Trouble with Potassium Carbonate and Centrifuges:  Mass Transfer and Scale-Up Effects in the Manufacture of ZD9331 POM Quinacetate

Moseley, Jonathan D.; Bansal, Parrninder; Bowden, Sharon A.; Couch, A. Edward M.; Hubacek, Ivo; Weingärtner, Günter

doi:10.1021/op0501693

Cited by 10 publications

(5 citation statements)

References 11 publications

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“…To a solution of the compound 2 (100 mg, 0.32 mmol) in THF (50 mL) under a nitrogen atmosphere was added the reducing agent (5 equivalents) and the mixture was stirred at -10 o C or heated under reflux. After the completion of the reaction, the mixture was quenched with saturated aqueous NH 4 Cl and extracted with methylene chloride (3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO 4 …”

Section: Methodsmentioning

confidence: 99%

“…After the completion of the reaction, the mixture was quenched with saturated aqueous NH 4 Cl and extracted with methylene chloride (3 × 10 mL). The combined organic extracts were dried over anhydrous MgSO 4 …”

Section: Methodsmentioning

confidence: 99%

“…4 This compound was synthesized by modifying the C6 position. Recently, Ismail et al designed and synthesized the carboxy-biphenylmethyl-quinazolin-4-one derivatives, on the basis of modeling and structure-activity studies, which could block the effects of angiotensin II by inhibiting the angiotensin-converting enzyme or rennin.…”

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confidence: 99%

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Study on the Selective Reduction of 1H-Quinazoline-2,4-diones

2008

Bulletin of the Korean Chemical Society

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The 1H-quinazoline-2,4-dione derivatives have attracted interests on their various biological activities including the selective serotonin-S 2 antagonist.1 These compounds are structurally similar with quinazoline and quinazolinone derivatives and conventionally synthesized by the coupling of isocyanate with the amine group as nucleophile and by cyclization under the heating and basic conditions.2 From this main skeleton, the modified compounds had been synthesized for the desired biological activities. Of these, nonpeptide antagonists for the human gonadotropinreleasing hormone receptor were synthesized by modifying the C2 position and varying R2 derivatives.3 Other example is the thymidylate synthase inhibitor, ZD9331, developed by AstraZeneca. 4 This compound was synthesized by modifying the C6 position. Recently, Ismail et al. designed and synthesized the carboxy-biphenylmethyl-quinazolin-4-one derivatives, on the basis of modeling and structure-activity studies, which could block the effects of angiotensin II by inhibiting the angiotensin-converting enzyme or rennin. 5According to these interesting structure-activity relationship, the development of new scaffold from 1H-quinazoline-2,4-dione has been issued by our program for the new drug discovery of Ca +2 channel blocker. For this purpose, according to our modeling team's suggestion, it was necessary to reduce selectively the C4 carbonyl function in 1H-quinazoline-2,4-dione to methylene group as shown in structure 4 and 6 (Scheme 2). Such a work as this C4 modified structure was reported by Desikan et al. 6 After obtaining these compounds, we can diversify this structure by modifying R1 and R2 groups, respectively. Although the various starting materials were employed to obtain this molecular scaffold, the method of direct reduction of C4 carbonyl function using synthetically well established 1H-quinazoline-2,4-dione compound will be simple and effective. These reactions have been accomplished by many research groups 7 and more recently, target-focused selective reductions were performed using the corresponding complex compounds.8 But to our knowledge, no result was reported about the direct reduction of the compound 1 using reducing agent. Here we report the selective reduction of C4 carbonyl function among three carbonyl functions by the various reducing agents.Firstly, the compound 2, which was prepared as described before, 2 was used as a substrate for reduction studies as shown in Scheme 1. It has three functional groups including ester, amide and urea. Sometimes amide bond is cleaved by the strong reducing reagent. Thus it is important to reduce C4 carbonyl group without the cleavage of amide bond. To try to find the appropriate reducing agent, the various reducing reagents were screened as shown in Table 1 and borane and aluminium hydride derivatives showed promising activities.In THF solution, these reactions were tried at the different temperatures such as -10 o C and under the reflux conditions. Besides the above reducing agents, sodium cyanobor...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Study on the Selective Reduction of 1H-Quinazoline-2,4-diones

2008

Bulletin of the Korean Chemical Society

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“…Reactions involving gases will be dependent on the gas pressure above a liquid or solid, or the solubility of gas in liquid, in which case pressure effectively becomes a surrogate measure of concentration or stoichiometry. Reactions involving suspended solids may be sensitive to the surface area and other properties of the solid, in addition to the type and speed of agitation and vessel geometry, which along with other mixing effects more familiar to engineers often affect reactions on scale-up. And an often overlooked but very important factor is the choice and nature of the solvent. − All these parameters will play a role in the reaction, although typically for a noncatalytic reaction, often only a few might be significant (Table ).…”

Section: Introductionmentioning

confidence: 99%

Beyond the Numbers: Charting Chemical Reaction Space

Murray

Tyler

Moseley

2013

Org. Process Res. Dev.

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We present here an informed estimate of the millions of parameter settings that might be required to optimise one typical transition-metal-catalysed reaction. We describe briefly how both Design of Experiments (DoE) and Principal Component Analysis (PCA) techniques may be combined to reduce the number of potential reaction settings to a practical number of experiments without losing critical information. A key feature of this approach is the ability to relate discrete or discontinuous parameters to one another. The methodology is presented so that any reaction may be assessed in a similar way. We believe this represents for the first time an informed estimate of the number of potential permutations that are possible for these types of reactions in particular, and therefore the enormity of the task in optimising them. The powerful combination of DoE and PCA applied systematically and in an experimentally directed approach is beneficial for optimising reactions, particularly challenging transition-metal-catalysed reactions. However, this approach is beneficial to all reactions, especially when dealing with discrete parameters, such as solvents for example.

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“…ZD9331 originated from a collaboration between Zeneca, the Institute of Cancer Research (Sutton, UK), and BTG International Limited (BTG) . Details of ZD9331's pharmacological profile are cited in a previous paper 1 …”

Section: Introductionmentioning

confidence: 99%

Chemical Development of ZD9331: Synthesis of a Bromomethylquinazolinone Avoiding a Nonselective Radical Bromination

Bentley

Godfrey

Warren

2006

Org. Process Res. Dev.

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An efficient regiospecific synthesis of ZD9331 Pivaloyloxymethyl (POM) Bromide (4) has been accomplished via ZD9331 Quinacetate HCl (15) avoiding a nonselective bromination. The original route used a radical bromination on a substrate with three methyl groups, which generated a range of bromomethyl derived compounds that carried through to the final active pharmaceutical ingredient (API). A strategy, based on the Zinin reaction, was developed to synthesize the required bromomethyl compound in a regioselective manner. This approach was successfully scaled to manufacture a tonne of material.

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Trouble with Potassium Carbonate and Centrifuges: Mass Transfer and Scale-Up Effects in the Manufacture of ZD9331 POM Quinacetate

Cited by 10 publications

References 11 publications

Study on the Selective Reduction of 1H-Quinazoline-2,4-diones

Study on the Selective Reduction of 1H-Quinazoline-2,4-diones

Beyond the Numbers: Charting Chemical Reaction Space

Chemical Development of ZD9331: Synthesis of a Bromomethylquinazolinone Avoiding a Nonselective Radical Bromination

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