Patent Review of Manufacturing Routes to Recently Approved

Subscriber access provided by LUNDS UNIV

Review

Patent Review of Manufacturing Routes to Recently Approved Oncology Drugs: Ibrutinib, Cobimetinib, and Alectinib David Hughes Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00304 • Publication Date (Web): 10 Oct 2016 Downloaded from http://pubs.acs.org on October 10, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 55

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

Organic Process Research & Development

Patent Review of Manufacturing Routes to Recently Approved Oncology Drugs: Ibrutinib, Cobimetinib, and Alectinib

David L. Hughes Cidara Therapeutics, Inc. 6310 Nancy Ridge Dr., STE 101 San Diego, CA 92121

ABSTRACT: This article reviews the patent literature on synthetic routes and API forms of recently approved orally active tyrosine kinase inhibitors for the treatment of cancer, including Imbruvica (ibrutinib), Cotellic (cobimetinib), and Alecensa (alectinib). Although the patents for ibruitinib published in the FDA Orange Book do not start expiring until late 2026, 13 patents have been filed on alternate routes and 11 on final forms of the API by the innovators and generic firms. Regarding cobimetinib, a non-scalable route used during discovery efforts required an alternate route for development; an efficient route was developed and used throughout clinical development and commercialization. A productive second generation eight-step linear route to alectinib, with an average yield of 89% per step, was designed and developed to support development and commercialization. -------------------------------------------------------------------------------------------------------------------A synthetic route designed by a medicinal chemist has a goal of enabling rapid preparation of analogs to interrogate chemical space as broadly as possible. Conversely, with a target molecule identified, the process chemist has the objective to develop the most efficient, robust, green and cost effective route and to define a final form that is stable, capable of being prepared in high 1 ACS Paragon Plus Environment


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

Page 2 of 55

purity, and is suitable for formulation by the intended route of delivery. While a few pharmaceutical companies allow and encourage journal publications, most of the information regarding manufacturing routes and final forms for approved drugs can only be found in the patent literature. Yet, for some recently approved drugs, a search of the patent literature has uncovered no process patents. Since a company would likely wish to publish at least the elements of the manufacturing route to protect their freedom to operate (ie, prevent another company from patenting their manufacturing route), the absence of process patents may suggest the manufacturing route has the same bond disconnections as the published medicinal chemistry route. In such cases, the medicinal chemistry route has likely provided an acceptable starting point for the process chemist and the route needs only development rather than redesign. For low volume drugs where cost of goods is not a driver for commercialization, a well-developed medicinal chemistry route may be perfectly fine for a manufacturing route. On the other hand, many medicinal chemistry routes simply cannot be developed into scalable or cost effective routes. Such circumstances provide the opportunity for process chemists to showcase their ingenuity in designing and developing the best route to the target and discovering the ideal final form. The current article is part 2 of an intended series of reviews1 that focuses on recently approved drugs with innovative manufacturing routes that are distinct from the medicinal chemistry route and where the majority of information on the manufacturing route and final form is found in the patent literature.2 Since the beginning of 2013 through Aug 31, 2016, the U.S. FDA has approved 129 new chemical entities. Of these, 20 small molecules and 12 biologics have been approved for the treatment of cancer, representing 25% of the newly registered drugs in the U.S. during this 2 ACS Paragon Plus Environment

Page 3 of 55

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


period. This article reviews synthetic routes and final forms of three small molecule oncology drugs approved during this period, the orally active tyrosine kinase inhibitors3 Imbruvica (ibrutinib), Cotellic (cobimetinib), and Alecensa (alectinib).

I.

IMBRUVICA (IBRUTINIB, PCI-32765)

Ibrutinib (marketed under the trade name Imbruvica) is an orally active drug approved for the treatment of certain lymphoma and leukemia cancers. As a Michael acceptor, ibrutinib forms a covalent bond with a cysteine residue (Cys 481) in the Bruton’s tyrosine kinase (BTK) active site, leading to inhibition of BTK activity. Ibrutinib was discovered at Celera Genomics. In April, 2006, Pharmacyclics acquired the rights to the Celera BTK program and initiated preclinical and clinical development of ibrutinib.4 In December 2011 Pharmacyclics and the Janssen division of Johnson and Johnson entered into an agreement to jointly develop and market

3 ACS Paragon Plus Environment


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

Page 4 of 55

ibrutinib. This joint development effort culminated in an NDA submission in June 2013 and approval four months later. In May 2015 Pharmacyclics was acquired by AbbVie. Both WuxiApptec (Nov 2013)5 and Lonza (Jan 2014)6 announced supply agreements with Pharmacyclics for production of commercial ibrutinib API. According to an article published by the American Chemical Society, inventory of API was available from Lonza to support rapid launch of the drug after approval.7 Medicinal Chemistry Route to Ibrutinib Two routes to ibrutinib are described in the composition of matter patents,8a-d a journal publication,8e and two book chapters.9,10 In the first route (Scheme 1), the pyrazolo ring system is constructed with the phenyl ether in place (intermediate 5), then the piperidine side chain 6 is added stereoselectively via a Mitsunobu reaction to generate 7. After deprotection, the acrylamide is installed by acylation with acryloyl chloride to afford ibrutinib. This route was used by the medicinal chemists to explore chemical space that permitted variations in the heterocycle. Scheme 1. Medicinal Chemistry Route to Ibrutinib


Page 5 of 55

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


The second Medicinal Chemistry route (Scheme 2) starts with the pyrazolo-pyrimidine 9 and requires only two steps, i.e., iodination and cross-coupling, to construct intermediate 5. The



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

Page 6 of 55

piperidine side chain is then appended as in Scheme 1 via a Mitsunobu reaction followed by installation of the acrylamide moiety. For analog preparation, this route locked in the heterocycle but allowed evaluation of a range of substituents off the heterocycle. Scheme 2. Alternate Medicinal Chemistry Route to Ibrutinib Intermediate

Manufacturing Route to Ibrutinib The apparent manufacturing route to ibrutinib is described in patent applications from Janssen (Scheme 3).11 In the first step, the chiral hydrazine 12-R is reacted with dinitrile 3 to generate 13 as a single regioisomer. Reaction with a large excess of formamidine at 115 oC affords 14, followed by deprotection of the Cbz group with Pd(OH)2 on carbon. The 3 steps from 3 to the ibrutinib penultimate intermediate 8 are carried out in a telescoped fashion with isolation of 8 by crystallization from MeOH/water in overall 80% yield with a purity of 92.5%. Also described are variations in which Boc or benzyl protecting groups are employed. Scheme 3. Apparent Manufacturing Route to Ibrutinib, Final Steps


Page 7 of 55

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


Racemic hydrazine 12 is prepared as a bis-HCl salt in three steps from N-Cbz-3-piperidone (15) via hydrazone formation with Boc-hydrazine, reduction with NaCNBH3, and acidic deprotection (Scheme 4). Claim 9 of the U.S. patent application11a states that 12 is resolved but the specification section of the patent provides no discussion nor experimental procedures for a resolution. This statement regarding a resolution is not included in the claims of the granted patent.11b A compound claim for chiral hydrazine 12-R was included in the patent application11a but this claim was not granted in the issued patent.11b A second U.S. patent application is pending that also includes a compound claim for 12-R as well as 13.12 A compound claim for 12R would be valuable as it would prevent other companies from using this compound in any



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

Page 8 of 55

synthetic approach until the process patent expires, which may be a few years after the ibrutinib compound patent expires. Scheme 4. Synthesis of Racemic Hydrazine 12

The inventors submit the new route (Scheme 3) has the following advantages versus the Medicinal Chemistry route (Scheme 1). •

More convergent synthesis via chiral hydrazine 12-R;

•

Avoids the use of non-green Mitsunobu chemistry that generates a large amount of waste and requires isolation by chromatography;

•

Avoids use of (S)-3-hydroxy-N-Boc-piperidine (6), an expensive intermediate that is used in large excess due to competing elimination in the Mitsunobu reaction;

•

Avoids use of hydrazine hydrate, a suspected carcinogen that exothermically decomposes at higher temperatures;

•

Replaces the 180 oC reaction of 4 with formamide with reaction of 13 with formamidine at 115 oC.


