A Practical Synthesis of a PI3K Inhibitor under Noncryogenic

Dec 16, 2012 - Discovery and Process Development of Class I PI3K and Class I PI3K/mTOR Inhibitors GDC-0941 and GDC-0980. Srinivasan BabuFrancis ...
0 downloads 0 Views 607KB Size
Subscriber access provided by UNIV OF ARIZONA

Full Paper

A Practical Synthesis of a PI3K Inhibitor Qingping Tian, Zhigang Cheng, Herbert M Yajima, Scott J Savage, Keena L Green, Theresa Humphries, Mark E Reynolds, Srinivasan Babu, Francis Gosselin, David Askin, Isao Kurimoto, Norihiko Hirata, Mitsuhiro Iwasaki, Yasuharu Shimasaki, and Takashi Miki Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op3002992 • Publication Date (Web): 16 Dec 2012 Downloaded from http://pubs.acs.org on December 25, 2012

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 27

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

A Practical Synthesis of a PI3K Inhibitor under Noncryogenic Conditions via Functionalization of a Lithium Triarylmagnesiate Intermediate Qingping Tian*, Zhigang Cheng, Herbert M. Yajima, Scott J. Savage, Keena L. Green, Theresa Humphries, Mark E. Reynolds, Srinivasan Babu, Francis Gosselin and David Askin Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 Isao Kurimoto, Norihiko Hirata, Mitsuhiro Iwasaki, Yasuharu Shimasaki and Takashi Miki Health & Crop Sciences Research Laboratory, Sumitomo Chemical Co., Ltd., 3 Utajima, Nishiyodogawa-ku, Osaka 555-0021, Japan RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to) *Corresponding author: [email protected]

ABSTRACT We report a practical synthesis of PI3K inhibitor GDC-0941. The synthesis was achieved using a convergent approach starting from a thienopyrimidine intermediate through a sequence of formylation and reductive amination followed by Suzuki-Miyaura cross-coupling.

Metalation of the

thienopyrimidine intermediate involving the intermediacy of triarylmagnesiates allowed formylation under non-cryogenic conditions to produce the corresponding aldehyde. ACS Paragon Plus Environment

We also investigated

Organic Process Research & Development

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

Page 2 of 27

aminoalkylation via a benzotriazolyl-piperazine substrate as an alternative to the reductive amination route. We evaluated both palladium and nickel catalyzed processes for the borylation and SuzukiMiyaura cross-coupling. Final deprotection and salt formation afforded the API. Introduction The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation, survival, migration and metabolism. The lipid kinases of the PI3K family are responsible for the phosphorylation of the 3'-hydroxyl group of phosphatidylinositols, leading to the activation of the serine / threonine protein kinase Akt and further downstream oncogenes.1

The PI3K pathway is one of the most

frequently activated pathways in tumors, with mutations in one of its components detected in a notable percentage of human cancers.2 Thus, the essential role of PI3K in human cancer has spurred the development of PI3K inhibitors.3 GDC-0941 (Pictilisib) is a novel small molecule PI3K inhibitor discovered at Genentech and is currently being evaluated as an anticancer agent (Figure 1).4 Substantial amounts of GDC-0941 were required to support on-going development activities. Herein we wish to report a robust and practical synthesis of GDC-0941 suitable for preparation of multi-kilogram quantities of GDC-0941.

Figure 1. Structure of PI3K Inhibitor GDC-0941 The synthesis is outlined retrosynthetically in Scheme 1. We envisioned that GDC-0941 could be prepared from chloropyrimidine 1 and indazole boronate 2 through a Suzuki-Miyaura cross-coupling. Further disconnection of 1 would lead to piperazine 3 and thienopyrimidine 4.

