Efficient syntheses of AZD4407 via thioether formation by nucleophilic attack of organometallic species on sulphur

Marie Lyne Alcaraz, Stéphanie Atkinson, Philip Cornwall, Alison C. Foster, Duncan M. Gill, Lesley A. Humphries, Philip S. Keegan, Richard Kemp, Eric Merifield, Robert A. Nixon, Allison J. Noble, Darren O'Beirne, Zakariya M. Patel, Jacob Perkins, Paul Rowan, Paul Sadler, John T. Singleton, James Tornos, Andrew J. Watts, Ian A. Woodland

Research output: Contribution to journalArticle

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Abstract

The development of two efficient strategies for the synthesis of AZD4407 is reported, both of which are considered suitable for large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2- methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protection and lithiation at thiophene C-2, reaction with a protected 5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing a leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approach starts from 2,4-dibromothiophene, which undergoes a selective Grignard exchange reaction at C-2 followed by reaction with similar protected mercapto-oxindole derivatives. Reprotection of the oxindole ring, followed by a second Grignard exchange, and reaction with (2S)-2- methyltetrahydropyran-4-one provides AZD4407 after acid-catalysed deprotection and epimerisation.

LanguageEnglish
Pages555-569
Number of pages15
JournalOrganic Process Research and Development
Volume9
Issue number5
Early online date15 Jul 2005
DOIs
Publication statusPublished - 1 Sep 2005
Externally publishedYes

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Sulfides
Organometallics
Sulfur
attack
Bearings (structural)
sulfur
Derivatives
Thiophenes
Acids
synthesis
Hydroxyl Radical
acids
thiophenes
chemistry
oxindole
rings

Cite this

Alcaraz, Marie Lyne ; Atkinson, Stéphanie ; Cornwall, Philip ; Foster, Alison C. ; Gill, Duncan M. ; Humphries, Lesley A. ; Keegan, Philip S. ; Kemp, Richard ; Merifield, Eric ; Nixon, Robert A. ; Noble, Allison J. ; O'Beirne, Darren ; Patel, Zakariya M. ; Perkins, Jacob ; Rowan, Paul ; Sadler, Paul ; Singleton, John T. ; Tornos, James ; Watts, Andrew J. ; Woodland, Ian A. / Efficient syntheses of AZD4407 via thioether formation by nucleophilic attack of organometallic species on sulphur. In: Organic Process Research and Development. 2005 ; Vol. 9, No. 5. pp. 555-569.
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abstract = "The development of two efficient strategies for the synthesis of AZD4407 is reported, both of which are considered suitable for large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2- methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protection and lithiation at thiophene C-2, reaction with a protected 5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing a leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approach starts from 2,4-dibromothiophene, which undergoes a selective Grignard exchange reaction at C-2 followed by reaction with similar protected mercapto-oxindole derivatives. Reprotection of the oxindole ring, followed by a second Grignard exchange, and reaction with (2S)-2- methyltetrahydropyran-4-one provides AZD4407 after acid-catalysed deprotection and epimerisation.",
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Alcaraz, ML, Atkinson, S, Cornwall, P, Foster, AC, Gill, DM, Humphries, LA, Keegan, PS, Kemp, R, Merifield, E, Nixon, RA, Noble, AJ, O'Beirne, D, Patel, ZM, Perkins, J, Rowan, P, Sadler, P, Singleton, JT, Tornos, J, Watts, AJ & Woodland, IA 2005, 'Efficient syntheses of AZD4407 via thioether formation by nucleophilic attack of organometallic species on sulphur', Organic Process Research and Development, vol. 9, no. 5, pp. 555-569. https://doi.org/10.1021/op0500483

Efficient syntheses of AZD4407 via thioether formation by nucleophilic attack of organometallic species on sulphur. / Alcaraz, Marie Lyne; Atkinson, Stéphanie; Cornwall, Philip; Foster, Alison C.; Gill, Duncan M.; Humphries, Lesley A.; Keegan, Philip S.; Kemp, Richard; Merifield, Eric; Nixon, Robert A.; Noble, Allison J.; O'Beirne, Darren; Patel, Zakariya M.; Perkins, Jacob; Rowan, Paul; Sadler, Paul; Singleton, John T.; Tornos, James; Watts, Andrew J.; Woodland, Ian A.

In: Organic Process Research and Development, Vol. 9, No. 5, 01.09.2005, p. 555-569.

Research output: Contribution to journalArticle

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T1 - Efficient syntheses of AZD4407 via thioether formation by nucleophilic attack of organometallic species on sulphur

AU - Alcaraz, Marie Lyne

AU - Atkinson, Stéphanie

AU - Cornwall, Philip

AU - Foster, Alison C.

AU - Gill, Duncan M.

AU - Humphries, Lesley A.

AU - Keegan, Philip S.

AU - Kemp, Richard

AU - Merifield, Eric

AU - Nixon, Robert A.

AU - Noble, Allison J.

AU - O'Beirne, Darren

AU - Patel, Zakariya M.

AU - Perkins, Jacob

AU - Rowan, Paul

AU - Sadler, Paul

AU - Singleton, John T.

AU - Tornos, James

AU - Watts, Andrew J.

AU - Woodland, Ian A.

PY - 2005/9/1

Y1 - 2005/9/1

N2 - The development of two efficient strategies for the synthesis of AZD4407 is reported, both of which are considered suitable for large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2- methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protection and lithiation at thiophene C-2, reaction with a protected 5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing a leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approach starts from 2,4-dibromothiophene, which undergoes a selective Grignard exchange reaction at C-2 followed by reaction with similar protected mercapto-oxindole derivatives. Reprotection of the oxindole ring, followed by a second Grignard exchange, and reaction with (2S)-2- methyltetrahydropyran-4-one provides AZD4407 after acid-catalysed deprotection and epimerisation.

AB - The development of two efficient strategies for the synthesis of AZD4407 is reported, both of which are considered suitable for large-scale manufacture. In the first approach, 3-bromothiophene is coupled with (2S)-2- methyltetrahydropyran-4-one using Grignard chemistry. Following hydroxyl protection and lithiation at thiophene C-2, reaction with a protected 5-mercapto-1-methyl-1,3-dihydro-indol-2-one derivative bearing a leaving group on sulphur provides AZD4407 after acid-catalysed deprotection and epimerisation. The second approach starts from 2,4-dibromothiophene, which undergoes a selective Grignard exchange reaction at C-2 followed by reaction with similar protected mercapto-oxindole derivatives. Reprotection of the oxindole ring, followed by a second Grignard exchange, and reaction with (2S)-2- methyltetrahydropyran-4-one provides AZD4407 after acid-catalysed deprotection and epimerisation.

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U2 - 10.1021/op0500483

DO - 10.1021/op0500483

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