Page 9 of 55

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


Drawbacks of this route are the length of the synthesis (10 steps from commercially available raw materials) and a resolution to install the chiral center in hydrazine 12-R. Regulatory Starting Materials According to the European Public Assessment Report (EPAR) for Imbruvica, the API is manufactured in six steps from well-defined starting materials.13 The four steps from intermediates 3 and 12-R are likely included in these six steps, suggesting the regulatory starting materials (the point at which cGMP manufacturing begins) are earlier than one or both of these compounds. While 3 may be one RSM, an earlier intermediate in the hydrazine synthesis such as 17 (Cbz or alternate protecting group) might be an RSM since the cGMP pocket would then include the step in which the chiral center is established. Alternate Routes to Ibrutinib With $1.3 billion in revenue in 2015, only the second full year on the market, ibrutinib has already generated a good deal of interest from generic drug manufacturers. The FDA Orange Book for Imbruvica lists 14 patents, the earliest of which expires on Dec 28, 2026.11c The patent on the manufacturing route,11b which is not yet included in the Orange Book, was filed in the U.S. in March 2013 and thus may have an expiration date many years beyond the compound patent expiry date, since patents generally are granted exclusivity for 20 years from the priority (filing) date. Thus, generic companies will not be able to manufacture ibrutinib by the Janssen patented route11b if they intend to market ibrutinib at the time the compound patent expires at the end of 2026. Instead, they will either have to use the non-patented Medicinal Chemistry routes (Schemes 1 and 2), which are far from ideal, or design and develop their own route. By conceiving, developing, and patenting a novel route(s), not only does the generic company



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

Page 10 of 55

secure freedom to operate once the compound patent expires, but also prevents other generic manufacturers from using such route(s) until its patent expiry, thus providing a barrier to entry to generic competitors. This accounts for the high patent activity on ibrutinib over the past two years. The alternate routes to ibrutinib, which are grouped into four categories, are outlined in the sections that follow. 1. Pyrazole formation with fully elaborated hydrazine A more convergent route to ibrutinib is described in a 2015 international patent application (Scheme 5).14 In this variation, pyrazole formation is carried out with the fully elaborated hydrazine fragment 18 incorporating the acrylamide moiety. Not only is this route more convergent but also avoids the protection/deprotection of the piperidine. The preparation of hydrazine 18 is not described. Synthesis of pyrazole 19 is carried out with triethylamine in refluxing EtOH, conditions similar to those used by the Janssen group.11 After crystallization from EtOH/water, 19 is isolated in 80% yield. Ibrutinib is then prepared by reaction of 19 with N,N-dimethylformamide dimethyl acetal in toluene with azeotropic removal of water. Crystallization affords ibrutinib in 73% yield, described on a 3 g scale. No details are provided on the purity of ibrutinib prepared by this process nor the stability of the acrylamide during the conversion of 18 to ibrutinib, key points should this route be considered as an alternate manufacturing route. In addition, 18 and 19 are Michael acceptors and potential genotoxic impurities (PGIs), but since ibrutinib is AMES negative,15 these intermediates will likely also be AMES negative and will not have to be controlled as PGIs nor handled as potent compounds.


Page 11 of 55

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


Scheme 5. Convergent Route to Ibrutinib with Fully Elaborated Hydrazine Fragment

2. Convergent Mitsunobu/Displacement Route While a Mitsunobu reaction may not be a viable option for the final step of ibrutinib at scale, one advantage of both Medicinal Chemistry routes (Schemes 1 and 2) is that (S)-N-Boc-3hydroxypiperidine can be prepared in a single step from piperidone 15 by enzymatic reduction using a ketone reductase (KRED),16 while preparation of hydrazine 12-R requires three steps followed by a resolution from this same starting material.11,12

In four separate patent applications, the Medicinal Cheimstry route starting with pyrazole 9 (Scheme 2) is revisited with the variation that the Mitsunobu reaction is conducted earlier in the sequence (Schemes 6 and 7), prior to installation of the diphenyl ether group.17-20 11 ACS Paragon Plus Environment


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

Page 12 of 55

According to the experimental section provided in the application from Arromax, product 20 of the Mitsunobu reaction is crystallized from MTBE in 75% yield, thus avoiding a chromatography to remove the Mitsunobu byproducts.17 No information is provided on the purity of the isolated material nor if it is contaminated with the Mitsunobu by-products. A significant drawback is that the reaction requires 2.2 equiv of alcohol 6, presumably due to elimination of the activated alcohol, as noted in the Janssen patents.11,12 The phenyl ether 7 is then formed by either Suzuki (70% yield) or Kumada coupling (61%) in modest yield (Scheme 6). 17

In a patent application from Mylan, the Mitsunobu reaction has been replaced with a mesylation/displacement sequence. The displacement reaction of 10-I is carried out in DMF with K2CO3 using 1.5 equiv. of the mesylate 6-Ms, added in 4 portions (Scheme 6). No yield nor enantioselectivity is provided.19

Similarly, a patent application from Sun Pharmaceutical describes a mesylate/displacement approach using either 10-I or 10-Br. With substrate 10-Br, the reaction is conducted in DMF with K2CO3 as base and the mesylate 6-Ms (2.7 equiv.) is added over 1 h at 70 oC. For substrate 10-I the reaction is conducted in NMP with Cs2CO3 at 120 oC using 3.5 equiv. of mesylate 6Ms.20 Scheme 6. Convergent Mitsunobu/Displacement Route to Ibrutinib, First Approach17,19,20


Page 13 of 55

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


In a similar approach (Scheme 7) described in a patent application from a group of 3 Chinese companies, the Mitsunobu reaction of 10-Br and 6 is conducted in THF solution then conc. HCl (10 equiv.) is added at the end of the reaction to cleave the Boc group, resulting in crystallization



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

Page 14 of 55

of the bis-HCl salt 21 in 70% yield across the two steps.18 The Suzuki-Miyaura reaction is then conducted with the unprotected piperidine 21 to afford penultimate intermediate 8. According to the experimental procedure provided, only 1.5 equiv. of chiral alcohol 6 is required for the Mitsunobu reaction. The Suzuki-Miyaura reaction can also be carried out with the acrylamide group already in place using the same conditions (not shown).18 Scheme 7. Convergent Mitsunobu Route to Ibrutinib, Second Approach18


Page 15 of 55

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


Regarding viability of the convergent Mitsunobu/mesylate displacement approach (Schemes 6 and 7) as potential manufacturing routes, a number of unknowns remain. 1. Cost. While commercial pricing of 6 and 9 are unknown, compound 9 is purportedly available in ton quantities from 34 companies21 and 6 uses the same starting material 15 as the current route. An excess of 6 is required for the Mitsunobu coupling or mesylate displacement, but development efforts have already reduced this excess to 1.5 equiv.18,19 so this route is likely cost competitive with the current manufacturing route (Scheme 3). 2. Purity. No details are provided regarding the chemical or chiral purity of ibrutinib produced by this approach but conducting the Mitsunobu step early in the sequence is an advantage since further removal of Mitsunobu byproducts can occur downstream. 3. Environmental. The Mitsunobu reaction generates a large amount of waste, but the resolution required for the current route (Scheme 4) is also non-green and the shorter Mitsunobu route (6 steps via Scheme 7, including one step each to prepare 6 and 11, versus 10 steps via Schemes 3 and 4) may be more productive and have a lower PMI (process mass intensity). The use of the mesylate adds an extra step (preparation of the mesylate) but overall should have a lower environmental impact than the Mitsunobu approach. To summarize, the short routes described in Schemes 6 and 7 appear capable of being developed into viable manufacturing routes. 3. Route Via Construction of Elaborated Pyrazole A route to ibrutinib devised by Sandoz scientists starts with dichloropyrimidine 22 and builds the pyrazole (Scheme 8).22 Key steps include a Friedel-Crafts reaction at the 4-position of diphenyl ether to generate 23, displacement of one aromatic chlorine with ammonia to form 24, followed by generation of the pyrazole 25 using either chiral hydrazine 12-R or the fully elaborated 15 ACS Paragon Plus Environment