ACS Paragon Plus Environment

Page 3 of 27

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

Scheme 1. Retrosynthetic Analysis

Results and Discussion Synthesis of Thienopyrimidine 4. The medicinal chemistry synthesis of thienopyrimidine 4 relied on condensation of commercially available methyl 3-aminothiophene 2-carboxylate (5) with urea at 190 ºC (Scheme 2, Route A).4 We sought milder conditions for the condensation reaction and replaced urea with potassium cyanate in aqueous AcOH and the reaction proceeded smoothly at rt to afford 6 in 77% yield (Scheme 2, Route B).5

Pyrimidinone 6 was then chlorinated with POCl3 to afford the

dichloropyrimidine 7. Subsequent site-selective SNAr reaction6 with morpholine in MeOH proceeded under mild conditions and gave thienopyrimidine 4 in 96% yield. Scheme 2. Synthesis of the Thienopyrimidine Core 4

We envisioned that intermediate 1 could be assembled from compounds 3 and 4 via a sequence of metalation, formylation and reductive amination.

In an alternative approach, the synthesis of

intermediate 1 would be achieved by a direct aminoalkylation.7 Reductive Amination Approach. The metalation and formylation of thienopyrimidine 4 is illustrated in Scheme 3. Thus, thienopyrimidine 4 was deprotonated with n-BuLi at –70 °C. Warming the reaction mixture to –50 °C achieved complete deprotonation as ascertained by 1H NMR spectroscopic analysis

ACS Paragon Plus Environment

Organic Process Research & Development

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

Page 4 of 27

of aliquots quenched into D2O. Formylation was performed by addition of DMF at –70 °C, followed by quenching the reaction mixture into cold aqueous HCl to afford the desired aldehyde 8. Scheme 3. Organolithium Formylation

Although metalation of the thiophene ring could be performed with n-BuLi under cryogenic conditions, the instability of the resulting organolithium species precluded its use on large scale.8 Lithium trialkylmagnesiates, have been used successfully in halogen-magnesium exchange,9 and for deprotonation of a variety of heterocycles including furans and thiophenes.10

Lithium

triarylmagnesiates are generally more stable than the corresponding organolithium species, and reactions can thus be performed under non-cryogenic conditions. To our delight, we found that use of n-Bu2i-PrMgLi allowed for deprotonation and formylation under non-cryogenic conditions (–10 °C) and provided aldehyde 8 in 87% yield (Scheme 4). The resulting lithium triarylmagnesiate 9 and the components of the reaction mixture (after addition of DMF) were stable at –5 °C for > 6 h.11 In an optimized procedure, i-PrMgCl and n-BuLi were added sequentially to a solution of 4 in THF at –10 °C. This operationally simple process proved easy to perform on 20 kg scale and obviated the need for a separate vessel to prepare n-Bu3MgLi as reported previously.10 Scheme 4. Improved Formylation Reaction

ACS Paragon Plus Environment

Page 5 of 27

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

The reductive amination of aldehyde 8 with piperazine 312 was performed using trimethyl orthoformate as the dehydrating agent (Scheme 5). We evaluated a variety of solvents (CH2Cl2, THF, toluene, EtOAc and CH3CN) for the reaction and found that CH3CN was superior and afforded the desired product 8 in 85% isolated yield. It was critical to allow sufficient time for complete iminium ion formation (ca. 2 h under the optimized conditions) before the addition of the reducing agent, NaBH(OAc)3. Otherwise, the corresponding alcohol 10 was observed at a higher level (> 10A% by HPLC) when the reducing agent was added after aging for < 2 h.

Scheme 5. Reductive Amination

O

O

O H HCl N

N S

+

N

OHC N

8

Cl

N S O O 3

N

1) NaOAc, CH3CN HC(OCH3)3, rt 2) NaBH(OAc)3 85%

N

S

N

N

N

+

HO

S

N

Cl N

Cl

N S O O

1

10

Aminoalkylation Approach. The reductive amination reaction performed well; however, there were concerns about the alcohol impurity 10 which was carried in the downstream chemistry resulting in formation of additional impurities that were difficult to remove. We therefore explored an alternative route involving aminoalkylation, as an effort to avoid the formation of the alcohol 10. We envisioned that the aminoalkylation could be performed by direct addition of lithium triarylmagnesiate 9 to an iminium equivalent of piperazine 3. As indicated in Scheme 6, the iminium salt 13 was generated from the aminal 11 or aminol ether 12.13 The resulting iminium salt was then subjected to the lithium triarylmagnesiate 9 to afford the desired product 1. However, a significant amount of the starting material 4 was observed in the crude product possibly due to the impurities present in the iminium salt.14

