WO2013046138A1 - Process for the preparation of scopine esters - Google Patents
Process for the preparation of scopine esters Download PDFInfo
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- WO2013046138A1 WO2013046138A1 PCT/IB2012/055138 IB2012055138W WO2013046138A1 WO 2013046138 A1 WO2013046138 A1 WO 2013046138A1 IB 2012055138 W IB2012055138 W IB 2012055138W WO 2013046138 A1 WO2013046138 A1 WO 2013046138A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
Definitions
- Tiotropium bromide (4) described in EP418716, is a potent anticholinergic agent specific for muscarinic receptors. As a drug, it has been approved for the treatment of respiratory disorders, such as asthma, COPD, chronic bronchitis and emphysema.
- Object of the present invention is a novel synthetic process for the synthesis of the scopine ester (3) , characterized by the use of reagents of improved industrial applicability and anyhow under not overly strong basic conditions inducing scopine conversion into scopoline (Scheme 6) which in turn can result as impurity, in the subsequent transesterification reaction, in scopoline ester.
- This ester is then quaternized with methyl bromide to obtain tiotropium bromide (Scheme 2) .
- Reagents of difficult industrial use, such as sodium metal, are used in the transesterification reaction. Best yield reported is of 70% (Example 3) and there is no information on HPLC purity obtained.
- Scheme 5 A recurring problem in prior art processes is the conversion, induced by basic conditions, of scopine into scopoline (Scheme 6) (Tetrahedron Letters, (1967), 14, 1283-1284., Die dar ein von Scopin aus Scopolamin) which in turn can result as impurity, in the subsequent transesterification reaction, in scopoline ester.
- NHCs are commercially available, but can also be conveniently prepared in situ (Scheme 7) by treatment of dihydroimidazolium or imidazolium salts of formula (7a) (wherein R' , R' ' and Y have the meanings reported in J. Org. Chem. (2004), 69, 209-212) with a base (generally potassium tert-butoxide) ,
- the reaction is conducted at room temperature and in the presence of molecular sieves (0.5 g/mmol) which capture released alcohol (e.g., 4A molecular sieves for methanol and 5A ones for ethanol) so as to shift the reaction towards the ester of the more complex alcohol.
- molecular sieves 0.5 g/mmol
- alkyl-substituted NHCs give better results (90-100% yields were reported for conversion of methyl acetate to benzyl acetate) than aryl-substituted ones (41-49% yields for the same reaction), and those generated from imidazolium salts give better results than those generated from dihydroimidazolium salts.
- Object of the present invention is a novel synthetic process for the synthesis of the scopine ester, characterized by the use of reagents of better industrial applicability and anyhow under basic (alkaline) conditions not so overly strong as to induce conversion of scopine to scopoline.
- R 1 and R 2 are independently selected from the group Ci-io alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups, and, preferably, from the group methyl, butyl, tert- butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl- phenyl, di-isopropyl-phenyl , and even more preferably from the group methyl, butyl, tert-butyl, hexyl, cyclohexyl.
- X represents a ion selected from the group CI, BF 4 , Br, PF 6 , I, CIO 4 , TfO, and preferably from the group CI, BF 4 ,
- This reaction entails the advantage of not using reagents potentially hazardous, nor reagents highly basic in a stoichiometric amount, and of using instead the NHCs in a catalytic amount.
- the scopine ester of formula (3) can be prepared through a transesterification reaction of scopine alcohol (1) with a suitable ester of formula (2) , wherein R is methyl, ethyl, propyl, vinyl, preferably methyl.
- the reaction is carried out in the presence of molecular sieves, by treatment with N-heterocyclic carbenes (NHC) of formula (8), preferably in a catalytic amount, wherein:
- R 1 and R 2 are independently selected from the group Ci-io alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups, and, preferably, from the group methyl, butyl, tert- butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl- phenyl, di-isopropyl-phenyl , and even more preferably from the group methyl, butyl, tert-butyl, hexyl, cyclohexyl .
- the alcohol (1) and the ester (2) are dissolved in an organic solvent selected from toluene, dichloromethane, THF, 2-MeTHF (2-methyltetrahydrofuran) , cyclopentylmethylether, DMF (dimethylformamide) and DMI (dimethyl-2-imidazolidinone) or mixtures thereof, preferably 2-MeTHF.
- organic solvent selected from toluene, dichloromethane, THF, 2-MeTHF (2-methyltetrahydrofuran) , cyclopentylmethylether, DMF (dimethylformamide) and DMI (dimethyl-2-imidazolidinone) or mixtures thereof, preferably 2-MeTHF.
- the temperature is maintained between 0° and 60 °C, preferably between 20° and 40°C, and even more preferably between 20° and 25°C.