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

Page 16 of 55

hydrazine 18. While pyrazole formation is claimed using both 12-R and 18, the only experimental procedure described uses achiral cyclohexyl hydrazine, perhaps suggesting the reaction with 12-R or 18 is not viable. No yields are provided for any steps.22 Scheme 8. Route to Ibrutinib via Pyrazole Construction, First Approach22

A similar route for construction of the pyrazole 5 is described by Zhejiang Jiuzhou Pharmaceutical Co. (Scheme 9) with excellent yields for all steps.23 The ketone 23 is prepared by addition of either the Grignard 27 (or lithium salt) of diphenyl ether to aldehyde 26 to form alcohol 28 in 83-95% yield, which is then oxidized with TEMPO/NBS in 88% yield. Intermediate 5 is formed via reaction of ketone 23 with hydrazine hydrate (93% yield) followed by ammonia in MeOH (89% yield).23 The patent application includes compound claims for 23 and 28. 23


Page 17 of 55

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


If installation of hydrazine 12-R or 18 can be implemented, then the approaches described in Schemes 8 and 9 are potentially short and viable manufacturing routes to ibrutinib. Scheme 9. Route to Ibrutinib via Pyrazole Construction, Second Approach23

4. Ibrutinib via Masked Acrylamide Sandoz has filed a patent application for a route to ibrutinib using a masked acrylamide that is installed via phase-transfer chemistry using bicyclic mesylate 30 (Scheme 10) followed by retro Diels-Alder reaction at 250 oC to reveal the acrylamide group.24 This patent application also describes installation of the piperidinyl group via phase transfer chemistry of 5 with mesylate 617 ACS Paragon Plus Environment


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

Page 18 of 55

Ms (not shown), thus avoiding the Mitsunobu chemistry used to install this fragment in the Medicinal Chemistry route (Scheme 1).24

Scheme 10. Ibrutinib via Masked Acrylamide

5. Alternate disconnections In a patent application with no examples, Janssen outlines a number of potential alternate routes to ibrutinib with the acrylamide group incorporated early in the synthesis, as summarized in Scheme 11.25 The routes via intermediates 35 and 36 are similar to those described in Schemes 6-8.18,22 18 ACS Paragon Plus Environment

Page 19 of 55

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


Scheme 11. Alternate Bond Disconnections for Ibrutinib

Ibrutinib Commercial API Form Anhydrous crystalline free base form A is the commercial form of the API and is claimed in U.S. Patent 9,296,753 granted to Pharmacyclics on March 29, 2016.26a



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

Page 20 of 55

Form A has low solubility in water (13 mg/L at pH 8) and high in vitro permeability and is therefore designated as a BCS Class 2 compound. 26 Since bioavailability is dependent on the particle size, micronized API is used in the formulated drug product.13 Absolute oral bioavailability using form A under fasted conditions is only 2.9%.15 A significant food effect is observed. In one clinical study, the bioavailability increased approximately 2-fold when dosed with a high fat breakfast. In a separate study, the bioavailability was 16% when dosed with food and grapefruit juice.15 Given the low bioavailability and large food effect, the crystalline free base is not the ideal API form, but since Imbruvica was developed and approved under the FDA’s accelerated approval program with only 111 patients, it is possible that Pharmacyclics and Janssen decided to continue development with an acceptable, but imperfect, API form and drug product formulation to gain rapid approval rather than risk bridging to a potentially improved form and formulation. The Pharmacyclics patent describes 2 other anhydrous forms (plus 3 solvates) but only anhydrous form A is claimed.26 Formation of anhydrous crystalline free base form A involves dissolution in MeOH at 45 oC, addition of water over a 3 h period at this temperature to induce crystallization, followed by cooling. This form can also be generated from aq. acetone, EtOH, and i-PrOH.26 Anhydrous form B is produced by dissolution in MeOH then adding water at room temperature to create supersaturation and initiate crystallization.26 Anhydrous form C is generated by crystallization from MeOH at room temperature.26 Of the 3 anhydrous polymorphs described by Pharmacyclics,26 form A has the highest melting point at 154 oC (form B melts at approximately 120 oC and form C at approximately 140 oC), suggesting form A is the thermodynamically most stable form. Forms B and C appear to be meta-stable polymorphs that can form under kinetically controlled conditions at room 20 ACS Paragon Plus Environment

Page 21 of 55

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


temperature. Crystallization of form A at 45 oC ensures that adequate energy is supplied to the system to convert either meta-stable anhydrous from to the thermodynamic form A. Alternate API Forms of Ibrutinib According to the FDA Orange Book, the patent on free base crystal form A26a expires Oct 30, 2033.11c This is an important patent – it has the potential to extend exclusivity for Imbruvica for an additional seven years beyond the compound patent expiry, which occurs at the end of 2026. A generic manufacturer will not be able to launch generic ibrutinib at the time the compound patent expires unless they have their own patented API form or an unencumbered form that has freedom of operation. Therefore, generic manufacturers have already invested considerable efforts to discover, develop, and patent alternate final forms.

As an additional hurdle, for approval of an ANDA (abbreviated new drug application) a generic company must establish bioequivalence of their ibrutinib dosage form to that of the originator drug.27 The U.S. FDA has already published the bioequivalence requirements for ibrutinib, which include both a fed and fasted studies of a 140 mg dose in healthy male and female subjects.28 With a bioavailability of 2.9%, an API that is currently micronized,13 and a significant food effect, this will not be a trivial undertaking considering that an alternate form of the API will have to be used in the bioequivalence studies. The good news for the generic companies is that (1) the bioequivalence studies can be conducted in healthy volunteers (if ibrutinib was cytotoxic these studies would have to be carried out in cancer patients and include a clinical endpoint);27 and (2) they have a ten year runway in which to study and optimize the form and formulation.



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

Page 22 of 55

Should a company decide to pursue an alternate form and/or formulation of ibrutinib with improved bioavailability relative to the originator’s, then a 505B(2) approval pathway would be required. In this approach, toxicity data generated by the originator company can be used to support the filing but an independent clinical trial must be conducted to prove efficacy and safety.29 The originator company (now Janssen and AbbVie) may also elect to develop an alternate form/formulation with improved bioavailability and lower dose as a line extension as the patent expiry date nears.

Patent applications have been filed on a number of new ibrutinib forms (Table 1). Most of the newly discovered forms are crystalline solvates of the free base that are of limited interest as API forms except as potential intermediates to viable anhydrous or amorphous forms.

