Highlights of the Recent U.S. Patent Literature - Organic Process

Highlights from the Patents pubs.acs.org/OPRD

Highlights of the Recent U.S. Patent Literature

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SUMMARY Three patent applications are reviewed that were published during 2015, including (1) an application by the pharmaceutical company, Novartis, for a process for the antimalarial drug candidate cipargamin, (2) an application by the University of Bradford, UK, for a solid-to-solid crystallization process to generate metastable polymorphs, and (3) an application by fine chemical company Cambrex for a new route to the antiepileptic (R)-lacosamide. Each application discloses previously unpublished chemistry. While medicinal chemists are avid followers of the patent literature in order to keep abreast of potential overlapping chemical space relevant to their particular programs, process chemists are generally indifferent to the patent literature. First of all, patents are not scientific publications but are documents written for legal and business purposes. As such, the scientific discussion is generally limited to just what is needed to support the claims with a focus on demonstrating what is new and useful about the invention. Other scientifically interesting aspects of the work that are not directly relevant to the claims are generally not discussed. Second, since published patent applications are not peer-reviewed and have yet to be reviewed by a patent examiner, the chemistry as described is often not reproducible, and many (or all) claims may not ultimately be granted. While irreproducibility is an issue with literature publications as well, patent applications pose a higher risk since much less analytical data and experimental details are provided than with peer-reviewed publications. Patent applicants are required to provide just enough detail such that one “skilled in the art” can reproduce the procedures, but often the sketchy experimental procedures leave much to imagination. The lack of scientific discussion in a patent application can be frustrating. In a literature publication, for example, if an asymmetric reaction is presented, data would be provided on ee’s or de’s under differing conditions, and the authors would likely provide perspective on how they arrived at the optimum conditions. But in a patent, no such context is providedonly the end results are presented. The discussion section of a patent, referred to as the specification or disclosure, is often focused on covering the widest scope possible for the chemistry and is not a scientific discussion of the results. Pertinent details are often missing, bringing up many questions for any reader who wishes to consider the chemistry for their particular application. With these caveats, however, patent applications are in many cases important scientific contributions. Since some companies do not encourage or allow publication by their scientists in peer-reviewed journals, patents may be the only disclosure of a synthetic process for a drug or drug candidate or a newly developed methodology. With this in mind, our goal is to review patents and patent applications that offer novel, important, and practical chemistry that is not covered in the scientific literature. © XXXX American Chemical Society

In this article, three patent applications are reviewed that were published during 2015, each disclosing previously unpublished chemistry: • A process for the antimalarial drug candidate cipargamin, filed by the pharmaceutical company Novartis; • A new route to the antiepileptic (R)-lacosamide, filed by the fine chemical company Cambrex; and • A solid-to-solid crystallization process to generate metastable polymorphs, filed by the University of Bradford, UK.

I. ENZYMATIC TRANSAMINATION AS A KEY STEP IN THE PREPARATION OF THE ANTIMALARIAL, CIPARGAMIN Patent Application Pub. Number: US 2015/0045562 A1 Publication Date: Feb 12, 2015 Title: Chemical Process for Preparing Spiroindolones and Intermediates Thereof Applicant: Novartis AG, Basel (CH) Assignee: Novartis AG, Basel (CH) Inventors: M. Crowe, M. Foulkes, G. Francese, D. Frimler, E. Kuesters, K. Laumen, Y. Li, C. Lin, J. Nazor, T. Ruch, D. Smith, S. Song, S. Teng Cipargamin (KAE609) is a spiroindolone drug candidate that Novartis is developing for the treatment of malaria. Representing a new mechanism for the treatment of parasites, cipargamin inhibits the P-type cation-transporter ATPase4 (PfATP4), thereby disrupting sodium regulation in the parasite. This patent application, with inventors from both Codexis and Novartis, discloses a process to prepare cipargamin featuring an enzymatic transamination to install a chiral primary amino group. The original 10-step process, outlined in Scheme 1, was described in the patent application WO 2009/132921.1 In this process, the chiral amine is installed via an enzymatic resolution via deacylation of the acetamide 2. In addition to the wasteful resolution, other inefficiencies of this route include protection/ deprotection (Ac/Boc, 2 to 4, and 5 to 6) and a three-step sequence to reduce the carboxylic acid to a methyl group (3 to 6). The new six-step chemical process described in the current application is outlined in Scheme 2. The isatin intermediate is prepared via the Sandmeyer isatin procedure from the readily available 2-chloro-3-fluoroaniline (no details provided but likely reagents are provided based on literature examples) followed by three steps to install the requisite methyl ketone starting material for the transamination reaction. For the transamination step, the enzyme ATA-256 was engineered by Codexis to accommodate the non-natural indole substrate 12. Since the substrate is not water-soluble, PEG 200 (approximately 20 vol %) is used as a cosolvent, an interesting selection given that DMSO or methanol are the most common cosolvents for enzymatic reactions. Isopropylamine is employed