ACS Paragon Plus Environment

Organic Process Research & Development

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

Page 6 of 27

Scheme 6. Synthesis of Intermediate 1 via Iminium Salt

The iminium salt was also generated in situ by treating the aminol ether 12 with a Lewis acid (Scheme 7), followed by addition of the lithium triarylmagnesiate 9. We identified ZnCl2 as the preferred Lewis acid with the desired product being obtained in ~ 80% yield. Scheme 7. Synthesis of 1 from Iminium Salt Generated in situ from Aminol Ether

To further improve the aminoalkylation process, our efforts were then focused on the benzotriazole substrates that have been widely used in the aminoalkylation reactions.15

Treatment of 3 with

benzotriazole, paraformadehyde and MeOH in the presence of KHCO3 afforded benzotriazolylpiperazine 14 in 90% yield after isolation by simple filtration (Scheme 8). Unlike the aminol ether 12, compound 14 is not hygroscopic and can be isolated as a bench-stable solid. Treatment of compound 14

ACS Paragon Plus Environment

Page 7 of 27

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

with ZnCl2 followed by addition to a solution of lithium triarylmagnesiate 9 afforded the desired product 1 in 93% yield (Scheme 8). Scheme 8. Aminoalkylation via Benzotriazolyl-Piperazine 14

This route achieved a slightly higher yield than the reductive amination route and did not generate the alcohol impurity 10. Although a large excess of ZnCl2 (4 equiv) was needed, this route offered a complementary process to the reductive amination. Synthesis of Indazole Boronate. Next, our attention was shifted to synthesis of indazole boronate 2 needed for the Suzuki-Miyaura cross-coupling reaction. The synthesis of the boronate is illustrated in Scheme 9. We selected the THP protecting group to improve the solubility of the Suzuki-Miyaura cross-coupling product and facilitate the removal of residual Pd and impurities. The synthesis began with diazotization of 3-chloro-2-methylaniline (15) and subsequent cyclization under basic conditions, producing 4-chloroindazole (16) in quantitative yield.

Installation of the THP group was then

performed with 3,4-dihydro-2H-pyran (DHP) in the presence of pyridinium p-toluenesulfonate (PPTS), leading to a mixture of indazole isomers 17a and 17b which were treated with bis(pinacolato)diboron in the presence of PdCl2(PPh3)2 and PCy3 to afford boronates 2a and 2b, respectively (Scheme 9, Method A).16

ACS Paragon Plus Environment

Organic Process Research & Development

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

Page 8 of 27

Scheme 9. Synthesis of the Boronates 2a and 2b

We found that the THP group at the 2-position could easily be removed after the cross-coupling reaction, but it proved difficult to deprotect the THP group at the 1-position. In general, the acidcatalyzed THP protection of indazole at the 2-position is favored kinetically and the 1-THP regioisomer is the thermodynamic product.16b As such, installation of the THP group at the 2-position was achieved under mildly acidic conditions.16b We applied the similar conditions in our process, and obtained a mixture of 2-THP and 1-THP products (Table 1, entry 1). We found that the site-selectivity of the protection was solvent-dependent and could be improved to 94:6 17a/17b using toluene/heptane (3:4, v/v) as solvent mixture (Table 1, entry 4). At higher temperature and with prolonged reaction time, the site-selectivity was eroded as the kinetically favored product 17a would slowly be converted to the thermodynamically favored product 17b. Under the optimized conditions, the reaction was performed at 40 ºC for 5 h. Palladium catalyzed borylation gave the desired 2-THP boronate ester 2a in 41% yield over two steps, and chromatographic purification was required for removal of the undesired 1-THP regioisomer 2b and residual Pd.