- NHC carbene (8) is formed separately by treatment of an imidazolium salt of formula (7), [in Table I, a series of non-limiting examples of compounds of formula (7) are reported], wherein:
- R 1 and R 2 are independently selected from the group Ci-10 alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups, and, preferably, from the group methyl, butyl, tert- butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl- phenyl, di-isopropyl-phenyl, and even more preferably from the group methyl, butyl, tert-butyl, hexyl, cyclohexyl .
- X represents a ion selected from the group CI, BF 4 , Br, PF 6 , I, CIO 4 , TfO and preferably from the group CI, BF 4
- the preferred compounds of formula (7) are reported in Table 1; among these, the most preferred ones are the compounds of formula (9) , (10) , (12) and (14) .
- the reaction was conducted in the presence of molecular sieves capturing the alcohol released (e.g., 4A molecular sieves for methanol and 5A ones for ethanol) so as to shift the reaction towards the ester of the more complex alcohol.
- molecular sieves were used in the ratio of 1 - O.lg of sieves per mmol of scopine base (1), preferably in the ratio of 0.5 g/mmol.
- Non-limiting examples of molecular sieves may be Molecular Sieves, 4A, Aldrich product number 208604 - beads, 8-12 mesh, and Molecular Sieves, 5A, Fluka product number 69848, rod 1/8 in, or Molecular Sieves, 5A, Aldrich product number 208620, beads, 8-12 mesh.
- the chemical reagents of the invention and the molecular sieves can be set up, mixed and reacted among them in any order.
- a solution of alkyl di- (2- thyenil ) glycolate (2) and scopine free base (1) is prepared, the molecular sieves are added thereto, the solution of N-heterocarbene (8) is separately prepared, and added to the first solution.
- a solution of NHC (8) is prepared, and subsequently the reagents (1) and (2), plus the molecular sieves are added thereto, in any order .
- the mixture was filtered, washing the sieves with 2-MeTHF (2 x 2.mL), and extracted, initially with water (8 mL) which contained 2M HBr (0.8 mL) and subsequently with water (4 mL) .
- the aqueous extracts were combined and washed with 2-MeTHF (4 mL) , and, after cooling to 0°C, solution pH was basified by addition of solid K 2 CO 3 .
- the mixture was kept under stirring at 0°C for about 30 minutes, then the obtained solid was filtered, washed with cold water (3 x 6 mL) and dried, initially over a filter, and subsequently at 45 °C under vacuum for 18 hours.
- a white solid was obtained (303 mg, 71%, HPLC purity: 99.92%).
- Example 5 with 11% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (10:1)
- Example 6 Synthesis of scopine ester (3) by using a NHC derived from 1 , 3-di-tert-butylimidazolium chloride with 8% mol NHC (with respect to compound (1) ) at room temperature in THF.
- 1,3-di- tert-butylimidazolium chloride (20 mg, 0.092 mmol), KOtBu/THF (80 yL, 0.080 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature.
- Example 7 Synthesis of scopine ester (3) using a NHC derived from l-hexyl-3-metylimidazolium tetrafluorborate with 11% mol NHC (with respect to compound (1) ) at room temperature in THF .
- Example 8 Synthesis of scopine ester (3) by using a NHC derived from 1 , 3-dicyclohexylimidazolium tetrafluorborate with 11% mol NHC (with respect to compound (1) ) at room temperature in THF .
- Example 9 Synthesis of scopine ester (3) by using an NHC derived from l-butyl-3-methylimidazolium tetrafluorborate in the absence of molecular sieves , with 5% mol NHC (with respect to compound (1) ) at room temperature in THF.
- l-butyl-3- methylimidazolium tetrafluorborate (12 pL, 0.064 mmol) , KOtBu/THF (52 pL, 0.052 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the ester-amine solution.
- Example 10 Synthesis of scopine ester (3) by using potassium tert-butoxide and molecular sieves.
- a solution of 22% methyl bromide in acetone was prepared by scrubbing gas into a dark glass bottle containing 1.6 kg of acetone and placed on scales until obtaining 1.95 kg of methyl bromide solution in acetone.
- the suspension maintained under mechanical stirring, was heated to 40 ⁇ 5°C until obtaining complete dissolution of the solid.
- the clear (pale yellow colored) solution was cooled to 20°C and, keeping the flask immersed in a water bath, a 22.1% (w/w) solution of methyl bromide in acetone: 636 mL, equal to about 1.8 eq. of MeBr, was rapidly dropped, by addition funnel, on the clear solution.
- reaction mixture was maintained under stirring at room temperature. after about 4 days (90-100 h) a sampling was carried out for reaction control.
- the reaction mixture appeared as a heterogeneous suspension made up of clear mother waters and grainy and heavy solid, which tended to rapidly settle on the flask bottom.
