USOO7652137B2
(12) United States Patent (10) Patent No.: US 7.652,137 B2 Graczyk et al. (45) Date of Patent: Jan. 26, 2010
(54) SYNTHESIS OF 5 SUBSTITUTED WO WO-99,51233 10, 1999 7-AZANDOLES AND 7-AZANDOLINES WO WO-00,26210 5, 2000 WO WO-00,26211 5, 2000 (75) Inventors: Piotr Pawel Graczyk, London (GB); WO WO-OO,35909 6, 2000 Afzal Khan, London (GB); Gurpreet WO WO-00, 35921 A1 6, 2000 Singh Bhatia, London (GB) WO WO-OOf 43393 T 2000 WO WO-OO,56710 9, 2000 (73) Assignee: Eisai R & D Management Co., Ltd. WO WO-00,64449 11, 2000 (JP) WO WO-OOf 64872 11, 2000 WO WO-01/12609 2, 2001 (*) Notice: Subject to any disclaimer, the term of this WO WO-O 1/47922 T 2001 patent is extended or adjusted under 35 WO WO-01/49288 T 2001 U.S.C. 154(b) by 450 days. WO WO-O2/10137 2, 2002 WO WO-O2, 16359 2, 2002 (21) Appl No.: 10A548.162 WO WO-O2/O81475 10, 2002 y x- - - 9 WO WO-03/028724 4/2003 (22) PCT Filed: Mar. 5, 2004 WO WO-03/082868 10, 2003 WO WO-03/082869 10, 2003 (86). PCT No.: PCT/GB2OO4/OOO946 WO WO-2004/O16609 2, 2004 WO WO-2004/O16610 2, 2004 S 371 (c)(1) WO WO-2004/078756 9, 2004 (2), (4) Date: Mar. 13, 2006 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2004/078757 Denmarket al., “Convergence of Mechanistic Pathways in the Pal PCT Pub. Date: Sep. 16, 2004 ladium(0)-Catalyzed Cross-Coupling of Alkenylsilacyclobutanes and Alkenylsilanols'. Organic Letters. vol. 2, No. 16, pp. 2491-2494. (65) Prior Publication Data (2000). Denamark et al., “Highly Stereospecific, Palladium-Catalyzed US 2006/0235042 A1 Oct. 19, 2006 Cross-Coupling of Alkenylsilanols' Organic Letters vol.2, No.4, pp. 565-568 (2000). (30) Foreign Application Priority Data Greene, T. and Wuts, P. Protective Groups in Organic Synthesis, 3rd Edition, Wiley, New York (1999). Mar. 6, 2003 (GB) ...... O305142.2 Hatanaka et al., “Cross-Coupling of Organosilanes with Organic Halides Mediated by Palladium Catalyst and (51) Int. Cl. Tris(diethylamino)sulfonium Difluorotrimethylsilicate” J. Org. CO7D 47L/04 (2006.01) Chem 53 pp. 918-920 (1988). (52) U.S. Cl...... 546/14: 546/113 (58) Field of Classification Search ...... 546/14, (Continued) 54.6/113 Primary Examiner Patricia L. Morris See application file for complete search history. (74) Attorney, Agent, or Firm Wilmer Cutler Pickering (56) References Cited Hale & Dorr LLP. U.S. PATENT DOCUMENTS (57) ABSTRACT 4,719,218 A 1, 1988 Bender et al. 5.439,917 A 8/1995 Briving et al. The present invention provides a novel substituted azaindo 5,714.495 A 2f1998 Viaud et al. line intermediate of formula (I) and a method for its synthesis. 6,642.375 B2 11/2003 Inomata et al. The novel substitued azaindoline intermediate (I) is provided 7,291,630 B2 1 1/2007 Graczyk et al. foruse in the manufacture of 5-substituted 7-azaindolines and 7,314,940 B2 1/2008 Graczyk et al. 5-substituted 7-azaindoles. 2002fOO13354 A1 1/2002 Cheng et al. 2005/0272761 A1 12/2005 Graczyk et al. 2006/0235042 A1 10/2006 Graczyk et al. 2006/027O646 A1 11/2006 Graczyk et al. (I) 2007/OO72896 A1 3/2007 Khan et al. FOREIGN PATENT DOCUMENTS EP OSO9974 10, 1992 EP O 737685 10, 1996 EP 1 106621 6, 2001 JP 06247966 9, 1994 WO WO-92/10498 A1 6, 1992 WO WO-92/10499 A1 6, 1992 WO WO-98.47899 10, 1998 WO WO-99/20624 4f1999 WO WO-99.21859 5, 1999 9 Claims, No Drawings US 7,652,137 B2 Page 2
Hatanaka et al., “Highly Selective Cross-Coupling Reactions of Harper et al., “Inhibitors of the JNK Signaling Pathway'. Drugs of Organosilicon Compounds Mediated by Fluoride Ion and a Palla the Future, vol. 26, No. 10, pp.957-973, 2001. dium Catalyst”. Synlett pp. 845-853 (1991). Henry et al. Bioorg. Med. Chem. Lett. 1998, 8,3335-3340. Krasnokutskaya et al., Khim. Geterotsikl. Soed No. 3 pp. 380-384 Houwing, et al., Preparation of N-Tosylmethylimino Compounds (1977). Littke et al., “Versatile Catalysts for the Suzuki Cross-Coupling of and their Use in the Synthesis of Oxazoles, Imidazoles and Pyrroles, Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Tetrahedron Letters No. 2, 1976. Mild Conditions”.J. Am. Chem. Soc. 122 pp. 4020-4028 (2000). International Search Report for PCT/GB2004/002099, mailed Dec. Littke et al., “Pd/P(t-Bu): A Mild and General Catalyst for Stille 2, 2004, 4 pages. Reactions of Aryl Chlorides and Aryl Bromides' J. Am. Chem. Soc. International Search Report for PCT/GB2005/000779, mailed Aug. 124 pp. 6343-6348 (2002). 12, 2005, 4 pages. Martin et al., “Palladium-Catalyzed Cross-Coupling Reactions of Kruber, Caplus, Copyright 2007 ACS on STN, 2 pages. Organoboronic Acids with Organic Electrophiles' Acta Chemica Kumar et al. “Synthesis of 7-AZaindole and 7-AZaoxindole Deriva Scandinavica 47, pp. 221-230 (1993). tives through a Palladium-Catalyzed Cross Coupling Reaction”. J. Merour et al., Synthesis and Reactivity of 7-AZaindoles (1H-Pyr Org. Chem, 57, pp. 6995-6998 (1992). rolo[2,3-bipyridine) Current Organic Chemistry 5 pp. 471-506 (2001). Lecointe, Reach-trhough Claims, International Pharmaceutical Mitchell, T. “Palladium-Catalysed Reactions of Organotin Com (2002)(also available at
Han, Z. et al., "Jun N-Terminal Kinase in Rheumatoid Arthritis.J. of Leroy et al., Tetrahedron: Asymmetry (1997), 8(19), 3309-3318. Pharmacol. Exper. Therap. 291(1): 124-130 (1999). Peng, J. and Andersen, J.K., “The Role of c-Jun N-Terminal Kinase Kontoyiannis et al., Immunity, (1999 Mar) vol. 10, No. 3, pp. 387- (JNK) in Parkinson's Disease.” Life 55(4-5): 267-271, Apr.-May 398. 2003. US 7,652,137 B2 1. 2 SYNTHESIS OF 5. SUBSTITUTED Chem. 2001, 5, 471). Functionalization of the 7-azaindole 7-AZANDOLES AND 7-AZANDOLINES system at position 5 is a fundamental transformation used in the synthesis of melatoninergic ligands and JNK inhibitors. The present invention provides a novel substituted azain Such functionalization is achieved by initial installation of the doline intermediate and a method for its synthesis. The inven 5 bromine atomat position 5, which is considered to be the key tion further provides the use of the intermediate in the manu step in each of these synthetic routes. However, despite the facture of 5-substituted 7-azaindolines and 5-substituted importance of this process, the most widely used approach to 7-azaindoles. introduce the bromine atom in position 5 requires dibromide The 7-azaindole system forms the core structure of various (2) as an intermediate (Scheme 1). The two bromine atoms at pharmaceutically important Substances such as antitumour 10 agents, ligands of melatoninergic receptor, dopamine D. C(3) serve as temporary and expensive temporary protection receptors, serotonin receptor, 5-HT6 receptor, p38 kinase against bromination of the five-membered ring. inhibitors, renin inhibitors, thrombin inhibitors, and antitus Synthesis of dibromide (2) is troublesome due to the use of sive agents. Furthermore, antifungal activity of Some 7-aza large excess of pyridinium perbromide (4 equivalents) and indoles in plant systems has recently been discovered. 15 difficult workup procedure. If direct conversion of (1) into (3) Synthesis and reactivity of 7-azaindoles has recently been is undertaken, large excess of bromine—usually over 12 extensively reviewed (Merour and Joseph Current Org. molar equivalents is required.
Br
pyridinium perbromide Br ------2 -BuOH NN2 Br t-BuOH, H2O N HN / HN Br
O (1) (2) (3)
Br2 t-BuOH, H2O
Furthermore, the subsequent reductive debromination of (3) to afford (4) is conducted with 10-fold excess of zinc in acetic acid or excess of saturated aqueous solution of ammo 40 nium chloride, which results in difficult workup and creation of large amount of waste. Compound (4), thus prepared has limited applicability for further functionalizations. The transformations known in the art are presented sche matically in Scheme 2. Compound (4) can be converted to 45 5-bromo-7-azaindole (6) via 5-bromo-7-azaindoline (5) and then to the relevant 5-methoxy derivative (7), and may also undergo palladium-catalyzed Suzuki and Stille couplings and carbonylation to afford (8), (9), and (10), respectively.
