摘要详情

ID / 提交时间

31 / 2023-08-06 08:48:17

标题

A Foray into Phosphorus Chemistry: My Experience with Carbon-Phosphorus Bond Construction in Pharmaceuticals

关键字

carbon-phosphorus bond; fosinopril sodium; Michaelis-Arbuzov reaction; tenofovir alafenamide fumarate; P-alkylation reaction; late-stage modification of bioactive molecules

主题及专题

New Technologies in Phosphorus Chemistry > 1) New reagents and methods in organophosphorus Chemistry

状态

摘要录用

作者

Qingwen Zhang / Shanghai Institute of Pharmaceutical Industry Co., Ltd.

摘要

Introduction of a phosphorus group on an sp³ hybridized carbon is a classic carbon-phosphorus bond construction paradigm, as exemplified in Michaelis-Arbuzov and Michaelis-Becker reactions.¹

My first encounter with organophosphorus chemistry is in the synthetic process development of generic fosinopril sodium, which is a unique phosphorus-containing angiotensin-converting enzyme (ACE) inhibitor for the treatment of hypertension and heart failure. When we started, a team led by Neal G. Anderson from the originator Bristol-Myers Squibb had published a state-of the-art process for the phosphinic acid intermediate 1 in the preparation of fosinopril sodium.² Intermediate 1 was accessed by a trimethylsilyl-modified Michaelis-Arbuzov reaction between phosphonous acid 2 and chloroacetic acid (3) in the presence of a 1:1 mixture of trimethylsilyl chloride (TMSCl) and hexamethyldisilazane (HMDS) in acetonitrile. The key was the iterative optimization of the addition sequence to allow for the safe control of the reaction exotherm, complicated by the reflux temperature which decreased with the consumption of HMDS. This very rugged process had been successfully scaled up to support the commercial production of fosinopril sodium API (active pharmaceutical ingredient) (Fig. 1).

Fig. 1 Synthesis of fosinopril sodium intermediate 1 via Michaelis-Arbuzov reaction

My recent encounter with organophosphorus chemistry is in the practical synthesis of tenofovir alafenamide fumarate (TAF), a new ProTide (McGuigan) prodrug of reverse transcriptase inhibitor tenofovir (PMPA). TAF is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing PMPA, inspired by a new retrosynthetic disconnection, centers on the construction of the strategic carbon-phosphorus bond (Fig. 2).³

Fig. 2 New retrosynthetic disconnection of tenofovir alafenamide (TA)

Our initial strategy was chloromethylation of the secondary hydroxyl in 5 followed by Michaelis–Arbuzov reaction of obtained 6 with silylated diphenyl phosphonate 7 (Fig. 3).³ To our surprise, chloromethylation of 5 with triformahyde and HCl gas gave mainly unreacted 5 and some deprotection product HPA. Then a sequential methylthiomethyl (MTM) ether formation and chlorination procedure was summoned to prepare 6. A systematically optimized Pummerer reaction with dimethyl sulfoxide, acetic acid and acetic anhydride delivered the desired MTM ether 8, which was subjected to sulphonyl chloride treatment in order to get the pursued chloromethylation intermediate 6. But our attempted trimethylsilyl-modified Michaelis-Arbuzov reaction between elusive 6 and silyl derivative 7 failed to give any desired product 9. Nevertheless, sodium salt of diphenyl phosphonate (10) prepared from equal molar of diphenyl phosphonate (4) and NaH was found able to trap this unstable and reactive species 6 in Michaelis-Becker fashion. From the resulting complex reaction mixture, 9 was obtained in 6% yield after careful column chromatography. Obviously, this is not suitable for any practical synthesis. In this critical moment, we wonder whether stable Pummerer product 8 itself could be activated to react with nucleophilic 7 to construct the strategic carbon-phosphorus bond. This type of reaction connecting thioacetal methylene carbon and activated tervalent phosphorus is referred to as P-alkylation herein. After screening a variety of combinations of NIS/Lewis acid and NIS/Brønsted acid, NIS/TfOH that in situ generated iodonium turned out to be the promoter of choice for this transformation. The systematical optimization of the P-alkylation was undertaken by scrutinizing the reaction solvents, material addition procedure, temperature, silylating reagents, and material molar ratio to reach an integrated protocol that returned the desired P-alkylation product 9 in 74% isolated yield.

Fig. 3 Activation of 5 for C-P bond construction to access 9

No (S)-9 was detected in obtained 9 by the chiral HPLC determination developed in-house, thus indicating that the (R) chirality of the secondary chiral carbon in 9 is preserved during the P-alkylation reaction. Based on the stereochemistry outcome, a reaction mechanism of the P-alkylation was proposed that the nucleophilic attack of the tervalent phosphorus in 7 at the thioacetal methylene carbon, promoted by superelectrophilic iodonium ion generated in situ from NIS/TfOH, to forge the carbon-phosphorus bond with a concerted leaving of methanesulfenyl iodide (CH₃SI) (Fig. 4).

Fig. 4 P-alkylation reaction and proposed mechanism thereof

Significantly, a novel methodology has been invented and systematically optimized to construct the carbon-phosphorus bond via the P-alkylation of silylated diphenyl phosphonate 7 (as acceptor) with MTM ether 8 (as donor) using NIS/TfOH combination as the promoter to give the chiral TAF intermediate 9 in good yield. Since phosphonic acids, phosphonates and phosphoramidates have found great applications in phosphorus-containing pharmaceuticals, this type of carbon-phosphorus connection reaction with defined stereochemistry could enrich chemist’s toolbox for the late-stage modification of druglike molecules and natural products to access valuable bioactive phosphonate derivatives. Extended study of this P-alkylation transformation is underway to explore the scope and elucidate the mechanism.

From a perspective point of view, my early career research experience with a TMS-modified Michaelis-Arbuzov reaction showed me its power to construct the carbon-phosphorus bond in an important cardiovascular drug at production scale. Later in my independent research, my team spent nearly eight years to land an interesting methodology to construct the carbon-phosphorus bond in a blockbuster antiviral drug chemically belonging to acyclic nucleoside phosphonates (ANPs). Now I am fascinated by amazing phosphorus chemistry.

Let's celebrate!