- the solid was filtered, and flask and solid were washed over a filter with: 863 mL of acetone/DMF mixture (5:1), 431 mL of acetone/DMF mixture (5:1), 2x431 mL of acetone.
- the solid thus obtained was dried over the filter under Nitrogen current for 2-3h. At the end of the drying the solid appeared white and powdery.
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Abstract
The present invention relates to a process for the preparation of scopine esters, as intermediates in the synthesis of tiotropium bromide. In particular, it relates to a transesterification process between scopine alcohol and an ester of a carboxyl acid in high yields and under conditions suitable for industrial use.
Description
PROCESS FOR THE PREPARATION OF SCOPINE ESTERS
DESCRIPTION FIELD OF THE INVENTION
Tiotropium bromide (4), described in EP418716, is a potent anticholinergic agent specific for muscarinic receptors. As a drug, it has been approved for the treatment of respiratory disorders, such as asthma, COPD, chronic bronchitis and emphysema.
Object of the present invention is a novel synthetic process for the synthesis of the scopine ester (3) , characterized by the use of reagents of improved industrial applicability and anyhow under not overly strong basic conditions inducing scopine conversion into scopoline (Scheme 6) which in turn can result as impurity, in the subsequent transesterification reaction, in scopoline ester.
STATE OF THE ART
A process for the preparation of tiotropium bromide was reported in EP418716. In this process, the first step consists in a transesterification of scopine (1) with methyl di- (2-thienyl) glycolate (2, R = Me) to form the di- (2-thienyl) glycolic acid scopine ester (3). This ester is then quaternized with methyl bromide to obtain tiotropium bromide (Scheme 2) . Reagents of difficult industrial use, such as sodium metal, are used in the transesterification reaction. Best yield reported is of 70% (Example 3) and there is no information on HPLC purity obtained.
Scheme 2
Another method of synthesis is described in US6486321, US656900, US6610849 and US 747153. In this case, starting occurs from tropenol (5) , which is transesterified with methyl di- (2-thienyl) glycolate, then epoxidation and quaternarization follow. This process requires a number of steps higher than the preceding one (Scheme 3) .
Scheme 3
An alternative process is that described by US6747154, envisaging a coupling reaction between the already quaternized scopine salt (6) and di- (2- thienyl ) glycolic acid activated with dicarbonyl imidazole and a stoichiometric amount of a strong base (imidazolyl lithium salt, generated with LiH and imidazole) (Scheme 4) . Experimental section and synthesis yield are not reported .
Scheme 4
Pat. Appln. US 2006/0047120 describes another approach: the reaction of scopine methobromide (6) with trimethylsilyl-protected sodium dithienyl glycolate obtained in situ (Scheme 5) .
Scheme 5 A recurring problem in prior art processes is the conversion, induced by basic conditions, of scopine into scopoline (Scheme 6) (Tetrahedron Letters, (1967), 14, 1283-1284., Die darstellung von Scopin aus Scopolamin) which in turn can result as impurity, in the subsequent transesterification reaction, in scopoline ester.
Scheme 6
Direct esterification methods prove to be of difficult applicability, owing to di- (2-thienyl) glycolic acid instability; in fact, a sample of this acid obtained by hydrolysis of its methyl ester rapidly became dark when left at room temperature, denoting an evident degradation thereof. Transesterification methods by use of N-heterocyclic carbenes (NHCs) are known in the literature. Nolan and coll. demonstrated that these compounds (used in a percent of 2.4 to 5.0% molar) are able to catalyze the transesterification of methyl, ethyl and vinyl esters with primary, secondary and even tertiary alcohols (in this latter case, use of catalyst in a 20% molar percent proved necessary, and the yield was only of 54%) [Journal of Organic Chemistry, (2003) , 68, 2812-2819, Efficient Transesterification/Acylation Reactions Mediated by N-Heterocyclic Carbenes Catalysis; Journal of Organic Chemistry (2004), 69, 209-212]. Some NHCs are commercially available, but can also be conveniently prepared in situ (Scheme 7) by treatment of dihydroimidazolium or imidazolium salts of formula (7a) (wherein R' , R' ' and Y have the meanings reported in J. Org. Chem. (2004), 69, 209-212) with a base (generally potassium tert-butoxide) ,
Scheme 7
The reaction is conducted at room temperature and in
the presence of molecular sieves (0.5 g/mmol) which capture released alcohol (e.g., 4A molecular sieves for methanol and 5A ones for ethanol) so as to shift the reaction towards the ester of the more complex alcohol. Generally, alkyl-substituted NHCs give better results (90-100% yields were reported for conversion of methyl acetate to benzyl acetate) than aryl-substituted ones (41-49% yields for the same reaction), and those generated from imidazolium salts give better results than those generated from dihydroimidazolium salts.