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DOI: 10.1021/acs.oprd.6b00004 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Patents

Scheme 1. Original Route to Cipargamin1

Scheme 2. Improved Route to Cipargamin Employing Transaminase Reaction

as the amine donor, a strategy that was adopted from the work of Merck and Codexis for the transamination of sitagliptin ketone.2 During the transamination, which is a reversible reaction, i-PrNH2 is converted to acetone, which can be readily removed by evaporation to drive the reaction to completion. The workup involves filtration to remove enzyme residues followed by pH swings in which the product is extracted into the aqueous layer under acidic conditions, then basified for extraction into the organic layer. Addition of (+)-camphorsulfonic acid (CSA) provides the amine 14 as the crystalline CSA salt. No details are provided on enantioselectivity for the transamination, and it is not clear if the (+)-CSA is required to upgrade the ee or whether this salt was selected based on physical properties and the ability to develop a scalable crystallization process. The final step to generate the spiroindole involves a diastereoselective condensation of the chiral amine with 5-chloroisatin (7) under acidic conditions. The diastereoselectivity of this reaction is not provided, nor any ee or de data for the final product. The spiroindole is also isolated as a (+)-CSA salt, which is then converted to the crystalline free base hemihydrate as the final form of cipargamin.

Regarding IP protection, as most readers know, defending process claims is difficult, and “work arounds” are often possible by changing, for example, a base or solvent. Compound claims are more secure, so obtaining claims on late stage intermediates is an effective strategy to discourage competitors from developing and implementing a process that involves such intermediates. To this point, in the current patent application, compounds 10, 11, and 12 are claimed. B




II. SOLID STATE POLYMORPH TRANSFORMATION USING A HEATED SCREW EXTRUDER Patent Application Pub. Number: US 2015/0165400 A1 Publication Date: Jun 18, 2015 Title: Crystallization Process Applicant: University of Bradford, Yorkshire (GB) Assignee: University of Bradford, Yorkshire (GB) Inventors: C. Kulkarni, R. Dhumal, A. Kelly, T. Gough, A. Paradkar Kulkarni and co-workers from University of Bradford in the UK describe a solid-to-solid crystallization transformation process via a twin screw extruder, using temperature and shear to generate metastable polymorphs. The inventors provide examples for the preparation of unique metastable polymorphs of the drugs artemisinin, chlorpropamide, carbamazepine, and piracetam and have shown these polymorphs are kinetically stable for up to 2 years. Polymorphs of crystalline compounds can have quite different bioavailabilities. In general, the more stable polymorph has lower solubility than less stable polymorphs, and, therefore, the less stable polymorphs may have increased bioavailability. The goal of the work by the Bradford group was to devise a method to generate metastable and more bioavailable polymorphs of known drugs. In addition, to be useful for medicinal purposes, the metastable polymorphs must be kinetically stable to ensure no transition to the more stable polymorph occurs during the intended shelf life of the drug. To achieve the desired crystalline transformation, the crystalline compound of interest is heated to 10 to 20 °C below the melting point and then extruded. Side-by-side twin intermeshing screw extruders were designed to overcome poor mixing observed with single screw extruders. The twinscrew extruders are typically run in starve-fed mode with partially filled channels to achieve the desired level of mixing and shear. While perhaps obvious, the melting point of the newly formed polymorph must be above the extruding temperature such that a melt does not occur during the process. The inventors provide an example of the production of the metastable triclinic form of artemisinin on a 100 g scale. Artemisinin is the key drug in the Artemisinin combination treatment (ACT), which has become the standard of care for malaria. Artemisinin has been in the news recently as Youyou Tu, the scientist who isolated this drug from traditional Chinese medicine, was awarded the 2015 Nobel Prize in chemistry. Artemisinin was originally obtained by isolation from the wormwood plant Artemisia annua and has been sourced by extraction from this plant for decades. Since the natural source only provides 1.7 g of drug per kilogram of dry plant material, the need for a more secure supply drove the development of a synthetic approach to artemisinin. The route recently developed and implemented at commercial scale is perhaps the most innovative production process for a synthetic API. The key intermediate, artemisinic acid, is produced via synthetic biology using technology developed in Keasling’s lab at Berkeley.3 This intermediate is then converted to artemisinin using a photochemical process developed by Sanofi scientists.4