Scheme 2 Br Br Br OMe
N N Mn(OAc)3 BH THF AcOH rs MeONa rn He- -- N 2 s N 2 Na2 CuBr, DMF Na2
HN HN 4 - / O (4) (5) (6) (7)
carbonylation Suzuki Stille CO, EtOH Ar-B(OH)2 Het SnBus US 7,652,137 B2 3 4
-continued COOEt Air Het N N S Na2 Na2 Na2
HN HN HN
(8) (9) (10)
It should be emphasized that reactivity of 5-bromo-7-aza 15 indole (6) in the palladium-catalysed coupling reactions like Suzuki and Stille reactions has not been reported, yet. Scheme 5 Sometimes the problems with installation of substituents at R R position 5 of the 7-azaindole system are circumvented by R \ R linking the desired group to the pyridine ring and Subse quently closing the pyrrole ring to form the 7-azaindole sys rs y Sn tem as shown below in Scheme 3 (X is usually halogen). NY HN Na2 25 SOMe HN (15) Scheme 3 R R These processes involve many synthetic steps, utilize dif ficult to synthesize intermediates and/or costly palladium rs - 1s catalysts. Furthermore, all the methods described above allow Na2 Nn 2 only a limited scope of substituents to be introduced at C(5). For instance, many Substituents easily accessible via carboan ion chemistry, like —CH(O)R. —SiR —SnR, have not NH2 been explored at all due to unavailability of synthetic meth (11) odology leading to 5-lithio-7-azaindole?azaindoline. Synthesis of the unsubstituted 7-azaindoline starting mate 40 rial has previously involved harsh conditions. Previous A similar method leading to the 7-azaindoline system (14) attempts to obtain the 7-azaindoline has involved high pres (which may be converted to the 7-azaindole skeleton) is based sure hydrogenation of 7-azaindole at 200°C., hydrogenation on the intramolecular Diels-Alder reaction of properly func over Pd/ö-Al-O at 150° C. and under 450 psi pressure and tionalised amino pyrimidines (13) (Scheme 4: R—H, NO). hydrogenation over Pd/C in neat trifluoroacetic acid under 50 45 psi. Such reduction methods are hindered as the hydrogenoly sis of 7-azaindole in the acidic medium catalysed by PtC) may lead to overreduction Scheme 4 Derivatisation of the 7-azaindoline system obtained by the R R 50 methods above is limited. Subsequent bromination of 7-aza indoline system (17) (Scheme 6) using dioxane dibromide, NBS or bromine to give bromide (5) is known. Limited func rn rs tionalization of (5) to the cyano derivative (18) has also been N 2N He- N 2 presented. 55
Scheme 6 st-1 s Br Me Me (13) (14) 60 N N NBS Na2 cHo, Nne Diels-Alder reaction of properly functionalised 1,2,4-tri HN HN azines (15) (Scheme 5) may also lead to the 7-azaindoline 65 skeleton (16), but the method works best in the absence of (17) (5) substituent at C(5), i.e. R—H. US 7,652,137 B2 5 6 invention provides the use of functionalised 7-azaindoline -continued derivatives as key intermediates. These intermediates can be CN rearomatized with DDQ to 7-azaindoles avoiding the use of heavy metal oxidants such as Mn(OAc) or MnO, (cf Scheme 2). The ability to avoid the use of heavy metal oxidants is rn particularly important when the resulting 5-functionalised-7- N 2 aZaindoles are used in medicine. Attempts have previously been made to use DDQ for simi HN lar purposes. However the obtained yields for rearomatization 10 of unprotected 7-azaindolines were prohibitively low, (i.e. (18) below 50%) indicating that the use of DDQ was not viable in a commercial synthesis (Taylor et al. Tetrahedron 1987, 43, Similar transformation involving a N-protected azaindo 5.145). The present invention demonstrates that proper choice line (19) (Scheme 7) has also been described. of protecting group, in particular the electron-donating silyl 15 group, allows this process to occur in a quantitative yield. The present invention therefore provides a method of rearomati Scheme 7 Zation which can be used on an industrial scale and eliminates Br C unwanted heavy metal residues in the product. Furthermore, O the present invention further provides a new, simple method to synthesise the starting unsubstituted 7-azaindoline, which N \ avoids using harsh conditions described in the literature. The O present invention therefore provides a significant advance in N 21 aq. Na2CO3 the production of 5-functionalised-7-azaindoles. The first aspect of the present invention provides a com H N 25 pound of formula (I) (5) Br (I)
30 Na2r) SnBus- Pd(PPh3)4 N N 35 O (19) 21 wherein X is an amino-protecting group, with the proviso that 40 X is not benzyloxycarbonyl (Cbz). In particular, X is preferably selected from R'S(O), (R'), Si, RC(O), ROCH R'NSO, ROC(O) , R (RO) rs CH-, RCHCH , RCH , PhC(O)CH-, N 21 CH=CH ClCHCH PhC Ph(4-pyridyl)C 45 MeN-, HO CH , ROCH , (R')SiOCH , N (RO), CH , t-BuOC(O)CH , Me-NCH and tetrahy dropyranylamine; wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, "N O Cheterocyclyl or C-carbocyclyl: optionally substituted 50 with one or more of C, alkyl, Si(R), OR, NO, CO., (20) COR, halogen, haloalkyl, SR, CN, NRCOR, COR CONRR, However, the nitrogen protecting group used in 5-bromo wherein R is hydrogen or C, alkyl, preferably R' is 7-azaindoline (19), benzyloxycarbonyl (Cbz), although easy methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl, with the to install, has a limited resistance. In particularitis unsuitable 55 proviso that when X is R'OC(O) , R' is not PhCH. for reactions involving strong bases Such as n-Bulli, sec When X is a dialkylsulfonamide (R'NSO ), R is pref BuLi, tert-Bulli, NaNH2, and Grignard reagents. Such reac erably alkyl, more preferably methyl. When X is a carbamate tions, especially with alkyllithiums, could open a novel way (ROC(O) ) R' is preferably alkyl, cycloalkyl, aryl or het for derivatization of the 7-azaindole system at C(5). However, eroaryl, more preferably CC1-CH, MeSiCHCH, t-butyl, the use of other protecting groups to protect the 5-bromo-7- 60 2,4-dimethylpent-3-yl, cyclohexyl, CC1-Me-COC(O), aZaindoline system is unknown in the art. 1-adamanty1, 2-adamanty1 or cyclohexyl. When X is N-(1- The production of 5-substituted-7-azaindoles therefore alkoxy)ethylamine (R' (R'O)CH ), R' is preferably alkyl, provides a number of problems in the art. There is therefore a more preferably Me or Et. When X is N-2-(hetero)arylethy need in the art for new methods of preparing such compounds. lamine (R'CH-CH ), R is preferably aryl or heteroaryl, To avoid the problems associated with the current state-of 65 more preferably 2-pyridyl, 4-pyridyl or 4-nitrophenyl. When the-art methods and to open new possibilities for functional X is arylmethylamine (RCH ), R is aryl or heteroaryl, ization of position 5 of the 7-azaindole system, the present more preferably Ph-, p-methoxyphenyl-, 3,4-dimethoxyphe US 7,652,137 B2 7 nyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 2-nitrophenyl or 2,4-dinitrophenyl. When X is N-alkoxymethylamine (ROCH ), R is alkyl, more preferably methyl, ethyl, CICHCH , MeSiCHCH t-butyl or PhCH2—. D CN When X is N-silyloxymethylamine (R')SiOCH ), R' M is alkyl, more preferably methyl or t-butyl. When X is N-di SO -- Her alkoxymethylamine (RO),CH ), R' is alkyl, more prefer CN ably methylor ethyl. WhenX is sulfonamide (R'S(O) ), R' 2 eq. is preferably 2,4,6-trimethylphenyl (mesity1), 4-methox yphenyl, phenyl or toluyl. 10 Such protecting groups must not deactivate the pyridine ring towards bromination, and must withstand the conditions of the Subsequent reactions, in particular these involving car boanion chemistry. X is therefore most preferably a silyl group (especially t-butyldimethylsilyl (TBS), triisopropylsi 15 lyl (TIPS) or t-butyldimethylphenylsilyl (TBDPS)), N-alkoxymethylamine (ROCH- ) wherein R' is preferably methyl or a sulfonamide R'S(O), wherein R' is preferably phenyl, methoxymethyl (MOM) or ethoxymethyl. Compound (I) of the present invention is a versatile inter mediate and allows the production of many 5-substituted 7-azaindoles. An alternative method of producing a compound of for The second aspect of the invention provides a method for synthesising a compound of formula (I) comprising bromi 25 mula (I) involves the protection of a compound of formula nating a compound of formula (II): (III) as illustrated.
Br 30 Br Br rs rs Na2 - - N4 rs rs N 2 Ho- N 2 N N 35 / / N N X X H / X (II) (I) (III) (I) 40 wherein X is a amino-protecting group as defined in the first aspect of the invention. In a preferred feature of the second aspect, X is preferably wherein X is selected from R'S(O) (R')Si, RC(O), selected from (R'),Sior R'OCH, wherein R' is Calkylor ROCH R'NSO, ROC(O) R' (RO)CH , Caryl, preferably methyl, ethyl, propyl n-butyl, tert-butyl 45 R"CHCH , RCH -, PhC(O)CH , CH=CH-, or phenyl. CICHCH , PhC , Ph.(4-pyridyl)C , Me-N , In a preferred feature of the second aspect, X is (R'),Siand HO CH-, ROCH , (R')SiOCH , (RO)2CH-, R" is independently C, alkyl or C. aryl, preferably t-BuOC(O)CH2—, MeNCH and tetrahydropyrany methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. 50 lamine; Bromination can be carried out using reagents and condi wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, tions known in the art. The reagents are preferably Br diox C. heterocyclyl or C. carbocyclyl: optionally substi ane dibromide, pyridinium perbromide or NBS. tuted with one or more of Calkyl, Si(R), OR, NO, CO., For the purposes of this invention, a compound of formula COR, halogen, haloalkyl, SR, CN, NRCOR, (II) can be provided from azaindoline using reagents and 55 methods well known in the art. Protecting groups such as COR CONRR, benzyl, acetamide, benzyl carbamate or p-toluenesulfona wherein R is hydrogen or C, alkyl, preferably R' is mide can be installed using standard methods known in the methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. art, which are described in T. W. Greene and P. G. M. Wuts The compound of formula (III) can be produced from Protective Groups in Organic Synthesis 3' Edn. Wiley, New 60 aZaindoline using reagents and methods well known in the York 1999: pages 494-626. art. Examples of Such brominations are indicated in Kras Alternatively, the protecting group X can be introduced prior to the formation of the azaindole skeleton, as illustrated nokutskaya et al. Khim. Geterotsikd. Soed. 1977, 3, 380, below wherein the p-toluenesulfonyl group is linked to the WO00/26210, WO00/26211, WO00/64449, Taylor et al. Tet nitrogen of the 7-azaindole system as a result of the reaction 65 rahedron, 1987, 43, 5145. between N-tosylaziridine and malonodinitrile (Chemische The third aspect of the invention provides a method for the Berichte 1985, 118, 4473). production of a compound of formula (IV) US 7,652,137 B2 9 10 tuted with one or more of Calkyl, Si(R), OR, NO, CO., COR, halogen, haloalkyl, SR, CN, NRCOR, Br M(R)- COR CONRR, wherein R is hydrogen or C, alkyl, preferably R' is methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. rs rs In a preferred feature of the fourth aspect, M can represent N 2 -> N 2 a metal such as Li, or metal alkyl group such as Sn(R), wherein R is a C- alkyl. N N The fifth aspect of the invention provides a method for the M / 10 X X production of a compound of formula (V) (I) (IV) Br Si(R) comprising the metal-halogen exchange with a metal of for 15 mula M(R), wherein each R is independently OH. C. alkyl, Calkoxy, halo or C. carbocyclyl, rs rs X is selected from R'S(O), (R'). Si, RC(O), ROCH, N 2 -> N 2 RNSO, ROC(O) R' (RO)CH RCHCH , N N RCH - PhC(O)CH , CH=CH-, CICHCH / / PhC , Ph.(4-pyridyl)C , MeN—, HO CH , X X ROCH , (R')SiOCH , (RO)2CH-, t-BuOC(O) (I) (V) CH , MeNCH- and tetrahydropyranylamine; wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, C. heterocyclyl or C. carbocyclyl: optionally Substi 25 comprising incubating a compound of formula (I) with a base tuted with one or more of Calkyl, Si(R), OR, NO, CO., and (R) Sizwherein R is a C alkyl, OH, oran Caryl COR, halogen, haloalkyl, SR, CN, NRCOR, group, Z is a halide preferably chloride or bromide and X is an COR CONRR, amino-protecting group, preferably selected from R'S(O), wherein R is hydrogen or C. alkyl, preferably R' is (R'),Si, RC(O), ROCH, RNSO, ROC(O) , R (RO) methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl 30 CH-, RCHCH , RCH , PhC(O)CH-, n is 1, 2, 3 or 4, and M is Li, Sn, B, Mg., Zn, In, Cu, Zr, or CH=CH , CICHCH , Ph.C. , Ph.(4-pyridyl)C , Pd. Me-N HO CH, , ROCH , (R)SiOCH , In a preferred feature of the reaction, the compound of (RO), CH , t-BuOC(O)CH , Me-NCH and tetrahy formula (IV) may undergo one or more further transmetala dropyranylamine; tion reactions for example by incubation with a metal halide 35 wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, such as ZnCl2, MgCl, PdCl, or (R),SnW wherein R is C. heterocyclyl or C. carbocyclyl: optionally substi C. alkyl, preferably methyl or butyl and W is halogen tuted with one or more of Calkyl, Si(R), OR, NO, CO., preferably Clor I. Preferred examples of metalhalides having COR, halogen, haloalkyl, SR, CN, NRCOR, the formula (R),SnW include BuSnI or MeSnCl. COR CONRR, The fourth aspect of the invention provides a compound of 40 wherein R is hydrogen or C, alkyl, preferably R' is formula (IV) methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. For the purposes of the fifth aspect, the base is preferably t-BuLi. (IV) 45 The sixth aspect of the invention provides a compound of M(R)- formula (V)
