Patent Review of Manufacturing Routes to Recently ApprovedOncology Drugs: Ibrutinib, Cobimetinib, and AlectinibDavid L. Hughes

Cidara Therapeutics, Inc., 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States

ABSTRACT: This article reviews the patent literature on synthetic routes and API forms of recently approved orally activetyrosine 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, 13patents have been filed on alternate routes and 11 on final forms of the API by the innovators and generic firms. Regardingcobimetinib, a nonscalable route used during discovery efforts required an alternate route for development; an efficient route wasdeveloped and used throughout clinical development and commercialization. A productive second-generation eight-step linearroute to alectinib, with an average yield of 89% per step, was designed and developed to support development andcommercialization.

A synthetic route designed by a medicinal chemist has agoal of enabling rapid preparation of analogs to inter-

rogate chemical space as broadly as possible. Conversely, with atarget molecule identified, the process chemist has the objectiveto develop the most efficient, robust, green, and cost-effectiveroute and to define a final form that is stable, capable of beingprepared in high purity, and is suitable for formulation by theintended route of delivery. While a few pharmaceuticalcompanies allow and encourage journal publications, most ofthe information regarding manufacturing routes and final formsfor approved drugs can only be found in the patent literature.Yet, for some recently approved drugs, a search of the patentliterature has uncovered no process patents. Since a companywould likely wish to publish at least the elements of themanufacturing route to protect their freedom to operate (i.e.,prevent another company from patenting their manufacturingroute), the absence of process patents may suggest themanufacturing route has the same bond disconnections as thepublished medicinal chemistry route. In such cases, themedicinal chemistry route has likely provided an acceptablestarting point for the process chemist, and the route needs onlydevelopment rather than redesign. For low volume drugs wherecost of goods is not a driver for commercialization, a well-developed medicinal chemistry route may be perfectly fine for amanufacturing route. On the other hand, many medicinalchemistry routes simply cannot be developed into scalable orcost-effective routes. Such circumstances provide the oppor-tunity for process chemists to showcase their ingenuity indesigning and developing the best route to the target anddiscovering the ideal final form.The current article is part 2 of an intended series of reviews1

that focuses on recently approved drugs with innovativemanufacturing routes that are distinct from the medicinalchemistry route and where the majority of information on themanufacturing route and the final form is found in the patentliterature.2

Since the beginning of 2013 through Aug 31, 2016, the U.S.FDA has approved 129 new chemical entities. Of these, 20small molecules and 12 biologics have been approved for the

treatment of cancer, representing 25% of the newly registereddrugs in the U.S. during this period. This article reviewssynthetic routes and final forms of three small moleculeoncology drugs approved during this period, the orally activetyrosine kinase inhibitors3 Imbruvica (ibrutinib), Cotellic(cobimetinib), and Alecensa (alectinib).

1. IMBRUVICA (IBRUTINIB, PCI-32765)Ibrutinib (marketed under the trade name Imbruvica) is anorally active drug approved for the treatment of certainlymphoma and leukemia cancers. As a Michael acceptor,ibrutinib forms a covalent bond with a cysteine residue (Cys481) in the Bruton’s tyrosine kinase (BTK) active site, leadingto inhibition of BTK activity. Ibrutinib was discovered at CeleraGenomics. In April, 2006, Pharmacyclics acquired the rights tothe Celera BTK program and initiated preclinical and clinicaldevelopment of ibrutinib.4 In December 2011 Pharmacyclicsand the Janssen division of Johnson and Johnson entered intoan agreement to jointly develop and market ibrutinib. This jointdevelopment effort culminated in an NDA submission in June

Received: September 8, 2016Published: October 10, 2016

Review

pubs.acs.org/OPRD

© 2016 American Chemical Society 1855 DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

2013 and approval four months later. In May 2015Pharmacyclics was acquired by AbbVie.Both WuxiApptec (Nov 2013)5 and Lonza (Jan 2014)6

announced supply agreements with Pharmacyclics for produc-tion of commercial ibrutinib API. According to an articlepublished by the American Chemical Society, the inventory ofAPI was available from Lonza to support rapid launch of thedrug after approval.7

1.1. Medicinal Chemistry Route to Ibrutinib. Tworoutes to ibrutinib are described in the composition of matterpatents,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 aMitsunobu reaction to generate 7. After deprotection, theacrylamide is installed by acylation with acryloyl chloride toafford ibrutinib. This route was used by the medicinal chemiststo explore chemical space that permitted variations in theheterocycle.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. Thepiperidine side chain is then appended as in Scheme 1 via aMitsunobu reaction followed by installation of the acrylamidemoiety. For analogue preparation, this route locked in the

heterocycle but allowed evaluation of a range of substituents offthe heterocycle.

1.2. Manufacturing Route to Ibrutinib. The apparentmanufacturing route to ibrutinib is described in patentapplications from Janssen (Scheme 3).11 In the first step, the

chiral hydrazine 12-R is reacted with dinitrile 3 to generate 13as a single regioisomer. Reaction with a large excess offormamidine at 115 °C affords 14, followed by deprotection ofthe Cbz group with Pd(OH)2 on carbon. The three steps from3 to the ibrutinib penultimate intermediate 8 are carried out ina telescoped fashion with isolation of 8 by crystallization fromMeOH/water in overall 80% yield with a purity of 92.5%. Alsodescribed are variations in which Boc or benzyl protectinggroups are employed.Racemic hydrazine 12 is prepared as a bis-HCl salt in three

steps from N-Cbz-3-piperidone (15) via hydrazone formationwith Boc-hydrazine, reduction with NaCNBH3, and acidicdeprotection (Scheme 4). Claim 9 of the U.S. patentapplication11a states that 12 is resolved, but the specificationsection of the patent provides no discussion nor experimentalprocedures for a resolution. This statement regarding aresolution is not included in the claims of the grantedpatent.11b A compound claim for chiral hydrazine 12-R was

Scheme 1. Medicinal Chemistry Route to Ibrutinib

Scheme 2. Alternate Medicinal Chemistry Route to IbrutinibIntermediate

Scheme 3. Apparent Manufacturing Route to Ibrutinib, FinalSteps

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1856

included in the patent application,11a but this claim was notgranted in the issued patent.11b A second U.S. patentapplication is pending that also includes a compound claimfor 12-R as well as 13.12 A compound claim for 12-R would bevaluable as it would prevent other companies from using thiscompound in any synthetic approach until the process patentexpires, which may be a few years after the ibrutinib compoundpatent expires.The inventors argue 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 nongreen Mitsunobu chemistry that

generates a large amount of waste and requires isolationby chromatography;

• Avoids use of (S)-3-hydroxy-N-Boc-piperidine (6), anexpensive intermediate that is used in large excess due tocompeting elimination in the Mitsunobu reaction;

• Avoids use of hydrazine hydrate, a suspected carcinogenthat exothermically decomposes at higher temperatures;

• Replaces the 180 °C reaction of 4 with formamide withthe reaction of 13 with formamidine at 115 °C.

