Exploratory Process Development of Lorlatinib - Organic Process

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Exploratory Process Development of Lorlatinib Bryan Li, Richard W Barnhart, Jacqui E Hoffman, Asaad Nematalla, Jeffrey Raggon, Paul F Richardson, Neal W Sach, and John D Weaver Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00210 • Publication Date (Web): 01 Aug 2018 Downloaded from http://pubs.acs.org on August 1, 2018

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Organic Process Research & Development

Exploratory Process Development of Lorlatinib Bryan Li,∗a Richard W. Barnhart,a Jacqui E. Hoffman,b Asaad Nematalla,a Jeffrey Raggon,a Paul Richardson,b Neal Sachb and John Weaver a a

Chemical Research and Development, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, CT 06340, USA b La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, USA ∗ To whom correspondence should be addressed: [email protected].

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Abstract: The original synthesis of lorlatinib (1) was applied and improved in the first GMP campaign. In this approach, a slow addition of the boronate ester was critical in suppressing the formation of a homocoupled impurity in the Suzuki-Miyaura coupling; and the chemoselective hydrolysis of methyl ester was accomplished with potassium trimethylsilanoate. The synthesis was completed with macrocyclic amidation followed by deprotection of the Boc groups. A thorough process safety evaluation of HATU enabled its use as the coupling reagent for the macrocylic amidation, which improved the yield and eliminated the only chromatographic operation in the synthetic sequence.

Key words: lorlatinib, HATU, macroamidation, TMSOK, chemoselective.

Introduction Crizotinib (Xalkori, Figure 1) is a leading therapy in treating non-small cell lung cancer (NSCLC) patients with expression of an abnormal anaplastic lymphoma kinase (ALK) gene. Despite its excellent efficacy and success since the launch in 2011, patients can develop resistance through the emergence of secondary point mutations in ALK/ROS1 kinase.1 Thus, new therapeutic agents with robust activities against the mutations are needed to respond to these unmet medical demands. 2 Recently, Pfizer researchers have discovered that lorlatinib 3 (1, Figure 1), a second generation ALK/ ROS1 inhibitor, has exquisite potency against ROS1 fusion kinases. It is currently being developed as a novel, orally available, and CNS-penetrant ALK/ROS1 inhibitor. 4 On Apr. 26, 2017, lorlatinib was granted breakthrough therapy designation from the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer, previously treated with one or more ALK inhibitors.5 On February 12, 2018, the FDA accepted and granted priority review to Pfizer’s New Drug Application for lorlatinib.6 Herein we describe the enabling of the original chemistry and exploratory development of the first GMP scale up route.



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NH

N N

O N Cl O Cl

N

N N

F O

NH2

H2N

F

Xalkori (crizotinib)

N

N

Lorlatinib (1)

Figure 1. Crizotinib and lorlatinib Results and Discussion We were initially tasked to prepare ~400 g of lorlatinib (1) to support pre-clinical studies. The original synthesis (Scheme 1) to prepare the initial 5 grams of the API started with a one-pot Suzuki-Miyaura coupling of bromopyridine 23 with bromopyrazole 33 to provide 4 as an intermediate. Hydrolysis of the methyl ester gave the carboxylic acid 5, subsequent deprotection of the Boc group provided the ultimate intermediate 6 as the HCl salt. The macrolactamization was effected with HATU7 to afford lorlatinib (1) in a 10% overall yield from 2. We decided to enable this route for the initial scale up to meet an aggressive delivery timeline. The objectives of the enabling were to address the following: (1) the formation, in the first step, of a significant amount (up to 30%) of homocoupled by-product (7, Figure 2) and its removal; (2) the formation, in the second step, of amide impurity 8 by competitive hydrolysis of the nitrile group during the methyl ester saponification; (3) the lack of crystalline intermediates for quality control before the API; (4) the use of HATU in the macrocyclic amidation step because our internal process safety assessment did not support its use in our scale-up facility8; and (5) the need for three silica gel chromatography purifications.


