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Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440 Shawn Allwein, Dale R Mowrey, Daniel Petrillo, James Reif, VIKRAM C PUROHIT, Karen Milkiewicz, Roger Bakale, Michael Christie, Mark Olsen, Christopher Neville, and Gregory Gilmartin Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017 Downloaded from http://pubs.acs.org on April 25, 2017

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Organic Process Research & Development

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440 Shawn P. Allwein †*, Dale R. Mowrey†, Daniel E. Petrillo†, James J. Reif†, Vikram C. Purohit†, Karen L. Milkiewicz†, Roger P. Bakale†, Michael A. Christie†, Mark A. Olsen§, Christopher J. Neville§, and Gregory J. Gilmartin§ †

Chemical Process Research & Development, §Analytical Development, Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, PA 19355.

*[email protected] RECEIVED DATE

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Graphic for use in TOC

Cl

N HO

Cl N Cl 2,4,5-trichloropyrimidine N

O

N

Cl

N

O 5-methoxytetralone

O

N H

N

N H

HN O

NH

TEV-37440


O

O

O

isotoic anhydride

2

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ABSTRACT. The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK) is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND-enabling activities within CMC. The identification and development of an improved route that was performed in the pilot plant to supply early-phase clinical supplies is discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination-hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

KEYWORDS: process optimization, ring expansion, selective nitration, amination-hydrogenation, diastereomeric salt resolution, anaplastic lymphoma kinase, focal adhesion kinase

Introduction In 2012, development of a new route to our lead anaplastic lymphoma kinase (ALK) inhibitor CEP28122 (1) was disclosed.1 This route utilized some unique synthetic approaches that included a selective nitration through a para-blocking group strategy, a one-pot amination-transfer hydrogenation to effect four reductions nearly simultaneously, an enzymatic resolution, and the leveraging of an in situ generated mixed mesylate hydrochloride salt to form the final API. While this process development was occurring, efforts from Discovery identified TEV-37440 (2) as a suitable backup with many pharmaceutical advantages over the lead compound.2 The most notable of these advantages was the dual kinase selectivity for both ALK and focal adhesion kinase (FAK). Having this dual kinase effect made TEV-37440 an ideal candidate for drug development, targeting non-small-cell lung cancer (NSCLC). From a synthetic point of view, TEV-37440 contains numerous structural similarities to its ACS Paragon Plus Environment

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lead development candidate CEP-28122 (Figure 1). The core ring system is again made up of three primary fragments with an identical central B-ring. While the C-ring is different, the challenging A-ring again contains chirality around a secondary amine of a similar 6-7 fused ring system. These similarities allow for many of the same strategies identified for CEP-28122 to be applied in the route development of TEV-37440. Described herein is the phase-appropriate development of the oncology development candidate TEV-37440. Highlights of this development include the use of a novel ring-expansion reaction, a selective nitration through a para-blocking group strategy, a single-pot aminationhydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt.

A-ring

B-ring

C-ring

CEP-28122, 1

A-ring

B-ring

C-ring

TEV-37440, 2

Figure 1. ALK Inhibitor CEP-28122 and ALK/FAK Dual Inhibitor TEV-37440

Medicinal Chemistry Route The initial synthetic strategy for TEV-37440 (2) centered on the synthesis of the A- and C-ring subunits and the sequential couplings that relied on the established reactivity of 2,4,5trichloropyrimidine (Scheme 1).2 Unlike CEP-28122, the A-ring of 2 did not contain symmetry around the 7-membered ring, so a ring expansion approach was pursued. This key transformation to 5 was accomplished through the use of stoichiometric amounts of thallium.3,4

The ring expansion was

followed by a non-selective nitration, resulting in mixture of nitration products (ortho, para, and overACS Paragon Plus Environment

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nitration on both positions). This mixture required difficult chromatography, and only afforded the desired product, 6, in low yield (99.5% purity and in 10.7% overall yield.15 Scheme 8:


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15 (cat) (Ph3P)CH3I KOtBu

Triton X, Oxone

HCl;

