WO2017055664A1 - Sal de ácido maleico de un intermedio de silodosina - Google Patents
Sal de ácido maleico de un intermedio de silodosina Download PDFInfo
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- WO2017055664A1 WO2017055664A1 PCT/ES2016/070682 ES2016070682W WO2017055664A1 WO 2017055664 A1 WO2017055664 A1 WO 2017055664A1 ES 2016070682 W ES2016070682 W ES 2016070682W WO 2017055664 A1 WO2017055664 A1 WO 2017055664A1
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- Prior art keywords
- formula
- salt
- compound
- silodosin
- process according
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- 0 *CCOc1ccccc1OCC(F)(F)F Chemical compound *CCOc1ccccc1OCC(F)(F)F 0.000 description 2
- HUKYYZXALLLJJL-HSZRJFAPSA-N C[C@H](Cc1cc(C#N)c2N(CCCOC(c3ccccc3)=O)CCc2c1)NCCOc1ccccc1OCC(F)(F)F Chemical compound C[C@H](Cc1cc(C#N)c2N(CCCOC(c3ccccc3)=O)CCc2c1)NCCOc1ccccc1OCC(F)(F)F HUKYYZXALLLJJL-HSZRJFAPSA-N 0.000 description 2
Classifications
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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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Definitions
- the present invention relates to a maleic acid salt of 3- ⁇ 7- cyano-5 - [(2R) -2 - ( ⁇ 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl ⁇ benzoate amino) propyl] -2,3-dihydro-1 H-indol-1-yl ⁇ propyl of formula (I)
- ⁇ -adrenergic receptor antagonist selective for 1A adrenergic receptors that are primarily located in the prostate, base and neck of the bladder, capsule and prostatic urethra.
- the blockage of these receptors causes relaxation of the smooth muscle that reduces resistance in the bladder outlet region without affecting the contractility of the detrusor smooth muscle, improving the symptoms of storage (irritative) and emptying (obstructive) associated with benign prostatic hyperplasia.
- the affinity of silodosin for 1 B adrenergic receptors located in the cardiovascular system is substantially lower. Due to these characteristics, silodosin is used in the treatment of the signs and symptoms of benign prostatic hyperplasia.
- EP 1 806 340 A1 describes the formation of an oxalate salt of the compound of formula (II) (intermediate in the synthesis of silodosin)
- EP 1 806 340 A1 describes obtaining the compound of formula (II) by an alkylation reaction of the amine of formula (III)
- WO 2012/147019 A1 describes a similar process comprising the formation of the tartrate salt of the compound of formula (II), also in solid form.
- the inventors have investigated alternative procedures for the synthesis of silodosin that allow obtaining said product on an industrial scale by facilitating the purification and handling steps of the process, in particular, alternative purification procedures of the compound of formula (II) (key intermediate in the production of silodosin).
- the inventors have attempted to purify the compound of formula (II) by forming the salts of maleate, glycolate, citrate, succinate, fumarate, hydrochloride, hydrobromide, sulfate, phosphate, acetate or methanesulfonate of the amine of formula ( II).
- maleic acid is the only one that yields a salt of the compound of formula (II) in solid form and, therefore, separable by filtration. and suitable for the separation of impurities, in particular of those impurities that remain in solution in the reaction medium at this stage of formation of said intermediate (II), and therefore advantageous for the production of silodosin on an industrial scale.
- the formation of an intermediate solid has advantages in terms of intermediate manipulation in silodosin production.
- the present invention relates to the maleic acid salt of formula (I)
- the invention relates to a process for the preparation of the maleic acid salt of formula (I)
- the invention relates to a method of preparing silodosin of formula (V)
- Figure 1 shows the powder X-ray diffractogram of the salt polymorph of formula (I) obtained in example 2.
- Figure 2 shows the powder X-ray diffractogram of the silodosin gamma polymorph obtained in examples 3 and 4.
- Figure 3 shows the powder X-ray diffractogram of the silodosin beta polymorph obtained in example 5
- the invention relates to the maleic acid salt of the formula
- maleic acid and 3- ⁇ 7-cyano-5 - [(2R) -2 - ( ⁇ 2- [2- (2,2,2-trifluoroethoxy) phenoxy] benzoate] ethyl ⁇ amino) propyl] -2,3-dihydro-1 H-indol-1-yl ⁇ propyl are in a molar ratio of about 1: 1, that is, that is, for every mole of 3- ⁇ 7 benzoate -ciano-5 - [(2R) -2 - ( ⁇ 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl ⁇ amino) propyl] -2,3-dihydro-1 H-indole-1- il ⁇ propyl present in the salt is one mole of maleic acid.
