Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide Core

Manjunatha Sulur, Parhalad Sharma, Ravi Ramakrishnan, Ravi Naidu, Eric Merifield, Duncan M. Gill, Adrian M. Clarke, Colin Thomson, Michael Butters, Sreekanth Bachu, Colin H. Benison, Nagaraju Dokka, Emily R. Fong, David R.J. Hose, Gareth P. Howell, Siobhan E. Mobberley, Simon C. Morton, Alexander K. Mullen, Jayan Rapai, Bharathi Tejas

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler-Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal-Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.

LanguageEnglish
Pages1746-1753
Number of pages8
JournalOrganic Process Research and Development
Volume16
Issue number11
Early online date18 Oct 2012
DOIs
Publication statusPublished - 16 Nov 2012
Externally publishedYes

Fingerprint

Aromatization
indoles
pyrroles
Amides
amides
Pyrroles
manufacturing
routes
synthesis
Oximes
chlorides
substitutes
Chlorides
rings
Substitution reactions
Crystalline materials
Substrates
indole
AZD1981

Cite this

Sulur, Manjunatha ; Sharma, Parhalad ; Ramakrishnan, Ravi ; Naidu, Ravi ; Merifield, Eric ; Gill, Duncan M. ; Clarke, Adrian M. ; Thomson, Colin ; Butters, Michael ; Bachu, Sreekanth ; Benison, Colin H. ; Dokka, Nagaraju ; Fong, Emily R. ; Hose, David R.J. ; Howell, Gareth P. ; Mobberley, Siobhan E. ; Morton, Simon C. ; Mullen, Alexander K. ; Rapai, Jayan ; Tejas, Bharathi. / Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide Core. In: Organic Process Research and Development. 2012 ; Vol. 16, No. 11. pp. 1746-1753.
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abstract = "A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler-Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal-Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40{\%} overall yield in six chemical steps, with two isolated crystalline intermediates.",
author = "Manjunatha Sulur and Parhalad Sharma and Ravi Ramakrishnan and Ravi Naidu and Eric Merifield and Gill, {Duncan M.} and Clarke, {Adrian M.} and Colin Thomson and Michael Butters and Sreekanth Bachu and Benison, {Colin H.} and Nagaraju Dokka and Fong, {Emily R.} and Hose, {David R.J.} and Howell, {Gareth P.} and Mobberley, {Siobhan E.} and Morton, {Simon C.} and Mullen, {Alexander K.} and Jayan Rapai and Bharathi Tejas",
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Sulur, M, Sharma, P, Ramakrishnan, R, Naidu, R, Merifield, E, Gill, DM, Clarke, AM, Thomson, C, Butters, M, Bachu, S, Benison, CH, Dokka, N, Fong, ER, Hose, DRJ, Howell, GP, Mobberley, SE, Morton, SC, Mullen, AK, Rapai, J & Tejas, B 2012, 'Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide Core', Organic Process Research and Development, vol. 16, no. 11, pp. 1746-1753. https://doi.org/10.1021/op300173z

Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide Core. / Sulur, Manjunatha; Sharma, Parhalad; Ramakrishnan, Ravi; Naidu, Ravi; Merifield, Eric; Gill, Duncan M.; Clarke, Adrian M.; Thomson, Colin; Butters, Michael; Bachu, Sreekanth; Benison, Colin H.; Dokka, Nagaraju; Fong, Emily R.; Hose, David R.J.; Howell, Gareth P.; Mobberley, Siobhan E.; Morton, Simon C.; Mullen, Alexander K.; Rapai, Jayan; Tejas, Bharathi.

In: Organic Process Research and Development, Vol. 16, No. 11, 16.11.2012, p. 1746-1753.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide Core

AU - Sulur, Manjunatha

AU - Sharma, Parhalad

AU - Ramakrishnan, Ravi

AU - Naidu, Ravi

AU - Merifield, Eric

AU - Gill, Duncan M.

AU - Clarke, Adrian M.

AU - Thomson, Colin

AU - Butters, Michael

AU - Bachu, Sreekanth

AU - Benison, Colin H.

AU - Dokka, Nagaraju

AU - Fong, Emily R.

AU - Hose, David R.J.

AU - Howell, Gareth P.

AU - Mobberley, Siobhan E.

AU - Morton, Simon C.

AU - Mullen, Alexander K.

AU - Rapai, Jayan

AU - Tejas, Bharathi

PY - 2012/11/16

Y1 - 2012/11/16

N2 - A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler-Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal-Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.

AB - A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler-Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal-Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.

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U2 - 10.1021/op300173z

DO - 10.1021/op300173z

M3 - Article

VL - 16

SP - 1746

EP - 1753

JO - Organic Process Research and Development

T2 - Organic Process Research and Development

JF - Organic Process Research and Development

SN - 1083-6160

IS - 11

ER -