SUMMARY
Object of the present invention is a novel synthetic process for the synthesis of the scopine ester, characterized by the use of reagents of better industrial applicability and anyhow under basic (alkaline) conditions not so overly strong as to induce conversion of scopine to scopoline.
It has surprisingly been found, and constitutes an object of the present invention, that the transesterification reaction of scopine (1) , with esters of di- (2-thienyl) glycolic acid (2) wherein R is selected from the group methyl, ethyl, propyl or vinyl, and preferably methyl, to obtain the corresponding ester (3) , can be effectively obtained by exploiting catalysis with NHCs generated from compounds of formula (7), e.g. those represented purely by way of example in Table I, in which :
R1 and R2 are independently selected from the group Ci-io alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups, and, preferably, from the group methyl, butyl, tert- butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl- phenyl, di-isopropyl-phenyl , and even more preferably from the group methyl, butyl, tert-butyl, hexyl, cyclohexyl.
X represents a ion selected from the group CI, BF4, Br, PF6, I, CIO4, TfO, and preferably from the group
CI, BF4,
being, among the compounds of formula (7) , absolutely preferred those of Table 1 with formula (9) , (10) , (12) and (14) , by treatment with a base selected from the group NaH, K2CO3, tBuOK (Scheme 8), in the presence of molecular sieves.
Scheme 8
This reaction entails the advantage of not using reagents potentially hazardous, nor reagents highly basic in a stoichiometric amount, and of using instead the NHCs in a catalytic amount.
It is also part of the present invention the treatment of the ester of formula (3) with a methylating agent, to obtain the tiotropium bromide of formula (4) according to methods already known in the art, as provided for in the synthetic scheme 2.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, the scopine ester of formula (3) can be prepared through a transesterification reaction of scopine alcohol (1) with a suitable ester of formula (2) , wherein R is methyl, ethyl, propyl, vinyl, preferably methyl. The reaction is carried out in the presence of molecular sieves, by treatment with N-heterocyclic carbenes (NHC) of formula (8), preferably in a catalytic amount, wherein:
R1 and R2 are independently selected from the
group Ci-io alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups, and, preferably, from the group methyl, butyl, tert- butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl- phenyl, di-isopropyl-phenyl , and even more preferably from the group methyl, butyl, tert-butyl, hexyl, cyclohexyl .
The alcohol (1) and the ester (2) are dissolved in an organic solvent selected from toluene, dichloromethane, THF, 2-MeTHF (2-methyltetrahydrofuran) , cyclopentylmethylether, DMF (dimethylformamide) and DMI (dimethyl-2-imidazolidinone) or mixtures thereof, preferably 2-MeTHF.
The temperature is maintained between 0° and 60 °C, preferably between 20° and 40°C, and even more preferably between 20° and 25°C.
The NHC carbene (8) is formed separately by treatment of an imidazolium salt of formula (7), [in Table I, a series of non-limiting examples of compounds of formula (7) are reported], wherein:
R1 and R2 are independently selected from the group Ci-10 alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups, and, preferably, from the group methyl, butyl, tert- butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl- phenyl, di-isopropyl-phenyl, and even more preferably from the group methyl, butyl, tert-butyl, hexyl, cyclohexyl .
X represents a ion selected from the group CI, BF4, Br, PF6, I, CIO4, TfO and preferably from the group CI, BF4
dissolved in one of the organic solvents above by addition of a sub-stoichiometric amount of a base selected from NaH, K2CO3, tBuOK, preferentially tBuOK.
The preferred compounds of formula (7) are reported in Table 1; among these, the most preferred ones are the compounds of formula (9) , (10) , (12) and (14) .
The use of NHCs, specifically in a catalytic amount, proved surprisingly effective for the synthesis of compound (3); in Example 10, valid as a mere comparison, a synthesis without NHCs is reported and the yields obtained were decidedly poor (of about 19%) .
The reaction was conducted in the presence of molecular sieves capturing the alcohol released (e.g., 4A molecular sieves for methanol and 5A ones for ethanol) so as to shift the reaction towards the ester of the more complex alcohol. The molecular sieves were used in the ratio of 1 - O.lg of sieves per mmol of scopine base (1), preferably in the ratio of 0.5 g/mmol. Non-limiting examples of molecular sieves may be Molecular Sieves, 4A, Aldrich product number 208604 - beads, 8-12 mesh, and Molecular Sieves, 5A, Fluka product number 69848, rod 1/8 in, or Molecular Sieves, 5A, Aldrich product number 208620, beads, 8-12 mesh.
The use of molecular sieves is essential for obtaining high yields; in Example 9, valid as a mere comparison, a synthesis without molecular sieves is reported: obtained yields were of about 7%.
