated washing with the alkane removed all non-polar by-products efficiently from the reaction mixture.
  • compound (II) is maintained in the aqueous phase at an acceptable level of purity.
  • Concentrated hydrochloric acid (30-40%, for example 30- 35%, typically 32% v/v) may be added to the reaction mixture at for example a temperature between 25 and 30 0 C.
  • the acid acts as a catalyst.
  • the reaction mixture (“A") may be agitated, e.g. stirred, for about 2-3 hours, typically 2 hours, at an ambient temperature, typically room temperature, e.g. 20-25 0 C, for example 25 0 C.
  • the reaction mixture A typically consists of compound (IV) in ethanol.
  • the reaction mixture A may be further diluted with an acetate, for example isopropyl acetate.
  • the mixture may be cooled to about 15-2O 0 C and a solution of sodium hydroxide (30-40% v/v, typically 32%) may be added in such a manner as to maintain the temperature at 15-2O 0 C.
  • the resulting two-phase mixture is phase separated and the organic phase is treated with a further portion of sodium hydroxide solution (30- 40% v/v, typically 32%).
  • the reaction mixture (“B”) is further washed with water.
  • the reaction mixture B typically consists of compound (V) in isopropylacetate and ethanol.
  • the reaction mixture B is concentrated in volume e.g. by distillation of the organic solvents, for example ethanol and isopropyl acetate under reduced pressure to eliminate ethanol.
  • the resulting residue is diluted with an acetate, typically isopropyl acetate to produce e.g. a solution.
  • the resulting mixture e.g. solution, is treated with a first portion of maleic acid, for example, a mixture of maleic acid in water.
  • the resulting mixture typically a suspension, is agitated for a period of, for example, more than 5 hours, for example, six hours, at an ambient temperature, for example, room temperature, e.g. 20-25 0 C, for example, 22 0 C.
  • the resulting mixture is treated with a second portion of maleic acid, for example, a mixture of maleic acid in water.
  • the resulting reaction mixture (“C") for example, suspension, may be further stirred for 30-90 minutes, typically 60 minutes, at an ambient temperature.
  • the resulting reaction mixture C may be filtered as the filter cake may be washed with an acetate, for example, isopropyl acetate and subsequently dried to give the new salt (X).
  • the maleic acid is preferably added in a total amount of between 0.3 and 0.7 equivalents. In a particular embodiment of step 4, the maleic acid is added in an amount totalling 0.5 equivalents.
  • the purity of 5-methoxy-3-indolaldehyde (III) is preferably greater than 99% purity. In cases where compound (III) is of less than 99% purity the reaction is preferably carried out at an internal temperature of about 3O 0 C.
  • hydrochloric acid (32%) can produce an exothermic reaction and lead to a raise in the internal temperature of about 5 0 C and thus temperature control e.g. cooling, may need to be performed in order to maintain the internal temperature at the desired level.
  • the side chain of the compound (II) has a high tolerability for water. This high tolerability therefore lends itself to the possibility of purifying a mixture containing compound (II) in a water/ethanol mixture. Indeed, it has been found that running the condensation reaction of step 2 in a water/ethanol mixture in the presence of hydrochloric acid, increases the yield in compound (IV) formed in the step 2 (but not isolated). In case of isolation of compound (IV) for example, the yield may be increased from 73% to 80%. In a particular case, where the conditions have been optimised, the yield may be raised as far as 88%. Such optimisation may be obtained by, for example, increasing the selectivity of the reaction which may be achieved by reducing the side reactions that can take place. By reducing the side reactions, the reaction products are no longer consumed and thus, the lower concentration of by-products means that there are less reactants lost in the mother liquor.
  • Step 2 the optimisation of Step 2 by eliminating, or at least reducing, the amount of by-products present has enabled significant improvements in the overall yield of this process.
  • Compound (X) may be agitated, e.g. stirred, in an organic solvent, for example, a mixture of organic solvents, typically a mixture of isopropyl acetate and methanol and the mixture may be cooled to about 15-2O 0 C and sodium hydroxide (30-40% v/v, typically 32%) may be added in such a manner as to maintain the temperature at 15- 2O 0 C.
  • an organic solvent for example, a mixture of organic solvents, typically a mixture of isopropyl acetate and methanol and the mixture may be cooled to about 15-2O 0 C and sodium hydroxide (30-40% v/v, typically 32%) may be added in such a manner as to maintain the temperature at 15- 2O 0 C.
  • the resulting two-phase mixture is then phase separated and the organic phase is treated with a further portion of sodium hydroxide solution.
  • the reaction mixture is then further washed with water.
  • the organic phase may then be concentrated under reduced pressure at an elevated temperature, for example, 50- 7O 0 C, and then cooled to 20-25 0 C and then further cooled to 0-2 0 C and preferably agitated, e.g. stirred, for at least one hour.
  • the resulting mixture may then be filtered and the filter cake washed with sufficient amounts of an acetate, for example, isopropyl acetate.
  • the filter cake may be washed with water and then dried at a temperature not exceeding, for example, 7O 0 C, under reduced pressure.