KNO3

NaHSO3

NCS 79%

TFA 91%

75%, 2 steps 16 123 kg

4

5-methoxytetralone, 3

17 73 kg

18 72 kg

Diastereomeric Salt Resolution Pd/C, H2

L-Tartaric Acid 35%

80%

9-Tartrate Salt A-Ring

8 51 kg

25 kg

NaOH; MsOH 75%

MeNH2

HCl 94%

B-Ring iPr2NEt 86%

isotoic anhydride, 14 B,C-Ring, 12

not isolated C-Ring, 11

TEV-37440, 2 21 kg

TEV-37440-3HCl-2H2O 22 kg

31 kg

Conclusion An efficient 9-step (8 longest linear) convergent, scalable process was developed for the preparation of TEV-37440. Significant improvements in the synthesis of the two fragments, the A and B,C-rings were demonstrated. A novel ring expansion, selective nitration and a one-pot amination/hydrogenation, followed by a diastereomeric salt resolution were used to prepare the enantiopure A-ring fragment. The B,C-ring fragment was generated in high overall yield as a through-process to avoid the handling of a mutagenic intermediate.

Finally, the two fragments were brought together in a coupling reaction

followed by salt and hydrate formation to the desired final physical form. The overall yield was improved significantly. A total of 22 kg of high-purity material was produced in two campaigns for preclinical studies and early-phase clinical supplies.


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Experimental Section All materials were purchased from commercial suppliers and used as supplied unless otherwise noted. 1

H NMR spectra were obtained using a Bruker 400 MHz spectrometer in the solvents indicated. Metals

analysis was performed by ICP. HPLC data was obtained on an Agilent 1100 or 1200 series instrument using one of the following methods: Method A used a Phenomenex Luna C-18, 3 µm, 2.0 X 50 mm column, 40 °C, 1 mL/min: 0-100% of 0.1% TFA acetonitrile / 0.1% TFA water over 10 min, hold 2 min then return to starting conditions for 2 min. Method A was used for in-process testing and assay of 4, 16, 17 and 18. Method B used an Agilent Zorbax Extend C18, 1.8 µm, 4.6 x 100 mm column, 40 °C, 0.8 mL/min: 15-50-60-96% of acetonitrile / 10 mM pH 9.4 ammonium bicarbonate aqueous buffer at 0, 4, 12, and 15 min, then hold for 3 min then return to starting conditions for 5 min. Method B was used for in-process testing and assay of 8, 9, 12 and 2. 5-Methoxy-1-methylene-tetralin (4) by (Ph3P)CH3Br.9 To a 50 L glass reactor was charged 5methoxytetralone (3.20 kg, 18.2 mol, limiting reagent), methyltriphenylphosphonium bromide (6.87 kg, 19.2 mol) and THF (12 L). In a separate vessel, potassium tert-butoxide (3.36 kg, 30.0 mol) was combined with THF (16 L) and stirred to complete dissolution. The tert-butoxide solution was added to the reactor at 30 °C over 1 hour. After stirring an additional 30 min, HPLC indicated complete conversion. Using distillation, the contents were concentrated to 6 volumes under reduced pressure. To this concentrate was added Celite (320 g) followed by n-heptane (16 L). The mixture was stirred for 30 min and then filtered, washing with additional n-heptane as needed. The organics were washed with water (10 L) two times. The organic layer was then concentrated to provide 2.64 kg of crude 4 in 98.7 A% purity, representing an 83% yield. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.00 Hz, 1H), 7.11 (dd, J = 8.0, 8.0 Hz, 1H), 6.72 (d, J= 8.0 Hz, 1H), 5.45 (d, J = 0.9 Hz, 1H), 4.94 (d, J = 0.9 Hz, 1H), 3.81 (s, 3H), 2.74 (t, J = 6.4 Hz, 2 H), 2.48 (m, 2H), 1.87 (m, 2H).10 ACS Paragon Plus Environment

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5-Methoxy-1-methylene-tetralin (4) by (Ph3P)CH3I.