(V) 50 Si(R)
55 wherein each R is independently -OH, C, alkyl, C. alkoxy, halo or C. carbocyclyl, n is 1, 2, 3 or 4. M is a metal preferably selected from Li, Sn, B, Mg., Zn, In, Cu, Zr, Pd or Zn and X is a amino-protecting group, preferably selected from R'S(O), (R'),Si, RC(O), ROCH, RNSO, ROC 60 wherein R is a C- alkyl, OH, oran C-2 aryl group, X is an (O) R' (RO)CH R'CHCH , RCH - PhC(O) amino-protecting group, preferably selected from R'S(O), CH-CH=CH-CICH2CH2—, PhC Ph(4-pyridyl) (R')Si, RC(O), ROCH RNSO, ROC(O) R' (RO) C , Me-N-, HO CH-, ROCH (R')SiOCH , CH-, RCHCH , RCH , PhC(O)CH , (RO)2CH , t-BuOC(O)CH , Me, NCH and tetrahy CH=CH ClCHCH PhC Ph(4-pyridyl)C dropyranylamine; 65 Me-N-, HO CH-, ROCH , (R')SiOCH , wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, (RO). CH , t-BuOC(O)CH , MeNCH and tetrahy C. heterocyclyl or C. carbocyclyl: optionally Substi dropyranylamine; US 7,652,137 B2 11 12 wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, The eighth aspect of the invention provides a compound of C. heterocyclyl or C. carbocyclyl: optionally substi formula (VI) tuted with one or more of Calkyl, Si(R), OR, NO, CO., COR, halogen, haloalkyl, SR, CN, NRCOR, COR CONRR, (VI) wherein R is hydrogen or C, alkyl, preferably R' is B(R) methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. The seventh aspect of the invention provides a method of producing a compound of formula (VI) 10 Br B(R)
1. base N 2. (R)-B N N 21 O(R)3B or N 21 15 (R3)B-B(R) wherein R is OH, or a group OR wherein R' is C alkyl N Pd catalyst N or C. aryl and wherein two or more R' groups may / / together form a 4 to 7 membered ring, and X is a amino X X protecting group, preferably selected from R'S(O), (R').Si. (I) (VI) RC(O), ROCH RNSO, ROC(O) , R' (RO)CH , R"CHCH , RCH -, PhC(O)CH , CH=CH-, comprising incubating a compound of formula (I) with bor CICHCH , PhC Ph(4-pyridyl)C , Me-N . onate (R)-B, (R).B Hor (R), B B(R), and a base or a HO CH-, ROCH , (R')SiOCH , (RO)2CH-, palladium catalyst such as PdCl or PdCl(1,1'-bis(diphe t-BuOC(O)CH , MeNCH and tetrahydropyrany nylphosphino) ferrocene), wherein R is OH or a group OR' 25 lamine; wherein R” is C, alkyl or Caryland wherein two or wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, more R groups may together form a 4 to 7 membered ring, C. heterocyclyl or C-2 carbocyclyl: optionally Substi and wherein X is an amino-protecting group, preferably tuted with one or more of Calkyl, Si(R), OR, NO, CO., selected from R'S(O), (R').Si. RC(O), ROCH, COR, halogen, haloalkyl, SR, CN, NRCOR, RNSO, ROC(O) R' (RO)CH R'CHCH , 30 COR CONRR, RCH - PhC(O)CH , CH=CH-, CICHCH wherein R is hydrogen or C, alkyl, preferably R' is PhC , Ph.(4-pyridyl)C—, Me-N , HO CH . methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. ROCH , (R')SiOCH , (RO)2CH-, t-BuOC(O) More preferably B(R) represents a pinacolester CH2—, MeNCH2— and tetrahydropyranylamine; The ninth aspect of the invention provides a method for the wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, 35 production of a compound of formula (VII) C. heterocyclyl or C. carbocyclyl: optionally Substi tuted with one or more of Calkyl, Si(R), OR, NO, CO., COR, halogen, haloalkyl, SR, CN, NRCOR, (VII) COR CONRR, wherein R is hydrogen or C. alkyl, preferably R' is 40 methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. More preferably, boronate is selected from H-B(OR"), (MeC O).B–B(O-CMe), and B(OR'). In a preferred feature of the seventh aspect, the production 45 of a compound of formula (VI) can be catalysed by the addi tion of a metal catalyst. In particular, the formation of a compound of formula (VI) can be catalysed by a palladium catalyst such as PdCl or PdCl(1,1'-bis(diphenylphosphino) 50 comprisinga) reaction of a compound of formula (IV) with an ferrocene) electrophile, or b) reaction of a compound of formula (IV) Example of such a boronation reaction is indicated below, with R-Z in the presence of a palladium catalyst or c) reac tion of a compound of formula (V) with R-Z in the presence of a palladium catalyst or d) reacting a compound of formula 55 (VI) with R-Z in the presence of a palladium catalyst; wherein R is an optionally substituted C-12 alkyl, C-12 Br O O O O alkenyl, COR carbocyclyl or heterocyclyl group; NY NY wherein R is optionally subsituted alkyl, carbocyclyl or N heterocyclyl; and H N PC(d 60 wherein, each substitutable carbon atom in R or R is Nn 2 2(dppf) optionally and independently substituted by one or more of Na2 C. alkyl, C-2 alkenyl, carbocyclyl, or heterocyclyl, halo N / gen, haloalkyl, OR', SR, NO, CN, NR'R'', X N NROCOR, NROCONR'R'', NROCORO, CORI, X 65 COR, CONR'R'', S(O).R., SONH S(O)R', SONR'R'', NRS(O).R', wherein each R' may be the same or different and is as defined below; wherein the C US 7,652,137 B2 13 14 alkyl optionally incorporates one or two insertions selected For the avoidance of doubt, when a group as defined above from the group consisting of-O-, -C(O)—, —N(R')—, contains two or more radicals, e.g. the radical R', as for —S(O)— and —S(O)— and wherein the C-2 alkyl, car example in the groups SONR'R'' and NR'COR', the two bocyclyl, or heterocyclyl group is optionally substituted by or more radicals e.g. R' may be the same or different. one or more of halogen, haloalkyl, OR', SR, NO, CN, It will be appreciated that the reaction set out as option b) NRORO, NROCOR 10, NROCONRORO, NROCOR 10, for the ninth aspect is a Stille reaction, which can be carried NROCOR, CORO, CORO, CONR), S(O).R.9, out according to Stille Angew. Chem., Inted, Engl. 1986, 25, SONH S(O)R'', or NRS(O).R'': 508; Mitchell Synthesis, 1992, 803, or Littke et al. J. Am. each substitutable nitrogenatom in R is optionally substi Chem. Soc. 2002, 124, 6343. tuted by R'', COR', SOR or COR'', wherein each R' 10 It will be appreciated that the reaction set out as option c) and R' may be the same or different and is as defined below: for the ninth aspect is a Hiyama reaction which can be carried the optionally substituted carbocyclyl or optionally substi out according to Hatanaka et al. J. Org. Chem. 1988, 53,918, tuted heterocyclyl group is optionally fused to an unsaturated, Hatanaka et al. Synlett, 1991, 845 or Tamao et al. Tetrahedron partially unsaturated or fully saturated five to seven mem Lett. 1989,30, 6051, or Denmarket al. Org. Lett. 2000, 2,565, bered ring containing Zero to three heteroatoms, each Satu 15 ibid. 2491. rated carbon in the optional fused ring is further optionally The reaction set out as option d) for the ninth aspect is a and independently substituted by —O. —S, —NNHR'. Suzuki reaction which can be carried out according to Suzuki NNR'R'', -N OR", =NNHCOR', =NNHCOR'', Pure Appl. Chem. 1991, 63,419, or Littke J. Am. Chem. Soc. =NNSOR', or—NR', wherein each R' may be the same 2000, 122, 4020. or different and is as defined below: For the purposes of this invention, a compound of formula R" is hydrogen, C-2 alkyl or aryl, optionally substituted (IV) is preferably incubated with an electrophile such as a by one or more of C. alkyl, halogen, Ca haloalkyl, OR', Calkylhalide for example methyl iodide, DMF, CO, or a SR 12, NO, CN, NR2R12, NR2COR 12, NR2CONR2R12, group R' C(O)H wherein R' is C, alkyl or Caryl. NRCOR, NRCOR, COR, COR, CONR, In a preferred feature of the ninth aspect, a compound of S(O).R., SONH S(O)R', SONR'R'', NRS(O).R', 25 formula (VII) is produced by the palladium-catalysed cou wherein the C-2 alkyl group optionally incorporates one or pling reaction between a stannane of formula (VIII) and a two insertions selected from the group consisting of —O , group R Y wherein R is a group as defined above and Y is N(R') , S(O)— and S(O.) , wherein each R' a halogen, may be the same or different and is as defined below: R'' is C. alkyl or aryl, optionally substituted by one or 30 more of Calkyl, halogen, Chaloalkyl, OR', SR'', NO. SnR3 R8 CN, NR2R12, NR2COR2, NR2CONR2R12, NR COR2, NR2COR2, COR2, COR2, CONR'2, S(O).R', SONH, S(O)R', SONR'R'', NRS(O).R', 35 rs rs wherein the C- alkyl group optionally incorporates one or Na2 -- Na2 two insertions selected from the group consisting of —O , N(R') , S(O)— and S(O) , wherein each R' N N / M may be the same or different and is as defined below: X X R" is hydrogen, C. alkyl, or C, a haloalkyl: 40 wherein X is a amino-protecting group, preferably selected (VIII) (VII) from R'S(O), (R'),Si, RC(O), ROCH, RNSO, ROC (O) R' (RO)CH R'CHCH , RCH - PhC(O) Compound (VIII) is formed by the transmetallation of a CH, CH=CH-CICHCH , Ph.C. , Ph.(4-pyridyl) compound of formula (I) or (IV) as described in the third C , Me-N-, HO CH-, ROCH (R')SiOCH , 45 aspect of the invention. (RO)2CH , t-BuOC(O)CH , Me, NCH and tetrahy For the purposes of all aspects of this invention, alkyl dropyranylamine; relates to both straight chain and branched alkyl radicals of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms and most wherein R' is C. alkyl, C-12 cycloalkyl, C. haloalkyl, preferably 1 to 4 carbon atoms including but not limited to C. heterocyclyl or C. carbocyclyl: optionally substi 50 methyl, ethyl, n-propyl, isopropyl. n-butyl, sec-butyl, isobu tuted with one or more of Calkyl, Si(R), OR, NO, CO., tyl, tert-butyl n-pentyl, n-hexyl, n-heptyl, n-octyl. In particu COR, halogen, haloalkyl, SR, CN, NRCOR, lar, alkyl relates to a group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. COR CONRR, 11 or 12 carbon atoms. The term alkyl also encompasses wherein R is hydrogen or C, alkyl, preferably R' is cycloalkyl radicals including but not limited to cyclopropyl. methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. 