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US20030166704A1 - New process - Google Patents

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US20030166704A1
US20030166704A1 US10/054,727 US5472701A US2003166704A1 US 20030166704 A1 US20030166704 A1 US 20030166704A1 US 5472701 A US5472701 A US 5472701A US 2003166704 A1 US2003166704 A1 US 2003166704A1
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US10/054,727
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Ronald Ogilvie
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Pfizer Corp SRL
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Pfizer Corp SRL
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Priority claimed from GBGB0031094.6A external-priority patent/GB0031094D0/en
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Priority to US10/054,727 priority Critical patent/US20030166704A1/en
Assigned to PFIZER INC. reassignment PFIZER INC. CONSENT TO ASSIGN Assignors: PFZIER LTD.
Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OGILVIE, RONALD JAMES
Publication of US20030166704A1 publication Critical patent/US20030166704A1/en
Priority to US10/974,670 priority patent/US7288662B2/en
Abandoned legal-status Critical Current

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic 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
    • A61K31/403Heterocyclic 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
    • A61K31/404Indoles, e.g. pindolol

Definitions

  • the present invention is concerned with an improved process for the preparation of the anti-migraine drug, (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (eletriptan), available commercially as the hydrobromide salt:
  • European Patent No. 0592438 describes the preparation of eletriptan by the catalytic reduction of (R)-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, which compound is prepared by (i) reacting N-benzyloxycarbonyl-D-proline acid chloride with 5-bromoindole in the presence of a Grignard reagent, (ii) reducing the resulting (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole to give (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and (iii) reacting same with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base.
  • the process of the invention comprises the preparation of eletriptan by the hydrolysis of (R)-1-acetyl-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, which compound may conveniently be prepared by (i) N-acetylating (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, (ii) reacting the resulting (R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base to give (R)-1-acetyl-5
  • the compound of formula (II) used in the process may be obtained by catalytic reduction of a compound of formula (III), typically using hydrogen or a hydrogen source in the presence of a suitable catalyst.
  • the reduction is typically carried out using hydrogen at a pressure of from 1 to 15 atmospheres or using a hydrogen source such as ammonium formate or formic acid.
  • Suitable catalysts include palladium on carbon, for example, 5% w/w Pd/C, Raney nickel, platinum oxide, rhodium, or ruthenium.
  • the reduction is conveniently carried out in the presence of an acid, for example, methanesulphonic acid, acetic acid, or trifluoroacetic acid.
  • the compound of formula (II) so obtained is conveniently slurried with cold aqueous tetrahydrofuran before hydrolysis to the compound of formula (I).
  • the invention specifically provides the aforementioned compound of formula (II) which has not hitherto been described.
  • the compound of formula (III) used in the process may be obtained by treating a compound of formula (IV) with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base in accordance with the process described in Example 57 of U.S. Pat. No. 5,607,951.
  • the compound of formula (IV) used in the process may be obtained by the N-acetylation of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, also in accordance with the process described in Example 57 of aforementioned U.S. Pat. No. 5,607,951.
  • Eletriptan obtained by the process of the invention may be converted to a pharmaceutically acceptable acid addition salt by treatment with an appropriate acid; said conversion may conveniently be carried out in situ without isolation of the compound of formula (I).
  • a particularly preferred salt is the hydrobromide obtained by treatment with hydrobromic acid.
  • dimer-free eletriptan and pharmaceutically acceptable salts thereof, particularly the hydrobromide, and pharmaceutical compositions comprising same are also provided.
  • step (a)(ii) drying the compound of formula (II) prior to hydrolysis may be avoided by using damp material slurried in aqueous tetrahydrofuran.
  • step (c) isolation of the compound of formula (I) before conversion to a salt may be avoided by forming the salt in situ.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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Abstract

The present invention provides an improved process for the preparation of the anti-migraine drug, (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (eletriptan), available commercially as the hydrobromide salt, and an intermediate and dimer-free products obtained from such process.