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As the strong binding affinity of palladium with the 2-aminopyridine moiety in 2 would both impact the efficiency of Suzuki-Miyaura coupling and present a challenge in removing heavy metal residue in the final API, we chose to prepare the Boc-protected 9.9 This derivatization of aniline 2 allowed the catalyst loading of PdCl2(dppf)2 to be reduced to 3 ~ 5 mol% to afford 10 as the C-C coupling product. Nevertheless, the homocoupled by-product 7a was still observed at significant levels despite strenuous efforts to exclude oxygen from the reaction system.10 We were able to suppress the formation of impurity 7a by feeding a toluene solution of 3 and 9 over 15 hours to the reaction mixture containing PdCl2(dppf)2 and CsF in toluene/water11 under reflux. This slow addition successfully controlled the formation of 7a at less than 3% (UPLC area) during the scale up. To purge 7/7a without resorting to chromatography, the crude product (10) was carried into the Boc deprotection effected with HCl (g) in iPrOAc. The ACD Lab predicted pKa values of 7 and 11 are 3.8 ± 0.1 and 6.4 ± 0.1, respectively; this pKa differential should allow the convenient purge of 7 by aqueous extraction under different pH conditions. Thus, after the completion of Boc-deprotection, the reaction mixture was pH adjusted to 4.5, which brought the desired product 11 into the aqueous phase, while impurity 7 was rejected into the organic phase (iPrOAc). The product-rich aqueous phase was pH adjusted to 9 – 10, and then submitted to extractive workup to result in complete purge of 7 from the product. The loss of product 11 from the aforementioned extractive manipulation was less than 2%. Subsequently, 11 was carried into the methyl ester hydrolysis after a solvent switch from isopropyl acetate to acetonitrile. We found that potassium trimethylsilanoate (TMSOK) gave a highly chemoselective hydrolysis12 and left the nitrile group intact. Furthermore, product 12 directly precipitated out of the reaction mixture as a crystalline potassium salt, resulting in a 66% yield in a three-step telescoped process without chromatography. The purity of isolated 12 was greater than 98% by UPLC (210 nm). For the macrocyclization reaction, we turned to the use of COMU as it had



been promoted as a safer and more efficient peptide coupling reagent than HATU.13 Thus, a DMF solution of 12 was added over the course of 14 h to the reaction mixture containing COMU in DMF/THF at 35 °C. Slow addition of the substrate solution to a large volume of solvents (50 L/kg total) was used to maintain a low concentration of 12 to minimize the competitive intermolecular coupling. After extractive work up, a silica gel pad was required to remove the COMU by-product, N,N-dimethylmorpholine-4-carboxamide. Next, the free base form of 1 was converted to its acetic acid solvate (the initial development form) in a 46% yield over the last two steps. With these process improvements, the overall yield from 9 to 1 was increased from the original 10% to 30% for the delivery of the preclinical batch (438 g) in the first scale up.

Scheme 1. Original Synthesis of Lorlatinib

a

Reagents and conditions: (a) 20 mol% cataCXium A, 10 mol % Pd(OAc)2, B2pin2, CsF, MeOH, H2O, 60°C, 3 h, 43%; (b) NaOH, MeOH, H2O, 40 °C, 3.5 h, 87%; (c) 4 M HCl in dioxane, MeOH, 40 °C, 2.5 h, 87%; (d) 1.4 equiv of HATU, 10 equiv of DIPEA, DMF, 0 °C, 30 min, slow reverse addition, 29%.

Figure 2. Impurities formed in the synthsis.