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To a glass-lined reactor was charged 5-

methoxytetralone (20.0 kg, 113.5 mol, limiting reagent), methyltriphenylphosphonium iodide (52.4 kg, 129.0 mol) and THF (100 L). In a separate vessel, potassium tert-butoxide (21.2 kg, 189.0 mol) was combined with THF (100 L) and stirred to complete dissolution. The tert-butoxide solution was added to the reactor at 20 °C over 3 h. After stirring an additional 30 min, a sample showed complete conversion by HPLC. Using distillation, the contents were concentrated to 6 volumes under reduced pressure. To this concentrate was added Dicalite® (4 kg) followed by n-heptane (100 L). The mixture was stirred for 30 min then filtered, washing with additional n-heptane as needed. The filtrate was then concentrated to provide crude 4 (98.5 A% purity). This material was used directly in the subsequent ring expansion. 1-Methoxy-6-methyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-ol•Sodium bisulfite salt (16). To the reactor containing crude 4 was added methyl tert-butyl ether (140 L). To the resulting solution was added 2-propanol (60 L), Triton X-405 (2.14 kg), water (140 L), and 2-iodo-5-methylbenzenesulfonic acid (15, 4.27 kg, 14 mol) as catalyst. At 22 °C, Oxone (52.4 kg) was added over 3 h. After an additional 2 h, a sample showed complete conversion. Sodium dithionite (85.7%, 11.6 kg) was added over 30 min to neutralize the excess Oxone (as confirmed by a negative peroxide paper test). Sodium hydroxide (13.6 kg) in water (75 L) was added to the batch followed by Dicalite® (4 kg). The reaction was filtered, washing as needed with methyl tert-butyl ether. The aqueous phase was removed and the organic phase was washed with brine (25% saturated, 75 L) and concentrated under vaccuum to a minimum stir volume to give crude ketone 5. To the concentrated ketone was added 2-propanol (140 L) and water (80 L). A solution of sodium bisulfite (62.2% SO2, 23.6 kg) in water (40 L) was prepared and added to the crude ketone at 20 °C over 2 h. The mixture was stirred overnight (16-24 h) then filtered, washing with 2-propanol as needed. The resulting solids were dried at 40 °C under vacuum for approximately 60 h to give 17.6 kg (corrected for purity related to residual solvent) of the bisulfite adduct 16 with 99.7 A% purity (75% overall yield). 1H NMR (400 MHz, DMSO-d6) δ 6.98 (d, J = 7.9, 7.9 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 7.4 ACS Paragon Plus Environment

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Hz, 1H), 4.28 (s, 1H), 3.77 (s, 3H), 3.26 (dd, J = 14.1, 5.8 Hz, 1H), 3.15 (ddd, J = 19.8, 14.1, 14.1 Hz, 2H), 2.21 (dd, J = 12.1, 12.1 Hz, 1H), 2.06-1.96 (m, 2H), 1.74-1.69 (m, 1H), 1.38-1.28 (m, 1H).10 4-Chloro-1-methoxy-5,7,8,9-tetrahydrobenzo[7]annulen-6-one (17). To a glass-lined reactor was charged bisulfite adduct 16 (19.2 kg, 65.3 mol, limiting reagent), acetonitrile (96 L) and water (57 L). The mixture was cooled to 15 °C before adding hydrochloric acid (35%, 124 L, 196 mol) over 30 min. After an additional 2.5 h, the reaction conversion to the ketone (5) was found to be complete. The batch was cooled to -5 °C and N-chlorosuccinimide (20.5 kg, 153.5 mol) was added in two portions to keep the reaction temperature below 0 °C. After the second addition, the reaction was stirred at 0 °C for 1.5 h before confirming reaction conversion to the chloride by HPLC. The batch was then cooled to -8 °C and a solution of NaOH (2.5 M, 143 kg) was added over 1 hour followed by the addition of methyl tert-butyl ether (123 L). The lower aqueous layer was discarded and the top organic layer was filtered. The filtrate was stirred with an aqueous solution of sodium hydrosulfite (0.5 M, 64 kg) at 15 °C for 1 h. The bottom aqueous layer was discarded and the top organic layer was filtered. The solution was partially distilled under vacuum and acetic acid (105 L) was added. Distillation was continued until there was less than 7% combined acetonitrile and methyl tert-butyl ether in the acetic acid. Water (60 L) was slowly added at room temperature to crystallize the product. This slurry was cooled to 0 °C, filtered and washed with 4:1 water/acetic acid as needed. The solids were dried under vacuum with a nitrogen sweep resulting in 11.56 kg (corrected for purity, 79% yield) of 17 with >95 A% purity. 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.91 (s, 2H), 3.82 (s, 3H), 2.96 (t, J = 6.7 Hz, 2H), 2.46 (dd, J = 7.1, 7.1 Hz, 2H), 1,99-1.92 (m, 2H).