- Said salt may also be in the form of solvate, in particular hydrate or alcoholate, such as isopropanolate.
- solvate should be understood as meaning any form of the salt of formula (I) which has another molecule (generally a polar solvent) attached through a non-covalent bond.
- Solvates especially include hydrates and alcoholates, for example isopropanolate.
- the present invention relates to a polymorph of compound of formula (I) characterized in that its powder X-ray diffractogram (registered with a copper X-ray source) has peaks at 1, 9, 14.6, 15.4, 17, 1, 18.4, 21, 0, 23.4 and 23.9 or 29 ⁇ 0.2 ° 2e.
- the polymorph of the compound of formula (I) is characterized in that its powder X-ray diffractogram (registered with a copper X-ray source) also has peaks at 1 1, 7, 14.4, 16.7 and 18.9 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ .
- the powder X-ray diffractogram (registered with a copper X-ray source) of said polymorph also has peaks at 19.0, 19.8, 22.2, 24.4 and 25, 1 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ . More preferably, the powder X-ray diffractogram (registered with a copper X-ray source) of said polymorph also has peaks at 3.0, 9.2, 9.4, 12.3, 14.9, 17 , 9, 20.2, 24.7, 25.9, 29.0, 29.3 and 30, 1 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ .
- the polymorph is characterized by powder X-ray diffractogram (registered with a copper X-ray source) presenting the peaks, and preferably also the relative intensities, shown in Table 1. Table 1. X-ray powder diffractogram of the compound of formula (I)
- said polymorph of the compound of formula (I) has a powder X-ray diffractogram (registered with a copper X-ray source) substantially like that shown in Figure 1.
- Said polymorph can be obtained by recrystallization of the compound of formula (I) from isopropanol.
- compound of formula (I) salt of formula (I)
- salt of maleic acid of formula (I) are used interchangeably and refer to the maleic acid salt of benzoate 3- ⁇ 7-cyano-5 - [(2R) -2 - ( ⁇ 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl ⁇ amino) propyl] -2,3-dihydro-1 H- indole-1-yl ⁇ propyl.
- the invention relates to a process for the preparation of the maleic acid salt of formula (I) defined above, comprising:
- Step a) is preferably carried out in a solvent selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tert-butanol, n-butanol and mixtures thereof, preferably isopropanol.
- Said solvent may optionally also contain, as other minor components present in no more than 20% v / v, preferably in no more than 15% v / v, more preferably in no more than 10% v / v, more preferably at no more than 5% v / v, even more preferably at no more than 1% v / v.
- Such minor components may be, among others, water and aprotic polar solvents.
- aprotic polar solvent refers to a polar solvent that does not have hydrogen atoms attached to an electronegative atom and capable of forming hydrogen bonds such as hydrogen atoms of the OH and NH groups and whose dielectric constant is at minus 3, said dielectric constant being the ratio between the electrical capacity of a capacitor full of solvent and the electrical capacity of the capacitor at 20-25 ° C.
- dielectric constant being the ratio between the electrical capacity of a capacitor full of solvent and the electrical capacity of the capacitor at 20-25 ° C.
- aprotic polar solvents examples include acetonitrile, tetrahydrofuran, ethyl acetate, butyl acetate, acetone, methyl isobutyl ketone, ethylmethyl ketone, dimethylformamide, dimethyl sulfoxide, dichloromethane, nitromethane and propylene carbonate, among others.
- the aprotic polar solvent present as a minor component of the solvent used in step a) is the aprotic polar solvent used in the preparation of the compound of formula (II), preferably acetonitrile.
- the volume of solvent suitable for step a) can be easily determined by the person skilled in the art and will depend on the particular solvent used. Preferably between 20 L and 60 L of solvent are used for each kg of maleic acid, more preferably between 30 L and 50 L of solvent for each kg of maleic acid, even more preferably between 35 L and 45 L for each kg of maleic acid , most preferably about 40 L per kg of maleic acid.
- the treatment of step a) is preferably carried out with stirring of the mixture of compound of formula (II), maleic acid and solvent until dissolved, more preferably at a temperature between 40 ° C and 60 ° C, even more preferably between 45 ° C and 55 ° C, most preferably about 50 ° C.