The chemical reagents of the invention and the molecular sieves can be set up, mixed and reacted among them in any order. E.g., a solution of alkyl di- (2- thyenil ) glycolate (2) and scopine free base (1) is prepared, the molecular sieves are added thereto, the solution of N-heterocarbene (8) is separately prepared, and added to the first solution. Or, a solution of NHC (8) is prepared, and subsequently the reagents (1) and (2), plus the molecular sieves are added thereto, in any order .
Table 1
EXAMPLES
The following are non-limiting examples of the present invention:
Synthesis of scopine ester (3) by using an NHC derived from l-butyl-3-methylimidazolium tetrafluorborate Example 1: with 7% mol NHC (with respect to compound (1) ) at room temperature in THF .
In an anhydrous flask containing about 7.85 g of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2), (R = Me, 3.97 g, 15.6 mmol) and
scopine free base (1), (2.61 g, 16.8 mmol), were dissolved in THF (14 mL) . Separately, in a flask, 1- butyl-3-methylimidazolium tetrafluorborate (210 yL, 1.12 mmol), KOtBu/THF (960 yL, 0.96 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the scopine solution. Syringe and flask were washed with THF (2 x 0.5 mL) and the reaction mixture was stirred at room temperature for 18 hours. An HPLC control showed 86% of expected product. After a total of 18 hours, the mixture was filtered, washing the sieves with THF (2 x 20. mL) . The filtrate was concentrated to dryness and the residue taken up with toluene (30 mL) and 1M HC1 (30 mL) . During phase separation, precipitation of a solid was observed; the resulting suspension was filtered, the solid washed with toluene (30 mL) and reunited to the separated aqueous phase. The pH of said aqueous suspension, cooled to 0°C, was basified by addition of solid K2CO3. The mixture was kept under stirring at 0°C for about 30 minutes, then the obtained solid was filtered, washed with cold water and dried, first over a filter, and subsequently at 45°C under vacuum for 18 hours. A white solid (3) was obtained; (4.30 g, 73%, HPLC purity = 99.89%).
Example 2: with 6% mol NHC (with respect to compound
(1)) at room temperature in dichloromethane-THF (20:1)
In an anhydrous flask containing about 5.0 g of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2), (R = Me; 2.63 g, 10.3 mmol), and scopine free base (1), (1.57 g, 10.1 mmol), were dissolved in CH2CI2 (8 mL) . In a separate flask, 1-butyl- 3-methylimidazolium tetrafluorborate (120 yL, 0.642 mmol), KOtBu/THF (500 yL, 0.500 mmol) and CH2C12 (1.0 mL) were stirred for 15 minutes at room temperature. Such mixture was then transferred with a syringe into the flask containing the scopine solution. Syringe and flask were washed with CH2CI2 (1.0 mL) and the reaction mixture
was stirred at room temperature for 16 hours. An HPLC control showed 77% of expected product. The mixture was filtered, washing the sieves with CH2CI2 (2 x lO.mL), and extracted with 1M HC1 (2 x 25 mL) . The aqueous phase was cooled to 0°C and the pH basified by addition of solid K2CO3. The mixture was extracted with CH2CI2 (2 x 25 mL) , the organic phase dried (Na2SC>4) , filtered, and the filtrate concentrated under vacuum. A solid was obtained (2.69 g, 73%) with a HPLC purity of 99.74%.
Example 3: with 12% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (29:1)
In an anhydrous flask containing about 500 mg of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2), (R = Me; 284 mg, 1.12 mmol) , and scopine free base (1), (165 mg, 1.06 mmol) were dissolved in 2-MeTHF (1 mL) . In a separate flask, l-butyl-3- methylimidazolium tetrafluorborate (24 yL, 0.13 mmol), KOtBu/THF (105 yL, 0.105 mmol) and 2-MeTHF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the ester/ammine solution. Syringe and flask were washed with 2-MeTHF (1.0 mL) and the reaction mixture was stirred at room temperature for 21.5 hours. An HPLC control showed 68% of expected product. The mixture was filtered, washing the sieves with 2-MeTHF (2 x 2.mL), and extracted with water (5 mL) which contained 2M HBr (0.8 mL) and subsequently with water (4 mL) . The aqueous extracts were combined and washed with 2-MeTHF (4 mL) , and, after cooling to 0°C, the pH was basified by addition of solid K2CO3. The mixture was extracted with CH2CI2 (2 x 6 mL) , the organic phase dried ( a2S04) , filtered, and the filtrate concentrated under vacuum. A white solid was obtained (296 mg, 74%, HPLC purity: 99.75%) .