Drawbacks of this route are the length of the synthesis (10steps from commercially available raw materials) and aresolution to install the chiral center in hydrazine 12-R.1.3. Regulatory Starting Materials. According to the

European Public Assessment Report (EPAR) for Imbruvica, theAPI is manufactured in six steps from well-defined startingmaterials.13 The four steps from intermediates 3 and 12-R arelikely included in these six steps, suggesting the regulatorystarting materials (the point at which cGMP manufacturingbegins) are earlier than one or both of these compounds. While3 may be one RSM, an earlier intermediate in the hydrazinesynthesis such as 17 (Cbz or alternate protecting group) mightbe an RSM since the cGMP pocket would then include the stepin which the chiral center is established.1.4. 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 fromgeneric drug manufacturers. The FDA Orange Book forImbruvica lists 14 patents, the earliest of which expires onDec 28, 2026.11c The patent on the manufacturing route,11b

which is not yet included in the Orange Book, was filed in theU.S. in March 2013 and thus may have an expiration date manyyears beyond the compound patent expiration date, sincepatents generally are granted exclusivity for 20 years from thepriority (filing) date. Thus, generic companies will not be ableto manufacture ibrutinib by the Janssen patented route11b ifthey intend to market ibrutinib at the time the compound

patent expires at the end of 2026. Instead, they will either haveto use the nonpatented Medicinal Chemistry routes (Schemes1 and 2), which are far from ideal, or design and develop theirown route. By conceiving, developing, and patenting a novelroute(s), not only does the generic company secure freedom tooperate once the compound patent expires but also preventsother generic manufacturers from using such route(s) until itspatent expiry, thus providing a barrier to entry to genericcompetitors. This accounts for the high patent activity onibrutinib over the past two years. The alternate routes toibrutinib, which are grouped into four categories, are outlinedin the sections that follow.

1.4.1. Pyrazole Formation with Fully Elaborated Hydra-zine. A more convergent route to ibrutinib is described in a2015 international patent application (Scheme 5).14 In this

variation, pyrazole formation is carried out with the fullyelaborated hydrazine fragment 18 incorporating the acrylamidemoiety. Not only is this route more convergent but also avoidsthe protection/deprotection of the piperidine. The preparationof hydrazine 18 is not described.The synthesis of pyrazole 19 is carried out with triethylamine

in refluxing EtOH, conditions similar to those used by theJanssen group.11 After crystallization from EtOH/water, 19 isisolated in 80% yield. Ibrutinib is then prepared by reaction of19 with N,N-dimethylformamide dimethyl acetal in toluenewith the azeotropic removal of water. Crystallization affordsibrutinib 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 theconversion of 18 to ibrutinib, key points should this route beconsidered as an alternate manufacturing route. In addition, 18and 19 are Michael acceptors and potential genotoxicimpurities (PGIs), but since ibrutinib is AMES negative,15

these intermediates will likely also be AMES negative and willnot have to be controlled as PGIs nor handled as potentcompounds.

1.4.2. Convergent Mitsunobu/Displacement Route. Whilea Mitsunobu reaction may not be a viable option for the finalstep of ibrutinib at scale, one advantage of both Medicinal

Scheme 4. Synthesis of Racemic Hydrazine 12

Scheme 5. Convergent Route to Ibrutinib with a FullyElaborated Hydrazine Fragment

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1857

Chemistry routes (Schemes 1 and 2) is that (S)-N-Boc-3-hydroxypiperidine can be prepared in a single step frompiperidone 15 by enzymatic reduction using a ketone reductase(KRED),16 while preparation of hydrazine 12-R requires threesteps followed by a resolution from this same startingmaterial.11,12

In four separate patent applications, the Medicinal Chemistryroute starting with pyrazole 9 (Scheme 2) is revisited with thevariation that the Mitsunobu reaction is conducted earlier in thesequence (Schemes 6 and 7), prior to installation of thediphenyl ether group.17−20

According to the experimental section provided in theapplication from Arromax, product 20 of the Mitsunobureaction is crystallized from MTBE in 75% yield, thus avoidinga chromatography to remove the Mitsunobu byproducts.17 Noinformation is provided on the purity of the isolated materialnor if it is contaminated with the Mitsunobu byproducts. Asignificant drawback is that the reaction requires 2.2 equiv ofalcohol 6, presumably due to elimination of the activatedalcohol, as noted in the Janssen patents.11,12 The phenyl ether 7is then formed by either Suzuki (70% yield) or Kumadacoupling (61%) in modest yield (Scheme 6).17

In a patent application from Mylan, the Mitsunobu reactionhas been replaced with a mesylation/displacement sequence.The displacement reaction of 10-I is carried out in DMF withK2CO3 using 1.5 equiv of the mesylate 6-Ms, added in four

portions (Scheme 6). No yield nor enantioselectivity isprovided.19

Similarly, a patent application from Sun Pharmaceuticaldescribes a mesylate/displacement approach using either 10-Ior 10-Br. With substrate 10-Br, the reaction is conducted inDMF with K2CO3 as a base, and the mesylate 6-Ms (2.7 equiv)is added over 1 h at 70 °C. For substrate 10-I the reaction isconducted in NMP with Cs2CO3 at 120 °C using 3.5 equiv ofmesylate 6-Ms.20

In a similar approach (Scheme 7) described in a patentapplication from a group of three Chinese companies, theMitsunobu reaction of 10-Br and 6 is conducted in THFsolution; then conc. HCl (10 equiv) is added at the end of thereaction to cleave the Boc group, resulting in crystallization ofthe bis-HCl salt 21 in 70% yield across the two steps.18 TheSuzuki−Miyaura reaction is then conducted with theunprotected piperidine 21 to afford penultimate intermediate8. According to the experimental procedure provided, only 1.5equiv of chiral alcohol 6 is required for the Mitsunobu reaction.The Suzuki−Miyaura reaction can also be carried out with theacrylamide group already in place using the same conditions(not shown).18

Regarding viability of the convergent Mitsunobu/mesylatedisplacement approach (Schemes 6 and 7) as potentialmanufacturing routes, a number of unknowns remain.