- said mixture is preferably cooled to a temperature not exceeding 25 ° C, more preferably between 15 ° C and 25 ° C, more preferably between 20 ° C and 25 ° C, even more preferably about 20 ° C, maintaining stirring, preferably between 10 h and 50 h, more preferably between 10 h and 40 h, more preferably between 10 h and 30 h, more preferably between 10 h and 20 h, more preferably at least 15 h.
- the maleic acid and the compound of formula (II) of step a) are in a molar ratio of between 1: 5: 1 and 1: 1, preferably between 1, 2: 1 and 1: 1 , more preferably between 1, 1: 1 and 1: 1, more preferably about 1, 1: 1.
- the ends of the aforementioned ranges should be considered part of said ranges unless otherwise indicated.
- the compound of formula (II) of step a) is obtained by treating the compound of formula (III) or a salt thereof
- leaving group refers to the fragment of the molecule that is displaced by the amino group of the compound of formula (III) to form compound (II).
- Outgoing groups are known to the person skilled in the art.
- suitable leaving groups for the compound of formula (IV) are CC 6 alkylsulfonyloxy, such as methanesulfonyloxy (CH 3 -SO 3 -); CC 6 haloalkylsulfonyloxy, such as trifluoromethanesulfonyloxy (CF 3 -SO 3 -); arylsulfonyloxy, such as benzenesulfonyloxy (Ph-S0 3 -), toluenesulfonyloxy ((p-CH 3 ) -Ph-S0 3 -), p-bromobenzenesulfonyloxy ((p-Br) -Ph-SO 3 -), o-nitrobenzenesulfony
- the leaving group is selected from the group consisting of C1-C 3 alkylsulfonyloxy, CC 3 haloalkylsulfonyloxy, ariisulfonyloxy, and halogen atom. More preferably, the leaving group is selected from the group consisting of methanesulfonyloxy, trifluoromethanesulfonyloxy, toluenesulfonyloxy, chlorine, bromine and iodine. Even more preferably, the leaving group is selected from the group consisting of methanesulfonyloxy, trifluoromethanesulfonyloxy and toluenesulfonyloxy. In the most preferred embodiment, the leaving group is methanesulfonyloxy.
- alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, which does not contain unsaturations, which has the number of carbon atoms indicated in each case (for example CC 6 means that it has 1 to 6 carbon atoms) and that it is attached to the rest of the molecule through a single bond.
- alkyl are methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, tere-butyl, pentyl, hexyl, etc.
- aryl refers to an aromatic hydrocarbon radical consisting of carbon atoms and hydrogen containing between 6 and 18 carbon atoms and which is attached to the rest of the molecule by a single bond, such as phenyl , naphthyl or anthracil, preferably phenyl.
- the aryl radical may be optionally substituted by one or more substituents (such as one, two or three substituents) independently selected from the group consisting of CC 6 alkyl (preferably C1-C3 alkyl), halogen and nitro (N0 2 ).
- alkylsulfonyloxy refers to an alkyl group as defined above that is attached to a sulfonyloxy group (- SO 3 -) and wherein said sulfonyloxy group is attached to the rest of the molecule by a single bond.
- alkylsulfonyloxy is methanesulfonyloxy.
- haloalkylsulfonyloxy refers to an alkylsulfonyloxy group as defined above, which further comprises one or more (such as one, two, three, four, five or six) halogen atoms as substituents of the alkyl group.
- Example of haloalkyisulfonyloxy is trifluoromethanesulfonyloxy.
- arylsulfonyloxy refers to an aryl group as defined above that is linked to a sulfonyloxy group (-S0 3 -) and wherein said sulfonyloxy group is attached to the rest of the molecule by a single bond.
- arylsulfonyloxy examples include benzenesulfonyloxy, toluenesulfonyloxy, p-bromobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy and p-nitrobenzenesulfonyloxy.
- the aprotic polar solvent used in obtaining the compound of formula (II) of step a) by treating the compound of formula (III) or a salt thereof with a compound of formula (IV) is selected from the group consisting of acetonitrile, tetrahydrofuran, ethyl acetate, butyl acetate, acetone, methyl isobutyl ketone, ethylmethyl ketone, dimethylformamide, dimethyl sulfoxide, dichloromethane, nitromethane and propylene carbonate. and mixture thereof.