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C NMR (100 MHz, CDCl3) δ 209.1,

155.4, 133.2, 130.1, 127.8, 125.3, 110.9, 55.9, 45.9, 41.4, 24.6, 23.4; HRMS (ESI) calcd for C12H14ClO2 [M+H]+: 225.0677, found 225.0673. 4-Chloro-1-methoxy-2-nitro-5,7,8,9-tetrahydrobenzo[7]annulen-6-one (18).

To a glass-lined

reactor was charged the chloro-ketone 17 (11.9 kg, 53.0 mol, limiting reagent) and trifluroacetic acid (30 L). The resulting solution was cooled to -10 °C before a solution containing potassium nitrate (5.47 kg, 54.1 mol) in trifloroacetic acid (30 L) was added slowly in portions keeping the reaction below -5 °C. ACS Paragon Plus Environment

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Fifteen min after this addition, reaction conversion was confirmed by HPLC.

The reaction was

quenched with a solution of sodium acetate (5.47 kg, 66.7 mol) in water (143 L), initially at 0° C and warming throughout the addition to room temperature. This quench resulted in a slurry which was aged for 30 min, filtered, and washed with water as needed. The solids were then dried under vacuum with a nitrogen sweep, resulting in 12.9 kg (corrected for purity, 91% yield) of 18 with >98 A% purity.

1

H

NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 3.99 (s, 2H), 3.91 (s, 3H), 3.08 (t, J = 6.7 Hz, 2H), 2.54 (dd, J = 7.1, 7.1 Hz, 2H), 2.10-2.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 206.1, 149.7, 143.1, 139.5, 138.6, 129.0, 125.9, 63.7, 46.0, 41.7, 24.9, 24.6; HRMS (ESI) calcd for C12H13ClNO4 [M+H]+: 270.0528, found 270.0520. 2-[4-(2-Amino-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)piperazin-1-yl]ethanol (13) by Transfer Hydrogenation. 1-(2-Hydroxylethyl)piperazine (38.6 g, 297 mmol) was charged to a 250 mL flask. Methanol (112 mL) was added and the flask was evacuated and filled with N2. Formic acid (21.8 g, 474 mmol) was added over 22 min via addition funnel. A 1 L reactor under nitrogen was charged with 18 (16.0 g, 59.3 mmol, limiting reagent), 10% Pd/C (16.0 g, 50% wet, Evonik), and methanol (118 mL). The reactor was evacuated and filled with N2 and heated to 80 °C. When the internal temperature of the slurry reached 65 °C, the solution of formate was added via addition funnel over 8 min. Methanol (32 mL) was used to rinse the flask and the addition funnel. The reaction was assayed every hour and was found to be complete (99.6 A% purity. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.74 (dd, J = 8.7, 4.1 Hz, 1H), 8.6 (d, J = 8.4 Hz, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (d, J = 8.1, 1H), 7.37 (ddd, J = 7.8, 7.8, 1.1, 1H), 7.10 (ddd, J = 7.6, 7.6, 1.0, 1H), 6.91 (d, J = 8.2 Hz, 1H), 4.35 (s, 1H), 3.59 (s, 3H), 3.49 (dd, J = 6.1, 6.1 Hz, 2H), 3.36 (br. s, 3H), 3.13-3.08 (m, 1H), 2.86-2.80 (part. ob. m, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.67-2.61 (m, 2H), 2.54-2.33 (m, 5H), 2.29-2.23 (m, 1H), 2.05-1.93 (m, 2H), 1.81-1.72 (m, 1H), 1.27-1.16 (m, 1H), 1.04 (d, J = 6.1 Hz, 2H); 13