1. Cost. While commercial pricing of 6 and 9 are unknown,compound 9 is purportedly available in ton quantitiesfrom 34 companies,21 and 6 uses the same startingmaterial 15 as the current route. An excess of 6 isrequired for the Mitsunobu coupling or mesylatedisplacement, but development efforts have alreadyreduced this excess to 1.5 equiv,18,19 so this route islikely cost-competitive with the current manufacturingroute (Scheme 3).

Scheme 6. Convergent Mitsunobu/Displacement Route toIbrutinib, First Approach17,19,20

Scheme 7. Convergent Mitsunobu Route to Ibrutinib,Second Approach18

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1858

2. Purity. No details are provided regarding the chemical orchiral purity of ibrutinib produced by this approach, butconducting the Mitsunobu step early in the sequence isan advantage since further removal of Mitsunobubyproducts can occur downstream.

3. Environment. The Mitsunobu reaction generates a largeamount of waste, but the resolution required for thecurrent route (Scheme 4) is also nongreen, and theshorter Mitsunobu route (six steps via Scheme 7,including one step each to prepare 6 and 11, versusten steps via Schemes 3 and 4) may be more productiveand have a lower PMI (process mass intensity). The useof the mesylate adds an extra step (preparation of themesylate), but overall should have a lower environmentalimpact than the Mitsunobu approach.

To summarize, the short routes described in Schemes 6 and7 appear capable of being developed into viable manufacturingroutes.1.4.3. Route Via Construction of Elaborated Pyrazole. A

route to ibrutinib devised by Sandoz scientists starts withdichloropyrimidine 22 and builds the pyrazole (Scheme 8).22

Key steps include a Friedel−Crafts reaction at the 4-position ofdiphenyl ether to generate 23, displacement of one aromaticchlorine with ammonia to form 24, followed by generation ofthe pyrazole 25 using either chiral hydrazine 12-R or the fullyelaborated hydrazine 18. While pyrazole formation is claimedusing both 12-R and 18, the only experimental proceduredescribed uses achiral cyclohexyl hydrazine, perhaps suggestingthe reaction with 12-R or 18 is not viable. No yields areprovided for any steps.22

A similar route for construction of the pyrazole 5 is describedby Zhejiang Jiuzhou Pharmaceutical Co. (Scheme 9) withexcellent yields for all steps.23 The ketone 23 is prepared byaddition of either the Grignard 27 (or lithium salt) of diphenylether 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 withhydrazine hydrate (93% yield) followed by ammonia in MeOH(89% yield).23 The patent application includes compoundclaims for 23 and 28.23

If installation of hydrazine 12-R or 18 can be implemented,then the approaches described in Schemes 8 and 9 arepotentially short and viable manufacturing routes to ibrutinib.

1.4.4. Ibrutinib via Masked Acrylamide. Sandoz has filed apatent application for a route to ibrutinib using a maskedacrylamide that is installed via phase-transfer chemistry usingbicyclic mesylate 30 (Scheme 10) followed by retro Diels−Alder reaction at 250 °C to reveal the acrylamide group.24 Thispatent application also describes installation of the piperidinylgroup via phase transfer chemistry of 5 with mesylate 6-Ms(not shown), thus avoiding the Mitsunobu chemistry used to

Scheme 8. Route to Ibrutinib via Pyrazole Construction,First Approach22

Scheme 9. Route to Ibrutinib via Pyrazole Construction,Second Approach23

Scheme 10. Ibrutinib via Masked Acrylamide

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1859

install this fragment in the Medicinal Chemistry route (Scheme1).24

1.4.5. Alternate Disconnections. In a patent applicationwith no examples, Janssen outlines a number of potentialalternate routes to ibrutinib with the acrylamide groupincorporated early in the synthesis, as summarized in Scheme11.25 The routes via intermediates 35 and 36 are similar tothose described in Schemes 6−8.18,22

1.5. Ibrutinib Commercial API Form. Anhydrouscrystalline free base form A is the commercial form of theAPI and is claimed in U.S. Patent 9,296,753 granted toPharmacyclics on March 29, 2016.26a

Form A has a low solubility in water (13 mg/L at pH 8) andhigh in vitro permeability and is therefore designated as a BCSClass 2 compound.26 Since bioavailability is dependent on theparticle size, micronized API is used in the formulated drugproduct.13

Absolute oral bioavailability using form A under fastedconditions is only 2.9%.15 A significant food effect is observed.In one clinical study, the bioavailability increased approximately2-fold when dosed with a high fat breakfast. In a separate study,the bioavailability was 16% when dosed with food andgrapefruit juice.15 Given the low bioavailability and large foodeffect, the crystalline free base is not the ideal API form, butsince Imbruvica was developed and approved under the FDA’saccelerated approval program with only 111 patients, it ispossible that Pharmacyclics and Janssen decided to continuedevelopment with an acceptable, but imperfect, API form anddrug product formulation to gain rapid approval rather than riskbridging to a potentially improved form and formulation.The Pharmacyclics patent describes two other anhydrous

forms (plus three solvates), but only anhydrous form A is

claimed.26 The formation of anhydrous crystalline free baseform A involves dissolution in MeOH at 45 °C, addition ofwater over a 3 h period at this temperature to inducecrystallization, followed by cooling. This form can also begenerated from aq. acetone, EtOH, and i-PrOH.26 Anhydrousform B is produced by dissolution in MeOH then adding waterat room temperature to create supersaturation and initiatecrystallization.26 Anhydrous form C is generated by crystal-lization from MeOH at room temperature.26

Of the three anhydrous polymorphs described by Pharma-cyclics,26 form A has the highest melting point at 154 °C (formB melts at approximately 120 °C and form C at approximately140 °C), suggesting form A is the thermodynamically moststable form. Forms B and C appear to be metastablepolymorphs that can form under kinetically controlledconditions at room temperature. Crystallization of form A at45 °C ensures that adequate energy is supplied to the system toconvert either metastable anhydrous from to the thermody-namic form A.