- the organic solvent used is acetonitrile.
- the tartaric acid salt of the compound of formula (III) preferably the acid salt (2R, 3R) - (+) - tartaric acid is used.
- a base is used.
- Said base can be an inorganic base such as an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide), an alkali metal carbonate (for example sodium carbonate, potassium carbonate, cesium carbonate), or also it can be an organic base, such as a di- or tri-alkylamine CC 6 (for example triethylamine, diethylamine and diisopropylamine).
- the base is an inorganic base, more preferably an alkali metal carbonate, even more preferably potassium carbonate.
- the base and the compound of formula (III) or a salt thereof are in a molar ratio of between 3: 1 and 1: 1, preferably between 2.5: 1 and 1: 1, more preferably 2: 1 and eleven.
- said treatment is preferably carried out with stirring at reflux temperature of the solvent.
- said treatment is carried out by stirring between 10 h and 50 h, more preferably between 10 h and 40 h, more preferably between 10 h and 30 h, more preferably about 24 h.
- the compound of formula (II) of step a) by treating the compound of formula (III) or a salt thereof with a compound of formula (IV), the compound of formula (IV) and the compound of Formula (III) or the salt thereof is in a molar ratio of between 1.5: 1, preferably between 1.2: 1.
- stage a) of treatment of the compound of formula (II) has been carried out
- the next step in the process of obtaining the salt of formula (I) is to isolate said salt (step b)), that is, to separate the salt of formula (I) from the reaction medium.
- Isolation of the salt of formula (I) can be carried out by methods common in the art such as centrifugation, filtration or combination of both.
- the salt of formula (I) can be purified (step c)) using usual techniques, for example, by washing with a solvent (in particular one or more washes, such as one, two or three washes), preferably with the solvent used in step a), by recrystallization or by combination of both techniques.
- a solvent in particular one or more washes, such as one, two or three washes
- the salt of formula (I) is purified by one or more washes with the solvent used in step a).
- silodosin preparation procedure in another aspect, relates to a method of preparing silodosin of formula (V)
- the salt of formula (I) is obtained by a procedure as defined above.
- the preparation of silodosin from said salt of formula (I) comprises the hydrolysis of the benzoic acid ester to give the corresponding alcohol group and the hydrolysis of the nitrile group to give the corresponding amido group and thus render silodosin. Said hydrolysis can occur simultaneously or first the ester group can be hydrolyzed and then the nitrile group. Said hydrolysis of the ester and nitrile can be carried out in the same reactor (known reaction "one pot") or by stages in different reactors, preferably they are carried out in the same reactor.
- the hydrolysis of the ester group can be carried out by usual reaction conditions of hydrolysis of an ester to give the corresponding alcohol, which are known to the person skilled in the art and are described, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure [Michael B. Smith and Jerry March, 6th edition, Wiley-Interscience, John Wile & Sons, Inc. Hoboken, New Jersey, 2007].
- said hydrolysis is carried out by treatment with a base such as an alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example sodium carbonate, potassium carbonate or cesium carbonate.
- a base such as an alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example sodium carbonate, potassium carbonate or cesium carbonate.
- the base used is an alkali metal hydroxide, more preferably sodium hydroxide.
- Said hydrolysis can also be carried out by treatment with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid.
- Hydrolysis of the nitrile group can be carried out by usual reaction conditions of hydrolysis of a nitrile to give the corresponding amide, which are known to those skilled in the art and are described, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure [Michael B. Smith and Jerry March, 6th edition, Wiley-Interscience, John Wile & Sons, Inc. Hoboken, New Jersey, 2007].
- said hydrolysis is carried out by treatment with a base such as an alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example sodium carbonate, potassium carbonate or cesium carbonate.
- a base such as an alkali metal hydroxide, for example sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example sodium carbonate, potassium carbonate or cesium carbonate.
- the base used is an alkali metal hydroxide, more preferably sodium hydroxide.
- Said hydrolysis can also be carried out by treatment with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid.
- hydrolysis of the nitrile group is carried out in the presence of an oxidizing agent, preferably hydrogen peroxide.
- the hydrolysis of the salt of formula (I) to give silodosin is carried out in the presence of a base or an acid, as defined above, more preferably in the presence of a base, even more preferably in the presence of an alkali metal hydroxide, preferably sodium hydroxide. Said treatment allows both the ester and nitrile of the salt of formula (I) to be hydrolyzed in addition to generating the salt free base.