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Scheme 2 First Scale up Synthesis of Lorlatinib

a

Reagents and conditions: (a) PdCl2(dppf) 5 mol%, CsF, toluene, H2O, 88°C; toluene solution of 3 and 9 was added over 12 -16 h. (b) HCl (g), iPrOAc, RT; (c) TMSOK, MeCN, 3h, RT, 66% overall last 3 steps; (d) COMU, TEA, DMF/THF; then AcOH, EtOAC; 46% or HATU, TEA DMF/EtOAc, 30 °C; then AcOH, EtOAc 56%.

After the delivery of the non-GMP batch for toxicology studies, the first GMP campaign was immediately initiated. A pilot run with bulk TMSOK revealed a reagent quality issue leading to a significant amount of nitrile hydrolysis byproduct (8). It was suspected that this batch of reagent contained a high level of potassium hydroxide. The most effective purification was found to be stirring an acetonitrile solution of TMSOK in neutral aluminum oxide (alumina) and filtering. The resultant TMSOK solution was used directly for the reaction, which gave a clean hydrolysis of the methyl ester on the scale up. As the synthesis suffered a large yield loss in the



cyclization step, we conducted a further screening of the coupling reagents, and determined the reaction rate14 was in the order of HATU > COMU > T3P > TPTU ≅TSTU. Since a faster reaction would reduce the substrate concentration, and hence lower the competitive intermolecular coupling impurities, we revisited the possibility of using HATU in our scale-up facility. Additional process safety testing was carried out in-house, followed by testing at an external process safety testing laboratory.15,16 Table 1 provides a brief description of the tests that were performed per UN guidelines.14 The test results for solid HATU and its 20 % w/w solution in DMF are summarized in Table 2. The Koenen test on solid HATU gave a limiting diameter of 1.5 mm, which is a positive result for Koenen Test UN 1 (b), but a negative result for Koenen Test UN 2 (b). Therefore, solid HATU shows “some effect” on heating under confinement, but not a “violent effect” upon heating under confinement. Negative results were obtained for UN Gap Test UN 2 (a) and the Time / Pressure Test UN 2 (c) (i). Therefore, solid HATU has been rigorously excluded from classification as a UN Class 1 explosive. When subjected to the BAM Fallhammer Test UN 3 (a) (ii) solid HATU showed an “explosion” at 60 J and decomposition at 50 J. No impact tests were performed below 50 J. A limiting impact energy of 60 J is considered a negative test result in the UN BAM Fallhammer test because it is well above the positive test criteria of “explosion” at 2 J or less. The BAM Friction UN 3 (b) (i) tests showed solid HATU to be insensitive to friction below a limiting load of 80 N. Solid HATU also passed the Solid Flammability Test and has been excluded from classification as a flammable solid of UN Class 4, Division 4.1.17 In addition to process safety test on solid HATU and its 20 % w/w solution in DMF, thermal stability units (TSUs) of the reaction mixture at various stages and work-up process streams indicated the reaction was safe to be scaled up in our internal facility. As in the preclinical campaign, the solution of 12 in DMF was added over a course of 14 h to the reaction mixture containing HATU in DMF/EtOAc at 35 °C. After aqueous workup, the crude


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product was treated with acetic acid, and the desired API form (acetic acid solvate) crystallized directly from the reaction mixture in 99.2% purity with no single impurity greater than 0.2%. 1.55 kg of the API was delivered from this campaign in 56% overall yield for the last two steps (cyclization and final form conversion); as compared to 46% yield from the preclinical campaign. The use of HATU represented a process improvement as it allowed the elimination of the only silica gel operation in the sequence and increased the throughput from 30% to 37% (overall from 9).