Regarding alternate free base forms that could be considered as viable API forms, anhydrous free base form I described by Crystal Pharmatech and Suzhou Pengxu Pharmatech has only slightly higher aqueous solubility than Form A and therefore would not be expected to have significantly different bioavailability.32 This could be a valuable form in an effort to obtain bioequivalence with the commercial anhydrous form A. Perrigo describes an anhydrous crystalline form VI, prepared by thermal desolvation of the DME solvate, but no characterization is provided.31 Table 1. Crystal Forms of Ibrutinib Form Company Designation

Characteristics

Solvent System


Page 23 of 55

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


A

Pharmacyclics26

Anhydrous FB

MeOH/water

B

Pharmacyclics26

Anhydrous FB

MeOH/water

C

Pharmacyclics26, Sandoz34

Anhydrous FB

MeOH21 or thermal desolvation of solvates34

D

Pharmacyclics26

MIBK solvate

MIBK

E

Pharmacyclics26

toluene solvate

toluene

F

Pharmacyclics26

MeOH solvate

MeOH

G

Teva, Assia Chem30

HOAc solvate

HOAc/water; HOAc/water/2-PrOH; HOAc/water/MeCN

J

Anisole solvate Not defined

Anisole; Anisole/MTBE Toluene/DMF

Anhydrous FB

2-PrOH, n-heptane

III

Teva, Assia Chem30 Teva, Assia Chem30 Crystal Pharmatech, Suzhou Pengxu Pharmatech32 Perrigo31, Sandoz34

1,4-Dioxane

IV

Perrigo31

1,4-Dioxane solvate DME solvate

V

Perrigo31

MeOH solvate

MeOH

VI

Perrigo31

Anhydrous FB

Conversion from DME solvate in humid air

VII

Perrigo31

Anisole solvate

Anisole/acetone

VIII

Perrigo31, Sandoz34

PhCl solvate

PhCl

IX

Perrigo31, Sandoz34

Anisole solvate

Anisole

none

Perrigo31, Sandoz34

CH2Cl2 solvate

CH2Cl2

none

Ratiopharm33

CH2Cl2/MTBE

none

Ratiopharm33

Anhydrous HCl salt Anhydrous HBr salt

K I

DME

CH2Cl2/MTBE 23

ACS Paragon Plus Environment


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

none

Zentiva35a

Sulfate salt

Page 24 of 55

EtOH or acetone

The HCl salt reported by Ratiopharm could potentially have improved bioavailability.33 While ibrutinib has a pKa of 3.74 and therefore can be protonated by strong acids, attempts to form salts with mineral acids such as HCl lead to Michael addition to the acrylamide, generating chloride 37. Ratiopharm has discovered that initial formation of the HCl salt using 1.25M HCl in 2-PrOH at -20 oC in CH2Cl2, followed by addition of MTBE while cold, then allowing the slurry to warm to ambient temperature, results in high recovery of the HCl salt with 5.36 The bioavailability of ibrutinib in fed female rats increases from 21% when dosed orally to 100% when dosed intraduodenally.36 If a corresponding increase in bioavailability is realized in humans, the dose could be substantially reduced with these formulations. 25 ACS Paragon Plus Environment


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

Page 26 of 55

Formulations that use amorphous ibrutinib free base may have increased bioavailability relative to the crystalline form currently used commercially but no such formulations have been published. The Perrigo patent application31 describes formation of amorphous ibrutinib by spray drying, lyophilization, and precipitation. Likewise, amorphous ibrutinib prepared by thermal desolvation of solvates, lyophilization, hot melt extrusion, and lyophilization are reported in the Sandoz patent application.34 Dr. Reddy’s Laboratories describes preparation of amorphous ibrutinib by precipitation or concentrating a solution to dryness.35b This team has also describes amorphous dispersions by mixing ibrutinib with various polymers and concentrating to dryness. However, none of these patent applications reports solubility or bioavailability studies to assess if amorphous ibrutinib free base could have increased exposure. II.

COTELLIC (COBIMETINIB, GDC-0973, XL518)

Cobimetinib (trade name Cotellic) is an orally active, selective inhibitor of mitogen-activated protein kinase (MEK) that was discovered by Exelixis and was developed in conjunction with Genentech, a member of the Roche Group. Cotellic was first approved in Switzerland on Aug 27, 2015, for use in combination with vemurafenib, a BRAF inhibitor, as a treatment for patients with advanced melanoma. In November 2015, the U.S. FDA approved cobimetinib for unresectable or metastatic melanoma in combination with vemurafenib.37 Medicinal Chemistry Route to Cobimetinib The final steps of the medicinal chemistry route to cobimetinib are presented in Scheme 12. The synthesis of the key intermediate, azetidine 47, is shown in Scheme 13.38

Scheme 12. Final Steps of Medicinal Chemistry Route to Cobimetinib 26 ACS Paragon Plus Environment

Page 27 of 55

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


In the preparation of cobimetinib (Scheme 12), diarylamine 40 is prepared by selective SNAr reaction of the lithium salt of aniline 39 at the 2-F position of 2,3,4-trifluorobenzoic acid (38),39 followed by formation of the acid fluoride 41 with cyanuric fluoride. Amide bond formation between 41 and 47 mediated by i-Pr2NEt furnishes 42. Acidic deprotection of the Boc group then affords cobimetinib.38



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

Page 28 of 55

Scheme 13. Synthesis of Azetidine Fragment 47

The primary issues with the Medicinal Chemistry route lie with the synthesis of azetidine 47 (Scheme 13). The deprotonation of N-Boc-piperidine with 2-BuLi/TMEDA and addition to ketone 43 affords racemic 44 in 13% isolated yield. Resolution is accomplished via preparation of the Mosher’s ester and separation of the resulting diastereomers by silica chromatography. The acylation of 44 is carried out with approximately 0.5 equiv of the acid chloride, which results in a dr of 4:1 favoring the desired diastereomer 45. After recycling the recovered starting material twice, the purified diastereomer 45 is recovered after chromatography in 32 % yield. The low yield in the reaction of lithiated Boc-piperidine with ketone 43 may be due to the poor reactivity of 43, which may make development of this approach unfeasible. Nonetheless, an


Page 29 of 55

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


asymmetric lithiation/addition could provide a quick entry to 46 and transform the Medicinal Chemistry route into a viable manufacturing route. Beak originally demonstrated asymmetric deprotonation and electrophilic reactions of N-Boc-pyrrolidine using the chiral ligand sparteine.40 This work has been extended by O’Brien and Gawley to asymmetric lithiation of Boc-piperidines employing more readily available chiral ligands.41 O’Brien has shown that NBoc-pyrrolidines can be lithiated and reacted with ketones such as benzophenone in high ee and yields, but no information is provided on potential application of asymmetric reactions of Bocpiperidines with ketones.42

Manufacturing Route to Cobemetinib

The apparent six-step manufacturing route to cobemetinib (Scheme 14) is described in two patent applications.43

Scheme 14. Manufacturing Route to Cobemetinib



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

Page 30 of 55


Page 31 of 55

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


The chiral center in the manufacturing route is derived from the chiral pool via 48, a building block introduced by Husson in 1983 and used to prepare several natural products that incorporate asymmetric piperidines.44 Compound 48 is prepared from (S)-phenylglycinol, KCN, and glutaraldehyde;44 an improved process was described in 2010 by process chemists from Exelixis.45 Several key features of 48 make it perfectly suited to enable a short asymmetric synthesis of cobemetinib, including:

(1) a rigid bicylic structure with a steric environment that directs reaction at one face of the derived carbanion to afford 50 with high diastereoselectivity;

(2) a cyano group which serves multiple functions: (a) to acidify the adjacent C-H bond to enable deprotonation of 48, (b) sterically small such that the addition reaction can be carried out below -70 oC to afford high yield and diastereoselectivity of 50, and (c) can be removed by a reductive decyanation with retention of stereochemistry (50 to 51); and

(3) a masked N-protecting group that can be removed by hydrogenation late in the sequence (53 to 54). Lithiation of 48 is accomplished with LDA at -70 to -80 oC in a solvent system of DMPU/THF (1:9). While maintaining the low temperature, Boc-azetidinone 49 is added. After 1 h, the reaction is quenched by addition of the cold mixture into an aq. HOAc solution at 0 oC, then crystallization is carried out from heptane/2-PrOH to afford addition product 50 with 92% purity. The yield and dr are not provided.