Example 4: with 10% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (10:1)
In an anhydrous flask, l-butyl-3-methylimidazolium
tetrafluorborate (23 pL, 0.12 mmol) , KOtBu/THF (100 pL, 0.100 mmol) and 2-MeTHF (1.0 mL) were stirred for 15 min at room temperature. Then, methyl di- (2-thyenil) glycolate (2), (R = Me; 288 mg, 1.13 mmol), scopine free base (1) , (191 mg, 1.23 mmol), and activated 4A molecular sieves (500 mg) were added. Said mixture was stirred at room temperature for 18 hours. An HPLC control showed 89% of expected product. The mixture was filtered, washing the sieves with 2-MeTHF (2 x 2.mL), and extracted, initially with water (8 mL) which contained 2M HBr (0.8 mL) and subsequently with water (4 mL) . The aqueous extracts were combined and washed with 2-MeTHF (4 mL) , and, after cooling to 0°C, solution pH was basified by addition of solid K2CO3. The mixture was kept under stirring at 0°C for about 30 minutes, then the obtained solid was filtered, washed with cold water (3 x 6 mL) and dried, initially over a filter, and subsequently at 45 °C under vacuum for 18 hours. A white solid was obtained (303 mg, 71%, HPLC purity: 99.92%).
A second batch of product (32 mg, 7.5%, HPLC purity:
100%) was recovered by filtration from mother waters.
Example 5: with 11% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (10:1)
In an anhydrous flask, l-butyl-3-methylimidazolium tetrafluorborate (1.00 mL, 5.35 mmol) and KOtBu/THF (4.70 mL, 4.70 mmol) were stirred for 15 min at room temperature. 2-MeTHF (48 mL) was added, followed by methyl di- (2-thyenil) glycolate (2), (R = Me; 13.29 g, 1.13 mmol), scopine free base (1) (7.42 g, 47.8 mmol), and activated 4A molecular sieves (26.36 g) . Said mixture was stirred at room temperature for 17 hours. An HPLC control showed 85% of expected product. The mixture was decanted, and the sieves washed with 2-MeTHF (2 x 50 mL) . To said organic solution water (100 mL) was added, the mixture cooled and the pH brought to 2 with addition of 2M HBr (5 x 5 mL) . Phases were separated and the organic phase extracted with water (100 mL) . The aqueous phases
were combined and washed with 2-MeTHF (100 mL) , and, after cooling, the pH was basified by addition of solid K2CO3. The mixture was kept under stirring at 0°C for about 30 minutes, then the obtained solid was filtered, washed with cold water (3 x 75 mL) and dried, initially over a filter, and subsequently at 40°C under vacuum for 18 hours. A white solid was obtained (14.43 g, 80%, HPLC purity: 99.89%) .
Example 6: Synthesis of scopine ester (3) by using a NHC derived from 1 , 3-di-tert-butylimidazolium chloride with 8% mol NHC (with respect to compound (1) ) at room temperature in THF.
In an anhydrous flask containing about 500 mg of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2, R = Me; 261 mg, 1.03 mmol) and scopine free base (1; 173 mg, 1.12 mmol) were dissolved in THF (1 mL) . In a separate anhydrous flask, 1,3-di- tert-butylimidazolium chloride (20 mg, 0.092 mmol), KOtBu/THF (80 yL, 0.080 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the ester-amine solution. Syringe and flask were washed with THF (1.0 mL) and the reaction mixture was stirred at room temperature for 22 hours. An HPLC control showed 70% of expected product. The mixture was filtered, washing the sieves with THF (2 x 2.mL) . The filtrate was concentrated to dryness and the residue taken up with toluene (4 mL) and water (4 mL) , and the pH was acidified (1-2) with 2M HBr. During phase separation, precipitation of a solid was observed; the resulting suspension was filtered, the solid washed with toluene (4 mL) and
reunited to the separated aqueous phase. The pH of said aqueous suspension, cooled to 0°C, was basified by addition of solid K2CO3. The mixture was kept under stirring at 0°C for about 30 minutes, then the mixture was extracted with CH2CI2 (2 x 6 mL) , the organic phase washed with water (2 x 4 mL) , dried (Na2SC>4) , filtered, and the filtrate concentrated under vacuum. A whitish solid was obtained (326 mg, 84%, HPLC purity: 98.45%).
Example 7: Synthesis of scopine ester (3) using a NHC derived from l-hexyl-3-metylimidazolium tetrafluorborate with 11% mol NHC (with respect to compound (1) ) at room temperature in THF .
