The Art of Process Chemistry

Nobuyoshi Yasuda

• Publisher: Wiley-VCH
• Year: 2010
• Print ISBN:
  9783527324705
• eBook ISBN:
  9783527633586
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Industrial & Technical Chemistry

Providing must-have knowledge for the pharmaceutical industry and process chemists in industry, this ready reference offers solutions for saving time and money and supplying -- in a sustainable way -- valuable products. Application-oriented and well structured, each chapter presents successful strategies for the latest modern drugs, showing how to provide very fast bulk quantities of drug candidates. Throughout, the text illustrates how all the key factors are interwoven and dependent on one another in creating optimized methods for optimal products.

1

Efavirenz^®, a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate

Nobuyoshi Yasuda and Lushi Tan

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz^® (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz^® was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.¹⁾ The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla^® (Figure 1.1).

Figure 1.1 NNRTI candidates.

Efavirenz^® (1) is the second NNRTI development candidate at Merck. Prior to the development of 1, we worked on the preparation of the first NNRTI development candidate 2 [2]. During synthetic studies on 2, we discovered and optimized an unprecedented asymmetric addition of an acetylide to a carbon–nitrogen double bond. The novel asymmetric addition method for the preparation of 2 also provided the foundation for the process development of Efavirenz^®. Therefore, in this chapter we will first discuss chemistries for the preparation of 2 in two parts; process development of large scale synthesis of 2 and new chemistries. Then, we will move into process development and its chemistries on Efavirenz^®.

1.1 First Drug Candidate 2

1.1.1 Project Development

1.1.1.1 Medicinal Route

The first NNTRI drug candidate 2 was selected for development in 1992. Compound 2 exhibits very potent antivirus activity of IC₅₀ = 12 nM (inhibition HIV-1 RT using rC-dG template/primer). The Medicinal Chemistry original preparation route is depicted in Scheme 1.1 [2].

Scheme 1.1 Medicinal original route.

Medicinal chemists at Merck prepared 2 in eight linear steps with an overall yield of 12%. Their starting material, 4-chloro-3-cyanoanline (3), was reacted with 4.2 equiv of cyclopropyl Grignard without protection of the aniline. The resulting imidate was trapped in situ with dimethoxycarbonate in THF at 55–60 °C to provide quinazolin-2(1H)-one 4 in 79% yield. The free nitrogen of 4 was protected with a p-methoxybenzyl (pMB) group in 75% yield by treatment with LiN(TMS)₂ and pMB chloride in DMF at 55–60 °C for 12 h. 1,2-Addition to the carbon-nitrogen double bond in 5 required 4 equiv of lithium 2-pyridylacetylide (6) in the presence of 4 equiv of Mg(OTf)₂. A racemic mixture of adduct 7 was obtained in 78% yield. TFA treatment of 7 provided the target molecule 8 as a racemic mixture in 73% isolated yield. Reaction of 8 with 3 equiv of camphanyl chloride 9 and DMAP provided a diastereomeric mixture of bis-camphanyl imidate 10 and its diastereomer, which was separated by silica gel column chromatography. The less polar isomer 10 had the desired stereochemistry and afforded 2 after solvolysis. The absolute stereochemistry of 2 was determined as S from the single crystal X-ray structure of the enatiomer of 10 (the more polar isomer).

1.1.1.1.1 Problems of the Original Route

Several limitations of the original method were identified at the beginning of the project as follows;

1) When we started this project, the starting material 3 was not commercially available on a large scale (currently, large amounts of 3 are available for around $1000 per kg).

2) A large excess of cyclopropyl Grignard was required.

3) Chiral separation of the racemic product required silica gel separation of bis-camphanyl derivatives.

4) Furthermore, camphanyl chloride is quite expensive ($113.5 per 5 g from Aldrich) and resolving a racemic mixture at the final step of the preparation is not an efficient method for large scale synthesis.

1.1.1.2 Process Development

Even though there are a few drawbacks, as mentioned above, we felt that the Medicinal Chemistry route was straightforward and we should be able to use the original synthetic scheme for a first delivery with modifications as follows;

1) Our starting material had to be changed due to the limited availability of 3. Our new starting material was readily available and was converted to 4, where our new route intercepted the original synthetic Scheme 1.1.

2) Protection of the nitrogen in 4 faced the classical N- versus O-alkylation selectivity issue, which was solved by selection of the solvent system. The original protecting group, pMB, was replaced with 9-anthrylmethyl (ANM), which provided the best enantioselectivity with the newly discovered asymmetric addition to the ketimine.

3) Asymmetric acetylene addition should be pursued to avoid the tedious final enantiomer separation by silica gel column after derivatization with an excess of expensive camphanyl chloride.

4) The final deprotection step must be modified to accommodate the new protective group (ANM) and an isolation method for a suitable crystalline form of 2 had to be developed.

1.1.1.2.1 Selection of the Starting Material

The starting material for the Medicinal route, 4-chloro-2-cyanoaniline (3), was difficult to obtain on a large scale. We decided to use affordable and readily available 4-chloroaniline (11), as our starting material [3] and we envisioned introduction of a ketone function by using ortho-directed Friedel–Craft acylation of a free aniline, which was reported by Sugasawa et al, in 1978 [4], as shown in Scheme 1.2. After optimization of the Sugasawa reaction based on the elucidated reaction mechanism as described later, the desired ortho-acylated aniline 13 was isolated in 82% yield from 4-chlorobutyronitrile (12) with 2 equiv of 11, 1.3 equiv of BCl₃ and 1.3 equiv of GaCl₃ at 100 °C for 20 h. The resulting chloro-ketone 13 was cyclized to the corresponding cyclopropyl ketone 14 in 95% yield by treatment with KOt-Bu. Reac­tion with 14 and 2.5 equiv of potassium cyanate in aqueous acetic acid nicely intercepted the same intermediate 4 in the original route, in 93% yield. It was important to use the corresponding HCl salt of 14, instead of a free base, as the starting material, as shown in Scheme 1.2. When the free aniline was used for the cyclization reaction, ∼10% of N-acetyl impurity 15 was generated under the same conditions.

Scheme 1.2 Selection of starting material.

1.1.1.2.2 Protection of Nitrogen in 4

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry cond...

Table of contents

• Cover
• Half title page
• Related Titles
• Title page
• Copyright page
• Preface
• List of Contributors
• 1 Efavirenz®, a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), and a Previous Structurally Related Development Candidate
• 2 CCR5 Receptor Antagonist
• 3 5α-Reductase Inhibitors – The Finasteride Story
• 4 Rizatriptan (Maxalt®): A 5-HT1D Receptor Agonist
• 5 SERM: Selective Estrogen Receptor Modulator
• 6 HIV Integrase Inhibitor: Raltegravir
• 7 Cyclopentane-Based NK1 Receptor Antagonist
• 8 Glucokinase Activator
• 9 CB1R Inverse Agonist – Taranabant
• Index