55 cyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl, cyclopentyl wherein R and R7 are independently selected from an or cyclohexyl. In particular, cycloalkyl relates to a group optionally substituted C-2 alkyl, C-2 alkenyl, COR. car having 3,4,5,6,7,8,9, 10, 11 or 12 carbonatoms. Cycloalkyl bocyclyl or heterocyclyl group and Z is a halogen preferably groups may be optionally Substituted or fused to one or more iodine, bromide or chlorine, or triflate. carbocyclyl or heterocyclyl group. Haloalkyl relates to an In a preferred feature of the ninth aspect, R is preferably 60 alkyl radical as defined above preferably having 1 to 8 carbon substituted with one or more of alkyl (e.g. methyl, ethyl or atoms, preferably 1 to 4 carbonatoms substituted with one or propyl), haloalkyl (preferably CF), halogen (e.g. F. Clor Br. more halide atoms for example one or more of F, Cl, Br or I, preferably F), OR', SR', SOR, N(R'), wherein R' is such as CHCHBr, CF or CC1. independently selected from hydrogen, C alkyl or The term “alkenyl' means a straight chain or branched haloalkyl and is preferably phenyl or napthyl. When R is 65 alkylenyl radical of 2 to 12 carbon atoms, preferably 2 to 6 phenyl it is preferably substituted in the 4-(para) position, by carbon atoms and most preferably 2 to 4 carbon atoms, and NR'R'', where R'' is independently H or C alkyl. containing one or more carbon-carbon double bonds and US 7,652,137 B2 15 16 includes but is not limited to ethylene, n-propyl-1-ene, n-pro pyl-2-ene, isopropylene, etc. In particular, alkenyl relates to a group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. R8 R8 The term “alkynyl' means a straight chain or branched alky nyl radical of 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2 to 4 carbon atoms, and contain rn rs ing one or more carbon-carbon triple bonds and includes but N 21 -- N 2 is not limited to ethynyl, 2-methylethynyl etc. In particular, alkynyl relates to a group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or N N / 10 / / 12 carbon atoms. X X “Carbocyclyl relates to a saturated, partly unsaturated or (VII) (IX) unsaturated 3-12 membered hydrocarbon ring preferably a 6-12 membered hydrocarbon ring, including cycloalkyl and aryl. 15 If the compounds of formula (IX) or derivatives thereof Aryl means an aromatic 3-12 membered hydrocarbon (for example compounds of formula (IX) wherein X is hydro preferably a 6-12 membered hydrocarbon containing one ring gen) are produced for use in medicine, an alternative method or being fused to one or more Saturated or unsaturated rings to aromatise compounds of formula (VII) is preferred. including but not limited to phenyl, napthyl, anthracenyl or The tenth aspect of the invention provides a method of phenanthracenyl. producing a compound of formula (XI) by the aromatisation “Heteroaryl' means an aromatic 3-12 membered aryl pref of a compound of formula (X) with DDQ wherein efficient erably a 6-12 membered aryl containing one or more heteroa oxidation of derivative (X) with DDQ to afford (XI) is pro toms selected from N, O or Sand containing one ring or being moted by the presence of electron-donating N-silyl group at fused to one or more Saturated or unsaturated rings and; 25 nitrogen in (X). “Heterocyclyl means a 3-12 membered ring system pref erably a 6-12 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. Scheme 4 In particular the terms “carbocyclyl”, “aryl, "heteroaryl and "heterocyclyl relate to a group having 3, 4, 5, 6, 7, 8, 9. 30 10, 11 or 12 carbon atoms. N N The heterocyclyl system can contain one ring or may be fused to one or more Saturated or unsaturated rings; the het erocyclyl can be fully saturated, partially saturated or unsat urated and includes but is not limited to heteroaryl and het 35 N N / erocarbocyclyl. Examples of carbocyclyl or heterocyclyl / M groups include but are not limited to cyclohexyl, phenyl, X X acridine, benzimidazole, benzofuran, benzothiophene, ben (X) (XI) ZOxazole, benzothiazole, carbazole, cinnoline, dioxin, diox ane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, 40 wherein X" is a silyl group (R')Si furan, imidazole, imidazoline, imidazolidine, indole, indo line, indolizine, indazole, isoindole, isoquinoline, isoxazole, R" is as defined in the first aspect isothiazole, morpholine, napthyridine, oxazole, oxadiazole, X" is Br or R Oxathiazole, Oxathiazolidine, oxazine, oxadiazine, phena and R is as defined in the ninth aspect Zine, phenothiazine, phenoxazine, phthalazine, piperazine, 45 piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyra Preferably X" is t-butyldimethylsilyl (TBS), triisopropylsi Zoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyr lyl (TIPS) or t-butyldimethylphenylsilyl (TBDPS). role, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazo As previously discussed, previous attempts in the art to line, quinolizine, tetrahydrofuran, tetrazine, tetrazole, rearomatise unprotected 7-azaindolines with DDQ resulted in thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, 50 undesirably low yields. The method set out in the tenth aspect thiazole, thiomorpholine, thianaphthalene, thiopyran, triaz of the inveniton utilises the presence of the electron-donating ine, triazole, and trithiane. N-silyl group to promote efficient oxidation of (X) with For the purpose of the present invention, the term “fused includes a polycyclic compound in which one ring contains DDQ. one or more atoms preferably one, two or three atoms in 55 This method allows the production of 5-substituted-7-aza common with one or more other ring. indole moieties without the need for a high excess of oxidant Halogen means F. Cl, Br or I, preferably F. and avoids the contamination of the product with heavy metal Compounds of formula (VII) can be converted into alter impurities (as can be seen for example with a MnO, or native compounds of formula (VII) by conventional methods 60 Mn(OAc)/AcOH medicated oxidation). known in the art. In particular, a compound of formula (VII) Removal of the group X can be carried out using method may undergo oxidation, reduction, addition, elimination, Sub known in the art. Suitable methods for removing specific X stitution or transmetallation reactions in order to produce a groups are set out in Greene and Wuts Protective Groups in further compound of formula (VII). Organic Synthesis, 3" Edition, Wiley, New York, 1999. For The compounds of formula (VII) can be aromatised to 65 example when X" is TBS, it can be removed by incubation 5-substituted 7-azaindoles (IX) using methods known in the with hydrochloric acid. Alternatively, when X" is PhSO, art, in particular Mn(OAc)/AcOH or MnO. removal can be afforded with KOH in EtOH. US 7,652,137 B2 17 18 The eleventh aspect of the invention provides a compound The thirteenth aspect of the invention provides a method of formula (XII) for the production of a compound of formula (IX)
(XII) 5 (IX) B(R)
10
15 wherein R is OHora group OR' wherein R is Calkylor comprising reacting a compound of formula (XII) with R-Z C-2 aryland wherein two or more R'groups may together in the presence of a palladium catalyst. form a 4 to 7 membered ring, and wherein X is a amino wherein R is an optionally substituted C-12 alkyl, C-12 protecting group, preferably selected from R'S(O), (R').Si. alkenyl, COR carbocyclyl or heterocyclyl group; RC(O), ROCH RNSO, ROC(O) , R' (RO)CH , wherein R is optionally substituted alkyl, carbocyclyl or RCHCH , RCH , PhC(O)CH , CH=CH-, heterocyclyl; and CICHCH PhC Ph(4-pyridyl)C , Me-N . wherein, each substitutable carbon atom in R or R is HO-CH , ROCH , (R')SiOCH , (RO)2CH-, optionally and independently substituted by one or more of t-BuOC(O)CH , MeNCH and tetrahydropyrany C. alkyl, C-2 alkenyl, carbocyclyl, or heterocyclyl, halo lamine; 25 gen, haloalkyl, OR', SR, NO, CN, NR'R'', wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, NROCOR'0, NROCONRIORIO, NROCOR 0, C. heterocyclyl or C. carbocyclyl: optionally Substi NRCOR, COR, COR, CONR'R'', S(O).R', tuted with one or more of Calkyl, Si(R), OR, NO, CO., SONH S(O)R 9, SONR'R'', NRS(O).R, wherein COR, halogen, haloalkyl, SR, CN, NRCOR, each R" may be the same or different and is as defined below: COR CONRR, 30 wherein the C- alkyl optionally incorporates one or two wherein R is hydrogen or C. alkyl, preferably R' is insertions selected from the group consisting of —O—, methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. C(O)—, N(R') , S(O) and —S(O)— and The twelfth aspect of the invention provides a method of wherein the C-2 alkyl, carbocyclyl, or heterocyclyl group is producing a compound of formula (XII) optionally substituted by one or more of halogen, haloalkyl, 35 OR 9, SR, NO, CN, NRORO, NROCOR'9, NROCONR'R'', NROCOR'9, NROCORO, CORI, Br B(R) COR, CONR), S(O).R., SONH S(O)R, or NRS (O).R': each substitutable nitrogenatom in R is optionally substi rs rs 40 tuted by R'', COR', SOR or COR', wherein each R' Na2 - N1 and R' may be the same or different and is as defined below: the optionally substituted carbocyclyl or optionally substi / - / / \ / tuted heterocyclyl group is optionally fused to an unsaturated, X X 45 partially unsaturated or fully saturated five to seven mem (XIII) (XII) bered ring containing Zero to three heteroatoms, each satu rated carbon in the optional fused ring is further optionally and independently substituted by —O. —S, —NNHR'. comprising incubating a compound of formula (XIII) with NNR'R'', -N OR", =NNHCOR', =NNHCOR'', (R),B and a base wherein R is OH, C, alkoxy or C. 50 =NNSOR', or—NR', wherein each R' may be the same aryloxy. Preferably, (R), B is selected from B(OR'), or different and is as defined below: wherein R' is alkyl, cycloalkyl or two R' groups may R" is hydrogen, C-12 alkyl or aryl, optionally substituted together form a 4 to 7 membered ring by one or more of C, alkyl, halogen, Chaloalkyl, OR'', wherein X is a amino-protecting group, preferably selected SR 12, NO, CN, NR'2R12, NR2COR2, NR CONR2R12, from R'S(O) (R')Si, RC(O), ROCH R'NSO, ROC 55 NRCOR, NRCOR, COR, COR, CONR, (O) , R' (RO)CH , RCHCH, , RCH, , PhC(O) S(O).R., SONH S(O)R', SONR'R'', NRS(O).R', CH-CH=CH-CICH2CH2—, PhC Ph(4-pyridyl) wherein the C-2 alkyl group optionally incorporates one or C , Me-N-, HO CH-, ROCH (R')SiOCH , two insertions selected from the group consisting of —O—, (RO)2CH , t-BuOC(O)CH , Me, NCH and tetrahy N(R') , S(O)— and S(O)—, wherein each R' dropyranylamine; 60 may be the same or different and is as defined below: wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, R'' is C. alkyl or aryl, optionally substituted by one or C. heterocyclyl or C. carbocyclyl: optionally Substi more of Calkyl, halogen, Chaloalkyl, OR', SR'', NO, tuted with one or more of Calkyl, Si(R), OR, NO, CO., CN, NR12R12, NR2COR2, NR12CONR2R12, COR, halogen, haloalkyl, SR, CN, NRCOR, NRCOR, NRCOR, COR, COR, CONR, COR CONRR, 65 S(O).R', SONHS(O)R', SO, NR'R'', NRS(O).R', wherein R is hydrogen or C. alkyl, preferably R' is wherein the C-2 alkyl group optionally incorporates one or methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. two insertions selected from the group consisting of —O—, US 7,652,137 B2 19 20 N(R') , S(O)— and S(O.) , wherein each R' may be the same or different and is as defined below: R" is hydrogen, C. alkyl, or C, a haloalkyl: (IX) wherein X is a amino-protecting group, preferably selected from R'S(O), (R'),Si, RC(O), ROCH, RNSO, ROC (O) R' (RO)CH R'CHCH , RCH - PhC(O) CH-CH=CH-CICH2CH2—, PhC Ph(4-pyridyl) C , Me-N-, HO CH-, ROCH (R')SiOCH , (RO)2CH , t-BuOC(O)CH , MeNCH and tetrahy 10 dropyranylamine; wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, C. heterocyclyl or C. carbocyclyl: optionally Substi comprising reacting a compound of formula (XII) with tuted with one or more of Calkyl, Si(R), OR, NO, CO., 15 R7-Z in the presence of a palladium catalyst COR, halogen, haloalkyl, SR, CN, NRCOR, wherein R is an optionally substituted C- alkyl, C COR CONRR, alkenyl, COR carbocyclyl or heterocyclyl group; wherein R is hydrogen or C, alkyl, preferably R' is wherein R is optionally substituted alkyl, carbocyclyl or methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. heterocyclyl; and wherein, each substitutable carbon atom in R or R is wherein R is independently selected from an optionally optionally and independently substituted by one or more of substituted C-12 alkyl, C-12 alkenyl, COR. carbocyclyl or C. alkyl, C- alkenyl, carbocyclyl, or heterocyclyl, heterocyclyl group and Z is a halogen or triflate preferably halogen, haloalkyl, OR', SR', NO, CN, NR'R'', iodine, bromine or chlorine. NR1OCOR 10 s NROCONRIOR 10, NROCOR 10, It will be appreciated that the reaction set