Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8

Apr 1, 2017 - Installation of the Phosphonoxymethyl Prodrug Moiety. Richard J. Fox,* .... (PXRD) data supported that, during the preage, lithium salt ...
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Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8. Installation of the Phosphonoxymethyl Prodrug Moiety Richard J. Fox,* Benjamin Cohen, Thomas E. La Cruz, James H. Simpson, Adam Freitag, Eric Saurer, Jonathan C. Tripp, Chien-Kuang Chen, Gregory L. Beutner, Victor W. Rosso, Elizabeth Borgeson, Andrew W. Glace, Martin D. Eastgate, Richard L. Schild, Jason T. Sweeney, and David A. Conlon

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Chemical & Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903-0191, United States ABSTRACT: The reaction optimization of an alkylation to enable the production of the penultimate intermediate of an HIVattachment inhibitor candidate is described. To address the challenges associated with the reactivity and stability of di-tert-butyl (chloromethyl) phosphate (2), and the poor solubility and reactivity of the starting BMS-626529-Li salt (1), strategic selection of Et4NI and 325 mesh K2CO3 as additives, and wet CH3CN as solvent were required. An aqueous workup protocol was also developed to selectively remove an undesired N-6 alkylation isomer. The final processing conditions resulted in the isolation of the penultimate compound 3 in 70% yield with high purity.



INTRODUCTION In the first paper in this series,1 we described the initial route to prepare 3, the final intermediate in the preparation of the highly potent HIV-attachment inhibitor BMS-663068,2 from di-tertbutyl (chloromethyl) phosphate (2) and the parent BMS626529 freebase (5). However, this route suffered from an extremely slow filtration of 5, low-yielding formation of 2, and challenges in suspending Cs2CO3 in the NMP reaction mixture. As a result of these challenges, we then described the development of a second-generation endgame which afforded 3 via a chloromethylation/phosphate displacement strategy.3 While this modified endgame enabled the production of >1000 kg of API, we more recently reported a proposed commercial route to BMS-663068 which led to a dramatic improvement in overall efficiency and a significant reduction in cost.4 Two of the key features in this new route were the return to the use of alkylation agent 2 as the electrophile for installation of the phosphonoxymethyl prodrug moiety,5 and modification of the parent BMS-626529 freebase starting material 5 to the corresponding BMS-626529-Li salt (1). Herein we describe the optimization of the processing conditions utilized to prepare 3 from BMS-626529-Li salt (1) (Scheme 1). Specifically, our development work focused on the strategic selection of reaction conditions to improve both the reactivity and stability of 2 and the reactivity and solubility of 1, as well as an aqueous workup protocol to selectively remove the undesired N-6 regioisomer (4).

regioselectivity was achieved with Et4NI and milled K2CO3 in CH3CN (entry 2, Table 1). Under these conditions, both the ratio of the regioisomers and the in-process solution yield remained ∼8:16 and ∼80%, respectively. These conditions were a significant improvement over the previous alkylation using freebase 5 because they eliminated both the challenge of Cs2CO3 suspension and the multiple washes necessary to remove the NMP. Furthermore, these conditions led to an increased stability of 2 (vide infra) which allowed for a reduction in the equivalents from 1.7 to 1.3. As stated in the preceding paper, due to the improved crystallinity and low solubility in most organic solvents, the corresponding lithium salt 1 was selected for isolation from the Ullmann coupling. Unfortunately, while these properties made the isolation of 1 favorable, they resulted in poor reactivity under the modified alkylation conditions (entry 3, Table 1). Increased temperature and/or addition of NMP as a cosolvent resulted in only modest reaction rate increases. However, to our delight, we found that the addition of 0.5 wt % water to the acetonitrile resulted in both reactivity and regioselectivity comparable to the initial conditions utilizing potassium salt 6 (i.e., entry 2 versus entry 7, Table 1). We found that the root cause for the observed rate enhancement was related to the solubility of 1. The solubility of 1 was measured as a function of water content in acetonitrile either by itself or in the presence of 1 equiv of Et4NI or 0.75 equiv of 325-mesh K2CO3. As shown in Figure 1, the solubility of 1 in wet CH3CN was greatly enhanced in the presence of K2CO3, compared to minor increases in solubility in the absence of K2CO3. This finding suggested that the significant increase in reactivity of 1 under the wet CH3CN/K2CO3



RESULTS AND DISCUSSION Initial Alkylation Studies. As described in the immediately preceding paper, during the development of the Ullmann coupling we tried to isolate the BMS-626529 potassium salt (6), and due to the concurrent development efforts on both the Ullman and alkylation steps, our initial alkylation studies utilized the BMS-626529-K salt (6). Starting from 6 and a crude solution of 2 in DCM,5 after an extensive screen of solvents and additives, we found the highest yield and © 2017 American Chemical Society

Special Issue: From Invention to Commercial Process Definition: The Story of the HIV Attachment Inhibitor BMS-663068 Received: April 1, 2017 Published: August 9, 2017 1166

DOI: 10.1021/acs.oprd.7b00135 Org. Process Res. Dev. 2017, 21, 1166−1173

Organic Process Research & Development

Article

Scheme 1. Preparation of 3

Table 1. Initial Alkylation Studies

entry 1 2 3 4 5 6 7

R H K Li Li Li Li Li

solvent (L/kg) NMP (10) CH3CN (10) CH3CN (10) CH3CN (10) CH3CN (10) CH3CN:NMP (10)f CH3CN (10)

temp. (°C) 30 35 35 50 65 35 35

equiv 2 a

1.7 1.3b 1.3 1.3 1.3 1.3 1.3

base (equiv)

additive (equiv)

Cs2CO3 (1.7) K2CO3 (0.75)c K2CO3 (0.75) K2CO3 (0.75) K2CO3 (0.75) K2CO3 (0.75) K2CO3 (0.75)

KI (1.2) Et4NI (1.0) Et4NI (1.0) Et4NI (1.0) Et4NI (1.0) Et4NI (1.0) Et4NI (1.0)

water (wt %)