- the hydrolysis is further carried out in the presence of an oxidizing agent, such as hydrogen peroxide.
- an oxidizing agent such as hydrogen peroxide.
- a suitable solvent for carrying out the hydrolysis of the salt of formula (I) is dimethylsulfoxide. Therefore, in a particular embodiment dimethyl sulfoxide is used as the solvent.
- Hydrolysis is preferably carried out with stirring at a temperature between 20 ° C and 60 ° C, even more preferably between 30 ° C and 50 ° C, most preferably about 40 ° C, preferably between 10 min and 60 min, more preferably between 10 min and 40 min, even more preferably between 15 min and 30 min.
- Silodosin can be isolated from the reaction medium by standard procedures in the art, such as liquid-liquid extraction, centrifugation, filtration or combination thereof. For example, by liquid-liquid extraction and filtration.
- the silodosin obtained can be purified by washing, recrystallization or combination of both. For example by washing with toluene, recrystallization from toluene or isopropyl acetate, both washing and recrystallization from toluene or washing with toluene and recrystallization from isopropyl acetate.
- Different silodosin polymorphs can also be obtained, such as the beta polymorph and the silodosin gamma polymorph, polymorphs previously described in EP 1 541 554 B1.
- the silodosin beta or gamma polymorphs have a D 90 particle size of 200 ⁇ to 800 ⁇ .
- the particle size of the silodosin or any of its polymorphs, whose D 90 is from 200 ⁇ to 800 ⁇ , can be reduced by techniques known to the person skilled in the art, such as grinding, micronization, crushing, or mixing of said techniques optionally accompanied by one or more screening operations.
- a reduction in particle size can be made by grinding and / or micronization.
- the notation D x which can also be written as D (v, 0, X) means that the X% by volume of the particles have a smaller diameter than the specified diameter D. Therefore, D90 (or D (v, 0, 9)) of 100 ⁇ means that 90% by volume of the particles have a diameter of less than 100 ⁇ .
- the notation D [4,3] refers to the mean particle diameter (by volume).
- the particle size can be determined by usual techniques known to the person skilled in the art, such as laser diffraction, in particular by a particle size analyzer Malvern model Mastersizer 2000 using the experimental protocol described in the corresponding section of materials and methods of the examples.
- the powder sample was placed between polyester films 3.6 microns thick.
- a PANalytical X'Pert PRO MPD ⁇ / ⁇ powder diffractometer of 540 mm radius or 240 mm radius was used in a convergent beam configuration with a mirror focusing and transmission geometry with the flat samples arranged between two low absorption films.
- Radiation Cu ⁇ ( ⁇ 1.5418 ⁇ ).
- Working power 45 kV - 40 mA.
- Dispersant Purified water, milli-Q grade
- Sample preparation In a watch glass, approximately 50 mg of sample is weighed, 3 to 5 drops of 0.2% Nonidet P40 (nonylphenylpolyethylene glycol) are added and mixed with a spatula to form a homogeneous paste trying to undo the particleboard agglomerates. The paste is transferred to a 50 ml glass_ with the help of 10 ml_ of water that is added with a dropper trying to drag the maximum sample. The solution is left in an ultrasonic bath for 1 minute, during which time the alignment and the bottom of the equipment is performed by recirculating water through the circuit.
- Nonidet P40 nonylphenylpolyethylene glycol
- the reactor was then cooled to 50 ° C and water (3 L) was charged into the reactor. He reactor contents were cooled and maintained at 20 ° C for 15 min. The phases were allowed to separate, the aqueous phase was removed and the remaining content was distilled under reduced pressure at 70 ° C. Isopropanol (IPA, 5 L) was charged into the reactor and a solution of maleic acid (0.25 kg) in isopropanol (5 L). The reaction mixture was heated to 50 ° C and maintained at this temperature until complete dissolution. The reactor contents were cooled and maintained at 20 ° C for at least 15 h. The suspension obtained was centrifuged, washed with isopropanol (3 L) and allowed to drain for 3 h. Then, the product obtained was dried under vacuum for 2 h at room temperature and for approximately 5 h at 35 ° C. The powder X-ray diffractogram of the solid obtained is shown in Figure 1 and the peaks are listed in Table 1 (described above).