In an anhydrous flask containing about 500 mg of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2), (R = Me; 256 mg, 1.01 mmol) , and scopine free base (1), (159 mg, 1.03 mmol), were dissolved in THF (1 mL) . In a separate flask, l-hexyl-3- 3-methylimidazolium tetrafluorborate (27 yL, 0.12 mmol), KOtBu/THF (100 yL, 0.100 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the ester-amine solution. Syringe and flask were washed with THF (1.0 mL) and the reaction mixture was stirred at room temperature for 16 hours. An HPLC control showed 70% of expected product. The mixture was filtered, washing the sieves with THF (2 x 2.mL) . The filtrate was concentrated to dryness and the residue taken up with toluene (4 mL) and water (4 mL) , and the pH was acidified (1-2) with 2M HBr. During phase separation, precipitation of a solid was observed; the resulting suspension was filtered, the solid washed with toluene (4 mL) and reunited to the separated aqueous phase. The pH of said aqueous suspension, cooled to 0°C, was basified by addition of solid K2CO3. The mixture was kept under stirring at 0°C for about 30 minutes, then the mixture was extracted with CH2CI2 (2 x 6 mL) , the organic phase washed with water (2 x 4 mL) , dried ( a2S04) , filtered,
and the filtrate concentrated under vacuum. A whitish solid was obtained (305 mg, 80%, HPLC purity = 99.18%).
Example 8: Synthesis of scopine ester (3) by using a NHC derived from 1 , 3-dicyclohexylimidazolium tetrafluorborate with 11% mol NHC (with respect to compound (1) ) at room temperature in THF .
In an anhydrous flask containing about 500 mg of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2), (R = Me; 295 mg, 1.16 mmol) , and scopine free base (1), 187 mg, 1.21 mmol) were dissolved in THF (1 mL) . In a separate anhydrous flask, 1,3- dicyclohexylimidazolium tetrafluorborate (44 mg, 0.14 mmol), KOtBu/THF (115 yL, 0.115 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the ester-amine solution. Syringe and flask were washed with THF (1.0 mL) and the reaction mixture was stirred at room temperature for 17.5 hours. An HPLC control showed 77% of expected product. The mixture was filtered, washing the sieves with THF (2 x 2.mL) . The filtrate was concentrated to dryness and the residue taken up with toluene (4 mL) and water (4 mL) , and the pH was acidified (1-2) with 2M HBr. During phase separation, precipitation of a solid was observed and the resulting suspension was filtered, the solid washed with toluene (4 mL) and dried over the filter. A cream-colored solid was obtained (354 mg, 67.5% (as HBr salt), HPLC purity: 98.71%) .
Example 9: Synthesis of scopine ester (3) by using an NHC derived from l-butyl-3-methylimidazolium tetrafluorborate in the absence of molecular sieves , with 5% mol NHC (with respect to compound (1) ) at room temperature in THF.
In an anhydrous flask, methyl di- (2- thyenil ) glycolate (2), (R = Me; 256 mg, 1.01 mmol), and scopine free base (1), (180 mg, 1.16 mmol) were dissolved in THF (1 mL) . In a separate anhydrous flask, l-butyl-3-
methylimidazolium tetrafluorborate (12 pL, 0.064 mmol) , KOtBu/THF (52 pL, 0.052 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the ester-amine solution. Syringe and flask were washed with THF (2 x 0.5 mL) and the reaction mixture was stirred at room temperature for 18 hours. An HPLC control shows only 7% of expected product. This scarce yield demonstrates the need to have molecular sieves in the reaction environment.
Example 10: Synthesis of scopine ester (3) by using potassium tert-butoxide and molecular sieves.
In an anhydrous flask, methyl di- (2- thyenil) glycolate (2), (R = Me, 2.54 g, 9.98 mmol), and scopine free base (1), (1.59 g, 10.2 mmol) were dissolved in THF (40 mL) . The solution was cooled and the activated 4A molecular sieves (7.63 g) added, in the form of powder. KOtBu/THF (200 pL, 0.200 mmol) was added, and the mixture stirred for 18 hours at 4 °C. An HPLC control shows no product expected. The mixture was brought to room temperature, KOtBu/THF (200 pL, 0.200 mmol) was added and the mixture left to reflux for 23 hours. An HPLC control showed only 19% of expected product. This result demonstrates the need to have the carbene precursor in the reaction environment.
A solution of 22% methyl bromide in acetone was prepared by scrubbing gas into a dark glass bottle containing 1.6 kg of acetone and placed on scales until obtaining 1.95 kg of methyl bromide solution in acetone.
In a reaction flask were charged, in this order:
scopine ester (3): 242.6g (0.6426 moles, 1 eq) DMF: 388 mL,
acetone: 1370 mL
(acetone/DMF ratio: about 3.5:1)
The suspension, maintained under mechanical stirring, was heated to 40±5°C until obtaining complete dissolution of the solid.
The clear (pale yellow colored) solution was cooled to 20°C and, keeping the flask immersed in a water bath, a 22.1% (w/w) solution of methyl bromide in acetone: 636 mL, equal to about 1.8 eq. of MeBr, was rapidly dropped, by addition funnel, on the clear solution.