Table 1: Description of Selected Tests (UN Transport of Dangerous Goods) Test Name Koenen UN 1 (b) Koenen UN 2 (b) UN Gap UN 2 (a) Time / Pressure UN 2 (c) (i) BAM Fallhammer UN 3 (a) (ii) BAM Friction UN 3 (b) (i) Flammability of Solids UN N.1

Abbreviated Test Criteria Explosion* with limiting diameter ≥ 1.0 mm Explosion* with limiting diameter ≥ 2.0 mm Tube is fragmented completely or witness plate is holed Time for pressure rise from 690 kPa to 2070 kPa is < 30 ms Explosion with limiting impact energy ≤ 2 J Explosion with lowest friction load < 80 N Time of burning is < 45 s or rate of burning is > 2.2 mm/s

Positive Result Shows some effect on heating under confinement Shows a violent effect on heating under confinement Sensitive to detonative shock Shows the ability to deflagrate rapidly Too dangerous for transport in the form in which it was tested Too dangerous for transport in the form in which it was tested Classified as a readily combustible powder of Class 4, Division 4.1

* A Koenen test trial result is evaluated as “explosion” if the tube is fragmented into three or more mainly large pieces which in some cases may be connected with each other by a narrow strip Table 2: Summary of HATU Test Results Test Name

Solid HATU Test Result

Koenen UN 1 (b) Koenen UN 2 (b) UN Gap UN 2 (a) Time / Pressure UN 2 (c) (i) BAM Fallhammer UN 3 (a) (ii) BAM Friction UN 3 (b) (i) Flammability of Solid UN N.1

Positive (+)13, 14, Note A Negative (–)13,14, Note C Negative (–)14, Note E Negative (–)14, Note F Negative (–)13, Note G Negative (–)13, Note I Negative (–)13, Note J

A= B= C= D= E= F=

DMF Solution Test Result (HATU 20 % w/w) Negative (–)13a, Note B Negative (–)13a, Note D Not tested Not tested Negative (–)13, Note H Not tested Not tested

“+” Limiting diameter = 1.5 mm, Some effect on heating under confinement “–” Limiting diameter > 2.0 mm, No effect on heating under confinement “–” Limiting diameter = 1.5 mm, No violent effect on heating under confinement “–” Limiting diameter > 2.0 mm, No violent effect on heating under confinement “–” No fragmentation of the tube no damage to the witness plate in either trial “–” Slow deflagration with a rise time of more than 30 ms (57-80 ms range) at a pressure of > 2,070 kPa in any of the five trial conducted G = “–” Not too dangerous for transport, Limiting impact energy = 60 J (Explosion, loud bang), Decomposition at 50 J (discoloration), No trials performed below 50 J H = “–” Not too dangerous for transport, Limiting impact energy > 60 J (no reaction), I = “–” Not too dangerous for transport, Limiting load > 360 N (no reaction) J = “–” Not a readily combustible powder of Class 4, Division 4.1.


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Summary The original synthetic sequence was improved to meet the preclinical demand of multi-hundred grams of lorlatinib (1). The use of bis-Boc starting material (9) and the fed-batch addition mode for the Suzuki-Miyaura coupling minimized the formation of the homocoupled impurity that was completely removed by acid-base extractive manipulations under careful pH control. TMSOK offered excellent selectivity for the hydrolysis of the methyl ester and allowed the isolation of the penultimate intermediate 12 as a crystalline salt. The macrocyclic amidation could be effected with either COMU or HATU; a comprehensive process safety testing was done on HATU and led to the conclusion that it could be handled safely in our internal production facilities. In addition, the use of HATU as the coupling reagent improved the yield and eliminated the only chromatographic operation in the sequence. Lorlatinib (1) has shown promising results in clinical studies, and the API demand started to escalate to support clinical development. Pfizer process chemistry team strives to develop more efficient and higher throughput synthesis and the results will be reported in due course.