1.6. Alternate API Forms of Ibrutinib. According to theFDA Orange Book, the patent on free base crystal form A26a

expires Oct 30, 2033.11c This is an important patentit has thepotential to extend exclusivity for Imbruvica for an additionalseven years beyond the compound patent expiry, which occursat the end of 2026. A generic manufacturer will not be able tolaunch generic ibrutinib at the time the compound patentexpires unless they have their own patented API form or anunencumbered form that has freedom of operation. Therefore,generic manufacturers have already invested considerableefforts to discover, develop, and patent alternate final forms.As an additional hurdle, for approval of an ANDA

(abbreviated new drug application) a generic company mustestablish bioequivalence of their ibrutinib dosage form to thatof the originator drug.27 The U.S. FDA has already publishedthe bioequivalence requirements for ibrutinib, which includeboth fed and fasted studies of a 140 mg dose in healthy maleand female subjects.28 With a bioavailability of 2.9%, an APIthat is currently micronized,13 and a significant food effect, thiswill not be a trivial undertaking considering that an alternateform of the API will have to be used in the bioequivalencestudies. The good news for the generic companies is that (1)the bioequivalence studies can be conducted in healthyvolunteers (if ibrutinib was cytotoxic these studies wouldhave to be carried out in cancer patients and include a clinicalend point);27 and (2) they have a ten year runway in which tostudy and optimize the form and formulation.Should a company decide to pursue an alternate form and/or

formulation of ibrutinib with improved bioavailability relative tothe originator’s, then a 505B(2) approval pathway would berequired. In this approach, toxicity data generated by theoriginator company can be used to support the filing, but anindependent clinical trial must be conducted to prove efficacyand safety.29 The originator company (now Janssen andAbbVie) may also elect to develop an alternate form/formulation with improved bioavailability and lower dose as aline extension as the patent expiration date nears.Patent applications have been filed on a number of new

ibrutinib forms (Table 1). Most of the newly discovered formsare crystalline solvates of the free base that are of limitedinterest as API forms except as potential intermediates to viableanhydrous or amorphous forms.Regarding alternate free base forms that could be considered

as viable API forms, anhydrous free base form I described by

Scheme 11. Alternate Bond Disconnections for Ibrutinib

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1860

Crystal Pharmatech and Suzhou Pengxu Pharmatech has onlyslightly higher aqueous solubility than Form A and thereforewould not be expected to have significantly differentbioavailability.32 This could be a valuable form in an effort toobtain bioequivalence with the commercial anhydrous form A.Perrigo describes an anhydrous crystalline form VI, prepared bythermal desolvation of the DME solvate, but no character-ization is provided.31

The HCl salt reported by Ratiopharm could potentially haveimproved bioavailability.33 While ibrutinib has a pKa of 3.74 andtherefore can be protonated by strong acids, attempts to formsalts with mineral acids such as HCl lead to Michael addition tothe acrylamide, generating chloride 37. Ratiopharm hasdiscovered that initial formation of the HCl salt using 1.25 MHCl in 2-PrOH at −20 °C in CH2Cl2, followed by the additionof MTBE while cold, then allowing the slurry to warm toambient temperature, results in high recovery of the HCl saltwith <0.1% of the acid addition byproduct 37.33 The process isdescribed on a 30 g scale in the patent application. Kinetic andthermodynamic solubilities were measured versus crystallineform A free base (Table 2). The HCl salt has substantiallyimproved solubility across all pH although dissolution is slow atpH 4.5 and 6.8. The particle size is not provided; milling couldafford an increased rate of dissolution if the particle size of the

HCl salt was large in these studies. No bioavailability data wereprovided for the HCl salt nor any data on long-term stability,key information if the HCl salt is to be considered as analternate API form.33

A patent application from Zentiva describes the formation ofcrystalline and amorphous ibrutinib sulfate salt.35a The sulfatesalt can be crystallized from EtOH or acetone, while theamorphous form is prepared by concentrating to dryness asolution of the salt in acetone. No information is provided onsolubility, stability, or bioavailability.35a

1.7. Ibrutinib Dosage Form. The dosage form forImbruvica is an immediate release 140 mg hard gelatin capsuleusing a standard formulation which includes the excipientsmicrocrystalline cellulose, croscarmellose sodium, sodium laurylsulfate, and magnesium stearate.13,26

The recommended dose of Imbruvica is four capsules (560mg) once daily for mantle cell lymphoma (MCL) and threecapsules (420 mg) once daily for chronic lymphocytic leukemia(CLL). The half-life of ibrutinib is 4−6 h.13

Given the low bioavailability (2.9% fasted) and the knownreactivity of ibrutinib with HCl,13 Principia Biopharma has fileda patent application for enteric coated and time-delayed releaseformulations that bypass the stomach and are released in thecolon, where the pH is >5.36 The bioavailability of ibrutinib infed female rats increases from 21% when dosed orally to 100%when dosed intraduodenally.36 If a corresponding increase inbioavailability is realized in humans, the dose could besubstantially reduced with these formulations.Formulations that use amorphous ibrutinib free base may

have increased bioavailability relative to the crystalline formcurrently used commercially, but no such formulations havebeen published. The Perrigo patent application31 describes theformation of amorphous ibrutinib by spray drying, lyophiliza-tion, and precipitation. Likewise, amorphous ibrutinib preparedby thermal desolvation of solvates, lyophilization, hot meltextrusion, and lyophilization are reported in the Sandoz patentapplication.34 Dr. Reddy’s Laboratories describes the prepara-tion of amorphous ibrutinib by precipitation or concentrating asolution to dryness.35b This team has also describes amorphousdispersions by mixing ibrutinib with various polymers andconcentrating to dryness. However, none of these patentapplications reports solubility or bioavailability studies to assessif amorphous ibrutinib free base could have increased exposure.