In a few hours of stirring at room temperature, a progressive precipitation of white solid was observed.
The reaction mixture was maintained under stirring at room temperature. after about 4 days (90-100 h) a sampling was carried out for reaction control.
The reaction mixture appeared as a heterogeneous suspension made up of clear mother waters and grainy and heavy solid, which tended to rapidly settle on the flask bottom.
The solid was filtered, and flask and solid were washed over a filter with: 863 mL of acetone/DMF mixture (5:1), 431 mL of acetone/DMF mixture (5:1), 2x431 mL of acetone. The solid thus obtained was dried over the filter under Nitrogen current for 2-3h.
At the end of the drying the solid appeared white and powdery.
Crude dry Tiotropium bromide weight: 295.1 g (yield=97.2%) .
Claims
1) A process of synthesis of the scopine ester formula (3) ,
as intermediate in the synthesis of tiotropium bromide, by transesterification reaction of scopine (1) with esters of di- (2-thienyl) glycolic acid (2)
characterized in that the reaction:
a) is catalyzed by an NHC (N-heterocyclic carbene) formula (8)
wherein R1 and R2 are independently selected from the group Ci_i0 alkyl, C5-7 cycloalkyl, adamantyl,
phenyl, phenyl substituted with up to three C1-4 alkyl groups ,
b) occurs in the presence of molecular sieves.
2) The process according to claim 1, wherein the NHC (N-heterocyclic carbene) reagent of formula (8) is obtainable by treatment of a compound of formula (7) with a base:
wherein R1 and R2 are independently selected from the group Ci_i0 alkyl, C5-7 cycloalkyl, adamantyl, phenyl, phenyl substituted with up to three C1-4 alkyl groups ,
- X represents a ion selected from the group CI,
BF4 , Br, PF6, I, CIO4, TfO
the base is selected from the group NaH, K2CO3, tBuOK .
3) The process according to claims 1 or 2, wherein R1 and R2 are independently selected from the group methyl, butyl, tert-butyl, hexyl, octyl, adamantyl, cyclohexyl, trimethyl-phenyl , di-isopropyl-phenyl .
4) The process according to any one of the claims 1 to 3, wherein the NHC is selected from the compounds having formula (9) , (10) , (12) and (14) of Table 1.
5) The process according to any one of the claims 1 a 4, wherein the amount of molecular sieves used is in the ratio of 0.1 g to 1 g per mmol of scopine (3) used.
6) The process according to claim 5, wherein the amount of molecular sieves used is in the ratio of 0.5g per mmol of scopine (3) used.
7) The process according to any one of the claims 1 a 6, wherein the reaction is conducted in an organic
solvent selected from toluene, dichloromethane, THF, 2- MeTHF (2-methyltetrahydrofuran) , cyclopentylmethylether, DMF (dimethylformamide) , DMI (dimethyl-2-imidazolidinone) or mixtures thereof.
8) The process according to claim 7, wherein the organic solvent is 2-MeTHF (2-methyltetrahydrofuran) .
9) The process according to any one of the claims 1 a 8, wherein the reaction temperature is maintained between 0° and 60° C.
10) The process according to claim 9, wherein the reaction temperature is maintained between 20° and 40° C.
11) The process according to claim 10, wherein the reaction temperature is maintained between 20° and 25° C.
12) A process of synthesis of tiotropium bromide (4) comprising the process of synthesis of the scopine ester of formula (3) according to any one of the claims 1 to 11, wherein the scopine ester of formula (3)
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CN104557905A (en) * | 2013-10-16 | 2015-04-29 | 天津金耀集团有限公司 | Preparation method of tiotropium bromide intermediate |
CN107827761A (en) * | 2017-11-07 | 2018-03-23 | 宿迁德威化工有限公司 | A kind of preparation method of organic aromatic amine compound |
CN114890997A (en) * | 2022-04-20 | 2022-08-12 | 江苏联环药业股份有限公司 | Preparation process of anticholinergic drug tiaogelium bromide |
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CN104557905A (en) * | 2013-10-16 | 2015-04-29 | 天津金耀集团有限公司 | Preparation method of tiotropium bromide intermediate |
CN104557905B (en) * | 2013-10-16 | 2018-02-23 | 天津金耀集团有限公司 | A kind of preparation method of Tiotropium Bromide intermediate |
CN107827761A (en) * | 2017-11-07 | 2018-03-23 | 宿迁德威化工有限公司 | A kind of preparation method of organic aromatic amine compound |
CN114890997A (en) * | 2022-04-20 | 2022-08-12 | 江苏联环药业股份有限公司 | Preparation process of anticholinergic drug tiaogelium bromide |
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