Experimental NMR spectra were recorded with a Bruker 400 spectrometer. Chemical shifts are reported in part per million (ppm) with CDCl3 or DMSO-d6 as an internal standard. HRMS data were obtained from Thermo LTQFT Ultra FTICR running in electrospray positive mode. LCMS was recorded with an HP-1100MSD using API-ES ionization mode. Reagents and solvents were obtained from commercial sources and used without further purifications, with the exception of bulk TMSOK, which is described in the process below. UPLC analyses were carried out in AcQuity H Class using a Water Atlantis T3 column (stable-bond C18, 3 µm, 3 mm×75 mm) with acetonitrile:



0.1% TFA aqueous buffer (95/5 to 5/95) as mobile phase (1.2 mL/min) and detection at 210 nm wavelength. Potassium (R)-2-(1-((2-amino-5-(5-carbamoyl-1-methyl-3-((methylamino)methyl)-1Hpyrazol-4-yl)pyridin-3-yl)oxy)ethyl)-4-fluorobenzoate (12): To a 200L glass-lined reactor purged with nitrogen was charged pyrazole 3 (4.66 kg, 15.7 mol, 1.0 equiv), pyridine 9 (9.70 kg, 15.7 mol, 1.0 equiv), and toluene (59 kg ). The contents of the reactor were agitated at 20 °C for 1h to give a complete solution. The reactor was drained into a drum and rinsed with toluene. To the same reactor was charged cesium fluoride (7.17 kg, 3 equiv), toluene (12.7 kg), water (19.4 kg), and PdCl2(dppf)•CH2Cl2 (0.64 kg, 0.05 equiv). The reactor contents were then heated to reflux (87 – 88 °C), and the solution of 3 and 9 in toluene stored in the drum was charged at a constant rate via a diaphragm pump over 15 h maintaining the internal temperature ≥80 °C. The reactor contents were agitated at reflux for 5h. The reaction was sampled and deemed complete by UPLC analysis. The reactor contents were cooled to 25 °C, filtered through diatomaceous earth, and rinsed with EtOAc (120 kg). The filtrate was distilled under vacuum to ~190 L, and cooled to 20 °C. The layers were settled and separated. The organic phase was vacuum distilled to ~13 L and solvent-exchanged with iPrOAc until KF analysis reached ≤0.1%. To the nitrogen purged reactor was charged iPrOAc (32.4 kg). The reactor jacket was cooled to 0 °C. HCl gas was charged sub-surface while maintaining the internal temperature at ≤10° C. The solution was warmed to a jacket temperature of 20 °C and held for 20 min. The solution was sampled and determined to be 3.9 N HCl via titration. The coupled product (10) solution in iPrOAc was charged to the HCl solution over 2.5 h maintaining an internal temperature ≤25°C. The contents were agitated at 20 °C for 20 h before being deemed complete by UPLC analysis. Water (50 kg)


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was charged to the reactor through a diaphragm pump over 40 min while maintaining an internal temperature ≤25 °C. The contents were agitated for 30 min at 20 °C before charging 2 N aqueous NaOH (130 kg) while maintaining the internal temperature ≤25° C to achieve a final pH of 5. The contents were agitated for 30 min, the layers separated, and the aqueous phase extracted with EtOAc (1 x 88 kg). The organic phase was discarded as waste. The aqueous phase was treated with Na2CO3 (6.2 kg) to achieve a final pH of 10, and then extracted with EtOAc (1 x 88 kg). The resulting organic phase was concentrated to a volume of ~ 26 L, and then solvent-exchanged with MeCN (130 kg) to reach a water content of ≤0.1% by KF. The resulting solution was polish filtered, followed by a rinse with anhydrous MeCN to give intermediate (11) (assumed 6.88 kg, 15.7 mol) as a solution in MeCN (10.5 kg) which was carried on to the next step. To an empty reactor was added TMSOK (technical grade, 3.3 kg, 25.4 mol), MeCN (16 kg) and aluminum oxide (6.6 kg). The contents were stirred under N2 for 3h at 20 °C and filtered. The filtrate was combined with the intermediate (11) (assumed 6.88 kg, 15.7 mol) solution in MeCN (10.5 kg) in a 200 L reactor. After stirring at 20 °C for 2 h, the reaction was complete as determined by UPLC analysis. The reactor contents were filtered, and the cake was washed with heptane (13 kg). The wet cake was dried (50 °C, 60 mmHg) to afford 4.80 kg of 12 (66% overall yield). 1H NMR (400MHz, DMSO-d6) δ 7.61 (t, 1H, J = 8.0 Hz), 7.55 (s, 1H), 7.38 (s, 1H), 7.12 (d, 1H, J = 8.0Hz), 6.86 (dt, 1H, J = 8.0 and 1.2 Hz), 6.76 (dd, 1H, J = 6.6 and 1.2 Hz), 6.05 (s, 2H), 4.02 (q, 1H, J = 7.6 Hz), 3.92 (s, 3H), 2.06 (s, 3H), 1.51 (d, 3H, J = 7.6 Hz).