C NMR (100 MHz, DMSO-d6) δ 168.9, 158.4, 155.0, 154.6, 148.7, 139.3, 137.1, 135.5, 131.3, 130.2,

127.8, 124.4, 121.7, 121.2, 121.0, 120.5, 104.9, 63.0, 62.0, 60.9, 60.4, 58.5, 53.7, 47.6, 38.1, 33.8, 26.3, 25.4; HRMS (ESI) calcd for C30H39ClN7O3 [M+H]+: 580.2797, found 580.2813. 2-[(5-Chloropyrimidin-4-yl)amino]-N-methyl-benzamide;2-[4-[(6S)-1-methoxy-2-(methylamino)6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl]piperazin-1-yl]ethanol

trihydrochloride

dihydrate

salt (2, salt). To a glass-lined reactor was charged free base TEV-37440 (2, 4.7 kg, 8.1 mol, limiting reagent) and n-butanol (87 kg). The resulting slurry was heated to 80 °C, giving a solution. A solution of hydrochloric acid (18%, 4.9 kg), ethanol (reagent, 2.8 kg) and methanol (2.5 kg) was prepared and added to the batch at 80 °C over 30 min, which resulted in crystallization of the salt. After holding the batch at 80 °C for 30 min, the mixture was cooled to 20 °C over 2 h, filtered, and washed with ethanol as needed. The product was dried in a filter-dryer under vacuum (60 °C) until the residual solvents were removed. Humidified nitrogen (40-60% RH) was then passed through the batch until the dihydrate formation was complete, resulting in 2.5 kg (94% yield) of TEV-37440 trihydrochloride-dihydrate (23HCl•2H2O) with >99.6 A% purity and >99.5% ee. HPLC was used to determine ee with the following method: Chiralpak IC, 5 µm, 250 X 4.6 mm column, 25 °C, 1 mL/min, isocratic with 48% Hexane / ACS Paragon Plus Environment

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48% Dichloromethane / 2% Ethanol / 2% Methanol / 0.1% Diethylamine, 20 min. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 12.20-11.60 (br. s, 1H), 9.96 (s, 1H), 9.04 (d, J = 4.5 Hz, 1H), 8.53 (s, 1H), 8.39 (d, J = 3.3 Hz, 1H), 7.88 (dd, J = 7.9, 1.1 Hz, 1H), 7.59 (d, J = 8.1, 1H), 7.47 (t, J = 8.1, 1H), 7.29 (ddd, J = 7.6, 7.6, 0.7 Hz, 1H) 7.05 (d, J = 7.6 Hz, 1H), 5.80-4.80 (br. s, 2H), 3.98-3.61 (m, 11H), 3.66 (part. ob. s, 3H), 3.42-3.14 (m, 7H), 2.81 (d, J = 4.5, 3H), 2.36-2.28 (m, 1H), 2.20-2.12 (m, 1H), 2.041.92 (m, 1H), 1.40-1.28 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 168.4, 156.3, 152.8, 149.5, 144.2, 137.3, 136.2, 135.2, 131.4, 128.8, 128.2, 125.1, 124.3, 122.4, 122.2, 122.0, 105.5, 63.8, 61.8, 58.0, 55.3, 48.7, 43.1, 35.7, 29.4, 26.3, 24.7; HRMS (ESI) calcd for C30H39ClN7O3 [M+H]+: 580.2797, found 580.2776. Heavy metals < 20 ppm. Palladium

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