The Medicinal Chemistry and Commercial Manufacturing Behind the

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Chapter 7

The Medicinal Chemistry and Commercial Manufacturing Behind the Discovery and Development of the Hedgehog Inhibitor Vismodegib Remy Angelaud,*,1 Daniel P. Sutherlin,*,2 Mark Reynolds,1 Scott Savage,1 and Andreas Stumpf1 1Small

Molecule Process Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California 94080, United States 2Discovery Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California 94080, United States *E-mail: [email protected].

Vismodegib is the first inhibitor of the hedgehog pathway to be approved for the treatment of metastatic or locally advanced BCC (basal cell carcinoma) and represents an important treatment option for patients where surgery is not recommended. The medicinal chemistry behind the discovery of this compound at Genentech is summarized, paying particular attention to key structural changes that were critical to the improvement of drug-like properties of the scaffold. Additionally, following the description of the synthesis that was used in the discovery phase of the program, we detail the synthetic route optimization and the implementation of the control strategy leading to the commercial manufacturing process of vismodegib.

© 2016 American Chemical Society Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


The Discovery of GDC-0449 The Hedgehog (Hh) pathway was originally identified as being critical in embryonic development. First discovered in the fruit fly, mutations in the Hh gene were found to disrupt normal segmentation during the development of the larvae (1). These findings were later extended to vertebrate embryogenesis as well where mutations in pathway genes led to defects in tissue patterning and differentiation (2). Examples of defects from germ line pathway mutations, while rare, include cyclopia, polydactyly (extra fingers or toes), and Gorlin’s syndrome (characterized by the formation of spontaneous basal-cell carcinomas in affected individuals) (3). The latter example connected the Hh pathway to oncology, an observation that was extended to sporatic basal cell carcinomas (4, 5). Additionaly, ~30% of pediatric meduloblastomas were found to harbor Hh pathway mutations (6, 7). This strong association of pathway activation to tumor growth, along with the knowledge that this pathway was much less active in the adult, made inhibition of the Hh pathway an attractive target for the generation of cancer therapeutics. Functionally, the extracellular Hh protein contributes to cell signaling by first binding to the transmembrane protein patched (PTCH), which functions to repress an additional membrane bound protein smoothened (SMO) (8, 9). Once Hh binds to PTCH, SMO is free to transmit a signal to the nucleus, ultimately through nuclear translocation of the GLI transcription factors. GLIs in turn transcribes a number of Hh pathway target genes, including GLI1 and PTCH1, that contribute to positive and negative feedback regulation of the Hh signal. Genentech’s initiation of a small molecule program targeting the Hh pathway began as a collaboration with Curis Pharmaceuticals, who had identified small molecule inhibitors of Hh signaling using a high throughput screen. The assay designed by Curis was performed in mouse S12 cells transfected with a Gli-luciferase reporter construct, which could be activated following addition of recombinant sonic hedgehog (SHH). Hit compounds were developed into several lead classes, one of which was exemplified by 1 (Table 1). While this compound was potent and efficacious in an allograft efficacy model, it was also unstable in dog microsomes and in pharmacokinetic (PK) studies, was moderately stable in human microsomes, and was poorly soluble at pH 6.5. Taken together, these pharmacokinetic and chemical property data suggested that there would be significant risk of high clearance in humans and solubility limited oral exposure, potentially limiting the ability to achieve maximal efficacy. Thus, improving the metabolic stability and solubility of 1 (Table 1) while maintaining the in vitro potency measured in the modified mouse S12 cell line became the primary goal of the medicinal chemistry program. Structure activity relationships (SAR) on the left hand portion of the molecule (benzimidazole in the case of 1), revealed that the hydrogen bond accepting nitrogen was important for potency while the hydrogen bonding donating NH of the heterocycle was not (10). This is illustrated by a 40-fold loss in potency when going from 1 to 2, an indole that only shares the NH of the heterocycle compared to the benzimidazole, and when comparing 1 with 3, where the NH of the benzimidazole has been methylated where the activity is roughly equivalent. This observation was further supported by analogs wherein the benzimidazole 216 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

was replaced with a smaller pyridyl ring. Only the 2-pyridyl analog 6 is potent when compared to the other two regioisomers 4 and 5, again illustrating the importance of the position of the nitrogen in the ring. Despite the three-fold drop in potency for 6 relative to 1, this compound demonstrated a significant improvement in in vitro and in vivo properties made this new inhibitor class promising for further followup.