Table 1. Crystal Forms of Ibrutinib

formdesignation company characteristics solvent system

A Pharmacyclics26 anhydrousFB

MeOH/water

B Pharmacyclics26 anhydrousFB

MeOH/water

C Pharmacyclics,26

Sandoz34anhydrousFB

MeOH21 or thermaldesolvation ofsolvates34

D Pharmacyclics26 MIBK solvate MIBKE Pharmacyclics26 toluene

solvatetoluene

F Pharmacyclics26 MeOHsolvate

MeOH

G Teva, Assia Chem30 HOAcsolvate

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

J Teva, Assia Chem30 anisolesolvate

anisole; anisole/MTBE

K Teva, Assia Chem30 not defined toluene/DMFI Crystal Pharmatech,

Suzhou PengxuPharmatech32

anhydrousFB

2-PrOH, n-heptane

III Perrigo,31 Sandoz34 1,4-dioxanesolvate

1,4-dioxane

IV Perrigo31 DME solvate DMEV Perrigo31 MeOH

solvateMeOH

VI Perrigo31 anhydrousFB

conversion from DMEsolvate in humid air

VII Perrigo31 anisolesolvate

anisole/acetone

VIII Perrigo,31 Sandoz34 PhCl solvate PhClIX Perrigo,31 Sandoz34 anisole

solvateanisole

none Perrigo,31 Sandoz34 CH2Cl2solvate

CH2Cl2

none Ratiopharm33 anhydrousHCl salt

CH2Cl2/MTBE

none Ratiopharm33 anhydrousHBr salt

CH2Cl2/MTBE

none Zentiva35a sulfate salt EtOH or acetone

Table 2. Comparison of the Solubility of Free Base Form Aand HCl Salt of Ibrutinib at 37 °C33

pH 1.2 pH 4.5 pH 6.8

solubility (mg/mL) 1 h 24 h 1 h 24 h 1 h 24 h

free base form A 2.64 2.64 0.01 0.01 0.01 0.01HCl salt 7.72 7.38 0.02 0.46 0.05 0.41

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1861

2. COTELLIC (COBIMETINIB, GDC-0973, XL518)

Cobimetinib (trade name Cotellic) is an orally active, selectiveinhibitor of mitogen-activated protein kinase (MEK) that wasdiscovered by Exelixis and was developed in conjunction withGenentech, a member of the Roche Group. Cotellic was firstapproved in Switzerland on Aug 27, 2015, for use incombination with vemurafenib, a BRAF inhibitor, as atreatment for patients with advanced melanoma. In November2015, the U.S. FDA approved cobimetinib for unresectable ormetastatic melanoma in combination with vemurafenib.37

2.1. Medicinal Chemistry Route to Cobimetinib. Thefinal steps of the medicinal chemistry route to cobimetinib arepresented in Scheme 12. The synthesis of the key intermediate,azetidine 47, is shown in Scheme 13.38

In the preparation of cobimetinib (Scheme 12), diarylamine40 is prepared by the selective SNAr reaction of the lithium saltof aniline 39 at the 2-F position of 2,3,4-trifluorobenzoic acid(38),39 followed by the formation of the acid fluoride 41 withcyanuric fluoride. Amide bond formation between 41 and 47mediated by i-Pr2NEt furnishes 42. Acidic deprotection of theBoc group then affords cobimetinib.38

The primary issues with the Medicinal Chemistry route liewith the synthesis of azetidine 47 (Scheme 13). Thedeprotonation of N-Boc-piperidine with 2-BuLi/TMEDA andthe addition to ketone 43 affords racemic 44 in 13% isolatedyield. Resolution is accomplished via preparation of theMosher’s ester and separation of the resulting diastereomersby silica chromatography. The acylation of 44 is carried outwith approximately 0.5 equiv of the acid chloride, which resultsin a dr of 4:1 favoring the desired diastereomer 45. After

recycling the recovered starting material twice, the purifieddiastereomer 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 maymake development of this approach unfeasible. Nonetheless, anasymmetric lithiation/addition could provide a quick entry to46 and transform the Medicinal Chemistry route into a viablemanufacturing route. Beak originally demonstrated asymmetricdeprotonation and electrophilic reactions of N-Boc-pyrrolidineusing the chiral ligand sparteine.40 This work has been extendedby O’Brien and Gawley to asymmetric lithiation of Boc-piperidines employing more readily available chiral ligands.41

O’Brien has shown that N-Boc-pyrrolidines can be lithiated andreacted with ketones such as benzophenone in high ee andyields, but no information is provided on potential applicationof asymmetric reactions of Boc-piperidines with ketones.42

2.2. Manufacturing Route to Cobemetinib. Theapparent six-step manufacturing route to cobemetinib (Scheme14) is described in two patent applications.43

The chiral center in the manufacturing route is derived fromthe chiral pool via 48, a building block introduced by Husson in1983 and used to prepare several natural products thatincorporate asymmetric piperidines.44 Compound 48 isprepared from (S)-phenylglycinol, KCN, and glutaraldehyde;44

an improved process was described in 2010 by process chemistsfrom Exelixis.45 Several key features of 48 make it perfectlysuited to enable a short asymmetric synthesis of cobemetinib,including:

(1) A rigid bicylic structure with a steric environment thatdirects reaction at one face of the derived carbanion toafford 50 with high diastereoselectivity;

(2) A cyano group which serves multiple functions: (a) toacidify the adjacent C−H bond to enable deprotonationof 48, (b) sterically small such that the addition reactioncan be carried out below −70 °C to afford high yield anddiastereoselectivity of 50, and (c) can be removed by areductive decyanation with retention of stereochemistry(50 to 51);

(3) A masked N-protecting group that can be removed byhydrogenation late in the sequence (53 to 54).

Scheme 12. Final Steps of Medicinal Chemistry Route toCobimetinib

Scheme 13. Synthesis of Azetidine Fragment 47

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1862

Lithiation of 48 is accomplished with LDA at −70 to −80 °Cin a solvent system of DMPU/THF (1:9). While maintainingthe low temperature, Boc-azetidinone 49 is added. After 1 h,the reaction is quenched by addition of the cold mixture into anaq. HOAc solution at 0 °C, then crystallization is carried outfrom heptane/2-PrOH to afford addition product 50 with 92%purity. The yield and dr are not provided.The next three steps are carried out in telescoped fashion.

The reductive decyanation and concomitant C−O reductivecleavage of aminal 50 are performed with sodium cyanobor-ohydride (1.7 equiv) and HOAc (2.1 equiv) in EtOH. Work-upwith toluene results in a toluene solution of 51 that isdeprotected using 7% aq. HCl as a two-phase reaction mixtureat 50 °C. The resulting HCl salt 52 in the aq. phase is takeninto the subsequent Schotten−Bauman reaction with 2,3,4-trifluorobenzoyl chloride in a two-phase aqueous/toluenereaction mixture. After work up the toluene layer containingproduct 53 is turned over to EtOH and the benzylic protectinggroup removed with 10% Pd/C to afford 54, which iscrystallized from 2-PrOH/MTBE in 50% yield. The final stepis an SNAr reaction with the lithium salt of aniline 39 to affordcobimetinib which is crystallized as the free base from toluenein 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 apatented compound and also preclude “work arounds” of theprocess claims that might be contemplated through use ofalternate reagents or solvents.