  • Compound (V) may be dissolved in ethyl acetate saturated with water and stirred at 50-55 0 C.
  • Activated carbon is added to the solution and the solution is filtered.
  • a solution of maleic acid in water is added at 50-55 0 C for over a period of 20-30 minutes to form a suspension.
  • the suspension is stirred for a further 15-30 minutes at 50-55 0 C and further 2 hours at 68-7O 0 C.
  • the mixture is cooled to approximately room temperature and the hydrogen maleate salt (Vl) is isolated by filtration and washed with ethyl acetate.
  • S-dodecylisothiosemicarbazide hydrobromide was mixed with absolute ethanol (280 ml) to form a suspension at 20 to 25° C and stirred for 20 minutes.
  • 1-Pentylamine (19.76 grams) was added drop- wise and at the end of the addition the mixture was heated to an internal temperature of 63 0 C (jacket 71 0 C) and stirred at this temperature for seven hours.
  • the mixture was distilled at 6O 0 C (jacket) at 25mbar to remove the absolute ethanol and the excess 1-pentylamine to produce a two-phase mixture.
  • the upper layer of the two- phase mixture contained the 1-dodecanethiol and the lower, orange, oily phase contained the product N-pentyl-hydrazinecarboximidamide hydrobromide (II).
  • the lower layer was diluted with water (120 ml) at room temperature and extracted with heptane (3 x 280 ml). The light orange cloudy aqueous phase was removed.
  • the reaction mixture was diluted with isopropyl acetate (400 ml).
  • a sodium hydroxide solution (30% v/v, 24 ml) over a period of ten minutes at a temperature of 2O 0 C (jacket).
  • the mixture was stirred at 2O 0 C (jacket) for a further 30 minutes.
  • the resulting two-phase mixture was separated and the upper organic layer was further treated with a sodium hydroxide solution (30% v/v, 24 ml) over a period of ten minutes each at a temperature of 2O 0 C (jacket).
  • the resulting mixture was stirred for a further 30 minutes at 2O 0 C (jacket).
  • the resulting two-phase mixture was separated and the organic layer was washed with water (50 ml).
  • the organic layer was distilled at a temperature of 6O 0 C (jacket) under a vacuum of between 230 to 280 mbar (approx. 350 ml of a mixture of isopropyl acetate/absolute ethanol).
  • the resulting concentrated reaction mixture was diluted with fresh isopropyl acetate (350 ml) and stirred. To this reaction mixture was added a first portion of a solution of maleic acid (2.94 grams) in water (5 ml) over a period of ten minutes.
  • the resulting suspension was stirred for a six hours at a temperature of between 20 to 25 0 C.
  • a second portion of a solution of maleic acid (4.41 grams) in water (7.5 ml) was added and stirred at room temperature for a further hour at a temperature of between 20 to 25 0 C.
  • the resulting beige/cream suspension was filtered and the filter cake washed with isopropyl acetate (5 x 30 ml). The filter cake was dried at 6O 0 C under a vacuum of 10 mbar overnight.
  • compound of example 2 (20 grams) was added to isopropylacetate (208 ml) and methanol (23 ml) to form a suspension.
  • a sodium hydroxide solution (30% v/v, 15 ml) diluted in water (19 ml) over a period of 30 minutes at a temperature of 17-2O 0 C (jacket).
  • the mixture was stirred at 2O 0 C (jacket) for a further 2 hours.
  • the resulting two-phase mixture was separated and the upper organic layer was further treated with a sodium hydroxide solution (30% v/v, 7 ml) diluted with water (19 ml) over a period of 30 minutes each at a temperature of 2O 0 C (jacket). The resulting mixture was stirred for a further 60 minutes at 2O 0 C (jacket). The resulting two-phase mixture was separated and the organic layer was washed with water (25 ml). The organic layer was concentrated at a temperature of 75 0 C (jacket) under a vacuum of between 200 to 280 mbar to an approx. volume of 50 ml. The resulting suspension is cooled to 2O 0 C then to O 0 C and stirred for further 2 hours.
  • a sodium hydroxide solution (30% v/v, 7 ml) diluted with water (19 ml) over a period of 30 minutes each at a temperature of 2O 0 C (jacket).
  • the resulting mixture was stirred for a
  • the resulting beige suspension was filtered and the filter cake washed with isopropyl acetate (2 x 25 ml) then water (4 x 25 ml). The filter cake was dried at 6O 0 C under a vacuum of 10 mbar overnight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un maléate de tégasérode (X) et un procédé amélioré de fabrication d'hydrogénomaléate de tégasérode.
PCT/EP2007/000748 2006-01-31 2007-01-29 Hémimaléate de tégasérode et procédé de synthèse WO2007104383A1 (fr)

Applications Claiming Priority (2)

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GB0601953A GB0601953D0 (en) 2006-01-31 2006-01-31 Organic compounds
GB0601953.3 2006-01-31

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WO2007104383A1 true WO2007104383A1 (fr) 2007-09-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505322A1 (fr) * 1991-03-22 1992-09-23 Sandoz Ltd. Aminoguanidines
WO2005058819A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2006002212A1 (fr) * 2004-06-23 2006-01-05 Dr. Reddy's Laboratories Ltd. Hemimaleate de tegaserode

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505322A1 (fr) * 1991-03-22 1992-09-23 Sandoz Ltd. Aminoguanidines
WO2005058819A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2006002212A1 (fr) * 2004-06-23 2006-01-05 Dr. Reddy's Laboratories Ltd. Hemimaleate de tegaserode

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