Quantitation of a Ketone Enolization and a Vinyl Sulfonate

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Quantitation of a Ketone Enolization and a Vinyl Sulfonate Stereoisomer Formation using In-line IR Spectroscopy and Modeling Kallakuri Suparna Rao, Frédéric St-Jean, and Archana Kumar Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00042 • Publication Date (Web): 22 Apr 2019 Downloaded from http://pubs.acs.org on April 22, 2019

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Organic Process Research & Development

Quantitation of a Ketone Enolization and a Vinyl Sulfonate Stereoisomer Formation using In-line IR Spectroscopy and Modeling Kallakuri Suparna Rao,† Frédéric St-Jean,‡ and Archana Kumar*† †

Department of Small Molecule Analytical Chemistry, ‡Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA

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ABSTRACT This study uses infrared (IR) spectroscopy to achieve process understanding during the synthesis of a tetrasubstituted acyclic olefin via ketone enolization and tosylation. ReactIR, an inline Fourier transform IR immersion probe, was used to monitor ketone enolate formation and tosylation in a two-step, one-pot reaction. A quantitative univariate model was constructed from the ketone carbonyl IR peak height of the starting material. This model was used to determine the rate of consumption of the starting material and to establish endpoints for various reaction conditions. For the second step of the reaction, the vinyl sulfonate formation, the entire IR spectrum was analyzed and offline HPLC data were collected to measure the ratio of E vs. Z tetrasubstituted vinyl tosylate products. Principal component analysis (PCA) and partial least squares (PLS) regression were employed to build a multivariate model that was then used to quantify and predict the relative amount of E and Z stereoisomers in situ. Sensitivity and applicability of the models were then validated using reaction data acquired across a variety of experimental conditions.

KEYWORDS PAT, inline FT-IR, ReactIR, chemometrics, multivariate modeling

INTRODUCTION Process analytical technology (PAT),1 also known as in situ analytics, is gaining increased utilization in the pharmaceutical industry, particularly in areas of continuous manufacturing and in applications where real-time analysis is required.2 Collecting real-time measurements using immersion probes help us enhance our understanding of chemical reactions and crystallizations. It also eliminates the need to physically interfere with reactions via sampling/quenching and analysis


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using time-consuming offline methods such as HPLC chromatography. This is particularly beneficial for reactions that are water and/or oxygen-sensitive, form transient intermediates, or are difficult to sample safely and accurately if they are heterogeneous, pressurized, or performed at elevated temperatures.3 Vibrational spectroscopic techniques, such as infrared and Raman, are commonly used in PAT applications, and can provide both qualitative and quantitative information. We sought to use infrared spectroscopy to investigate the formation of a key vinyl sulfonate intermediate during the synthesis of GDC-0810,4 an active pharmaceutical ingredient (API) that features an acyclic tetrasubstituted all-carbon olefin5 (Scheme 1). In this reaction, the stereoselectivity of a two-step reaction converting ketone 1 to tetrasubstituted vinyl tosylate 3-E was critical to avoid the formation and carry-over of 3-Z, which can react in downstream chemistry to form the undesired stereoisomer of the API. This case study describes the use of ReactIR (an in-line Fourier transform IR immersion probe) along with univariate and multivariate modeling to enable: 1) real-time monitoring of ketone 1 consumption and metal enolates 2-Z, 2-E formation; 2) quantitation of the conversion of 1; and 3) in situ quantitation of the minor stereoisomer 3-Z using different reaction conditions (Scheme 1). Scheme 1. Enolate Formation and Tosylation Reactions to Generate Intermediates 3-Z and 3-E En Route to GDC-0810


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RESULTS AND DISCUSSION Prior to the incorporation of in-line measurements, the reaction from ketone 1 to vinyl tosylates 3-Z and 3-E using metal alkoxides was studied by means of sampling and offline HPLC analysis only (Scheme 1). This approach was met with one major challenge: accurate sampling to measure the conversion of 1 to reactive metal enolates 2-E and 2-Z was poorly reproducible (Scheme 1, Step 1). This is due to the moisture and oxygen sensitive nature of the metal alkoxide intermediates. Although an empirical investigation of reaction conditions eventually provided higher yields and selectivity for the desired product 3-E, a more suitable and accurate means of reaction monitoring was necessary to enhance reaction understanding, especially the E versus Z selectivity during product formation. Changes to the reaction temperature, stoichiometry and nature of the base all had an impact on the reaction conversion, rate and ratio of stereoisomers (Table 1). To better understand the rate of formation of the lithium enolate intermediate 2 to the vinyl tosylate product 3, the electrophile was added stepwise, and infrared signals associated with the intermediate and product were monitored (Figure 1).6 Two quantitative models were then developed to measure reaction rate in Step 1 enolate formation (via a univariate model) and accurately track formation of the 3-Z isomer in Step 2 vinyl tosylate formation (via a multivariate model). Table 1. Base Effect on Conversion and E/Z Selectivity for Product 3


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Entrya

Reaction

Base

conv.b

3 (E and Z) (A%)b

3-Z Isomer (A%)b

1 2c

A B

LiOtBu LiOtBu

89 91

89 91

7.5 5.9

3d 4e

C D

LiOtBud LiOtBu

73 81

73 81

6.3 10.5

5

E

KOtBu

94

94

15.3

6 7

F G

NaHMDS LiOtBu

94 88

94 88

33.6 7.0

8

H

KOtBu

90

90

16.1

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a

See materials and methods section for detailed experimental procedure. Unless otherwise noted, all reactions were performed on 7.5 mmol scale at 25 °C with 140 mol% of base and quenched with 140 mol % of Ts2O. b Based on HPLC A% at 220 nm, where 1, 3-Z and 3-E have a very similar response factor (

Quantitation of a Ketone Enolization and a Vinyl Sulfonate

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