The most stable polymorph of crystalline artemisinin is the orthorhombic form. The Bradford team converts this to the triclinic form by feeding 100 g of artemisinin at a rate of 3 g/min into a 16 mm twin screw extruder operating at 20 rpm, a temperature of 140−145 °C, and a residence time of 12 min. The DSC of the starting orthorhombic form shows a close double melt initiating at approximately 155 °C; thus, the polymorph conversion occurs at 10 to 15 °C below the melting temperature of the orthorhombic form. The triclinic crystal form of the resulting product is confirmed by X-ray powder diffraction (XRPD). No polymorph transformation occurred at an operating temperature of 120 °C. While the 1H NMR spectra of the pre- and postconversion samples are provided and appear to be comparable, the HPLC impurity profiles of material are not provided so it is unclear if any degradation occurs during the heating and extruding process. This is a critical point since even small amounts of new impurities generated during the process would require qualification in toxicology studies prior to approval for human use. Stability studies (storage temperature not provided) indicate the triclinic polymorph that is produced maintains its crystal form for up to 2 years. On the other hand, addition of small amounts of solvent cause turnover to the orthorhombic form, ranging from 5 min with acetone to 15 days with cyclohexane, while no conversion occurred over a 2 month period in water, a solvent in which artemisinin has very low solubility. The triclinic form can also be prepared by crystallization from cyclohexane at 80 °C, but even after drying, conversion to the orthorhombic form occurs within a week. The amount of residual solvent in this study was not provided nor the storage temperature during which conversion occurred. However, in a separate experiment, addition of 0.2 g of cyclohexane to 3 g of triclinic artemisinin resulted in conversion to the orthorhombic form in 15 days. The conversion to the more stable form with only a minimum amount of solvent underscores the importance of the solid-tosolid protocol developed by the Bradford team, which offers a unique method of obtaining a kinetically stable polymorph. The advantage of the triclinic form arises from increased rate and extent of dissolution, leading to improved bioavailability in animal models. Based on in vitro dissolution studies with water as a medium, the triclinic form has 4-fold greater drug release vs the orthorhombic form over a 20 h study at 37 °C. Oral bioavailability in fasted rats (average area-under-the curve (AUC) over 24 h involving 6 rats in each arm) increased 2-fold for the triclinic form, which suggests the dose required for human efficacy could be significantly lowered if the bioavailability gains translate from rats to human. In addition, a suitable formulation must be developed that maintains the triclinic form during processing and storage.

III. RESOLUTION/RACEMIZATION PROCESS FOR (R)-LACOSAMIDE Patent Application Pub. Number: US 2015/0299105 A1 Publication Date: Oct 22, 2015 Title: New Process C




Scheme 5. Route to (R)-Lacosamide from D-Serine with Cbz Protecting Group

Applicant: Cambrex Karlskoga AB, Sweden and Cambrex Profarmaco Milano, Italy Assignee: Cambrex Karlskoga AB, Sweden and Cambrex Profarmaco Milano, Italy Inventors: S. Radaelli, G. Zurlo, L. Eklund, M. Eek, A. Maasalu, M. Schmidt (R)-Lacosamide, marketed by UCB under the trade name VIMPAT, was approved by the EU in August 2008 and US FDA in October 2008 as a therapy to treat seizures in patients with epilepsy. According to the UCB Web site, revenue for VIIMPAT in 2014 was €471 million.5 In October 2015, Cambrex filed a patent application that describes a new process for the preparation of (R)-lacosamide featuring a resolution/racemization process to install the chiral amine. In this section we compare the Cambrex process to (1) the original literature routes where the chirality is derived from the chiral pool, D-serine (Schemes 3, 4, and 5),6,7 (2) routes Scheme 3. Route A to (R)-Lacosamide from D-Serine with No Protecting Groups

