Synthesis of novel substituted isoquinolones

Briet, Nicolas; Brookes, Michael H.; Davenport, Richard; Galvin, Frances; Gilbert, Philip J.; Mack, Stephen R.; Sabin, Verity

doi:10.1016/s0040-4020(02)00573-2

Cited by 29 publications

(12 citation statements)

References 16 publications

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“…Treatment of 8 with phosphorus oxychloride (POCl 3 ) at 80°C provided an acid chloride (14), which was used for the next reaction without further purification. The reaction of 14 with 3 in the presence of triethylamine (Et 3 N) gave an amide (15). The use of potassium carbonate (K 2 CO 3 ) in DMF is effective in the case of intramolecular cyclization of 4, 12) while intramolecular cyclization of 15 using this method did not proceed, and the starting material (15) was recovered.…”

Section: Resultsmentioning

confidence: 99%

“…However, this protocol was not to be applied, because m-CPBA is potentially explosive and requires purification before use. 13) Oxidation of the methyl sulfide (6) with 30% aqueous H 2 O 2 in the presence of sodium tungstate (Na 2 WO 4 ) and acetic acid (AcOH) as a catalyst, 14,15) gave sulfone (7) accompanied by a small amount of by-product. Contamination by the small amount of by-product in 7 would affect the purity of KRP-103 (1).…”

Section: Resultsmentioning

confidence: 99%

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Process Development and Large-Scale Synthesis of NK1 Antagonist

Araya

Kanazawa

Akita

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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The tachykinin neuropeptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), are neurotransmitters or neuromodulatory agents. Each of these structurally related neuropeptides has a preferred receptor: the NK 1 receptor for SP, the NK 2 receptor for NKA, and the NK 3 receptor for NKB. The NK 1 and NK 2 receptors are widely distributed in the central nervous system (CNS) and peripheral tissue; NK 3 may be more localized in the CNS.1) Of these peptides, SP 2) is known to exhibit a wide variety of biological responses, both centrally and peripherally. Through binding to the NK 1 receptor, SP has been implicated in the transmission of pain and stress signals, inflammation, and the contraction of smooth muscle. Therefore, NK 1 antagonists may be efficacious for the clinical treatment of a wide range of diseases. In particular, we were interested in the relationship between tachykinin and the activation of the micturition-related refluxes, 3,4) with a view to possible application in the treatment of pollakiuria and urinary incontinence. Recently, the Kyorin Discovery Chemistry group reported the design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b]]oxazocin-5-one (1, KRP-103) was identified as an effective NK 1 antagonist, and was promoted for development as a drug candidate for the treatment of pollakiuria and urinary incontinence.5-7) As a continuation of this research, a large quantity of 1 was required to support the preclinical and clinical development work. Furthermore, the reduced production cost of 1 was a requested requirement in the early stage. The first synthesis of 1 by the Discovery Chemistry group is shown in Chart 1.Condensation of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (2) 8) with 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3), 9) via acid chloride produced a condensation product (4), which was subjected to nucleophilic intramolecular cyclization to afford pyrimido[4,5-b][1,5]oxazocine (5). Suzuki coupling reaction of 5 with otolylboronic acid provided the coupled product (6), which was subjected to oxidation to afford a sulfone (7). Finally, nucleophilic displacement of 7 with 1-acetylpiperazine provided KRP-103 (1).5-7) However, this method was impractical for the preparation of large quantities of material for preclinical development, because it required multiple chromatographic purifications and was not cost competitive. The formation of compound (6) by way of Suzuki coupling process of 5 with o-tolylboronic acid might be substituted for Knoevenagel condensation reaction between o-tolualdehyde and malonate followed by construction of 4-aryl-6-oxo-1,6-dihydropyrimidine skeleton. Herein, we describe a new practical process for the synthesis of 1, which requires no chromatographic purification and is cost-effective to large-scale production of KRP-103 (1). obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Process Development and Large-Scale Synthesis of NK1 Antagonist

Araya

Kanazawa

Akita

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The intramolecular capture of an isocyanate intermediate generated from the corresponding carboxylic acid has been reported for both cinnamic 41 and dihydrocinnamic acid derivatives. 28,[42][43][44][45][46][47] The conditions previously described for substrates possessing a tethered indole group were extended to those with a pendant aromatic substituent.…”

Section: Scheme 8 Synthesis Of the Azepine Derivatives 16a And 16bmentioning

confidence: 98%

Efficient Synthesis of Tetrahydro-β-carbolin-1-one and Dihydroisoquinolin-1-one Derivatives as Versatile Intermediates

Judd¹,

Mahon²,

Caggiano³

2009

Synthesis

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“…Rf (cyclohexaneethyl acetate 9 : 1) = 0.45. Procedure B for tandem reaction (Tables 3-6, compounds [15][16][17][18][19][20][21][22][23] In a flamed dried round bottom flask was added NaOtBu (68.23 mg, 0.71 mmol, 3.0 eq. ), xantphos (6.8 mg, 0.012 mmol, 5 mol%), Pd 2 dba 3 (10.8 mg, 0.012 mmol, 5 mol%).…”

Section: General Considerationsmentioning

confidence: 99%

“…13 Since the pioneering report on isoquinolone derivatives' synthesis by Gabriel and Coleman, 14 developing innovative strategies to build up this scaffold is an ongoing effort in heterocyclic chemistry, and many different synthetic pathways have been designed. [15][16][17][18][19][20][21][22] Recently, transition-metal-based catalysis has often been utilized for the synthesis of various heterocyclic compounds, including isoquinolone. 23 Among these, intramolecular annulation of 2-alkynyl benzamide, 24 intramolecular cyclization of 2-alkynyl acyl azide, 25 and the nickel-catalyzed annulation of 2-halobenzamides with alkynes, 26 have been reported.…”

Section: Introductionmentioning

confidence: 99%

A new access to 3-substituted-1(2H)-isoquinolone by tandem palladium-catalyzed intramolecular aminocarbonylation annulation

2012

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An original tribromide derivative based, palladium-catalyzed synthesis of 3-substituted-1(2H)-isoquinolone is described based on a regioselective Suzuki-Miyaura C-C coupling on o-halo-(2,2-dihalovinyl)-benzene followed by a palladium catalyzed amination-carbonylation-cyclization reaction. This sequence efficiently proceeds to build up isoquinolone in fair to good yields over a one-pot 3-bond synthesis reaction.

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Synthesis of novel substituted isoquinolones

Cited by 29 publications

References 16 publications

Process Development and Large-Scale Synthesis of NK1 Antagonist

Process Development and Large-Scale Synthesis of NK1 Antagonist

Efficient Synthesis of Tetrahydro-β-carbolin-1-one and Dihydroisoquinolin-1-one Derivatives as Versatile Intermediates

A new access to 3-substituted-1(2H)-isoquinolone by tandem palladium-catalyzed intramolecular aminocarbonylation annulation

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