Description

  • The present invention is concerned with an improved process for the preparation of the anti-migraine drug, (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (eletriptan), available commercially as the hydrobromide salt: [0001]
    Figure US20030166704A1-20030904-C00001
  • and with an intermediate and dimer-free products obtained thereby. [0002]
  • European Patent No. 0592438 describes the preparation of eletriptan by the catalytic reduction of (R)-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, which compound is prepared by (i) reacting N-benzyloxycarbonyl-D-proline acid chloride with 5-bromoindole in the presence of a Grignard reagent, (ii) reducing the resulting (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole to give (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and (iii) reacting same with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base. [0003]
  • The complete sequence may be represented as follows: [0004]
    Figure US20030166704A1-20030904-C00002
  • While the foregoing sequence produces eletriptan of formula (I) in reasonable yield, it has been found that the (R)-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole precursor is prone to dimerise when attempting to recrystallise in impure form and/or drying prior to catalytic reduction: [0005]
    Figure US20030166704A1-20030904-C00003
  • Not only does the formation of this dimeric impurity reduce the yield of eletriptan, but, perhaps more importantly, it requires the costly and time-consuming removal of said dimer in order to provide hydrobromide salt of sufficient purity to meet the stringent standards required for regulatory approval. [0006]
  • As a result of this difficulty, we have now developed an alternative route to eletriptan which avoids the use of a precursor which is prone to dimerisation. Specifically, the process of the invention comprises the preparation of eletriptan by the hydrolysis of (R)-1-acetyl-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, which compound may conveniently be prepared by (i) N-acetylating (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, (ii) reacting the resulting (R)-1-acetyl-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base to give (R)-1-acetyl-5-(2-benzenesulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and (iii) catalytically reducing same. [0007]
  • The complete sequence may be represented as follows: [0008]
    Figure US20030166704A1-20030904-C00004
  • By the use of this process, it is possible to avoid the formation of unwanted dimer and thereby obtain eletriptan of high purity in good yield without the subsequent costly and time-consuming purification steps needed to remove the dimeric impurity. Thus according to the present invention, there is provided a process for the preparation of a compound of formula (I) which comprises hydrolysis of a compound of formula (II), typically under basic conditions, more especially potassium carbonate in methanol/water. [0009]
  • According to another aspect of the invention, the compound of formula (II) used in the process may be obtained by catalytic reduction of a compound of formula (III), typically using hydrogen or a hydrogen source in the presence of a suitable catalyst. The reduction is typically carried out using hydrogen at a pressure of from 1 to 15 atmospheres or using a hydrogen source such as ammonium formate or formic acid. Suitable catalysts include palladium on carbon, for example, 5% w/w Pd/C, Raney nickel, platinum oxide, rhodium, or ruthenium. The reduction is conveniently carried out in the presence of an acid, for example, methanesulphonic acid, acetic acid, or trifluoroacetic acid. The compound of formula (II) so obtained is conveniently slurried with cold aqueous tetrahydrofuran before hydrolysis to the compound of formula (I). [0010]
  • The invention specifically provides the aforementioned compound of formula (II) which has not hitherto been described. [0011]
  • According to yet another aspect of the invention, the compound of formula (III) used in the process may be obtained by treating a compound of formula (IV) with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base in accordance with the process described in Example 57 of U.S. Pat. No. 5,607,951. [0012]
  • According to yet a further aspect of the invention, the compound of formula (IV) used in the process may be obtained by the N-acetylation of (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole, also in accordance with the process described in Example 57 of aforementioned U.S. Pat. No. 5,607,951. [0013]
  • Eletriptan obtained by the process of the invention may be converted to a pharmaceutically acceptable acid addition salt by treatment with an appropriate acid; said conversion may conveniently be carried out in situ without isolation of the compound of formula (I). A particularly preferred salt is the hydrobromide obtained by treatment with hydrobromic acid. [0014]
  • Thus according to the present invention, there is also provided dimer-free eletriptan and pharmaceutically acceptable salts thereof, particularly the hydrobromide, and pharmaceutical compositions comprising same. [0015]
  • EXAMPLE
  • The process of the invention may be illustrated by the following example of the preparation of (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (I) and its hydrobromide salt: [0016]
  • (a) Preparation of (R)-1-acetyl-5-(2-benzenesulphonylethyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (II) [0017]
  • To a solution of the compound of formula (III) (200 g) prepared by the method described in Example 57 of aforementioned U.S. Pat. No. 5,607,951 in acetone (2.0L) was added water (0.5L). Methanesulphonic acid (43.2 g, 0.95 equiv.) was added dropwise and the resulting solution stirred for 5 minutes before adding 5% w/w Pd/C catalyst (89.0 g, Johnson Mattey Type 58, 50% wet). The solution was hydrogenated at room temperature at 200 psi hydrogen for 18 hours. [0018]
  • The catalyst was removed by filtration and the filtrate stripped to give an acetone-free slurry. To this was added dropwise 40% aqu. NaOH (30 mL) followed by water (1.5L). The resulting slurry was stirred for 20 minutes and further 40% aqu. NaOH (20 mL) added. After granulation for 2 hours under vigorous stirring, the suspension was filtered and sucked dry for 30 minutes to give a beige damp solid which was either [0019]
  • (i) dried at 45° C. to give the desired product (193.0 g, yield 95%) or [0020]
  • (ii) taken up in tetrahydrofuran (1.6L) to which was added water (1.5L in total) over 10 minutes. The resulting suspension was stirred vigorously for 18 hours, filtered and sucked dry for 30 minutes to give the desired product as a beige damp solid (corrected weight 129.0 g, yield 67%). [0021]
  • Either form may be used directly in step (b): [0022]
  • (b) Preparation of (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (I) [0023]
  • To a solution of the compound of formula (II) (95.9 g) from step (a)(i) or (ii) in acetone (1L) and methanol (0.1L) was added K[0024] 2CO3 (46.8 g, 1.5 equiv.) and the resulting mixture stirred for 24 hours. To this was added charcoal (50 g) followed an hour later by anhy. MgSO4 (300 g). The resulting suspension was stirred for 1 hour and filtered. The filtrate was stripped to give a damp solid which was dried in vacuo at 45° C. to give the desired product (79.3 g, 91.8%).
  • In the case where the compound of formula (I) is to be converted to a pharmaceutically acceptable acid addition salt, isolation of the compound of formula (I) may be avoided by directly treating the solution obtained by hydrolysis with the appropriate acid, for example, hydrobromic acid to give the hydrobromide salt: [0025]
  • (c) Preparation of (R)-5-(2-benzenesulphonylethyl)-3-N-methylpyrrolidin-2-ylmethyl)-1H-indole (I) and in situ hydrobromination thereof [0026]
  • To a solution of the compound of formula (II) (95.9 g) from step (a)(i) or (ii) in acetone (1L) and methanol (0.1L) was added K[0027] 2CO3 (46.8 g, 1.5 equiv.) and the resulting mixture stirred for 24 hours. To this was added charcoal (50 g) followed an hour later by anhy. MgSO4 (300 g). The resulting suspension was stirred for 1 hour and filtered.
  • The filtrate was partially concentrated by azeotropic distillation to remove methanol and the volume readjusted to 0.45L with acetone. A solution of 48% w/v HBr (33.2 g, 0.95 equiv.) in acetone (50 mL) was added dropwise and the resulting suspension stirred for 72 hours. This was filtered, sucked dry for 30 minutes and dried in vacuo at 45° C. to give the desired product as slightly beige crystals (71.8 g, 68.5%). [0028]
  • In a preferred embodiment of the invention, certain steps may be ‘telescoped’ in order to reduce handling and accelerate processing time. For example, as indicated in step (a)(ii), drying the compound of formula (II) prior to hydrolysis may be avoided by using damp material slurried in aqueous tetrahydrofuran. Likewise, as indicated in step (c), isolation of the compound of formula (I) before conversion to a salt may be avoided by forming the salt in situ. [0029]