out is a Suzuki 25 NRCOR, COR, COR, CONR'R'', S(O).R', reaction which can be carried out according to Suzuki Pure SONH, S(O)R 9, SONR'R'', NRS(O).R, wherein Appl. Chem., 1991, 63, 419, or Littke J. Am. Chem. Soc. each R" may be the same or different and is as defined below: wherein: the C-2 alkyl optionally incorporates one or two 2000, 122, 4020. insertions selected from the group consisting of —O—, The fourteenth aspect of the invention provides a com 30 C(O)—, N(R') , S(O)— and S(O)— and pound of formula (XIV) wherein the C- alkyl, carbocyclyl, or heterocyclyl group is optionally substituted by one or more of halogen, haloalkyl, OR', SR, NO, CN, NR'R'', NROCOR', NROCONROR1, NROCOR1, NROCORO, COR 10, 35 (XIV) COR, CONR', S(O).R', SONH S(O)R'', or NR'S Si(R) (O).R'9; each substitutable nitrogenatom in R is optionally substi tuted by R'', COR', SOR' or COR', wherein each R' and R'' may be the same or different and is as defined below: 40 the optionally substituted carbocyclyl or optionally substi tuted heterocyclyl group is optionally fused to an unsaturated, partially unsaturated or fully saturated five to seven mem bered ring containing Zero to three heteroatoms, each satu rated carbon in the optional fused ring is further optionally 45 and independently substituted by =O, =S, =NNHR'. NNR'R'', -N OR", =NNHCOR', =NNHCOR'', =NNSOR', or—NR', wherein each R' may be the same wherein R is a C-alkyl, OH, oran C-2 aryl group, X is an or different and is as defined below: amino-protecting group, preferably selected from R'S(O), 50 R" is hydrogen, C-12 alkyl or aryl, optionally substituted (R')Si, RC(O), ROCH R'NSO, ROC(O) R' (RO) by one or more of C, alkyl, halogen, Chaloalkyl, OR'', CH-, RCHCH-, RCH , PhC(O)CH , SR 12, NO, CN, NR'2R12, NR2COR2, NR CONR2R12, CH=CH ClCHCH PhC Ph(4-pyridyl)C NR'2COR2, NR COR2, COR2, COR2, CONR'2. Me-N-, HO CH-, ROCH , (R')SiOCH , S(O).R', SONH, S(O)R', SONR'R'', NRS(O).R', 55 wherein the C-2 alkyl group optionally incorporates one or (RO), CH , t-BuOC(O)CH , MeNCH and tetrahy two insertions selected from the group consisting of —O—, dropyranylamine; N(R') , S(O)— and S(O)—, wherein each R' wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, may be the same or different and is as defined below: C. heterocyclyl or C. carbocyclyl: optionally Substi R'' is C alkyl or aryl, optionally substituted by one or tuted with one or more of Calkyl, Si(R), OR, NO, CO., 60 more of Calkyl, halogen, Chaloalkyl, OR', SR'', NO, COR, halogen, haloalkyl, SR, CN, NRCOR, CN, NR12R12, NR2COR2, NR12CONR2R12, COR CONRR, NRCOR, NRCOR, COR, COR, CONR, wherein R is hydrogen or C. alkyl, preferably R' is S(O).R., SONH, S(O)R', SO, NR'R'', NRS(O).R', methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. wherein the C-2 alkyl group optionally incorporates one or 65 two insertions selected from the group consisting of —O—, The fifteenth aspect of the invention provides a method for N(R') , S(O)— and S(O)—, wherein each R' the production of compound of formula (IX) may be the same or different and is as defined below: US 7,652,137 B2 21 22 R" is hydrogen, C. alkyl, or C, a haloalkyl: wherein X is a amino-protecting group, preferably selected (XV) from R'S(O) (R')Si, RC(O), ROCH R'NSO, ROC R8 (O) , R' (RO)CH , RCHCH, , RCH, , PhC(O) CH-CH=CH-CICH2CH2—, PhC Ph(4-pyridyl) N C , Me-N-, HO CH-, ROCH (R')SiOCH , (RO)2CH , t-BuOC(O)CH , Me, NCH and tetrahy N 21 dropyranylamine; wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, 10 N C. heterocyclyl or C. carbocyclyl: optionally Substi tuted with one or more of Calkyl, Si(R), OR, NO, CO., COR, halogen, haloalkyl, SR, CN, NRCOR, comprisinga) a reaction of a compound of formula (III) with R B(OR') in the presence of a palladium catalyst COR CONRR, 15 wherein R is hydrogen or C. alkyl, preferably R' is methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. (III) wherein R is independently selected from an optionally Br substituted C-12 alkyl, C-12 alkenyl, COR. carbocyclyl or heterocyclyl group and Z is a halogen or triflate preferably N iodide, bromide or chloride. NN-2 It will be appreciated that the reaction set out is a Hiyama reaction which can be carried out according to Hatanaka et al. N J. Org. Chem. 1988, 53,918, Hatanaka et al. Synlett 1991,845 25 H or Tamao et al. Tetrahedron Lett. 1989, 30, 6051, or Denmark et al. Org. Lett. 2000, 2,565, ibid. 2491. b) reacting a compound of formula (III) with R. Sn(R), in The sixteenth aspect of the invention provides a method of the presence of a palladium catalyst c) reacting a compound producing 7-azaindoline from 7-azaindole, comprising the of formula (III) with R. Si(R) in the presence of a fluoride reaction of 7-azaindole with a formic acid-triethylamine mix 30 and a palladium catalyst; ture in the presence of a palladium catalyst, followed by wherein R is as defined in the ninth aspect incubation with sodium hydroxide. In a preferred feature R is substituted aryl, preferably substituted phenyl or optionally substituted five-membered heterocyclyl: 35 wherein R' is hydrogen, Ce alkyl or C. aryl and wherein two or more R' groups may together form a 4 to 7 membered ring; In a preferred feature R' is hydrogen, —CMeCMe , / methyl, ethyl. N N 40 wherein R is as defined in the third aspect R" is as defined in the fifth aspect In a preferred feature R is C, alkyl, most preferably This method avoids using high pressure, gaseous hydro methyl, ethyl, propyl and butyl. gen, avoids concomitant formation of overreduced products 45 For the avoidance of doubt, when a group as defined above and occurs at relatively low temperature. contains two or more radicals, e.g. the radical R', as for The seventeenth aspect provides a compound of formula example in SiR'R'', the two or more radicals e.g. R* may be (XV) the same or different. It will be appreciated that the reaction set out in option a) 50 for the eighteenth aspect is a Suzuki coupling reaction which (XV) R8 can be carried out according to Suzuki Pure Appl. Chem. 1991, 63,419; and Martin and Yang Acta Chem. Scand. 1993, 47, 221, or Littke J. Am. Chem. Soc. 2000, 122, 4020. It will be appreciated that the reaction set out in option b) rs 55 for the eighteenth aspect is a Stille coupling reaction which N 2 can be carried out according to Stille Angew. Chem. Int. Ed. 1986, 25, 508; Mitchell, Synthesis 1992, 803, or Littke et al. N H J. Am. Chem. Soc. 2002, 124, 6343. It will be appreciated that the reaction set out in option c) 60 for the eighteenth aspect is a Hiyama coupling reaction which can be carried out according to Hatanaka and Hiyama J. Org. wherein R is as defined in the ninth aspect Chem. 1988, 53, 918; Hatanaka and Hiyama Synlett. 1991, In a preferred feature R is substituted aryl, preferably 845; Tamao et al. Tetrahedron Lett. 1989, 30, 6051, or Den substituted phenyl or optionally substituted five-membered market al. Org. Lett. 2000, 2,565, ibid. 2491. heterocyclyl or aryl-C(O). 65 In a preferred feature of the eighteenth aspect a compound The eighteenth aspect provides a method for the produc of formula (III) is incubated with an arylboronic acid R. B tion of a compound of formula (XV) (OH), heteroaryl boronic acid R. B(OH), aryltrialkyl US 7,652,137 B2 23 24 stannane R. Sn(R), or heteroaryltrialkylstannane R. Sn For the avoidance of doubt, when a group as defined above (R), where R is as defined above and R is C alkyl. contains two or more radicals, e.g. the radical R', as for Compound (III) is formed by bromination of 7-azaindoline example in NR'R'', the two or more radicals e.g. R' may be according to methods known in the art. the same or different. The nineteenth aspect provides a method for the produc- 5 tion of a compound of formula (VII) It will be appreciated that the reaction set out in option a) for the nineteenth aspect is a Suzuki coupling reaction which can be carried out according to Suzuki Pure Appl. Chem. (VII) 1991, 63,419; and Martin and Yang Acta Chem. Scand. 1993, 10 47, 221, or Littke J. Am. Chem. Soc. 2000, 122, 4020. It will be appreciated that the reaction set out in option b) rs for the nineteenth aspect is a Stille coupling reaction which Na2 can be carried out according to Stille Angew. Chem. Int. Ed. 15 1986 25, 508; Mitchell, Synthesis 1992, 803, or Littke et al. J. N Am. Chem. Soc. 2002, 124, 6343. A X It will be appreciated that the reaction set out in option c) for the nineteenth aspect is a Hiyama coupling reaction which can be carried out according to Hatanaka and Hiyama J. Org. comprising a) a reaction of a compound of formula (I) with Chem. 1988, 53,918; Hatanaka and Hiyama Synlett. 1991, R B(OR"), in the presence of a palladium catalyst; 845; Tamao et al. Tetrahedron Lett. 1989, 30, 6051, or Den market al. Org. Lett. 2000, 2,565, ibid. 2491. In a preferred feature of the nineteenth aspect a compound (I) of formula (I) is incubated with an arylboronic acid R. B (OH), heteroaryl boronic acid R. B(OH), aryltrialkyl stannane R. Sn(R), or heteroaryltrialkylstannane R. Sn (R), where R is as defined above and R is C alkyl. The twentieth aspect provides a compound of formula 30 (XIII)
b) reacting a compound of formula (I) with R. Sn(R) in 35 (XIII) the presence of a palladium catalyst or c) reacting a com pound of formula (I) with R. Si(R) in the presence of a fluoride and a palladium catalyst; wherein R is as defined in the ninth aspect In a preferred feature R is substituted aryl, preferably 40 substituted phenyl or optionally substituted five-membered heterocyclyl: wherein X is an amino-protecting group as defined in the first aspect, preferably selected from R'S(O), (R').Si. R'C (O), ROCH R'NSO, ROC(O) R' (RO)CH , 45 RCHCH , RCH , PhC(O)CH , CH=CH-, CICHCH , PhC , Ph.(4-pyridyl)C , Me-N , HO-CH , ROCH , (R')SiOCH , (RO)2CH-, t-BuOC(O)CH , MeNCH and tetrahydropyrany 50 wherein X is an amino-protecting group as defined in the first lamine; aspect, preferably selected from R'S(O), (R'),Si, RC(O), wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, ROCH R'NSO, ROC(O) R' (RO)CH , C. heterocyclyl or C. carbocyclyl: optionally substi RCHCH , RCH -, PhC(O)CH , CH=CH-, tuted with one or more of Calkyl, Si(R), OR, NO, CO., CICHCH , PhC Ph(4-pyridyl)C , Me-N . CO.R., halogen, haloalkyl, SR, CN, NRCOR, ss HO CH-, ROCH , (R')SiOCH , (RO)2CH-, COR CONRR, t-BuOC(O)CH , MeNCH and tetrahydropyrany wherein R is hydrogen or C, alkyl, preferably R' is lamine; methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. wherein R' is hydrogen, C. alkyl or C-2 aryl and wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, wherein two or more R' groups may together form a 4 to 7 60 C. heterocyclyl or C-2 carbocyclyl: optionally Substi membered ring; tuted with one or more of Calkyl, Si(R), OR, NO, CO., In a preferred feature R' is hydrogen, —CMeCMe. , COR, halogen, haloalkyl, SR, CN, NRCOR, methyl, ethyl. COR CONRR, wherein R is as defined in the third aspect wherein R is hydrogen or C alkyl, preferably R' is In a preferred feature R is C, alkyl, most preferably 65 methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. methyl, ethyl, propyl and butyl. The twenty first aspect provides a method for the produc R" is as defined in the fifth aspect tion of a compound of formula (XVI) US 7,652,137 B2 26 The twenty-second aspect provides a method for the pro duction of a compound of formula (IX) (XVI) R8 (IX) N 21
10 comprising a) a reaction of a compound of formula (XVII) with R. B(OR") in the presence ofapalladium catalyst; or 15 comprising a) a reaction of a compound of formula (XIII) (XVII) Br with R. B(OR') in the presenceofapalladium catalyst; or
N (XIII) Br Na2
