Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline

Abstract

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug.

Scheme 1. Overview of the BDQ (3) Synthetic Methods Previously Described in the Literature

Scheme 2. Possible Mechanism for Chirality Transfer via the Formation of Lithium Complex Intermediates

Scheme 3. Overview of the Reaction Outcome When Chiral Ethanolamines Derived from Amino Acids Were Combined with Lithium Pyrrolidide Base

Scheme 4. Chiral Lithium Amides That Promote Enantioselectivity toward BDQ (3) and Quinoline 1 Deprotonation

Scheme 5. Decrease of the Equivalent Amount of Chiral Base 11 While Increasing Lithium Pyrrolidide

Scheme 6. Reversibility of Lithiation Reaction and Equilibrium Shift toward Enolate 16 during Temperature Increase

Scheme 7. Comparison of the Reaction Outcome at Different Temperatures

Figure 1

Effect of temperature on the 1,2-addition reaction in 2-MeTHF. Reaction conditions (500 mg scale of 1): Lithiation: 1 h, quinoline 1 (1.0 equiv, 5 V), and chiral amine 11 (1.5 equiv), LiBr (2.3 equiv), n-BuLi (1.8 M, 1.3 equiv) in 5 V of solvent. 1,2-Addition: 1 h, 40 min, ketone 2 (1.2 equiv, 5 V). HPLC A% was obtained after reaction quench with 25% solution of NH₄Cl (see Supporting Information General Procedure D).

Figure 2

Effect of 2-MeTHF/THF ratios on the 1,2-addition reaction at −40 °C. Reaction conditions (500 mg scale of 1): Lithiation: 1 h, quinoline 1 (1.0 equiv, 5 V), chiral amine 13 (1.5 equiv), LiBr (2.3 equiv), n-BuLi (1.8 M, 1.3 equiv) in 5 V of solvent. 1,2-Addition: 1 h and 40 min, ketone 2 (1.2 equiv, 5 V). HPLC A% obtained after reaction quench with 25% solution of NH₄Cl (see Supporting Information General Procedure D).

Figure 3

Variation of reaction concentration in THF at −78 °C and 2-MeTHF at −40 °C. Reaction conditions (500 mg scale of 1): Formation of lithium amide base (step 1): 20 min at −20 °C to −30 °C, chiral amine 11 (1.5 equiv), LiBr (2.3 equiv), n-BuLi (1.8 M, 1.3 equiv). Lithiation (step 2): 1 h, quinoline 1 (1.0 equiv) at −40 °C or −78 °C. 1,2-Addition (step 3): 1 h 40 min, ketone 2 (1.2 equiv) at −40 °C or −78 °C. Division of solvent volumes for 15, 20, 25, and 30 V: lithium amide base diluted in 5 V, 10 V, 10 V, 10 V, quinoline 1 in 5 V, 5 V, 10 V, 10 V, and ketone 2 in 5 V, 5 V, 5 V, 10 V. HPLC A% obtained after reaction quench with 25% solution of NH₄Cl (see Supporting Information General Procedure D).

Scheme 8. Main Side Reactions Detected in the Developed Asymmetric Methodology for the BA Reaction

Figure 4

Variation of the THF water content percentage and its effect on the reaction outcome. Reaction conditions (1.0 g scale of 1, THF, – 78 °C): Formation of lithium amide base (step 1): 20 min at −20 to −30 °C, chiral amine 11 (1.5 equiv), LiBr (2.3 equiv), n-BuLi (1.8 M, 1.3 equiv) in 5 V of solvent. Lithiation (step 2): 1 h, quinoline 1 (1.0 equiv) in 5 V. 1,2-Addition (step 3): 1 h 40 min, ketone 2 (1.2 equiv) in 5 V. HPLC A% obtained after reaction quench with 25% solution of NH₄Cl (see Supporting Information General Procedure D).

Scheme 9. Use of Chiral Lithium Amide of 11 to Promote Enhanced Stereoselectivity toward BDQ (3)