Claims (23)

1. A process for the preparation of a compound of formula (I)
Figure US20030166704A1-20030904-C00005
which comprises hydrolysis of a compound of formula (II)
Figure US20030166704A1-20030904-C00006
2. A process according to claim 1 which is carried out under basic conditions.
3. A process according to claim 2 wherein said hydrolysis is performed using potassium carbonate in methanol/water.
4. A process according to claim 1 wherein the compound of formula (II) is obtained by catalytic reduction of a compound of formula (III)
Figure US20030166704A1-20030904-C00007
5. A process according to claim 4 wherein said reduction is carried out using hydrogen or a hydrogen source in the presence of a suitable catalyst.
6. A process according to claim 5 wherein said reduction is carried out using hydrogen at a pressure of from 1 to 15 atmospheres.
7. A process according to claim 5 wherein said reduction is carried out using a hydrogen source which is ammonium formate or formic acid.
8. A process according to according to claim 4 wherein said catalyst is palladium on carbon, Raney nickel, platinum oxide, rhodium, or ruthenium.
9. A process according to claim 8 wherein said catalyst is 5% w/w palladium on carbon.
10. A process according to claim 4 wherein the catalytic reduction is carried out in the presence of an acid.
11. A process according to claim 10 wherein said acid is methanesulphonic acid, acetic acid, or trifluoroacetic acid.
12. A process according to claim 4 wherein the compound of formula (II) obtained by catalytic reduction is slurried with cold aqueous tetrahydrofuran before hydrolysis to the compound of formula (I).
13. A process according to claim 4 wherein the compound of formula (III) is obtained by treating a compound of formula (IV)
Figure US20030166704A1-20030904-C00008
with phenyl vinyl sulphone in the presence of a palladium catalyst, a triarylphosphine and a base.
14. A process according to claim 13 wherein the compound of formula (IV) is obtained by N-acetylating (R)-5-bromo-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole.
15. A process according to claim 1 wherein the compound of formula (I) so obtained is converted to a pharmaceutically acceptable acid addition salt by treatment with an appropriate acid.
16. A process according to claim 15 wherein said conversion is carried out in situ without isolation of the compound of formula (I).
17. A process according to claim 15 wherein the acid is hydrobromic acid and the resulting salt is the hydrobromide.
18. The compound of formula (II):
Figure US20030166704A1-20030904-C00009
19. Eletriptan which is substantially free of
Figure US20030166704A1-20030904-C00010
20. A pharmaceutically acceptable acid addition salt of eletriptan which is substantially free of
Figure US20030166704A1-20030904-C00011
21. A pharmaceutically acceptable acid addition salt of eletriptan according to claim 20 which is the hydrobromide.
22. A pharmaceutical composition comprising eletriptan or a pharmaceutically acceptable acid addition salt thereof which is substantially free of
Figure US20030166704A1-20030904-C00012
and a suitable carrier or excipient.
23. A composition according to claim 22 wherein said pharmaceutically acceptable acid addition salt is the hydrobromide.
US10/054,727 2000-12-20 2001-11-13 New process Abandoned US20030166704A1 (en)