The next 3 steps are carried out in telescoped fashion. The reductive decyanation and concomitant C-O reductive cleavage of aminal 50 are performed with sodium cyanoborohydride 31 ACS Paragon Plus Environment


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

Page 32 of 55

(1.7 equiv.) and HOAc (2.1 equiv.) in EtOH. Work up with toluene results in a toluene solution of 51 that is deprotected using 7% aq. HCl as a two-phase reaction mixture at 50 oC. The resulting HCl salt 52 in the aq. phase is taken into the subsequent Schotten-Bauman reaction with 2,3,4-trifluorobenzoyl chloride in a two-phase aqueous/toluene reaction mixture. After work up the toluene layer containing product 53 is turned over to EtOH and the benzylic protecting group removed with 10% Pd/C to afford 54, which is crystallized from 2-PrOH/MTBE in 50% yield. The final step is an SNAr reaction with the lithium salt of aniline 39 to afford cobimetinib which is crystallized as the free base from toluene in 90% yield. Compounds 50 through 54 are claimed in the patent application.43 Compound claims are valuable since they prevent competitors from using any routes that intersect with a patented compound and also preclude “work arounds” of the process claims that might be contemplated through use of alternate reagents or solvents.

Regulatory Starting Materials According to the European Pharmaceutical Assessment Report (EPAR),46 the API is synthesized in 6 chemical steps with a telescoped sequence that includes five non-isolated steps, followed by a salt formation step. This corresponds to the route outlined in Scheme 14.

Alternate Route #1 to Cobemetinib

Two alternate synthetic approaches have been published as Chinese patent applications. The first is based on addition of 2-bromopyridine to Boc-azetidinone 49, then reduction of the pyridine 56 to piperidine 57 (Scheme 15).47 The synthesis generates the penultimate intermediate as a racemate (42-Rac), which is resolved using preparative chiral chromatography. While chiral


Page 33 of 55

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


chromatography at scale has become more feasible in the past decade, the inability to recover the undesired enantiomer by racemization results in a yield of 39% in the chromatography, a low yield for the penultimate step of a potential manufacturing route. The route also requires a protecting group switch from Boc (55) to trifluoroacetate (56) for the Pt-catalyzed reduction of the pyridine ring, making the entire route nine steps to cobimetinib free base, three steps longer than the current manufacturing route if the chromatography is counted as a step. This approach could be feasible as a manufacturing route if the protecting group switch can be avoided and if the reduction of the pyridine ring can be conducted in an asymmetric fashion to avoid the HPLC chiral separation.48 Scheme 15. Alternate Route to Cobimetinib via Pyridine Reduction and HPLC Resolution



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

Page 34 of 55


Page 35 of 55

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


Alternate Route #2 to Cobemetinib

The second alternate route to cobemetinib starts with enantiomerically pure (S)-2-pipecolic acid and builds the azetidine ring (Scheme 16).49 (S)-2-Pipecolic acid is commercially available and can be prepared enzymatically from L-lysine (Mercian process) or picolinonitrile (Lonza process).50 Preparation of intermediate 47 requires a lengthy 8 steps, although many of these steps are telescoped as outlined in Scheme 16, and the overall yield to 47 is a respectable 32% on gram scale. Another drawback of this route is use of Mitsunobu chemistry to form the azetidine (63 to 47), a reaction that generates a high waste load. On a positive note, while many Mitsunobu reactions require chromatography for purification, in this case the product 47 can be isolated by crystallization from n-hexane/MeOH.

Scheme 16. Alternate Route to Cobimetinib Involving Construction of the Azetidine



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

Page 36 of 55

Final API Form and Dosage Form The final form of the API is a crystalline hemi-fumarate salt. Very little information is available on preparation and characterization of this salt. According to the EPAR,46 cobimetinib hemifumarate exists as a single polymorph. Solubility at 37ºC is 0.72 mg/mL in water and 48.2 mg/mL in 0.1 M HCl.51 The bioavailability is 46% and is unaffected by food.


Page 37 of 55

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


The oral dosage form is a film-coated tablet containing cobimetinib hemi-fumarate equivalent to 20 mg cobimetinib as active substance.49 The recommended dose is 60 mg (3 x 20 mg tablets) once daily. III.

ALECENSA (ALECTINIB, RO5424802, CH5424802)

Alectinib (marketed as Alecensa) is an orally active inhibitor of anaplastic lymphoma kinase (ALK) for the treatment of ALK-positive non-small cell lung cancer (NSCLC). Alectinib was discovered by Chugai, a member of the Hoffmann-La Roche group. The drug was first approved in Japan in July 2014. The U.S. FDA approved alectinib in December 2015.52 A marketing application was filed in Europe in September 2015 but the drug has not yet been approved in Europe as of Aug 31, 2016. Medicinal Chemistry Route to Alectinib The Medicinal Chemistry route is nine linear steps, not including salt formation, starting from 7methoxy-2-tetralone (Scheme 17). The overall yield is approximately 1%.53 Besides the overall low yield, which could likely be significantly improved with appropriate development, the route has two drawbacks. 1. The Fischer indole reaction of 66 with 3-cyanophenyl hydrazine delivers a 1:1 mixture of regioisomers. The desired regioisomer 67 is isolated by crystallization, but in a yield of only 25%. 2. The ethyl group is introduced late via a Sonigashira reaction of 72 with TIPS-acetylene, followed by desilylation with TBAF to generate acetylene intermediate 73, which is then hydrogenated to the ethyl group to furnish alectinib in an overall three-step sequence with a yield of 14% across the 3 steps. 37 ACS Paragon Plus Environment


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

Page 38 of 55

Scheme 17. Medicinal Chemistry Route to Alectinib

Second Generation Route to Alectinib A second generation route that addresses the issues with the original route is presented in Scheme 18.54 At eight linear steps, this route is only one step shorter than the original route, but


Page 39 of 55

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


the ethyl group is introduced efficiently, the indole is formed by an alternate route that furnishes a single regioisomer, and the overall yield is 38%, an average of 89% per chemical step. Scheme 18. Second Generation Route to Alectinib

The second generation approach starts with installing the ethyl group in two steps via the Molander variation of Suzuki-Miyaura cross coupling using vinyltrifluoroborate followed by hydrogenation to afford 76.



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

Page 40 of 55

The indole is constructed in four steps from carboxylic acid 76 by iodination ortho to the ethyl group to furnish 77 followed by a 2-carbon chain extension of the carboxylic acid with malonate half ester to form ketoester 78. Next an SNAr reaction of the malonate with 4-chloro-3nitrobenzonitrile (79) affords 80, followed by nitro reduction and ring closure to provide indole 81. The piperidinyl side chain is incorporated via a Pd-catalyzed C-N cross coupling with 71 to afford 75. Deprotection of the t-butyl ester is carried out using TMS-Cl in trifluoroethanol followed by work up with NaOH.55 An intramolecular Friedel-Crafts reaction of the resulting carboxylic acid 83 mediated by Ac2O closes the final ring of the tetracycle to produce alectinib. The description of this route is embedded in the experimental section of the compound patent at batch sizes ranging from 30 g to 1400 g.54 Alternate Route to Alectinib A more convergent route to alectinib was published as an international patent application (Scheme 19).56 The key step in this approach is an acid-catalyzed Friedel-Crafts reaction of the tertiary alcohol 89 with cyanoindole 86 which affords 83, intersecting this same penultimate intermediate as the manufacturing route (Scheme 18). This route is seven steps from commercially available raw materials with a longest linear sequence of five steps. Yields average 87% for the five reported steps. 6-Cyanoindole (85) is formed via a Leimgruber-Batcho reaction via published chemistry57 followed by acylation at the 3-position of the indole with trichloroacetyl chloride to generate the methyl ester 86.