/ 25 b) reacting a compound of formula (XVII) with R. Sn(R), in the presence of a palladium catalyst c) reacting a compound of formula (XVII) with R. Si(R) in the presence of a 30 fluoride and a palladium catalyst; wherein R is as defined in the ninth aspect b) reacting a compound of formula (XIII) with R. Sn(R), In a preferred feature R is substituted aryl, preferably in the presence of a palladium catalyst c) reacting a compound substituted phenyl or optionally substituted five-membered of formula (XIII) with R. Si(R) in the presence of a fluo heterocyclyl: 35 ride and a palladium catalyst; wherein R is as defined in the third aspect wherein R is as defined in the third aspect In a preferred feature R is C, alkyl, most preferably wherein R is as defined in the fifth aspect methyl, ethyl, propyl and butyl. wherein R is as defined in the ninth aspect wherein R is as defined in the fifth aspect In a preferred feature R is substituted aryl, preferably wherein R' is as defined in the seventh aspect 40 substituted phenyl or optionally substituted five-membered In a preferred feature R' is hydrogen, —CMeCMe. , heterocyclyl: methyl, ethyl. wherein X is an amino-protecting group as defined in the For the avoidance of doubt, when a group as defined above first aspect of the invention, preferably selected from R'S contains two or more radicals, e.g. the radical R, as for (O) (R')Si, RC(O), ROCH R'NSO, ROC(O) , example in SnRR, the two or more radicals e.g. R may be 45 R(RO)CH , RCHCH, , RCH, , PhC(O)CH, , the same or different. CH=CH ClCHCH PhC Ph(4-pyridyl)C It will be appreciated that the reaction set out in option a) Me-N-, HO CH-, ROCH , (R')SiOCH , for the twenty first aspect is a Suzuki coupling reaction which (RO). CH , t-BuOC(O)CH , MeNCH and tetrahy can be carried out according to Suzuki Pure Appl. Chem. dropyranylamine; 1991, 63,419; and Martin and Yang Acta Chem. Scand. 1993, 50 wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, 47, 221, or Littke J. Am. Chem. Soc. 2000, 122, 4020. C. heterocyclyl or C-2 carbocyclyl: optionally Substi It will be appreciated that the reaction set out in option b) tuted with one or more of Calkyl, Si(R), OR, NO, CO., for the twenty first aspect is a Stille coupling reaction which COR, halogen, haloalkyl, SR, CN, NRCOR, can be carried out according to Stille Angew. Chem. Int. Ed. COR CONRR, 1986, 25, 508; Mitchell, Synthesis 1992, 803, or Littke et al. 55 wherein R is hydrogen or C alkyl, preferably R' is J. Am. Chem. Soc. 2002, 124, 6343. methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. It will be appreciated that the reaction set out in option c) wherein R' is as defined in the seventh aspect for the twenty first aspect is a Hiyama coupling reaction In a preferred feature R' is hydrogen, —CMeCMe. , which can be carried out according to Hatanaka and Hiyama methyl, ethyl. J. Org. Chem. 1988, 53, 918; Hatanaka and Hiyama Synlett. 60 1991, 845; Tamao et al. Tetrahedron Lett. 1989, 30, 6051, or In a preferred feature R is C, alkyl, most preferably Denmarket al. Org. Lett. 2000, 2,565, ibid. 2491. methyl, ethyl, propyl and butyl. In a preferred feature of the twenty first aspect a compound R" is hydrogen, C. alkyl, or Chaloalkyl; of formula (I) is incubated with an arylboronic acid R B For the avoidance of doubt, when a group as defined above (OH), heteroaryl boronic acid R. B(OH), aryltrialkyl 65 contains two or more radicals, e.g. the radical R, as for stannane R. Sn(R), or heteroaryltrialkylstannane R. Sn example in SnRR, the two or more radicals e.g. R may be (R), where R is as defined above and R is C, alkyl. the same or different. US 7,652,137 B2 27 28 It will be appreciated that the reaction set out in option a) wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, for the twenty-second aspect is a Suzuki coupling reaction C. heterocyclyl or C. carbocyclyl: optionally substi which can be carried out according to Suzuki Pure Appl. tuted with one or more of Calkyl, Si(R), OR, NO, CO., Chem. 1991, 63, 419; and Martin and Yang Acta Chem. COR, halogen, haloalkyl, SR, CN, NRCOR, Scand. 1993, 47,221, or Littke J. Am. Chem. Soc. 2000, 122, COR CONRR, 4O2O. wherein R is hydrogen or C, alkyl, preferably R' is It will be appreciated that the reaction set out in option b) methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. for the twenty-second aspect is a Stille coupling reaction It will be appreciated that the reaction set out in the twenty which can be carried out according to Stille Angew. Chem. Int. third aspect is a Stille coupling reaction which can be carried Ed. 1986, 25, 508; Mitchell, Synthesis 1992, 803, or Littke et 10 out according to Stille Angew. Chem. Int. Ed. 1986, 25, 508; al. J. Am. Chem. Soc. 2002, 124, 6343. Mitchell, Synthesis 1992, 803, or Littke et al. J. Am. Chem. It will be appreciated that the reaction set out in option c) Soc. 2002, 124, 6343. for the twenty-second aspect is a Hiyama coupling reaction The twenty fourth aspect provides a compound of formula which can be carried out according to Hatanaka and Hiyama (XVIII) J. Org. Chem. 1988, 53, 918; Hatanaka and Hiyama Synlett. 15 1991, 845; Tamao et al. Tetrahedron Lett. 1989, 30, 6051, or (XVIII) Denmarket al. Org. Lett. 2000, 2,565, ibid. 2491. Sn(R)3 In a preferred feature of the twenty-second aspect a com pound of formula (I) is incubated with an aryl boronic acid R B(OH), heteroaryl boronic acid R. B(OH), aryltri alkyl stannane R. Sn(R), or heteroaryltrialkylstannane R. Sn(R), where R is as defined above and R is Ca alkyl. The twenty third aspect of the invention provides an alter native method for the production of a compound of formula 25 (IX) wherein R is as defined in the third aspect (IX) wherein X is an amino-protecting group as defined in the 30 first aspect, preferably selected from R'S(O), (R').Si. R'C (O), ROCH R'NSO, ROC(O) R' (RO)CH , RCHCH , RCH -, PhC(O)CH , CH=CH-, CICHCH , PhC Ph(4-pyridyl)C , Me-N . HO CH-, ROCH , (R')SiOCH , (RO)CH-, 35 t-BuOC(O)CH2—, MeNCH and tetrahydropyrany lamine; wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, C. heterocyclyl or C-2 carbocyclyl: optionally Substi tuted with one or more of Calkyl, Si(R), OR, NO, CO., 40 COR, halogen, haloalkyl, SR, CN, NRCOR, comprising a reaction of a compound of formula (XVIII) with COR CONRR, R-Z in the presence of a palladium catalyst wherein R is hydrogen or C, alkyl, preferably R' is methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. The twenty fifth aspect of the invention provides a method (XVIII) 45 Sn(R) of producing a compound of formula (XVIII)
Br Sn(R) 50 rs rs Nn 2 Nn 2 \ / / 55 M M X X wherein R is as defined in the third aspect (XIII) (XVIII) wherein RandR are as defined in the ninth aspect wherein Z is defined in the fifth aspect wherein X is an amino-protecting group as defined in the 60 comprising incubating a compound of formula (XIII) with a first aspect, preferably selected from R'S(O), (R').Si. RC base followed by addition of (R).Sin W (O), ROCH R'NSO, ROC(O) R' (RO)CH , wherein R and Ware as defined in the third aspect RCHCH , RCH , PhC(O)CH , CH=CH-, wherein X is an amino-protecting group as defined in the CICHCH PhC Ph(4-pyridyl)C , Me-N . first aspect, preferably selected from R'S(O), (R').Si. R'C HO-CH , ROCH , (R')SiOCH , (RO)2CH-, 65 (O), ROCH R'NSO, ROC(O) R' (RO)CH , t-BuOC(O)CH MeNCH and tetrahydropyrany RCHCH , RCH - PhC(O)CH , CH=CH-, lamine; CICHCH , PhC Ph(4-pyridyl)C , Me-N . US 7,652,137 B2 29 30 HO-CH , ROCH , (R')SiOCH , (RO)2CH-, wherein R' is C, alkyl, C-12 cycloalkyl, C. haloalkyl, t-BuOC(O)CH , MeNCH and tetrahydropyrany C. heterocyclyl or C-2 carbocyclyl: optionally Substi lamine; tuted with one or more of Calkyl, Si(R), OR, NO, CO., wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, COR, halogen, haloalkyl, SR, CN, NRCOR, C. heterocyclyl or C. carbocyclyl: optionally Substi tuted with one or more of Calkyl, Si(R), OR, NO, CO., COR CONRR, COR, halogen, haloalkyl, SR, CN, NRCOR, wherein R is hydrogen or C, alkyl, preferably R' is COR CONRR, methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. wherein R is hydrogen or C. alkyl, preferably R' is The twenty eighth aspect provides a compound of formula methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. 10 (XVIa) The twenty sixth aspect provides a compound of formula (VIIa) 9 (XVIa) O R (VIIa) 15
N Na2
H /
25 wherein R is as defined in the ninth aspect wherein R is as defined in the ninth aspect The present invention encompasses one or more com wherein X is an amino-protecting group as defined in the pounds as defined in the first, fourth, fifth, sixth, seventh, first aspect, preferably selected from R'S(O), (R').Si. R'C ninth, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, (O), ROCH, RNSO, ROC(O) , R (RO)CH , 30 eighteenth, twentieth, twenty fourth, twenty sixth, twenty RCHCH , RCH , PhC(O)CH , CH=CH-, seventh and twenty eighth aspects of the invention and as set CICHCH , PhC , Ph.(4-pyridyl)C , Me-N-, out below: HO-CH , ROCH , (R')SiOCH , (RO)CH-, t-BuOC(O)CH MeNCH and tetrahydropyrany lamine; 35 Br Br Br Li wherein R' is C, alkyl, C-12 cycloalkyl, Chaloalkyl, C. heterocyclyl or C-carbocyclyl: optionally Substituted with one or more of C, alkyl, Si(R), OR, NO, CO., COR, halogen, haloalkyl, SR, CN, NRCOR, rN N N S COR CONRR, Na2 Nn 2 Na2 Na2 wherein R is hydrogen or C, alkyl, preferably R' is N N / N N methyl, ethyl, propyl. n-butyl, tert-butyl or phenyl. M A / M The twenty seventh aspect provides a compound of for TBS TBS PhSO TBS mula (IXa) SnBus SnBus B(OR)2 SiMe3 45 (IXa) rN N N S Na2 Na2 Na2 Na2 50 N N / N / N M A M H TBS TBS TBS R = H, Me OMe 55 OMe
O wherein R is as defined in the ninth aspect SiMe3 wherein X is an amino-protecting group as defined in the 60 first aspect, preferably selected from R'S(O), (R').Si. RC (O), ROCH R'NSO, ROC(O) R' (RO)CH , rN n RCHCH , RCH , PhC(O)CH , CH=CH-, Na2 Na2 CICHCH PhC Ph(4-pyridyl)C , Me-N . HO-CH , ROCH , (R')SiOCH , (RO)2CH-, 65 / / t-BuOC(O)CH MeNCH and tetrahydropyrany H H lamine; US 7,652,137 B2 31 32 2,3-Dihydro-1H-pyrrolo2,3-bipyridine (2) -continued
CF
NMe2 N N 1. HCOOH-EtN Me N 2 Po?C N 2 / 2. NaOH 10 HN HN O 21
1 2
rs rN n 15 Nn 2 Na2 Na2 98% Formic acid (37.5 mL, 0.97 mol) was added to a - / stirred and cooled (ice bath) neat EtN (150 mL, 1.08 mol). A H N N two-phase system, which was formed, was then added to a mixture of 7-azaindole (50.0 g, 0.424 mol), formic acid (750 mL), and 10% palladium on activated carbon (26.75 g, Degussa type), and stirred at 80° C. for 4d. The mixture was All features of each of the aspects apply to all other aspects cooled to r.t. the catalyst was filtered off and washed with mutatis mutandis. formic acid (100 mL). The filtrate and washings were com The invention will now be illustrated by reference to one or 25 bined and concentrated in vacuum. The residual liquid was more of the following non-limiting examples. cooled (ice bath) and basified to pH 13 by slow addition of 50% aqueous NaOH (total of about 500 mL). Then, the mix EXPERIMENTAL ture was refluxed for 2 huntil TLC showed completion. Ice was added in amount sufficient to lower the temperature of the Synthesis of N-protected 5-bromo-7-azaindolines 4 30 mixture to 20°C. The two-phase system was then extracted and 6 with AcOEt (5x500 mL). Combined extracts were washed
Br
N N 1. HCOOH-EtN rn rn N 21 Po?C N 2 TBSC N 2 Br2 N 2 / 2. NaOH NaH pyridine HN HN N N / / TBS TBS 1 2 3 4 Br2 pyridine
Br Br rs N NN2 TAPSOC Na2
HN N PhOS 5 US 7,652,137 B2 33 34 with brine, dried MgSO, and concentrated in vacuum. The derivative 4 (1.13 g, 77%) as a pale yellow oil. "H NMR (400 residual brown solid was separated by means of SGC with MHz: CDC1) & 0.31 (s, 6H), 0.95 (s, 9H), 2.99 (t, J=9.1 Hz, AcOEt:MeOH as eluent to afford recovered 1 (12.57g, 25%) 2H), 3.67 (t, J=9.1 Hz, 2H), 7.20 (m, 1H), 7.79 (m. 1H). and desired 2 (36.05 g, 71%). H NMR (400 MHz, CDC1) & 3.05 (t, J=8.4 Hz, 2H), 3.60 (t, J–8.4 Hz, 2H), 4.52 (bs, 1H), 5-Bromo-2,3-dihydro-1H-pyrrolo2,3-bipyridine (5) 6.49 (dd, J=7.0, 5.3 Hz, 1H), 7.23 (dq, J=7.0, 1.3 Hz, 1H), 7.81 (ddt, J=5.3, 1.3, 1.1 Hz, 1H).