Table 1. Potency SAR for Benzimidazole Replacements

We then turned our attention to the amide portion of the molecule. The SAR (10) of the aryl amide of 6 was systematically explored through a series of libraries varying individual components represented in the parent aryl group. The simplified phenyl ring used in 7, was 20-fold less potent than 6 (Table 2). Comparing 7 to the pyridyl analogs 8-10 demonstrated that the heterocyclic nitrogen did not contribute significantly to the potency loss. In contrast, chloro analogs 11-13 showed that hydrophobic groups ortho to the amide bond (highlighted by 11) were beneficial only in this position. Further exploration showed that larger, and often polar groups were preferred in the para-position, as exemplified by the methyl sulfone 14, which was equipotent to 6. Compound 15 (GDC-0449) was designed by combining the methylsulfone in 14 with the ortho-chlorine from 11, resulting in a three-fold boost in potency relative to the pyridyl-biphenyl 6. 217

Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Table 2. Potency SAR for the Amide Portion of the 2-Pyridyl Biaryl Scaffold Leading to Vismodegib

The contribution that these structural changes had to the improved in vitro and in vivo properties of the molecule are outlined in Table 3. As it was previously discussed, benzimidazole 1 had moderate to poor in vitro and in vivo stability and low solubility at neutral pH that limited exposure in animals and created significant risks to clinical development. Replacement of the benzimidazole in 1 to a pyridyl to yield 6 greatly improved the PK in dogs and the predicted stability in humans. Despite these improvements, solubility at neutral pH was only marginally improved prompting our exploration of novel aryl amides resulting in 15 / GDC-0449 which in turn became Vismodegib. Importantly, Vismodegib maintained the metabolic stability exemplified by 6 and demonstrated an additional 10-fold improvement in solubility, a feature that contributed to improved oral bioavailability relative to similar analogs (data not shown). Additionally, Vismodegib was compared head to head in a PK/PD assay with 6 and methylsulfone 14 and resulting in greater pathway suppression, in part due 218


to improved exposure in vivo and was also shown to be effective in an efficacy model, substantially reversing the growth of an explanted meduloblastoma tumor that was dependent on the Hh pathway for growth. This and additional positive preclinical data contributed to the nomination of this compound for clinical development (11).


Table 3. Summary of Key Molecules in the Lead Optimization up to Vismodegib

The medicinal chemistry route to 15, and related analogs was designed to first install the left hand heterocyle on the central ring prior to amide coupling. This modular approach made for rapid and efficient exploration of SAR. Specifically for 15, synthesis began with a Sandmeyer reaction performed on aniline 16 to install an iodine that could be used as a handle for further modifications (Scheme 1) (10). 2-Pyridylzinc iodide was then used in a cross coupling reaction on 17 to forge the pyridyl biaryl core 18. Subsequent reduction of the nitro group with iron filings and acetic acid generated the amine 19. This compound was then used in a standard amide bond coupling with commercially available 2-chloro4-methylsulfonylbenzoic acid to complete the synthesis of 15. 219 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Scheme 1. Medicinal Chemistry Route to Vismodegib

Development Work Towards the Manufacture of Vismodegib The commercial manufacturing route to vismodegib (12) was based on a systematic evaluation, understanding and refining of the functional relationships that link material attributes and process parameters to the active pharmaceutical ingredient critical quality attributes (CQAs). Critical process parameters (CPPs) and critical material attributes (CMAs) were identified through prior knowledge and from the results of design of experiments (DOE). The set points of the process parameters and operating ranges were then established to ensure the process performance qualification. Finally, an appropriate control strategy was established using the process understanding. The development and optimization towards the manufacturing process focused on the following CQAs: •

•

the control of the potential residual genotoxic (mutagenic) impurities (GTIs) in the API introduced by the nitro aromatic starting material 18 and during its reduction to the corresponding aniline 19 (safety). the control of the polymorphic phase and the particle size distribution (PSD) of the API since it impacted the dissolution of the corresponding capsule drug product (efficacy).