13

C NMR (100MHz, DMSO-d6) 169.3, 150.9, 148.3, 143.7, 143.6, 139.4, 137.5, 131.5,

131.4, 125.5, 117.6, 113.9, 112.8, 112.6, 112.1, 110.0, 81.8, 46.2, 39.5, 38.2, 35.5, 25.0, 24.0. LCMS (M+1)+ 429.97, 258.53, 148.81.



Lorlatinib; 7-Amino-12-fluoro-10,15,16,17-tetrahydro-2,10(R),16-trimethyl-15-oxo-2H-4,8Methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile acetic acid solvate (1): To Reactor A was charged 12 (3.41 kg, 7.38 mol) and DMF (20 L). The material was stirred into a solution. To the mixture was introduced 3 N HCl (g) solution in CPME (3.98 L, 11.9 mol) After stirring for 5 min, Diisopropylethylamine (3.86 kg, 29.8 mol) was then added. This resulting solution was held for further use. To Reactor B was charged HATU (5.67 kg, 14.92 mol) and DMF (2.3 L), giving a clear solution. EtOAc (46 L) was added, and the resulting slurry was warmed to 40 °C. The starting material solution from Reactor A was fed to Reactor B slowly using a diaphragm pump over 16 h. After the addition, the reaction was sampled and showed to be complete by UPLC. 1 N aq. Na2CO3 solution (20 L) was added. The layers were separated, and the aq. phase was back extracted with EtOAc (46 L). The organic phases were combined, washed with 1 N Na2CO3 solution (16 L x 2), and then brine solution (16 L x 2). The EtOAc phase was concentrated (45 °C, 100 mmHg) to 35 L, polish filtered, and concentrated again to a final volume of ~ 15 L. AcOH (0.9 kg, 14.9 mol) was added. After stirring for 3 h at 20 °C, the resulting slurry was filtered. The filter cake was rinsed with EtOAc (4 L) then n-heptane (4 L).The filter cake was dried under vacuum oven at 45 °C to give 1.93 kg (4.13 mol, 56%) of the desired product, 1. All spectroscopic data were consistent to those previously reported.3

Acknowledgements The authors thank Drs. Stéphane Caron and J. Chris McWilliams for their suggestions during preparation of the manuscript.


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References and Notes 1. Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors.

Davare, M. A.; Vellore, N. A.; Wagner, J. B.; Eide, C. A.; Goodman, J. R.; Drilon, A.; Deininger, M. W.; O’Hare, T.; Druker, B. J. Proc. Natl. Acad. Sci. 2015, 112, E5381-5390. 2. Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non–Small Cell Lung Cancer. Sang, J.; Acquaviva, J.; Friedland, J.C.; Smith, D. L.; Sequeira, M.; Zhang, C.; Jiang, Q.; Xue, L.; Lovly, C. M.; Jimenez, J-P.; Shaw, A. T.; Doebele. R. C.; He, S.; Bates. R.C.; Camidge. D. R.; Morris, S. W.; El-Hariry, I.; Proia, D.A. Cancer Disc. 2013, 3, 430-443. 3. Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations. Johnson, T.W.; Richardson, P.F.; Bailey, S.; Brooun, A.; Burke, B.J.; Collins, M.R.; Cui, J.J.; Deal, J.G.; Deng, Y.L.; Dinh, D.; Engstrom, L.D.; He, M,; Hoffman, J.; Huang, Q.; Kania, R.S.; Kath, J.C.; Lam, H.; Lam, J.L.; Le, P.T.; Lingardo, L.; Liu, W.; McTigue, M.; Palmer, C.L.; Sach, N.W.; Smeal,T.; Smith,G.L.; Stewart, A.E.; Timofeevski, S.; Zhu, H.; Zhu, J.; Zou, H.Y.; Edwards, M.P. J. Med. Chem. 2014, 57(11), 4720-4744. 4. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations Zou, H. Y.; Lia, Q.; Engstrom, L.D.; Westa,