Page 41 of 55

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


Fragment 89 is prepared in two steps. SNAr reaction of 3-bromo-4-ethylacetophenone 87 with the piperidine side chain 71 under microwave conditions generates 88 followed by reaction with with methyl Grignard to afford tertiary alcohol 89. Since acetophenone 87 is poorly activated for an SNAr reaction, the high temperatures generated by microwave heating are necessary to effect this transformation. Scale up of this chemistry would likely require continuous processing for either microwave application or high temperature conditions and would be a major challenge should this approach be considered as a manufacturing route.58 Alternatively, a Pd-catalyzed cross-coupling could be considered, similar to the chemistry used to convert 81 to 82 (Scheme 18). 3-Bromo-4-ethylacetophenone (87) is not available at commercial scale but can be prepared by selective bromination of commercially available 4-ethylacetophenone using AlCl3/Br2 in 59% yield.59 Scheme 19. Alternate Route to Alectinib



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

Page 42 of 55

Alectinib API Form and Dosage Form The two issued patents describe preparation of the HCl salt53a, 54 and mesylate salt of alectibnib.53a The patents include no specific claims for either crystalline salt form but a broad claim for an oral formulation was secured as well as a claim for any form having a solubility in water below 100 mg/L.54 The solubility of the HCl salt in aqueous solution ranges from 0.5 mg/L at pH 6 to 1.3 mg/L at pH 1 and is reported as ranging from 22-35 mg/L in unbuffered water.53a The HCl salt is the final form of the API. Two methods of preparation of the HCl salt are described. In both procedures, the free base is dissolved in 17 volumes of a solvent mixture consisting of 10 parts methyl ethyl ketone, 4 parts water, and 3 parts HOAc. In method one, this mixture is slowly added to a solution of 30 volumes of ethanol and 2 volumes 2 N HCl at room temperature, resulting in crystallization of the HCl salt.54 In the other method, 1 volume of 2N 42 ACS Paragon Plus Environment

Page 43 of 55

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


HCl is added to the dissolved free base at 60 oC followed by 25 volumes of ethanol to induce crystallization.53a Particle size reduction is accomplished via jet milling. The mesylate salt is prepared from 200 volumes of a DMA/EtOAc mixture at 90 oC.53a The absolute bioavailability of alectinib hydrochloride is 37%.60 When administered with a high fat meal, a 3-fold increase in exposure was noted, which includes alectinib and its major active metabolite M4, 90.60,61 No significant changes were noted in bioavailability when alectinib was co-administered with the proton pump inhibitor, esomeprazole.60

The recommended dose of alectinib in the U.S. is 600 mg twice daily with food. The dosage form is a 150 mg immediate release capsule. 62 In Japan, capsule doses of 20 mg and 40 mg are available.63 SUMMARY Ibrutinib Seven approaches to ibrutinib have been described in the patent literature. The manufacturing route consists of 10 steps from commercially available raw materials and requires a resolution of hydrazine 12 to install the chiral center. Patent applications have been filed on four alternate 43 ACS Paragon Plus Environment


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

Page 44 of 55

approaches that have fewer steps and may be viable manufacturing routes if purity and stability are acceptable. Anhydrous crystalline free base form A is the final form of ibrutinib API, having a bioavailability of only 2.9%. As such, a number of alternate API forms have been investigated. Of these, the HCl salt has increased solubility relative to the free base and may be an improved API form if it has adequate stability. A formulation that releases drug into the small intestine has also shown enhanced bioavailability in a rat model. Cobimetinib While cobimetinib is a small volume product with likely no cost drivers, an alternate route to this drug was required since the Medicinal Chemistry was not viable for scale up due to a low yielding and unproductive resolution that required chromatographic separation of diastereomers. An efficient manufacturing route was designed and developed with the chirality derived from the chiral pool. The EPAR notes that “the same synthetic route has been used throughout the development from toxicological studies to the commercial batches.”46 Patent applications on two alternate routes have been filed. The final form of cobimetinib is a hemifumarate salt. Alectinib The probable manufacturing route to alectinib involves 8 linear steps with an average yield per step of 89%. The final form of the API is the HCl salt, which is formulated in a standard immediate release capsule. ABBREVIATIONS: AMES, named after Bruce Ames, a biological assay to assess the mutagenic potential of chemical compounds; ANDA, abbreviated new drug application; API, active pharmaceutical ingredient; AUC, area under the curve; BCS, Biopharmaceutical Classification System; Boc, t-butyloxy carbonyl; CDI, carbonyl diimidazole; cGMP, current 44 ACS Paragon Plus Environment

Page 45 of 55

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


Good Manufacturing Practices; DIAD, diisopropylazo dicarboxylate; DMA, N,Ndimethylacetamide, DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMF-DMA, N,Ndimethylformamide dimethyl acetal; , DME, dimethoxyethane; DMPU, 1,3-dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidinone, EPAR, European Public Assessment Report; FB, free base; LDA, lithium diisopropylamide; MEK, mitogen-activated protein kinase; MIBK, methyl isobutyl ketone; NBS, N-bromosuccinimide; NIS, N-iodosuccinimide; (NHC)Pd(allyl)Cl, allylchloro[1,3bis(2,6-diisopropylphenyl)imidazol-2-ylidene]palladium(II); PyBop, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; RSM, regulatory starting material; TEMPO, 2,2,6,6-tetramethylpiperidin-1-yl)oxyl; TFE, trifluoroethanol.

REFERENCES (1) Hughes, D. L. Org. Process Res. Dev. 2016, 20, 1404-1415. (2) Information on synthetic routes to approved drugs, including patents and journal publications, can be found on the web sites of Pharmacodia (http://www.pharmacodia.com/en) and Anthony Crasto (https://newdrugapprovals.org/author/amcrasto/). (accessed Oct 3, 2016) (3) The “tinib” suffix is reserved for tyrosine kinase inhibitors. http://druginfo.nlm.nih.gov/drugportal/jsp/drugportal/DrugNameGenericStems.jsp (accessed Sep 4, 2016). (4) http://www.prnewswire.com/news-releases/celera-genomics-announces-sale-of-therapeuticprograms-to-pharmacyclics-56115072.html (accessed Sep 4, 2016). (5) http://wxpress.wuxiapptec.com/wuxi-partner-pharmacyclics/ (accessed Sep 4, 2016).



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

Page 46 of 55

(6) http://www.lonza.com/about-lonza/media-center/news/2014/140113-Pharmacyclics.aspx (accessed Sep 4, 2016). (7) https://www.acs.org/content/acs/en/molecule-of-the-week/archive/i/ibrutinib.html (accessed Sep 4, 2016). (8) (a) Honigberg, L.; Verner, E.; Pan, Z. Inhibitors of Bruton's Tyrosine Kinase. PCT Int. Patent Application WO 2008/039218 A3, May 29, 2008. (b) Pan, Z.; Li, S. J.; Schereens, H.; Honigberg, L.; Verner, E. Bruton's Tyrosine Kinase Activity Probe and Method of Using. PCT Int. Patent Application WO 2008/054827 A2, May 8, 2008. (c) Chen, W.; Loury, D. J.; Mody, T. D. Pyrazolo-pyrimidine Inhibitors of Bruton’s Tyrosine Kinase. U.S. Patent 7,718,662 B1, May 18, 2010. (d) Honigberg, L.; Verner, E.; Pan, Z. Inhibitors of Bruton's Tyrosine Kinase. U.S. Patent 7,514,444 B2, April 7, 2009. (e) Pan, Z.; Scheerens, H.; Li, S.J.; Schultz, B. E.; Sprengeler, P. A.; Burrill, L. C.; Mendonca, R. V.; Sweeney, M. D.; Scott, K. C. K.; Grothaus, P. G.; Jeffery, D. A.; Spoerke, J. M.; Honigberg, L. A.; Young, P. R.; Dalrymple, S. A.; Palmer, J. T. ChemMedChem 2007, 2, 58-61. (9) Liu, H.; Pan, Z. Ibrutinib (Imbruvica): The First-in-Class BTK Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom’s Macroglobulinemia. In Innovative Drug Synthesis; Li. J. J.; Johnson, D. S., Eds., John Wiley & Sons, Inc.: Hoboken, NJ, 2016, Chapter 8, 157-165. (10)

Owens, T. Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton’s Tyrosine Kinase. In

Bioactive Carboxylic Compound Classes, Pharmaceuticals and Agrochemicals; Lamberth, C.; Dinges, J., Eds., Wiley-VCH: Weinheim, Germany, 2016, Chapter 14, 199-208. (11)

