Development of an Efficient, Safe, and Environmentally Friendly

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Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084 Andreas Stumpf, Andrew McClory, Herbert Yajima, Nathaniel Segraves, Remy Angelaud, and Francis Gosselin Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00011 • Publication Date (Web): 11 Mar 2016 Downloaded from http://pubs.acs.org on March 12, 2016

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Organic Process Research & Development

Table of Contents Graphic

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KEYWORDS. Phase Transfer Catalysis. Annulation. Safety Calorimetry. Pd-Catalyzed SuzukiMiyaura Cross-Coupling. PMI Reduction. Purine.

ABSTRACT. An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals.


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GDC-0084 (Figure 1)1, a potent and selective dual inhibitor of PI3K / mTOR with the ability to penetrate the blood-brain barrier, has been discovered in our laboratories for the treatment of various brain cancers.2 As part of the development program for this drug candidate, we required multikilogram amounts of API to support human clinical studies. Figure 1. Structure of GDC-0084 and ORTEP Representation O N N O

N

N N

N N

NH 2 !

GDC-0084

The discovery chemistry synthesis of GDC-0084 served as the starting point for the endeavor (Scheme 1). The route began with a selective THP protection of 2,6-dichloro-9H-purine 1, followed by a regioselective substitution with morpholine to give purine 3. Subsequent deprotonation with n-butyllithium3 and trapping with acetone furnished tertiary alcohol 4, which underwent an acid-mediated cleavage of the THP group to afford aminoalcohol 5. Alkylation with 2-bromoethyl acetate, followed by ester hydrolysis, then provided diol 6, which was subjected to a SN1 ring closure to furnish cyclic ether 7. Finally, a microwave-promoted Suzuki cross-coupling with pinacolboronate 8 produced GDC-0084.


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Scheme 1. Discovery Chemistry Synthesis of GDC-0084

At the outset we recognized that this route could be shortened by 2 steps if a direct annulation between aminoalcohol 5 and a suitable vicinal electrophile could be achieved to forge fused morpholine 7. Such a strategic change would also potentially lower the amount of an unproductive elimination side product formed in the SN1 cyclization (9, vide infra). Additionally, the use of chromatography at several steps, the presence of residual heavy metals in the API, and the need for a robust API crystallization process all needed to be addressed in the development of a scalable, phase-appropriate route to GDC-0084.


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First Generation Synthesis In order to accelerate the development timelines, compounds 5 and 84 were selected as starting materials and outsourced in advance of the first API batch. Compound 5 was manufactured on 30 kg scale in an overall yield of 91% and a purity of 99.5A% by HPLC. Each step of the proposed synthesis was then optimized in order to improve the yields and enable efficient access to GDC0084 with high purity. Stage 1: Annulation of Aminoalcohol 5 to Form Fused Morpholine 7 Our first objective was to establish a direct formation of fused morpholine 7 from aminoalcohol 5. Indeed, an initial screen of vicinal electrophiles5 identified 1,2-dibromoethane as a competent partner for annulation with 5 to construct alkylation product 7. The effect of solvent6 and base7 at 90 ºC8 were then examined in an effort to improve the conversion and minimize the formation of elimination product 9 (Table 1). Conversion was found to be highest in CH3CN and DMF (entries 1, 2, 5, and 6), with the latter solvent performing slightly better. Cesium carbonate (entry 1) and potassium carbonate (entry 5) were found to function similarly in terms of conversion, while the latter afforded a slightly lower amount of elimination side product 9. The reaction was observed to be exothermic, thus dose-control measures were investigated in order to mitigate the safety risk. Slow addition of 1,2-dibromoethane to a mixture of 5 and K2CO3 (entry 9) did not adversely affect the conversion but did lead to the formation of a new impurity, dimer 11, in 4A% (Figure 2). On the other hand, portion-wise addition of substrate 5 to a mixture of 1,2-dibromoethane and K2CO3 (entry 10) suppressed the formation of 11 to

Development of an Efficient, Safe, and Environmentally Friendly

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