2.3. Regulatory Starting Materials. According to theEuropean Pharmaceutical Assessment Report (EPAR),46 theAPI is synthesized in six chemical steps with a telescopedsequence that includes five nonisolated steps, followed by a saltformation step. This corresponds to the route outlined inScheme 14.

2.4. Alternate Route No. 1 to Cobemetinib. Twoalternate synthetic approaches have been published as Chinesepatent applications. The first is based on the addition of 2-bromopyridine to Boc-azetidinone 49, then reduction of thepyridine 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 chromatography at scale has become more feasiblein the past decade, the inability to recover the undesiredenantiomer by racemization results in a yield of 39% in thechromatography, a low yield for the penultimate step of a

Scheme 14. Manufacturing Route to Cobemetinib

Scheme 15. Alternate Route to Cobimetinib via PyridineReduction and HPLC Resolution

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1863

potential manufacturing route. The route also requires aprotecting group switch from Boc (55) to trifluoroacetate (56)for the Pt-catalyzed reduction of the pyridine ring, making theentire route nine steps to cobimetinib free base, three stepslonger than the current manufacturing route if the chromatog-raphy is counted as a step. This approach could be feasible as amanufacturing route if the protecting group switch can beavoided and if the reduction of the pyridine ring can beconducted in an asymmetric fashion to avoid the HPLC chiralseparation.48

2.5. Alternate Route No. 2 to Cobemetinib. The secondalternate route to cobemetinib starts with enantiomerically pure(S)-2-pipecolic acid and builds the azetidine ring (Scheme16).49 (S)-2-Pipecolic acid is commercially available and can be

prepared enzymatically from L-lysine (Mercian process) orpicolinonitrile (Lonza process).50 Preparation of intermediate47 requires a lengthy eight steps, although many of these stepsare telescoped as outlined in Scheme 16, and the overall yieldto 47 is a respectable 32% on gram scale. Another drawback ofthis route is use of Mitsunobu chemistry to form the azetidine(63 to 47), a reaction that generates a high waste load. On apositive note, while many Mitsunobu reactions requirechromatography for purification, in this case the product 47can be isolated by crystallization from n-hexane/MeOH.2.6. Final API Form and Dosage Form. The final form of

the API is a crystalline hemifumarate salt. Very littleinformation is available on preparation and characterization ofthis salt. According to the EPAR,46 cobimetinib hemifumarateexists as a single polymorph. Solubility at 37 °C is 0.72 mg/mLin water and 48.2 mg/mL in 0.1 M HCl.51 The bioavailability is46% and is unaffected by food.The oral dosage form is a film-coated tablet containing

cobimetinib hemifumarate equivalent to 20 mg cobimetinib as

active substance.49 The recommended dose is 60 mg (3 × 20mg tablets) once daily.

3. ALECENSA (ALECTINIB, RO5424802, CH5424802)Alectinib (marketed as Alecensa) is an orally active inhibitor ofanaplastic lymphoma kinase (ALK) for the treatment of ALK-positive nonsmall cell lung cancer (NSCLC). Alectinib wasdiscovered by Chugai, a member of the Hoffmann-La Rochegroup. The drug was first approved in Japan in July 2014. TheU.S. FDA approved alectinib in December 2015.52 A marketingapplication was filed in Europe in September 2015, but the drughas not yet been approved in Europe as of Aug 31, 2016.

3.1. Medicinal Chemistry Route to Alectinib. TheMedicinal Chemistry route is nine linear steps, not includingsalt formation, starting from 7-methoxy-2-tetralone (Scheme17). The overall yield is approximately 1%.53

Besides the overall low yield, which could likely besignificantly improved with appropriate development, theroute has two drawbacks.

1. The Fischer indole reaction of 66 with 3-cyanophenylhydrazine delivers a 1:1 mixture of regioisomers. Thedesired regioisomer 67 is isolated by crystallization, butin a yield of only 25%.

2. The ethyl group is introduced late via a Sonigashirareaction of 72 with TIPS−acetylene, followed bydesilylation with TBAF to generate acetylene intermedi-ate 73, which is then hydrogenated to the ethyl group tofurnish alectinib in an overall three-step sequence with ayield of 14% across the three steps.

3.2. Second-Generation Route to Alectinib. A second-generation route that addresses the issues with the originalroute is presented in Scheme 18.54 At eight linear steps, thisroute is only one step shorter than the original route, but theethyl group is introduced efficiently, the indole is formed by analternate route that furnishes a single regioisomer, and theoverall yield is 38%, an average of 89% per chemical step.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 byhydrogenation to afford 76.The indole is constructed in four steps from carboxylic acid

76 by iodination ortho to the ethyl group to furnish 77followed by a 2-carbon chain extension of the carboxylic acidwith malonate half ester to form ketoester 78. Next an SNArreaction of the malonate with 4-chloro-3-nitrobenzonitrile (79)affords 80, followed by nitro reduction and ring closure toprovide indole 81.The piperidinyl side chain is incorporated via a Pd-catalyzed

C−N cross coupling with 71 to afford 75. Deprotection of thet-butyl ester is carried out using TMS-Cl in trifluoroethanolfollowed by work up with NaOH.55 An intramolecular Friedel−Crafts reaction of the resulting carboxylic acid 83 mediated byAc2O 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 sizesranging from 30 to 1400 g.54

3.3. Alternate Route to Alectinib. A more convergentroute to alectinib was published as an international patentapplication (Scheme 19).56 The key step in this approach is anacid-catalyzed Friedel−Crafts reaction of the tertiary alcohol 89with cyanoindole 86 which affords 83, intersecting this samepenultimate intermediate as the manufacturing route (Scheme

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

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1864

18). This route is seven steps from commercially available rawmaterials with a longest linear sequence of five steps. Yieldsaverage 87% for the five reported steps.6-Cyanoindole (85) is formed via a Leimgruber−Batcho

reaction via published chemistry57 followed by acylation at the3-position of the indole with trichloroacetyl chloride togenerate the methyl ester 86.Fragment 89 is prepared in two steps. SNAr reaction of 3-

bromo-4-ethylacetophenone 87 with the piperidine side chain71 under microwave conditions generates 88 followed byreaction with with methyl Grignard to afford tertiary alcohol89.Since acetophenone 87 is poorly activated for an SNAr

reaction, the high temperatures generated by microwaveheating are necessary to effect this transformation. Scale upof this chemistry would likely require continuous processing foreither microwave application or high temperature conditionsand would be a major challenge should this approach beconsidered as a manufacturing route.58 Alternatively, a Pd-catalyzed cross-coupling could be considered, similar to thechemistry 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 brominationof commercially available 4-ethylacetophenone using AlCl3/Br2in 59% yield.59