Cbz, methylation of the hydroxyl group with AgO/MeI, formation of the benzyl amide, hydrogenolysis to cleave the Cbz group, followed by acetylation. This route has improved step yields, with overall 50% yield, but still requires 5 equiv AgO and 10 equiv MeI for the methylation. More than a dozen patents and patent applications have been published which address the drawbacks of the original routes. Not all can be reviewed here, but the focus of most of the reported work is to employ alternate protecting groups and to carry out the methylation under conditions that do not require AgO. The route via Scheme 4 is attractive since it is short and requires no protecting groups. In a patent that published in December, 2014, scientists from MSN Laboratories report modest improvements in all three steps of this approach.8 Acylation of the amine with acetic anhydride in HOAc occurs in 96% yield (no purity provided), which is followed by benzamide formation mediated by isobutyl chloroformate in 45% yield after purification. Methylation is carried out under phase transfer conditions with dimethyl sulfate. The yield for the methylation is 30% using toluene as solvent but is about 50% using dichloromethane. Purification by recrystallization proceeds in 70% yield using EtOAc, so the overall yield for the three-step route is only 15%.8 Ranbaxy scientists have addressed the O-methylation step by using a trityl group to protect the amine and using either KOH/MeI in DMSO (48% yield) or NaH/imidazole/MeI in THF (60−77% yield) for the methylation.9 Sun Pharma scientists have used a Boc protecting group of the amine and carry out the methylation under phase transfer conditions with dimethyl sulfate. The entire process is carried out as a through process with only a final isolation of lacosamide, but no yields are provided for any of the transformations.10 Another group of

Scheme 4. Route B to (R)-Lacosamide from D-Serine with No Protecting Groups

starting with D-serine with improvements over the original route,8−12 and (3) a recently published process from Sanofi, which installs the chiral center via use of a chiral auxiliary and crystallization to separate diastereomers.13 Three routes to (R)-lacosamide from D-serine were described in 1998 by Kohn and co-workers in two patents6 and a journal publication.7 The patents6 describe two routes which do not require protecting groups (Schemes 3 and 4), but the yields are low, partial racemization occurs, and 5 equiv of AgO are required for the methylation with MeI (10 equiv). The third route (Scheme 5) involves protection of the amine with D




as a salt with N-formyl-L-leucine, leading to an isolated yield of 84% with 99% ee of the amine component. (R)-Lacosamide is then prepared by acylation in 85% yield. The final product is crystallized from i-PrOAc and provides a polymorph melting at 146 °C, which is claimed by Cambrex as a novel polymorph. The four-step process provides (R)-lacosamide in 53% overall yield with >99% ee. A completely different approach to (R)-lacosamide (Scheme 7) was recently published by Sanofi13 and was also the subject of

Indian scientists use benzhydryl or Boc amine protecting groups and carry out the methylation using KOH/dimethyl sulfate in DCM or NaH/MeI in DMF (methylation yields 60−70%).11 Cadila scientists protect the amine nitrogen with Boc and the hydroxyl group with benzyl, then install the acetyl amide and benzyl amide selectively, followed by hydrogenation to remove the O-benzyl group, and conduct as a final step the O-methylation using phase transfer conditions with dimethyl sulfate (many examples but best crude yield 69% for the methylation).12 In a completely different approach, scientists from Council of Scientific and Industrial Research use a starting material from the chiral pool, O-benzyl-(S)-glycidyl ether, but the sequence requires 7 steps and a Mitsunobu step to install an azide which is reduced to the desired amine.14 The Cambrex process provides an alternative route to (R)-lacosamide, starting with commercially available racemic methyl 2,3-dichloroproprionate (Scheme 6). The patent

Scheme 7. Sanofi Route to (R)-Lacosamide

Scheme 6. Cambrex Route to (R)-Lacosamide

a previous patent application published in 2013.15 This route features a novel Ugi reaction that assembles the core structure of (R)-lacosamide in a single step. Use of (S)-1-(4-methoxyphenyl)1-methylethylamine in the Ugi reaction affords a 69:31 mixture of diastereomers, with the desired diastereomer 20 favored. Unfortunately, it is the undesired diastereomer that is least soluble, so the undesired diastereomer is removed first by crystallization, then the desired diastereomer is recovered by crystallization from the mother liquors. After a number of recycles, a 52−55% yield of the pure diastereomer is isolated. Removal of the protecting group with formic acid/anisole affords (R)-lacosamide in overall 41% yield. Similar to the Cambrex patent, the final lacosamide is isolated by crystallization from i-PrOAc to form a polymorph having a melting point of 146 °C. The 3 routes to (R)-lacosamide are compared in Table 1. The original route from D-serine has an overall yield of 50% but is not commercially viable due to the large amounts of AgO and MeI that are required for the methylation. The alternative methylation conditions reported in the patent literature use conditions that are scalable but offer modest methylation yields (up to 70% crude yields) with a variety of different protecting groups. The Sanofi route is practical, having been conducted at

application also provides an example of the preparation of methyl 2,3-dibromoproprionate from bromine and methyl acrylate, but this material is not used in subsequent transformations. The dichloro compound is converted in one pot to compound 17 by conversion of the primary chloride to the methyl ether with NaOMe in MeOH followed by reaction of the secondary chloride with benzylamine, with an overall yield of 80%. No information is provided regarding the selectivity for this process. The amino-benzyl group is selectively removed by hydrogenation and the resulting amine 18 is subjected to a resolution-racemization process using 5-nitrosalicylaldehyde to form an intermediate imine that can be racemized under the reaction conditions. The desired isomer 19 is crystallized E