M.; Appleman, V.; Katy A. Wong, K.A.; McTigue, M.; Deng, Y-L.; Liu, W.; Brooun, A.; Timofeevski, S.; McDonnell, S.R.P.; Jiang, P.; Falk, M.D.; Lappin, P. B.; Affolter, T.; Nichols, T.; Hu, W.; Lam, J.; Johnson, T. W.; Smeal,T.; Charest, A.; Fantin, V. R. Proc. Natl Acad. Sci. 2015, 112, 3493-3498. 5. http://finance.yahoo.com/news/pfizer-next-generation-alk-ros1-120000233.html accessed on January 22, 2018. 6. https://www.drugs.com/nda/lorlatinib_180212.html, accessed on April 30, 2018. 7. Evaluation of combined use of Oxyma and HATU in aggregating peptide sequences. Caporale, A.; Doti, N.; Sandomenico, A.; Ruvo, M. J. Peptide Sci. 2017, 23, 272-281. 8. Development of a Practical Large-Scale Synthesis of Denagliptin Tosylate. Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T; Boehler, E.; Irdam, E.; Osterhout, M. H. Org. Process Res. Dev. 2009, 13, 900-906. 9. Our initial intention was to make the mono-Boc, but the reaction always gave a mixture of mono- and bis-Boc compounds, so it was deemed more feasible to make the bis-Boc intermediate. 10. Development of an Impurity Control Strategy Supporting Synthesis of LY451395. Miller, W. D.; Fray, A.H.; Quatroche, J. T.; Sturgill, C.D. Org. Process Res. Dev. 2007, 11, 359-364. 11. The reaction system was evacuated and refilled with N2 three times to exclude oxygen before the addition of 9. 12. (a) Total Synthesis of Bafilomycin V1: A Methanolysis Product of the Macrolide Bafilomycin C2. Marshall, J. A. Adams, N. D. J. Org. Chem. 2002, 67, 733-740. (b) Scope and Limitations of Sodium and Potassium Trimethylsilanolate as Reagents for Conversion of


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Esters to Carboxylic Acids. Lovrić, M.; Cepanec, I.; Litvić, M.; Bartolinčić, A.; Vinković, V. Croat. Chem. Acta. 2007, 80, 109-115. 13. COMU: A Safer and More Effective Replacement for Benzotriazole‐Based Uronium Coupling Reagents. El-Faham, A.; Subirós-Funosas, R.; Prohens, R.; Albericio, F. Chem. Eur. J. 2009, 15, 9404-9416. 14. The reaction rate was determined by quenching the reaction mixture with a large excess of pyrrolidine and comparing the ratio of the desired coupled product and the corresponding amide formed with pyrrolidine. 15. Chilworth Technology Limited (DEKRA Process Safety), Beta House Southampton Science Park, Southampton SO16 7NS, UK. 16. Safety Consulting Engineers, Inc. (DEKRA Process Safety), 2131 Hammond Drive, Schaumburg, Illinois, 60173. 17. UN Recommendations on the Transport of Dangerous Goods, Manual of Tests and Criteria.


Exploratory Process Development of Lorlatinib - Organic Process

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