3.4. Alectinib API Form and Dosage Form. The twoissued patents describe the preparation of the HCl salt53a,54 andmesylate salt of alectibnib.53a The patents include no specificclaims for either crystalline salt form, but a broad claim for anoral formulation was secured as well as a claim for any form

having a solubility in water below 100 mg/L.54 The solubility ofthe HCl salt in aqueous solution ranges from 0.5 mg/L at pH 6to 1.3 mg/L at pH 1 and is reported as ranging from 22 to 35mg/L in unbuffered water.53a

The HCl salt is the final form of the API. Two methods ofpreparation of the HCl salt are described. In both procedures,the free base is dissolved in 17 volumes of a solvent mixtureconsisting of 10 parts methyl ethyl ketone, 4 parts water, and 3parts HOAc. In method one, this mixture is slowly added to asolution of 30 volumes of ethanol and 2 volumes of 2 N HCl atroom temperature, resulting in the crystallization of the HClsalt.54 In the other method, 1 volume of 2 N HCl is added tothe dissolved free base at 60 °C followed by 25 volumes ofethanol to induce crystallization.53a Particle size reduction isaccomplished via jet milling.The mesylate salt is prepared from 200 volumes of a DMA/

EtOAc mixture at 90 °C.53a

The absolute bioavailability of alectinib hydrochloride is37%.60 When administered with a high fat meal, a 3-foldincrease in exposure was noted, which includes alectinib and itsmajor active metabolite M4, 90.60,61 No significant changeswere noted in bioavailability when alectinib was coadministeredwith the proton pump inhibitor, esomeprazole.60

The recommended dose of alectinib in the U.S. is 600 mgtwice daily with food. The dosage form is a 150 mg immediaterelease capsule.62 In Japan, capsule doses of 20 mg and 40 mgare available.63

Scheme 17. Medicinal Chemistry Route to Alectinib

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1865

4. SUMMARY

4.1. Ibrutinib. Seven approaches to ibrutinib have beendescribed in the patent literature. The manufacturing routeconsists of 10 steps from commercially available raw materialsand requires a resolution of hydrazine 12 to install the chiralcenter. Patent applications have been filed on four alternateapproaches that have fewer steps and may be viablemanufacturing routes if the purity and stability are acceptable.Anhydrous crystalline free base form A is the final form ofibrutinib API, having a bioavailability of only 2.9%. As such, a

number of alternate API forms have been investigated. Ofthese, the HCl salt has increased solubility relative to the freebase and may be an improved API form if it has adequatestability. A formulation that releases drug into the smallintestine has also shown enhanced bioavailability in a rat model.

4.2. Cobimetinib. While cobimetinib is a small volumeproduct with likely no cost drivers, an alternate route to thisdrug was required since the Medicinal Chemistry was not viablefor scale up due to a low yielding and unproductive resolutionthat required chromatographic separation of diastereomers. An

Scheme 18. Second Generation Route to Alectinib

Scheme 19. Alternate Route to Alectinib

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1866

efficient manufacturing route was designed and developed withthe chirality derived from the chiral pool. The EPAR notes that“the same synthetic route has been used throughout thedevelopment from toxicological studies to the commercialbatches.”46 Patent applications on two alternate routes havebeen filed. The final form of cobimetinib is a hemifumarate salt.4.3. Alectinib. The probable manufacturing route to

alectinib involves eight linear steps with an average yield perstep of 89%. The final form of the API is the HCl salt, which isformulated in a standard immediate release capsule.

■ AUTHOR INFORMATIONNotesThe author declares no competing financial interest.

■ ABBREVIATIONSAMES, named after Bruce Ames, a biological assay to assess themutagenic potential of chemical compounds; ANDA, abbre-viated new drug application; API, active pharmaceuticalingredient; AUC, area under the curve; BCS, Biopharmaceut-ical Classification System; Boc, t-butyloxy carbonyl; CDI,carbonyl diimidazole; cGMP, current Good ManufacturingPractices; DIAD, diisopropylazo dicarboxylate; DMA, N,N-dimethylacetamide; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzo-quinone; DMF-DMA, N,N-dimethylformamide dimethyl ace-tal; DME, dimethoxyethane; DMPU, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; EPAR, European Public As-sessment Report; FB, free base; LDA, lithium diisopropyla-mide; MEK, mitogen-activated protein kinase; MIBK, methylisobutyl ketone; NBS, N-bromosuccinimide; NIS, N-iodosucci-nimide; (NHC)Pd(allyl)Cl, allylchloro[1,3-bis(2,6-diisopropyl-phenyl)imidazol-2-ylidene]palladium (II); PyBop, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate;RSM, regulatory starting material; TEMPO, (2,2,6,6-tetrame-thylpiperidin-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, includingpatents and journal publications, can be found on the web sites ofPharmacodia (http://www.pharmacodia.com/en) and Anthony Cras-to (https://newdrugapprovals.org/author/amcrasto/). (accessed Oct3, 2016).(3) The “tinib” suffix is reserved for tyrosine kinase inhibitors. http://d r u g i n f o . n l m . n i h . g o v / d r u g p o r t a l / j s p / d r u g p o r t a l /DrugNameGenericStems.jsp (accessed Sep 4, 2016).(4) http://www.prnewswire.com/news-releases/celera-genomics-announces-sale-of-therapeutic-programs-to-pharmacyclics-56115072.html (accessed Sep 4, 2016).(5) http://wxpress.wuxiapptec.com/wuxi-partner-pharmacyclics/(accessed Sep 4, 2016).(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’sTyrosine 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 ofUsing. PCT Int. Patent Application WO 2008/054827 A2, May 8,2008. (c) Chen, W.; Loury, D. J.; Mody, T. D. Pyrazolo-pyrimidineInhibitors of Bruton’s Tyrosine Kinase. U.S. Patent 7,718,662 B1, May18, 2010. (d) Honigberg, L.; Verner, E.; Pan, Z. Inhibitors of Bruton’sTyrosine 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 BTKInhibitor for Mantle Cell Lymphoma, Chronic LymphocyticLeukemia, and Waldenstrom’s Macroglobulinemia. In InnovativeDrug Synthesis; Li, J. J., Johnson, D. S., Eds.; John Wiley & Sons,Inc.: Hoboken, NJ, 2016; Chapter 8, pp 157−165.(10) Owens, T. Ibrutinib, a Carboxylic Acid Amide Inhibitor ofBruton’s Tyrosine Kinase. In Bioactive Carboxylic Compound Classes,Pharmaceuticals and Agrochemicals; Lamberth, C., Dinges, J., Eds.,Wiley-VCH: Weinheim, Germany, 2016; Chapter 14, pp 199−208.(11) (a) Pye, P.; Ben Heim, C.; Conza, M.; Houpis, I. N. Processesand Intermediates for Preparing a Medicament. U.S. PatentApplication 2014/0275126, September 18, 2014. (b) Pye, P.; BenHeim, C.; Conza, M.; Houpis, I. N. Processes and Intermediates forPreparing 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=205552&Product_No=001 (accessed Sep 5, 2016).(12) Pye, P.; Ben Heim, C.; Conza, M.; Houpis, I. N. Processes andIntermediates for Preparing a Medicament. U.S. Patent Application2015/0376193 A1, December 31, 2015.(13) EPAR for Imbruvica: 24 July 2014 EMA/CHMP/645137/2014Committee 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 (ac-cessed Oct 3, 2016).(14) Xu, X. Method for Preparing Ibrutinib. PCT Int. PatentApplication 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/hea l th/documents/community- reg i s ter/2014/20141021129815/anx_129815_en.pdf (accessed Sep 4, 2016).(16) Ju, X.; Tang, Y.; Liang, X.; Hou, M.; Wan, Z.; Tao, J. Org. ProcessRes. Dev. 2014, 18, 827−830.(17) Hong, J.; Liu, G. Synthesis Method of Ibrutinib. Chinese PatentApplication CN104557945, April 29, 2015.(18) Zhang, X.; Kong, R.; Liu, X.; Chen, S.; Chen, X.; Yang, L.;Zhang, A.; Cheng, X. Method for Preparing Ibrutinib. PCT Int. PatentApplication 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 forthe 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. IbrutinibIntermediate Compounds, Preparation Methods and Uses Thereof.PCT Int. Patent Application WO 2016/000476, January 7, 2016.