(a) Pye, P.; Ben Heim, C.; Conza, M.; Houpis, I. N. Processes and Intermediates for

Preparing a Medicament. U.S. Patent Application 2014/0275126, September 18, 2014. (b)


Page 47 of 55

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


Pye, P.; Ben Heim, C.; Conza, M.; Houpis, I. N. Processes and Intermediates for Preparing a Medicament. U.S. Patent 9,156,847 B2, October 13, 2015. (c) FDA Orange Book patents listed for Imbruvica: http://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Appl_type=N&Appl_No=20 5552&Product_No=001 (accessed Sep 5, 2016). (12)

Pye, P.; Ben Heim, C.; Conza, M.; Houpis, I. N. Processes and Intermediates for

Preparing a Medicament. U.S. Patent Application 2015/0376193 A1, December 31, 2015. (13)

EPAR for Imbruvica: 24 July 2014 EMA/CHMP/645137/2014 Committee for Medicinal

Products for Human Use (CHMP) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/003791/WC500177777.pdf (accessed Oct 3, 2016). (14)

Xu, X. Method for Preparing Ibrutinib. PCT Int. Patent Application WO 2015/074464,

May 28, 2015. (15)

(a) FDA biopharmaceutical report for Imbruvica.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205552s007lbl.pdf (accessed Sep 4, 2016). (b) EU community register annex: http://ec.europa.eu/health/documents/communityregister/2014/20141021129815/anx_129815_en.pdf (accessed Sep 4, 2016). (16)

Ju, X.; Tang, Y.; Liang, X.; Hou, M.; Wan, Z.; Tao, J Org. Process Res. Dev. 2014, 18,

827–830. DOI: 10.1021/op500022y (17)

Hong, J.; Liu, G. Synthesis Method of Ibrutinib. Chinese Patent Application

CN104557945, April 29, 2015.



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

(18)

Page 48 of 55

Zhang, X.; Kong, R.; Liu, X.; Chen, S.; Chen, X.; Yang, L.; Zhang, A.; Cheng, X.

Method for Preparing Ibrutinib. PCT Int. Patent Application WO 2016/127915, August 18, 2016. (19)

Jayachandra, S.; Sebastaian, S.; Rao, J.; Naidu, H.; Adla, M.; Saggella, S. R.; Dandala,

R. Process for the Preparation of Ibrutinib. PCT Int. Patent Application WO 2016/132383, August 25, 2016. (20)

Sharma, K.; Thanki, B. P.; Khanna, M. S.; Prasad, M. Process for the Preparation of

Ibrutinib. PCT Int. Patent Application WO 2016/079693, May 26, 2016. (21)

http://www.chemicalbook.com/ChemicalProductProperty_EN_CB3112436.htm

(accessed Sep 4, 2016). (22)

Rose, C.; Silberger, H.; Schreiner, E.; Felzmann, W.; Maras, N. Synthesis of Substituted

1H-Pyrazolo[3,4-d]pyrimidines. PCT Int. Application WO 2016/066673 A1, May 6, 2016. (23)

Hua, Y.; Zhang, X.; Gao, Y.; Li, Y.; Che, D. Ibrutinib Intermediate Compounds,

Preparation Methods and Uses Thereof. PCT Int. Patent Application WO 2016/000476, January 7, 2016. (24)

Felzmann, W.; Brunner, S.; Lengauer, H. Active Acrylamides. PCT Int. Patent

Application WO 2016/066726, May 6, 2016. (25)

Benhaim, C.; Chen, W.; Goldman, E.; Horvath, A.; Pye, P.; Smyth, M. S.; Verner, E. J.;

Hathaway, R. P. Synthesis of a Bruton’s Tyosine Kinase Inhibitor. PCT Int. Patent Application WO 2016/115356, July 21, 2016. (26)

(a) Smyth, M.; Goldman, E.; Wirth, D. D.; Purro, N. Crystalline Forms of a Bruton’s

Tyrosine Kinase Inhibitor. U.S. Patent 9,296,753 B2, March 29, 2016. (b) Smyth, M.; Goldman, E.; Wirth, D. D.; Purro, N. Crystalline Forms of a Bruton’s Tyrosine Kinase


Page 49 of 55

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


Inhibitor. U.S. Patent Application 2013/0338172 A1, December 19, 2013. (c) Smyth, M.; Goldman, E.; Wirth, D. D.; Purro, N. Crystalline Forms of a Bruton’s Tyrosine Kinase Inhibitor. U.S. Patent Application 2014/0336203 A1, November 13, 2013. (d) Purro, N.; Smyth, M.; Goldman, E.; Wirth, D. D. Crystalline Forms of a Bruton’s Tyrosine Kinase Inhibitor. U.S. Patent Application 2015/0158871 A1, June 11, 2015. (27)

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc

es/ucm377465.pdf. (28)

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid

ances/UCM436829.pdf. (29)

http://www.regprofessional.com/resources/505(b)(2).pdf.

(30)

Cohen, M.; Cohen, Y.; Mittelman, A.; Ben Moha-Lerman, E.; Tzanani, I.; Levenfeld, L.

Solid State Forms of Ibrutinib. PCT Int. Patent Application WO 2016/025720, February 2, 2016. (31)

Adin, I.; Kerivonos, S.; Rozenblat, Y.; Weisman, A.; Fernadez Casares, A.; Ten Figas,

G.; Ben-Daniel, R. Ibrutinib Solid Forms and Production Process Therefor. PCT Int. Patent Application WO 2015/145415, March 23, 2015. (32)

Chen, M.; Zhang, Y.; Yang, C.; Zhang, X.; Lu, F.; Ge, H.; Wang, P.; Li, P. Crystalline

Form 1 of Ibrutinib. PCT Int. Patent Application WO 2015/081180, November 26, 2014. (33)

Rabe, S.; Erdmann, M.; Albrecht, W. Acid Addition Salt of Ibrutinib. PCT Int. Patent

Application WO 2016/050422, April 7, 2016. (34)

Martin, N.; Schreiner, E.; Kelk, N.; Reece, H. Physical Forms of Ibrutinib, a Bruton’s

Kinase Inhibitor. PCT Int. Patent Application WO 2016/079216, May 26, 2016. (35)

(a) Zvatora, P.; Dammer, O.; Tkadlecova, M.; Krejcik, L.; Beranek, J. Ibrutinib Sulphate

Salt. PCT Int. Patent Application WO 2016/127960, August 18, 2016. (b) Peddy, V.; Velaga, 49 ACS Paragon Plus Environment


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

Page 50 of 55

D. J. R.; Rangineni, S. Process for the Preparation of Amorphous Ibrutinib. PCT Int. Patent Application WO 2016/088074, June 9, 2016. (36)

Goldstein, D. M. Formulations Comprising Ibrutinib. U.S. Patent Application

2015/0140085, May 21, 2015. (37)

(a) http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm471934.htm

(accessed Sep 4, 2016). (b) Garnock-Jones, K. P. Drugs 2015, 75, 1823-1830.

(38) (a) Rice, K. D.; Aay, N.; Anand, N. K.; Blazey, C. M.; Bowles, O. J.; Bussenius, J.; Costanzo, S.; Curtis, J. K.; Defina, S. C.; Dubenko, L.; Engst, S.; Joshi, A. A.; Kennedy, A.R.; Kim, A. I.; Koltun, E. S.; Lougheed, J. C.; Manalo, J. L.; Martini, J.-F.; Nuss, J. M.; Peto, C. J.; Tsang, T. H.; Yu, P.; Johnston, S. ACS Med. Chem. Lett. 2012, 3, 416-421. (b) Aay, N.; Anand, N. K.; Blazey, C. M.; Bowles, O. J.; Bussenius, J.; Costanzo, S.; Curtis, J. K.; Defina, S. C.; Dubenko, L.; Joshi, A. A.; Kennedy, A.R.; Kim, A. I.; Koltun, E. S.; Manalo, J. L.; Peto, C. J.; Rice, K. D.; Tsang, T. H. Azetidines as MEK inhibitors for the Treatment of Proliferative Diseases. U.S. Patent 7,803,839 B2, September 28, 2010. (c) Lamb, P. Methods of Using MEK Inhibitors. U.S. Patent 7,999,006 B2, August 16, 2011.