Table 1. Comparison of 3 Approaches to (R)-Lacosamide route chiral source number of steps overall yield as reported advantages disadvantages

D-serine

approach

Cambrex rac/res resolution−racemization 4 54%

chiral auxiliary 4 41%

Chiral starting (D-serine) material now readily available and inexpensive Methylation continues to be a difficult step

High yielding resolution/racemization process to install chiral center Modest overall yields, use of benzyl protecting group

Short route, builds complexity quickly through Ugi reaction Cumbersome and low yielding crystallization to remove undesired diastereomer

(7) Kohn, H. Anticonvulsant Enantiomeric Amino Acid Derivatives. US Patent 5,773,475, June 30, 1998; Re-issued as RE 38,551, July 6, 2004. Kohn, H.; Andurkar, S. V. Anticonvulsant Enantiomeric Amino Acid Derivatives. US Patent 6,048,899, April 11, 2000. These patents are owned by Research Corporation Technologies Inc. and licensed by UCB. (8) Reddy, M. S.; Eswaraiah, S.; Srinivas, A.; Satyanarayana, R. Process for Preparing (R)-2-Acetamido-N-Benzyl-3-Methoxy-Propionamide. US Patent 8.907,132, December 9, 2014. (9) (a) Madra, M. K.; Singh, P. K.; Khanduri, C. H. Intermediate Compounds and their Use in the Preparation of Lacosamide. US Patent 8,093,426, January 10, 2012. (b) Madra, M. K.; Singh, P. K.; Khanduri, C. H. Intermediate Compounds and their Use in the Preparation of Lacosamide. US Patent 8,378,142, February 19, 2013. (10) Patel, M. M.; Mohite, V. D.; Khambampati, S.; Chitturi, T.; Thennati, R. US Patent Application 2013/0102811 A1, April 25, 2013. (11) Garimella, K. N.; Danda, S. R.; Budidet, S. R.; Katuroju, S.; Kaki, G. R.; Yatcherla, S. R.; Aminul, I.; Meenakshisunderam, S. US Patent Application 2013/0123537, May 16, 2013. (12) Pandey, B.; Shah, K. Processes for the Preparation of Lacosamide and Intermediates Thereof. US Patent 8,853,439, October 7, 2014. (13) Wehlan, H.; Oehme, J.; Schafer, A.; Rossen, K. Org. Process Res. Dev. 2015, 19, 1980−1986. (14) Murugan, M.; Mujahid, M.; Majumdar, P. P. Process for the Synthesis of Antiepileptic Drug Lacosamide. US Patent 8,748,660, June 10, 2014. (15) Wehlan, H.; Rossen, K.; Oehme, J.; Kral, V. Process for the production of N-substituted 2-(acetylamino)-N′-benzyl-3-methoxypropanamides, WO 2013072330 A1, May 23, 2013. (16) Evonik corporate presentations on the biocatalytic route to Dserine. http://corporate.evonik.com/_layouts/Websites/Internet/ DownloadCenterFileHandler.ashx?fileid=1435, p 12−15; accessed 02-Jan-2016.

the 50 kg scale, but suffers from a cumbersome isolation of the desired diastereomer in modest yield.13 The Cambrex route proceeds in good yields for each step, appears to be scalable, and uses only inexpensive materials. The impetus for designing routes that avoid D-serine was likely driven by the high price for this unnatural amino acid. However, in recent years, a number of approaches to unnatural amino acids have been devised that have resulted in these amino acids now being available at reasonable costs. In particular, Evonik has developed a biocatalytic route to D-serine from glycine and formaldehyde that should provide an inexpensive source of this material.16 Since the dose of lacosamide is 300−400 mg per day, cost of goods will be a significant factor as generics enter the market. It appears that each of the approaches outlined herein have the opportunity for development of a low-cost route to (R)-lacosamide.

David L. Hughes*

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

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

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ABBREVIATIONS IP, intellectual property; XRPD, X-ray diffraction; PEG, polyethylene glycol; DSC, differential scanning calorimetry

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Sanofi Ugi route

chiral pool 5 20−50%

REFERENCES

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Highlights of the Recent U.S. Patent Literature - Organic Process

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