1-(tert-Butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyr Br rolo2,3-bipyridine (3) 10 rs rn N 21 Br2 N 21 He 15 pyridine Nrs 2 TBSC Nrs 21 HN HN NaH 2 5
HN N M TBS A solution of Br (18.1 mL, 56.2 g, 0.351 mol) in dry 2 3 CHCl (250 mL) was added dropwise over a period of 1 h 45 minto a stirred and cooled (-5°C.) solution of 2 (42.22 g, To a stirred and cooled (0°C.) solution of 7-azaindoline 2 0.351 mol) in dry CHCl (410 mL)-pyridine (40 mL). The (6.6 g., 54.9 mmol) in N,N-dimethylacetamide (18.5 mL) was yellow suspension was stirred at 0°C. for 45 min and poured added a 60% dispersion of sodium hydride in mineral oil (3.3 25 into a mixture of saturated aqueous NaHCOs (800 mL) and g, 82.4 mmol) portionwise. The mixture was stirred for 30 saturated aqueous NaSO (100 mL). Methanol (10 mL) was min and a solution of TBSC1 (12.41 g, 82.4 mmol) in N.N- added and the lower organic layer was separated and dried dimethylacetamide (25.1 mL) was added dropwise. The mix over MgSO. The aqueous layer was extracted with AcOEt: ture was allowed to warm slowly tort. Following a further 18 MeOH=99:1 (7x1000 mL). These extracts were also dried h stirring the mixture was partitioned between AcOEt and 30 saturated brine. The aqueous layer was extracted with AcOEt with MgSO4. The organic Solutions were combined and con (2x). The combined organic solutions were washed with centrated to afford 5 (59.17 g. 85%), which was used in the brine, dried (MgSO), filtered and concentrated. The residue next step without further purification. "H NMR (400 MHz, was purified by silicagel chromatography (SGC) using hexa CDC1) & 3.07 (tt, J–8.4, 1.1 Hz, 2H), 3.64 (t, J=8.4 Hz, 2H), ne: AcOEt as eluent (in gradient) to afford the desired 3 (8.15 35 4.47 (bs, 1H), 7.31 (m, 1H), 7.85 (dt, J=2.1, 0.9 HZ, 1H). g, 63%) as a pale yellow oil. "H NMR (400 MHz: CDC1) & 0.33 (s, 6H), 0.97 (s.9H), 2.99 (t, J=9.1 Hz, 2H), 3.65 (t, J=9.1 1-Benzenesulfonyl-5-bromo-2,3-dihydro-1H-pyrrolo Hz, 2H), 6.38 (d. J=5.2 Hz, 1H), 7.14 (d. J=1.7 Hz, 1H), 7.79 2,3-bipyridine (6) (dd, J=1.7, 5.2 Hz, 1H). 40 5-Bromo-1-(tert-butyl-dimethyl-silanyl)-2,3-dihy dro-1H-pyrrolo2,3-bipyridine (4) Br Br N N 45 Br as a rs rn HN N N 2 Br2 N 21 50 PhOS 5 6 Hepyridine N N M ? TBS TBS To a 0°C. stirred solution of 5-bromo-azaindoline 5 (150 3 4 mg, 0.75 mmol) in N,N-dimethylacetamide (7 mL) was 55 added in one portion 60% dispersion of NaH in mineral oil To a stirred and cooled (0°C.) solution of the azaindoline (38 mg, 0.94 mmol). After 0.5 h benzenesulfonyl chloride 3 (1.1 g, 4.7 mmol) in CHCl (25 mL) and pyridine (0.46 mL, (0.12 mL, 0.94 mmol) in N,N-dimethylacetamide (1 mL) was 5.6 mmol) was added dropwise a solution of bromine (0.24 added dropwise, and the mixture allowed to slowly warm to mL, 4.7 mmol) in CHCl (15 mL) over a period of 13 min. 60 rt. After 2 days the mixture was partitioned between AcOEt After a further 20 min stirring the mixture was diluted with a brine. The aqueous layer was extracted with AcOEt (2x). The NaHCO. NaSO (1:1 V/v) solution and stirred vigorously combined organic solutions were dried (MgSO), filtered and for 50 min. The resulting mixture was partitioned and the concentrated. The residue was purified by preparative TLC aqueous layer extracted with CHCl (3x). The combined (PTLC) with CH2Cl as eluent to afford the azaindoline 6 (21 organic extracts were dried (MgSO4), filtered and concen 65 mg, 8%) as a solid. "H NMR (400 MHz: CDC1) & 3.04 (t, trated. The residue was purified by SGC with hexane:AcOEt J=8.6 Hz, 2H), 4.08 (t, J=8.6 Hz, 2H), 7.45-7.51 (m, 3H), as eluent (in gradient up to 1.3% AcOEt) to afford the bromo 7.56-7.60 (m. 1H), 8.08 (m, 2H), 8.18 (m. 1H). US 7,652,137 B2 35 36 Use of 5-bromo-7-azaindoline 4 in the metal-halogen 1-(tert-Butyl-dimethyl-silanyl)-5-methyl-1H-pyrrolo exchange and Subsequent reactions 2,3-bipyridine (8) Reaction with Alkyl Halides. Synthesis of 5-methyl Deriva tive 9 5 Me Me
N N Scheme 2 DDQ. Br Me 10 Nn 2 Na2 N N / N N M M 1. t-BuLi DDQ TBS TBS Na2 2. MeI Nn 2 15 7 8
N N ? / To a stirred solution of the crude azaindoline 7 (0.64 mmol) TBS TBS in CHCl (10 mL) was added DDQ (145 mg, 0.64 mmol) in 4 7 one portion. After 20 min the resulting black mixture was 2O diluted with saturated aqueous NaHCO solution and stirred vigorously for 15 min. The aqueous layer was extracted with Me Me CHCl (2x) and the combined organic solutions were dried (MgSO), filtered and concentrated to affordazaindole 8 as a brown oil, which was used directly in the next step without N N 25 purification. 10% HC Na2 MeOH Nn 2 5-Methyl-1H-pyrrolo2,3-bipyridine (9) - / / M TBS 30 8 9 Me Me N N 10% HC 35 Na2 MeOH Na2 1-(tert-Butyl-dimethyl-silanyl)-5-methyl-2,3-dihy / / M dro-1H-pyrrolo2,3-bipyridine (7) TBS 8 9 40 To a stirred solution of the crude azaindole 8 (0.64 mmol) in MeOH (6 mL) was added a 10% solution of HCl in metha Br Me nol (3 mL). After 20 min the mixture was concentrated and 45 partitioned between AcOEt and saturated aqueous NaHCO solution. The aqueous layer was extracted with AcOEt (2x) rs 1. t-BuLi rs and the combined organic solutions were dried (MgSO4), N 21 -2. MeI - N 21 filtered and concentrated. The residue was purified by PTLC using 5% MeOH in CHCl to afford the desired methyl N N M M 50 derivative 9 (68 mg, 81% over 3 steps). H NMR (400 MHz: TBS TBS CDC1) & 2.45 (s.3H), 6.42 (d, J-34 Hz, 1H), 7.34 (d, J-34 4 7 HZ, 1H), 7.76 (d. J=1.7 Hz, 1H),8.19 (d. J=1.7 Hz, 1H), 10.92 (brs, NH). Reaction with CO. Synthesis of Acid 12. 55 To a stirred and cooled (-78°C.) solution of bromide 4 (0.20 g, 0.64 mmol) in Et2O (2.5 mL) was added dropwise a Br COOH 1.5M solution of tert-BuLi in pentane (0.89 mL, 1.34 mmol). After 38 min Mel (0.1 mL, 1.61 mmol) was added dropwise and the mixture allowed to gradually warm to r.t. After 12 h 60 rn rn Na2 1. t-BuLi NN-2 DDQ the mixture was partitioned between CHCl and saturated Hs He aqueous NaHCO Solution. The aqueous layer was extracted 2. CO N N with CHCl (2x). The combined organic extracts were dried M M (MgSO), and concentrated to afford 7 as a yellow oily resi 65 TBS TBS due, which was used directly in the next step without purifi 4 10 cation. US 7,652,137 B2 37 38 MeOH-20:1 and filtered through silicagel pad. The filtrate -continued was concentrated and used directly in the next step.