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1867

(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’sTyosine Kinase Inhibitor. PCT Int. Patent Application WO 2016/115356, July 21, 2016.(26) (a) Smyth, M.; Goldman, E.; Wirth, D. D.; Purro, N. CrystallineForms of a Bruton’s Tyrosine Kinase Inhibitor. U.S. Patent 9,296,753B2, March 29, 2016. (b) Smyth, M.; Goldman, E.; Wirth, D. D.; Purro,N. Crystalline Forms of a Bruton’s Tyrosine Kinase Inhibitor. U.S.Patent Application 2013/0338172 A1, December 19, 2013. (c) Smyth,M.; Goldman, E.; Wirth, D. D.; Purro, N. Crystalline Forms of aBruton’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 KinaseInhibitor. U.S. Patent Application 2015/0158871 A1, June 11, 2015.( 2 7 ) h t t p : / / w w w . f d a . g o v / d o w n l o a d s / d r u g s /guidancecomplianceregulatoryinformation/guidances/ucm377465.pdf.( 2 8 ) h t t p : / / w w w . f d a . g o v / d o w n l o a d s / D r u g s /GuidanceCompl ianceRegula toryInformat ion/Guidances/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.; FernadezCasares, A.; Ten Figas, G.; Ben-Daniel, R. Ibrutinib Solid Forms andProduction 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 ApplicationWO 2015/081180, November 26, 2014.(33) Rabe, S.; Erdmann, M.; Albrecht, W. Acid Addition Salt ofIbrutinib. PCT Int. Patent Application WO 2016/050422, April 7,2016.(34) Martin, N.; Schreiner, E.; Kelk, N.; Reece, H. Physical Forms ofIbrutinib, a Bruton’s Kinase Inhibitor. PCT Int. Patent ApplicationWO 2016/079216, May 26, 2016.(35) (a) Zvatora, P.; Dammer, O.; Tkadlecova, M.; Krejcik, L.;Beranek, J. Ibrutinib Sulphate Salt. PCT Int. Patent Application WO2016/127960, August 18, 2016. (b) Peddy, V.; Velaga, 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 forthe 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-Bromoor 4-iodo phenylamino) benzoic Acid Derivatives. U.S. Patent7,019,033 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, 2ndEd., Elsevier, Oxford, UK, 2012, Chapter 3, 97−178.(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 forMaking 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 Usein the Treatment of Cancer. U.S. Patent Application 2015/0210668A1, 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-Piperidin-2-yl)-azetidin-3-ol and Its Use Derivatives,Chinese Patent Application CN 104725352 A, June 24, 2015.(48) Asymmetric hydrogenation of pyridines remains an unsolvedproblem in organic chemistry. The best results to date requirequaternization 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.; 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.; deVries, J. G.; Piarulli, U.; Gennari, C.; Lefort, L. Adv. Synth. Catal. 2016,358, 2589−2593.(49) Xu, X. Cobemetinib Preparation. Chinese Patent ApplicationCN 105330643A, February 17, 2016.(50) Stinson, S. C. Chem. Eng. News 2001, 79 (28), 65−84. July 9http://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 2015, 75, 75−82.(53) Medicinal Chemistry route as described in Scheme 17:(a) Furumoto, K.; Shiraki, K.; Hirayama, T. Composition ComprisingTetracyclic 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. PatentApplication 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.; Tsukuda,T.; Oikawa, N. Bioorg. Med. Chem. 2012, 20, 1271−1280.(e) Furumoto, K.; Shiraki, K.; Hirayama, T. Composition ComprisingTetracyclic 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. Patent9,126,931 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. PatentApplication WO 2016/074532, May 19, 2016.(57) Bentley, D. J.; Slawin, A. M. Z.; Moody, C. J. Org. Lett. 2006, 8,1975−1978.

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1868

(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 2006, 24 (3), 41−45. May/June 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.(60) 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).

Organic Process Research & Development Review

DOI: 10.1021/acs.oprd.6b00304Org. Process Res. Dev. 2016, 20, 1855−1869

1869