The original Discovery synthesis of vismodegib was not suitable for large scale production because of a considerable waste generation and its poor scalability. Therefore, we proposed the development and optimization of an efficient, scaleable route suitable for the manufacturing of vismodegib as illustrated in Scheme 2, by focusing on the following four key stages: • •

in Stage 1, we carry out catalytic hydrogenation of the aromatic nitro group in compound 18. in Stage 2, we convert acid 20 to the corresponding acid chloride. 220


•


•

in Stage 3, we react compounds 19 and 21 in Schotten-Baumann acylation to form vismodegib. in Stage 4, we control the physical properties (polymorphic form, residual solvents and PSD) of vismodegib through recrystallization.

Scheme 2. Vismodegib Proposed Synthesis. From ref. (12), copyright American Chemical Society, 2016.

First we devised an alternative route to the synthesis of the starting material 18 to minimize the cost associated with the initial palladium-catalyzed Negishi coupling (13) shown in Scheme 1. Knoevenagel condensation of 2-chloro-5-nitrobenzoyl chloride with dimethyl malonate followed by decarboxylation provided 2-chloro-5-nitroacetophenone 23. Condensation (14, 15) of 23 and oxo-dihydropyrimidinium chloride 24 in the presence of ammonium acetate in acetic acid furnished the desired aromatic nitro compound 18 in 70% overall yield with >99.5 A% purity by HPLC after crystallization from acetone/water (Scheme 3).

Scheme 3. Oxo-dihydropyrimidinium Route to 18 221 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

The second starting material 2-chloro-4-(methylsulfonyl)benzoic acid (20) was commercially available and was directly purchased in >99.5 A% purity with a reproducible impurity profile. Both starting materials 18 and 20 are well characterized and their respective manufacturing processes routinely produce them in high purity with no single impurities >0.2 A% by HPLC. Now that we had a robust supply chain for both starting materials in hand, we focused our effort towards Stage 1of the manufacturing process to implement a catalytic hydrogenation of 18.


Stage 1: Hydrogenation of Nitroaromatic 18 to Aniline 19 Although selective catalytic hydrogenation of nitroaromatic compounds to the corresponding aromatic amines is a well-known process in the literature (16–19), our initial attempts evaluating the effect of catalysts such as Pd(OH)2/C, Pd/C, and Pt/C, hydrogen pressure (50-110 psig) and temperature (25-80 °C) on the reduction reaction resulted in the formation of aniline 19 with various impurity profiles. Particularly, hydroxylamine 25 and its associated by-products (20–23), 26, 27 and 28 were generated at room temperature and low pressure from incomplete reduction. On the other hand, when the hydrogenation was performed at high temperature and high pressure, over-reduction led to des-chloro amine 29 and piperidine 30 as indicated in Scheme 4. Plainly, the reaction conditions would need to be balanced.

Scheme 4. Under- and Over-Reduced Impurities Generated during Hydrogenation of 18. From ref (12), copyright American Chemical Society, 2016. This was clearly a problem since most of these impurities gave a structural alert when using predictive quantitative structure-activity relationship (QSAR) (24) methods to predict mutagenicity and therefore require an Ames25 test to assess their mutagenic potential. Hydroxylamine 25 was found to be Ames-positive and is therefore considered a genotoxic impurity (GTI) in the process. Furthermore, impurities 25, 28, 29 and 30 could potentially be acylated during the next stage of manufacturing and lead in turn to even more by-products. 222 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Based on literature precedent (25, 26), combinations of 1% Pt + 2% V/C catalyst in the presence of acid additives (HCl and AcOH) were tested in MeOH (for solubility of 18). By using a combination of 1% Pt + 2% V/C in MeOH/AcOH (9:1) at 60 °C and 88 psig (6 bar) the desired aniline 19 was obtained in ~97 A% by HPLC. More importantly, hydroxylamine amine 25, a GTI in the process, was not detected with this catalyst. However, slight variations in reaction conditions had a tremendous impact on the outcome of the hydrogenation. For example, diazene impurity 27 was produced exclusively in 95 A% when using 1 wt% of catalyst loading in pure AcOH. To better understand the criticality of the process parameters, a statistical DOE was performed (Table 4) under 6 bar of hydrogen for 3 h on 1 g of nitroaromatic 18. An extract of the DOE monitoring aniline 19, hydroxylamine 25 and des-chloro 29 as response factors is reported in Table 4.