- Example 4 Synthesis of the silodosin gamma polymorph Silodosin reactor obtained in example 3 (1 kg), water (5 L) and toluene (18 L) were loaded into a reactor and stirred at 65 ° C. The mixture was allowed to decant and the aqueous phase was removed. The mixture was stirred and heated at 65 ° C until complete dissolution. The solution was cooled to 50 ° C and seeded with gamma silodosin. The reactor contents were cooled and the suspension was stirred at 25 ° C for at least 2 h. The suspension was centrifuged, washed with toluene and allowed to drain.
- the powder X-ray diffractogram of the silodosin gamma polymorph is shown in Figure 2.
- the obtained polymorph gamma silodosin has a D 90 of 200 ⁇ to 800 ⁇ .
- the solid obtained is ground and micronized to obtain gamma polymorph silodosin with the following particle sizes:
- silodosin reactor obtained in example 4 (1 kg) and isopropyl acetate (15 L) were loaded into a reactor. The mixture was stirred and heated at 70-75 ° C until completely dissolved. It was cooled to 50 ° C and seeded with silodosin beta form. It was stirred at 50 ° C for 30 min. It was cooled gradually to 0-5 ° C and maintained at this temperature for 1 h. The product was centrifuged and washed with isopropyl acetate (5 L). It was dried at 75 ° C under vacuum for 4 h. The X-ray powder diffractogram of the silodosin beta polymorph obtained is shown in Figure 3.
- silodosin formulations were prepared by simple mixing of the components, first the silodosin (using the particle sizes and polymorphs described in examples 4 and 5) with the mannitol and subsequently with the rest of the formulation ingredients. Finally it was encapsulated and introduced in PVC-PVDC blisters 90 g / m 2 (polyvinyl chloride-polyvinylidene chloride). One part was introduced into bottles of HDPE (high density polyethylene).
- HDPE high density polyethylene
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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JP2018517287A JP6877415B2 (ja) | 2015-09-30 | 2016-09-29 | シロドシン中間体のマレイン酸塩 |
KR1020187012164A KR20180095795A (ko) | 2015-09-30 | 2016-09-29 | 실로도신 중간체의 말레산 염 |
CA3000580A CA3000580A1 (en) | 2015-09-30 | 2016-09-29 | Maleic acid salt of a silodosin intermediate |
EP16850424.9A EP3357907B1 (en) | 2015-09-30 | 2016-09-29 | Maleic acid salt of a silodosin intermediate |
US15/763,689 US10421719B2 (en) | 2015-09-30 | 2016-09-29 | Maleic acid salt of a silodosin intermediate |
Applications Claiming Priority (2)
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ES201531398A ES2607639B1 (es) | 2015-09-30 | 2015-09-30 | Sal de ácido maleico de un intermedio de silodosina |
ESP201531398 | 2015-09-30 |
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WO2017055664A1 true WO2017055664A1 (es) | 2017-04-06 |
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EP (1) | EP3357907B1 (es) |
JP (1) | JP6877415B2 (es) |
KR (1) | KR20180095795A (es) |
CA (1) | CA3000580A1 (es) |
ES (1) | ES2607639B1 (es) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3354283A2 (en) | 2017-06-20 | 2018-08-01 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmaceutical capsule composition comprising silodosin |
JP2019523777A (ja) * | 2017-05-10 | 2019-08-29 | 浙江天宇薬業股▲ふん▼有限公司 | シロドシンおよびその中間体の合成方法 |
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JP2019523777A (ja) * | 2017-05-10 | 2019-08-29 | 浙江天宇薬業股▲ふん▼有限公司 | シロドシンおよびその中間体の合成方法 |
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WO2020237645A1 (zh) * | 2019-05-31 | 2020-12-03 | 上海汇伦生命科技有限公司 | 赛洛多辛中间体的制备方法 |
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ES2607639B1 (es) | 2018-02-28 |
KR20180095795A (ko) | 2018-08-28 |
US20180265469A1 (en) | 2018-09-20 |
EP3357907A4 (en) | 2018-08-15 |
EP3357907A1 (en) | 2018-08-08 |
EP3357907B1 (en) | 2022-11-30 |
ES2607639A1 (es) | 2017-04-03 |
US10421719B2 (en) | 2019-09-24 |
CA3000580A1 (en) | 2017-04-06 |
JP2018530556A (ja) | 2018-10-18 |
JP6877415B2 (ja) | 2021-05-26 |
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