ACS Paragon Plus Environment

Page 9 of 27

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

Table 1. Regioselectivity of THP Protection of Indazole 16 in Various Solvents entry

solvents

17a : 17b

1

CH2Cl2

77 : 23

2

CH3CN

10 : 90

3

DMF

45 : 55

4

Toluene/heptane (3:4, v/v)

94 : 6

We next investigated the Ni-catalyzed borylation of indazoles 17a and 17b (Scheme 9, Method B).17 We found that in reactions using 4 mol% of Ni(NO3)2•6H2O/PPh3 as catalyst, the product could be isolated in 53% yield over two steps and 99A% HPLC by a simple crystallization. Furthermore, residual Ni was readily removed from the process stream by simple aqueous washes. Although a relatively higher loading of the Ni catalyst (4 mol%) was employed, the process was still cost-effective due to the significantly lower cost of the Ni catalyst, Ni(NO3)2•6H2O, compared to the expensive Pd catalyst. As a further improvement relative to metal-catalyzed borylation, we opted to replace the boronates with the corresponding boronic acids 18a and 18b in the Suzuki-Miyaura cross-coupling reaction. Indazoles 21a / 21b were prepared from 3-bromo-2-methylaniline (19) in two steps employing the sequence used in Scheme 9. Halogen-metal exchange on indazoles 21a/21b and borylation with B(O-iPr)3 gave the desired boronic acids in 60% yield (Scheme 10).18

ACS Paragon Plus Environment

Organic Process Research & Development

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

Page 10 of 27

Scheme 10. Synthesis of Indazole Boronic Acid

Suzuki-Miyaura Cross-coupling. With intermediate 1 and the boronic acid 18a in hand, we turned to the Suzuki-Miyaura cross-coupling reaction to provide the THP protected GDC-0941 22. We explored the use of both Pd and Ni catalysts for the reaction and identified PdCl2(PPh3)2 in aqueous Na2CO3/1,4dioxane and Ni(NO3)2•6H2O/PPh3 in K3PO4/CH3CN as the catalyst systems of choice (Scheme 11). In the Ni-catalyzed reaction, we found that boronic acid 18a performed better than the corresponding boronate esters 2a and 2b and boronic acid 18b.19 The removal of the residual Pd contaminate required the use of the expensive scavengers (Florisil® and Thio-Silica ®) and large volume of solvents. In contrast, the residual Ni catalyst could be easily removed from the crude reaction mixture through an aqueous ammonia wash and crystallization. This route afforded the THP protected GDC-0941 22 in 79% yield as the final key bond forming step. Scheme 11. Pd or Ni-catalyzed Suzuki-Miyaura Cross-coupling Reaction O N S

N

N

N

N S O O

HO

1

+ Cl

B

OH

O

Method A: 1. PdCl2(PPh3)2, Na2CO3 1,4-dioxane, 88 oC 2. Florisil/Thio-Silica 60%

N THP Method B: N Ni(NO3)2 6H2O, PPh3 K3PO4, CH3CN, 60 oC 18a 79%

N S

N

N

N

N S O O

ACS Paragon Plus Environment

22

THP N N

Page 11 of 27

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

End-Game Chemistry.

Organic Process Research & Development

The bis-methanesulfonate salt of GDC-0941 was identified as a suitable

crystal form for development. Deprotection of the THP group and salt formation was performed in one operation by using methanesulfonic acid in aqueous MeOH (H2O/MeOH, 1:19 (v/v)) and the product was isolated by simple filtration (Scheme 12). The crude product was then purified by recrystallization from MeOH/H2O to afford GDC-0941 in 90% yield, HPLC: >99 A%, ICPMS analysis: 4 kg). (9) (a) Gallou, F.; Haenggi, R.; Hirt, H.; Marterer, W.; Schaefer, F.; Seeger-Weibel, M. Tetrahedron Lett. 2008, 49, 5024−5027; (b) Mase, T.; Houpis, I.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.; Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres, P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Tschaen, D.; Wada, T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. J. Org. Chem. 2001, 66, 6775−6786. (c) Dolman, S. J.; Gosselin, F.; O'Shea, P. D.; Davies, I. W. Tetrahedron 2006, 62, 5092−5098. (10) (a) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Bischoff, L.; Trécourt, F.; Quéguiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R. J. Org. Chem. 2005, 70, 5190−5196. (b) Mongin, F.; Bucher, A.; Baureau, J.P.; Bayh, O.; Awad, H.; Trécourt, F. Tetrahedron Lett. 2005, 46, 7989−7992. (c) Bayh, O.; Awad, H.; Mongin, F.; Hoarau, C.; Trécourt, F.; Quéguiner, G.; Marsais, F.; Blanco, F.; Abarca, B.; Ballesteros, R. Tetrahedron 2005, 61, 4779−4784. (11) The stability of the lithium triarylmagnesiate was investigated in the same way as described for the organolithium species in footnote 8.