Table 4. DOE Process Optimization to 19

223 Abdel-Magid et al.; Comprehensive Accounts of Pharmaceutical Research and Development: From Discovery to Late-Stage ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.

From these experiments it was clear that when using the %Pt + 2%V/C catalyst in MeOH/AcOH within the investigated range: • • • • •


•

Formation of hydroxylamine 25 was no longer significant. Formation of des-chloro 29 was only seen in the high catalyst loading experiments, even then it is only formed in low levels (NMT 0.35 A%). The impact of acetic acid concentration was small in the range evaluated. Increased reaction temperatures and catalyst loadings led to higher aniline 19 levels but also higher levels of the deschloro impurity, 29. Catalyst loads under 5 wt% resulted in low levels of conversion within the investigated reaction time of 3 h. The ideal temperature ranges between 40 and 60 °C.

Based on these experiments, optimal conditions were arrived at. These were then slightly modified in order to make them more conducive to manufacturing (for instance, the total volume was slightly increased to assure good dissolution, the acetic acid amount was slightly lowered to minimize the need for its neutralization later in the work up), leading to the final ranges of parameters (Table 5). On scale (20 kg), the completion of the reaction was monitored by hydrogen uptake as determined by a flow of 10 and the resulting solid was isolated by centrifugation. On commercial production, this step is routinely run on 18 kg scale of 18 and produces amine 19 in 95-98 % yield (corrected for residue on drying) with >99.9 A% purity by HPLC (residual Pt and V, 99% conversion to acid chloride 21 within the range investigated and demonstrated that the reaction proceeds to completion with as little as 1.2 molar equivalents of SOCl2 and 0.05 wt of DMF in 6 volumes (6 mL/g) of DCM. While the first generation process performed well at the proposed commercial scale (approximately 20 kg of 20), we decided to replace dichloromethane as the Stage 1 solvent with toluene for safety (due to toluene’s higher boiling point) and environmental reasons. As the reagent stoichiometry data generated in dichloromethane should apply regardless of solvent, these data were used as a starting point for further optimization of the process. The low end of the reaction temperature range in toluene was limited to 65 °C for safety reasons, ensuring that the reagents are consumed at a faster rate than they are charged, avoiding a potential adiabatic exothermic runaway reaction if a build-up were to occur. The upper end of the temperature range was limited by the boiling point of the reaction mixture (~107–109 °C) at atmospheric pressure. Thus, the reaction was routinely run at 70 °C. Additionally, a large volume of HCl and SO2 by-product gases (191 L/kg of 20) had to be removed from the production 225



vessel. Thus, the gas evolution rate must be low enough to ensure that there was no build up of pressure in the vessel, and this was achieved by controlling the addition rate. Complete dissolution signaled the end of reaction. The homogeneous solution was then partially concentrated at atmospheric pressure, which serves to remove excess thionyl chloride, HCl, and SO2 reaction gases, and then cooled to 10 °C while the compound crystallized out (solubility of 21 at isolation temperature was approximately 2%). Isolating the intermediate at higher dilution will not lead to a significant yield loss. On scale, this step was run reproducibly on 23 kg of 20 and provided acid chloride 21 in 92-95% isolated yield (28) (corrected for residue on drying) with >99.8 A% purity by HPLC. The only impurity detected at this Stage was the starting acid 20 in 15 wt% at 20 °C) and because crude vismodegib could be isolated directly from THF/water mixture through crystallization. As it was likely that the base used in Stage 3 would have an impact not only on the reaction, but also on the level of inorganic impurities in vismodegib, the type and amount of base was studied. Due to the higher solubility of potassium salts over sodium salts in water (K2CO3: 111 g/mL; Na2CO3: 21.5 g/mL at 20 °C) a study was designed to compare the use of the two bases and their stoichiometry with respect to reaction completion and inorganic impurities as measured by residue on ignition (ROI) (Table 8). 226