Priority Applications (2)

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US10/054,727 US20030166704A1 (en) 2000-12-20 2001-11-13 New process
US10/974,670 US7288662B2 (en) 2000-12-20 2004-10-26 Process for the preparation of eletriptan

Applications Claiming Priority (4)

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GBGB0031094.6A GB0031094D0 (en) 2000-12-20 2000-12-20 New Process
GB0031094.6 2000-12-20
US26075201P 2001-01-10 2001-01-10
US10/054,727 US20030166704A1 (en) 2000-12-20 2001-11-13 New process

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020663A1 (en) * 2003-07-23 2005-01-27 Furlong Patrick Joseph Process
US8754239B2 (en) 2010-01-19 2014-06-17 Sms Pharmaceuticals Limited Process for preparing eletriptan hydrobromide having α-form

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009142771A2 (en) * 2008-05-22 2009-11-26 Plus Chemicals, S.A. Salts of (r)-5-(2-phenylsulphonylethenyl)-3-(n- methylpyrrolidin-2-ylmethyl)-1h-indole, 5-bromo-3-[(r)-1- methyl-pyrrolidin-2- ylmethyl]-1h-indole and of eletriptan
ES2431359T3 (en) * 2008-10-31 2013-11-26 Biophore India Pharmaceuticals Pvt. Ltd. New procedure for the preparation of Eletriptan
IT1393700B1 (en) * 2009-04-22 2012-05-08 F S I Fabbrica Italiana Sint SYNTHESIS OF 3 - {[(2R) -1-METHYLPYROLIDIN-2-IL] METHYL} -5- [2- (PHENILSULFONYL) ETYL] -1H-INDOL
WO2011004391A2 (en) 2009-06-25 2011-01-13 Matrix Laboratories Ltd An improved process for the preparation of eletriptan and its salt thereof

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US5545644A (en) * 1990-10-15 1996-08-13 Pfizer Inc. Indole derivatives
US5607951A (en) * 1990-10-15 1997-03-04 Pfizer Inc Indole derivatives
US6110940A (en) * 1994-08-27 2000-08-29 Pfizer Inc. Salts of an anti-migraine indole derivative

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006973A1 (en) 1990-10-15 1992-04-30 Pfizer Inc. Indole derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545644A (en) * 1990-10-15 1996-08-13 Pfizer Inc. Indole derivatives
US5607951A (en) * 1990-10-15 1997-03-04 Pfizer Inc Indole derivatives
US6110940A (en) * 1994-08-27 2000-08-29 Pfizer Inc. Salts of an anti-migraine indole derivative

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050020663A1 (en) * 2003-07-23 2005-01-27 Furlong Patrick Joseph Process
US6927296B2 (en) * 2003-07-23 2005-08-09 Pfizer Inc. Process
US20050245591A1 (en) * 2003-07-23 2005-11-03 Pfizer Inc. Process
US7164030B2 (en) 2003-07-23 2007-01-16 Pfizer Inc. Process
US8754239B2 (en) 2010-01-19 2014-06-17 Sms Pharmaceuticals Limited Process for preparing eletriptan hydrobromide having α-form

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US20050059828A1 (en) 2005-03-17

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