Compound 4 was recovered in 97% after the lithium

ACS Paragon Plus Environment

Organic Process Research & Development

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

Page 26 of 27

triarylmagnesiate solution was aged at −5 oC for 6 h. The reaction mixture after addition of DMF was also stable as no change on the HPLC purity and the assay yield of the aldehyde product 8 was observed after the reaction mixture was aged at −5 oC for 20 h. (12) Sulfonylation of N-Boc-piperazine with methanesulfonyl chloride and deprotection with HCl in EtOH gave piperazine•HCl 3 in 85% yield. (13) (a) Heaney, H.; Papageorgiou, G.; Wilkins, R. Tetrahedron, 1997, 53, 2941−2958. (b) Bryson, T. A.; Bonitz, G. H.; Reichel, C. J.; Dardis, R. E. J. Org. Chem. 1980, 45, 524−525. (14) The assay purity of the isolated iminium iodide salt was only 90% based on quantitative 1H NMR analysis. One of the major impurities in the iminium salt was tentatively assigned as the residual 3 based on the 1H NMR data. In addition, other iminium salts (chloride, trifluoromethanesulfonate and trifluoroacetate) were also investigated, but the iodide salt performed best in the reaction. (15) (a) Katritzky, A. R.; Manju, K.; Singh, S. K.; Meher, N. K. Tetrahedron 2005, 61, 2555−2581. (b) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409−548. (c) Katritzky, A. R.; Suzuki, K.; He, H. J. Org. Chem. 2002, 67, 3109−3114. (16) (a) Sun, J.; Teleha, C. A.; Yan, J.; Rogers, J. D.; Nugiel, D. A. J. Org. Chem. 1997, 62, 5627−5629. (b) Slade, D. J.; Pelz, N. F.; Bodnar, W.; Lampe, J. W.; Watson, P. S. J. Org. Chem. 2009, 74, 6331−6334. (17) (a) Morgan, A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym. Sci. 2000, 76, 1257−1268. (b) Leowanawat, P.; Resmerita, A.-M.; Moldoveanu, C.; Liu, C.; Zhang, N.; Wilson, D. A.; Hoang, L. M.; Rosen, B. M.; Percec, V. J. Org. Chem. 2010, 75, 7822−7828. (c) Murata, M.; Sambommatsu, T.; Oda, T.; Watanabe, S.; Masuda, Y. Heterocycles, 2010, 80, 213−218. (18) Li, W.; Nelson, D. P.; Jensen, M.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394−5397. ACS Paragon Plus Environment

Page 27 of 27

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

(19) For Ni-catalyzed Suzuki-Miyaura cross-coupling, see: (a) Haneda, S.; Sudo, K.; Hayasi, M. Heterocycles 2012, 84, 569−575. (b) Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352−6363. (20) (a) Lundin, C.; North, M.; Erixon, K.; Walters, K.; Jenssen, D.; Goldman, A.S.H.; Helleday, T. Nucleic Acids Research, 2005, 33, 3799−3811. (b) Alzaga, R.; Ryan, R. W.; Taylor-Worth, K.; Lipczynski, A. M.; Szucs,R.; Sandra, P. J. Pharm. Biomed. Anal. 2007, 45, 472−479. (21) Teasdale, A.; Eyley, S. C.; Delaney, E.; Jacq, K.; Taylor-Worth, K.; Lipczynski, A.; Reif, V.; Elder, D. P.; Facchine, K. L.; Golec, S.; Oestrich, R. S.; Sandra, P.; David, F. Org. Proc. Res. Dev. 2009, 13, 429−433. (22) The source of the methyl methanesulfonate in the product was from the starting material, methanesulfonic acid which contained