Table 8. Impact of Type and Stoichiometry of the Base

Use of acid chloride 21 in 1.1 molar equivalent excess ensured that all amine 19 was consumed. The solvent ratio (THF/water) was designed so amine 19 was fully soluble at the beginning of the reaction. Before addition of 21, the THF/water ratio is 60:40 and solubility of 19 is ~7.5 wt% and well in range of the solubility of ~5.3 wt% in 50:50 THF/water at 20 °C. The results from Table 8 screen clearly showed that K2CO3 was a more effective base, giving higher yields and purities. However, the type of base had no impact on the ROI. So, 0.66 molar equivalent of K2CO3 was chosen based on the resulting yield and purity. Using an excess of base also reduced yield loss from the higher solubility of the vismodegib HCl salt in the aqueous layer. To ensure good purging of the potassium salt of 20, a pH check to verify that the aqueous layer was basic (pH > 7) was implemented. For the isolation, the aqueous layer was drained after completion of the reaction and THF was removed by distillation under atmospheric pressure with concomitant addition of water. The batch was then seeded with vismodegib and the remaining THF was distilled off until a boiling point of 82 °C was reached. At this temperature point, the ratio of water/THF was 97.5:2.5 (verified by KF-titration). After cooling to 15 °C (the solubility of vismodegib was 99.9 A% HPLC purity. Table 9 summarizes the operating ranges and criticality assessment for the Stage 3 amide formation. 227


Table 9. Stage 3 Operating Ranges Comparison and Criticality Assessment. Reproduced from ref. (12). Copyright 2016 American Chemical Society.

Target

Normal Operating Range

Key for Yield or Purity

Critical Process Parameter

Acid chloride 21 (molar equivalents)

1.1

± 1%

Yes

No

THF (wt)

5.3

± 5%

No

No

Potassium Carbonate (molar equivalents)

0.66

± 5%

Yes

No

Water (wt)

4.3

± 5%

No

No

Reaction Temperature

2 °C

0–5 °C

No

No

Final Temperature

20 °C

15–30 °C

No

No


Parameter

Stage 4: Control of Vismodegib Physical Properties Stage 4 consists of three steps: • • •

crystallization delivered the API with the required polymorphic form and purity drying ensured acceptable residual solvent levels milling the API furnished the specified particle size distribution (PSD)

Two polymorphic forms of the API were identified during development: Form A and Form B. The latter is the thermodynamically more stable polymorph observed to date as shown in a differential scanning calorimetry (DSC) trace (Figure 1) containing a mixture of Form A ( m.p. = 177 °C) and Form B (m.p.= 187 °C). Form B formation in Stage 4 of the manufacturing process is controlled by seeding the crystallization with the appropriate Form B material. Importantly, however, upon seeding with a mixture of Forms A and B, a mixture of the two forms was obtained, so seeding with the correct polymorph is critical. Vismodegib is poorly soluble in most organic solvents like iso-propyl acetate, 1- or 2-propanol, toluene or acetonitrile (4 ppm by LC-MS with selective ion monitoring, giving a purging of >2500X for these 2 nitro GTIs. Therefore 22 and 23 could be specified at 1 ppm, giving a purging factor of >10,000X. This purging factor justified the specification for 25 of 76% over 4 steps) with the required critical quality attributes.

Scheme 5. Vismodegib Manufacturing Process

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32. ICH M7. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk; Step 4 version, June 23, 2014. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Multidisciplinary/M7/M7_Step_4.pdf 33. Threshold of Toxicological Concern or TTC corresponding to a theoretical 10-5 excess lifetime risk of cancer.

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The Medicinal Chemistry and Commercial Manufacturing Behind the

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