(39) Barrett, S. D.; Bridges, A. J.; Cody, D. R.; Doherty, A. M.; Dudley, D. T.; Saltiel, A. R.; Schroeder, M. C.; Tecle, H. 2-(4-Bromo or 4-iodo phenylamino) benzoic Acid Derivatives. U.S. Patent 7,019,033 B2, March 28, 2006. (40) Wu, S.; Lee, S.; Beak, P. J. Am. Chem. Soc., 1996, 118, 715–721. (41) Gawley, R. E.; Aube, J. Principles of Asymmetric Synthesis, 2nd Ed., Oxford, UK: Elsevier, 2012, Chapter 3, 97-178.


Page 51 of 55

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


(42) Gelardi, G.; Barker, G.; O’Brien, P.; Blakemore, D. C. Org. Lett. 2013, 15, 5424–5427.

(43) (a) Naganathan, S.; Guz, N.; Pfeifer, M. Novel Process for Making Compounds for Use in the Treatment of Cancer. PCT Int. Patent Application WO 2014/059422 A1, April 17, 2014. (b) Naganathan, S.; Guz, N.; Pfeiffer, M.; Sowell, C. G.; Bostick, T.; Yang, J.; Srivastava, A. Novel Process for Making Compounds for Use in the Treatment of Cancer. U.S. Patent Application 2015/0210668 A1, July 30, 2015. (44) (a) Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P. J. Am. Chem. Soc. 1983, 105, 7754–7755. (b) Royer, J.; Husson, H.-P. J. Org. Chem. 1985, 50, 670–673. (c) Cutri, S.; Bonin, M.; Husson, H.-P. J. Org. Chem. 2003, 68, 2645–2651.

(45) Guz, N.; Pfeiffer, M.; Dickman, D. Org. Process Res. Dev. 2010, 14, 1476–1478.

(46) EPAR for Cotellic: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/003960/WC500198565.pdf (accessed Oct 3, 2016). (47) Li, Z.; Cao, Z.; Wang, G.; Hu, P.; Zhou, Z.-g.; Gao, Q.; Zheng, B. A Crystal of 3-Piperidin2-yl)-azetidin-3-ol and Its Use Derivatives, Chinese Patent Application CN 104725352 A, June 24, 2015. (48) Asymmetric hydrogenation of pyridines remains an unsolved problem in organic chemistry. The best results to date require quaternization of the pyridine. (a) Ye, Z.-S., Chen, M.-W., Chen, Q.-A., Shi, L., Duan, Y.; Zhou, Y.-G. Angew. Chem. Int. Ed. 2012, 51, 10181–10184. (b) Chang, M.; Huang, Y.; Liu, S.; Chen, Y.; Krska, S. W.; Davies, I. W.; Zhang, X. Angew. Chem. Int. Ed. 2014, 53, 12761–12764. (c) Renom-Carrasco, M.; Gajewski, P.; Pignataro, L.;



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

Page 52 of 55

de Vries, J. G.; Piarulli, U.; Gennari, C.; Lefort, L. Chem. Eur. J. 2016, 22, 9528-9532. (d) Renom-Carrasco, M.; Gajewski, P.; Pignataro, L.; de Vries, J. G.; Piarulli, U.; Gennari, C.; Lefort, L. Adv. Synth. Catal. 2016, 358, 2589-2593.

(49) Xu, X. Cobemetinib Preparation. Chinese Patent Application CN 105330643A, February 17, 2016.

(50) Stinson, S. C. Chem. Eng. News July 9, 2001, 79 (28), 65-84. http://pubs.acs.org/cen/coverstory/7928/print/7928finechemicals.html (accessed Sep 4, 2016).

(51) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000ChemR.pdf (accessed Sep 4, 2016). (52) McKeage, K. Drugs 2014, 75, 75–82. (53) Medicinal Chemistry route as described in Scheme 17: (a) Furumoto, K.; Shiraki, K.; Hirayama, T. Composition Comprising Tetracyclic Compound. U.S. Patent 9,365,514 B2, June 14, 2016. (b) Kinoshita, K.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Ishii, N.; Sakamoto, H.; Hong, W. S.; Park, M. J.; Ono, Y.; Kato, Y.; Morikami, K.; Emura, T.; Oikawa, N. Tetracyclic Compound. PCT Int. Patent Application WO 2010/143664, December 16, 2010. (c) Kinoshita, K.; Kobayashi, T.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Hattori, K.; Miyagi, T.; Hong, W.-S.; Park, M.-J.; Takanashi, K.; Tsukaguchi, T.; Sakamoto, H.; Tsukuda, T.; Oikawa, N. J. Med. Chem. 2011, 54, 6286–6294. (d) Kinoshita, K.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Hara, S.; Ohwada, J.; Miyagi, T.; Kobayashi, T.; Takanashi, K.; Tsukaguchi, T.; Sakamoto, H.;


Page 53 of 55

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


Tsukuda, T.; Oikawa, N. Bioorg. Med. Chem. 2012, 20, 1271–1280. (e) Furumoto, K.; Shiraki, K.; Hirayama, T. Composition Comprising Tetracyclic Compound. U.S. Patent Application 2013/0143877 A1, June 6, 2013. (f) Kinoshita, K.; Asoh, K.; Furuichi, N.; Ito, T.; Kawada, H.; Ishii, N.; Sakamoto, H.; Hong, W. S.; Park, M. J.; Ono, Y.; Kato, Y.; Morikami, K.; Emura, T.; Oikawa, N. Tetracyclic Compound. U.S. Patent Application 2015/0150845 A1, June 4, 2015. (54)

The route in Scheme 18 is described in Examples 797 to 805: Kinoshita, K.; Asoh, K.;

Furuichi, N.; Ito, T.; Kawada, H.; Ishii, N.; Sakamoto, H.; Hong, W. S.; Park, M. J.; Ono, Y.; Kato, Y.; Morikami, K.; Emura, T.; Oikawa, N. Tetracyclic Compound. U.S. Patent 9,126,931 B2, September 8, 2015. (55)

TMSCl/TFE deprotection: Alsina, J.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1996, 37,

4195-4198. (56)

Xu, X. Method for Preparing Alectinib. PCT Int. Patent Application WO 2016/074532,

May 19, 2016. (57)

Bentley, D. J.; Slawin, A. M. Z.; Moody, C. J. Org. Lett. 2006, 8, 1975-1978.

(58)

(a) Sauks, J. M.; Mallik, D.; Lawryshyn, Y.; Bender, T.; Organ, M. Org. Process Res.

Dev. 2014, 18, 1310–1314. (b) Baxendale, I. R.; Pitts, M. R. Chemistry Today, May/June 2006, 24(3), 41-45. http://community.dur.ac.uk/i.r.baxendale/papers/ChemistryToday2006.24.41.pdf (accessed Sep 4, 2016). (59)

Pearson, D. E.; Pope, H. W.; Hargrove, W. W.; Stamper, W. E. J. Org. Chem. 1958, 23,

1412-1419.



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

(60)

Page 54 of 55

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208434Orig1s000ClinPharmR.

pdf (accessed Sep 4, 2016). (61)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208434Orig1s000SumR.pdf

(accessed Sep 4, 2016). (62)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208434s000lbl.pdf (accessed

Sep 4, 2016). (63)

http://www.pmda.go.jp/drugs/2014/P201400094/index.html (accessed Sep 4, 2016).


Page 55 of 55

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


Table of Contents Graphic 64x46mm (300 x 300 DPI)

ACS Paragon Plus Environment

Patent Review of Manufacturing Routes to Recently Approved

Recommend Documents