COOH COOH 1H-Pyrrolo2,3-bipyridine-5-carboxylic acid (12) rs rs Nn 2 10% HC Na2 / HerMeOH / COOH COOH N HN M TBS 11 12 rs rs Na2 DDQ Na 10% HC He- He
15 N N / MeOH M / TBS TBS 1-(tert-Butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyr 10 11 rolo2,3-bipyridine-5-carboxylic acid (10)
COOH
Br COOH rs 25 Na2 N N 1. t-BuLi HN / 21 2. CO2 21 12
N N M M TBS TBS A solution of crude acid 10 in CH2Cl2 (5 mL) was treated 4 10 with DDQ in small portions until TLC analysis revealed no starting material left. The mixture was concentrated to afford 35 a solid residue containing azaindole 11. The residue was dissolved in a 5% solution of HCl in MeCH (5 mL), and To a stirred and cooled (-78°C.) solution of the bromide 4 stirred at r,t. After 1.5 h the mixture was concentrated and (205 mg, 0.65 mmol) in EtO (4 mL) was added dropwise a diluted with CHCl and saturated brine. The mixture was 1.5M solution of tert-butyllithium in pentane (0.92 mL, 1.37 basified with 50% NaOH solution to pH 11. The organic layer mmol). After 40 min., dry gaseous CO was introduced into 40 was discarded. The aqueous layer was neutralized with 6 M the reaction vessel. Progress of the reaction was followed by HCl and extracted with AcOEt (4x). The combined organic TLC analysis. After complete consumption of starting mate extracts were dried (MgSO), filtered and concentrated. The rial 4 the reaction was quenched by the addition of saturated residue was purified by PTLC using CH.Cl:MeOH=9:1 as aqueous NaHCO solution. The mixture was allowed to warm eluent to afford acid 12 (3.19 mg, 3% over 3 steps). H NMR to room temperature, and diluted with CH2Cl2. The aqueous 45 (400 MHz: CDOD) & 6.58 (d. J=3.5 Hz, 1H), 7.42 (d. J=3.5 layer was extracted with CHCl (2x), and the combined HZ, 1H), 8.58 (d. J=2.0 Hz, 1H), 8.85 (d. J=1.7 Hz, 1H). organic solutions were dried (MgSO), filtered and concen Reaction with DMF, Synthesis of Alcohol 15 and Aldehyde trated. The residual yellow oil was dissolved in CHCl2: 16.
OH OH Br CHO rn rn rn rn Na2 1. t-BuLi Na2 NaBH4 Na2 DDQ Na2 He-2. DMF He- He / N N N N M / / M TBS TBS TBS TBS 4 13 14 15 pDo US 7,652,137 B2 39 40
-continued CHO COOH
N N Na2 NaCIO Na2 / NaH2PO4 / M M TBS TBS
1-(tert-Butyl-dimethyl-silanyl)-2,3-dihydro-1H-pyr 15 MeOH) to afford alcohol 14 (0.67 g, 24%). H NMR (400 rolo2,3-bipyridine-5-carbaldehyde (13) MHz. CDC1,) & 0.31 (s, 6H), 0.94 (s, 9H), 2.97 (t, J=8.2 Hz, 2H), 3.65 (t, J–8.2 Hz, 2H), 4.39 (s. 2H), 7.19 (s, 1H), 7.69 (s. 1H). Br CHO 1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo2,3-b pyridin-5-yl)-methanol (15)
rn 1. t-BuLi rn Her Na2 2. DMF Nn 2 OH OH 25 N N M / TBS TBS N N 4 13 DDQ N 2 Ho- N 2 30 To a stirred and cooled (-78°C.) solution of the bromide 4 N N / (5.00 g, 15.96 mmol) in EtO (92 mL) was added dropwise / / 1.5M solution of tert-butyllithium in pentane (22.3 mL, 33.5 TBS TBS mmol). After 45 min additional stirring at -78°C., DMF (5.6 14 mL, 72.3 mmol) was added dropwise, and the mixture was 35 allowed to slowly warm to r.t. After 20 h the mixture was partitioned between saturated aqueous NaHCO solution and DDQ (53 mg, 0.23 mmol) was added in three equal por CH2Cl2. The organic layer was separated, dried (MgSO4), tions to a stirred solution of alcohol 14 (54 mg., 0.20 mmol) in and concentrated to afford the crude aldehyde 13 (4.32 g). "H a mixture of CHCl (15 mL) and 0.2 M pH 7 phosphate NMR (400 MHz:CDC1) & 0.32(s, 6H), 0.92 (s.9H), 3.02(m, 40 buffer (0.15 mL). When TLC analysis showed complete con 2H), 3.70 (m, 2H), 7.55 (d. J=2.0 Hz, 1H), 8.16 (d. J=2.0 Hz, Sumption of the starting material, the mixture was diluted 1H), 9.61 (s, 1H). with saturated aqueous NaHCO (16 mL) and stirred vigor ously for 1 h. Then the mixture was extracted with AcOEt 1-(tert-Butyl-dimethyl-silanyl)-2,3-dihydro-1H (2x). The combined organic extracts were washed with Satu pyrrolo2,3-bipyridine-5-yl)-methanol (14) 45 rated brine (1x), dried (MgSO) and concentrated. The resi due was purified by PTLC with benzene as eluent to afford alcohol 15 (16 mg,31%). "H NMR (400 MHz: CDC1) & 0.63 (s, 6H), 0.93 (s.9H), 4.77 (s. 2H), 6.52 (d. J–3.5 Hz, 1H), 7.26 OH (d. J=3.5 Hz, 1H), 7.89 (d. J=2.0 Hz, 1H), 8.28 (d, J-2.0 Hz, CHO 1H). N N 1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo2,3-b pyridine-5-carbaldehyde (16) NaBH4 Na2 -- N
N N / / CHO CHO TBS TBS N N 60 DDQ To a stirred and cooled (0°C.) solution of crude 13 (2.77 g. 21 -- N n2 10.6 mmol) in EtOH (100 mL) was added NaBH (0.48 mg, 12.7 mmol) in a single portion. The mixture was allowed to N N / warm to r.t. After 20 h the mixture was concentrated and TBS TBS partitioned between CHCl-brine. The organic layer was 65 13 16 dried (MgSO) and concentrated. The residue was purified by SGC with CHCl2:MeCH as eluent (gradient up to 5% US 7,652,137 B2 41 42 To a stirred solution of the alcohol 13 (54 mg., 0.20 mmol) in a mixture of CH2Cl (15 mL) and 0.2 M pH 7 phosphate -continued buffer (0.15 mL) was added DDQ (53 mg, 0.23 mmol) in three equal portions. When TLC analysis showed complete consumption of the starting material, the mixture was diluted with saturated aqueous NaHCO, (16 mL) and stirred vigor ously for 1 h. The mixture was then extracted with AcOEt N (2x). The combined organic Solutions were washed with Satu rated brine (1x), dried (MgSO) and concentrated. The resi 10 Na2 due was purified by PTLC with benzene as eluent to afford aldehyde 16 (11 mg, 21%). H NMR (400 MHz: CDC1) & N M 0.66 (s, 6H), 0.94 (s, 9H), 6.67 (d. J=3.5 Hz, 1H), 7.34 (d. TBS J=3.5 Hz, 1H),8.37 (d. J=2.0 Hz, 1H),8.76 (d.J=2.0 Hz, 1H), 18 10.11 (s, 1H). 15 1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo2,3-b 1-(tert-Butyl-dimethyl-silanyl)-5-tributylstannanyl-2, pyridine-5-carboxylic acid (11) 3-dihydro-1H-pyrrolo2,3-bipyridine (17)
Br SnBus CHO COOH 25 N N 1. t-BuLi N rs Na2 Ho2. n-Busni Ne NaClO Na2 He Na2 NaH2PO4 /N /N / / 30 TBS TBS / M 4 17 TBS TBS 16 11 To a stirred and cooled (-90° C.) solution of bromide 4 35 (206 mg, 0.66 mmol) in THF (2.5 mL) was added dropwise 1.5 M solution of tert-butyllithium in pentane (1 mL, 1.51 To a stirred and cooled (0°C.) solution of aldehyde 16 (115 mmol). After 35 min additional stirring at -90° C., tri-n- mg, 0.44 mmol) in tert-butanol (3.1 mL) and 2-methyl-2- butyltin iodide (0.23 mL, 0.79 mmol) was added in one por butene (0.77 mL) was added a solution of NaClO (194 mg. tion. The mixture was stirred at -90° C. for 10 min, -78° C. 2.1 mmol) and NaH2POHO (244 mg, 1.8 mmol) in water 40 for 40 min, and then allowed to warm to r.t. The mixture was (2.31 mL) dropwise. When 16 was consumed (TLC) the partitioned between AcOEt-brine. The aqueous layer was mixture was partitioned between AcOEt and water. The extracted with AcOEt (3x) and the combined organic solu organic layer was washed with Saturated brine (1X), dried tions were dried (MgSO), and concentrated to afford the (MgSO), filtered and concentrated to afford acid 11 (20 mg. crude stannane 17, which was used in the next step without 16%) as an off-white solid. "H NMR (400 MHz: CDC1) & 45 purification. 0.66 (s, 6H), 0.94 (s, 9H), 6.65 (s, 1H), 7.32 (s, 1H), 8.61 (s, 5-Benzyl-2,3-dihydro-1H-pyrrolo2,3-bipyridine 1H) and 9.03 (s, 1H). (18)
Metal-Metal Exchange Stannylation. Synthesis of Benzyl 50 Derivative 18.
SnBus 55 N 1. PhCH2Br Br SnBus (PPh3)2PdCl2 N Na2 10, HC Meon I NN 2 rs rs 60 N N 2 1. t-BuLi N 2 PhCH-B2E3r 2. n-BusSnI TBS HN N N 17 18 / M TBS TBS 4 17 65 To a stirred solution of the crude stannane 17 (172 mg, 0.33 mmol) in THF (2.5 mL) was added PhCHBr (0.03 mL, 0.27 mmol) and (Ph-P)PdCl (5 mg, 0.007 mmol). The mixture US 7,652,137 B2 43 44 was refluxed under N for 19 h, cooled, and partitioned (2,3-Dihydro-1H-pyrrolo2,3-bipyridin-5-yl)-p-tolyl between AcOEt-brine. The aqueous layer was extracted with methanol (19) AcOEt (2x). The combined organic solutions were dried (MgSO), and concentrated in vacuum. The residual yellow oil was dissolved in MeOH (3 mL) and treated with a 10% solution of HCl in MeCH (2 mL). The mixture was stirred for Br 2.5 h, neutralized with saturated aqueous NaHCO, solution and extracted with AcOEt (2x). The combined organic N 1. t-BuLi extracts were dried (MgSO), concentrated, and purified by 10 N 2. Me PTLC with CHC1:MeOH=95:5 as eluent to afford the 5-benzyl derivative 18 (8 mg, 11% over 2 steps). "H NMR (400 MHz: CDC1) & 2.99 (t, J=8.1 Hz, 2H), 3.60(t, J=8.3 Hz, N 29 2H), 3.79 (s. 2H), 7.06-7.31 (m, 7H), 7.69 (brs, NH). TBS 15 Reaction with Aldehyde. Synthesis of Alcohol 19 and Ketone 2O.
Br OH
N 1. t-BuLi N 2. Me 25
N 29 TBS 19 4 30
To a stirred and cooled (-78°C.) solution of the bromide 4 (100 mg, 0.32 mmol) in EtO (1.8 mL) was added dropwise 35 1.5M solution of tert-butyllithium in pentane (0.45 mL, 0.67 mmol). The mixture was stirred for an additional 0.6 hat -78° Me C. p-tolylaldehyde (0.04 mL, 0.32 mmol) was added, and the mixture slowly allowed to warm to rt. After 18 h the mixture OH was partitioned between AcOEt-brine. The aqueous layer was MnO2 40 He extracted with AcOEt (2x). The combined organic solutions were dried (MgSO), concentrated, and the residue was puri rs fied by PTLC with CHC1:MeOH=95:5 as eluent to afford N 21 alcohol 19 (15 mg, 19%) as a white solid. "H NMR (400 45 MHz: CDC1) & 2.34 (s.3H), 5.99 (s, 1H), 6.45 (d. J=3.5 Hz, HN 1H), 7.16 (d. J=7.8 Hz, 2H), 7.30-7.32 (m,3H), 7.93 (d. J=1.8 19 HZ, 1H), 8.32 (d. J=2.0 Hz, 1H) and 9.77 (brs, NH). (1H-Pyrrolo2,3-bipyridin-5-yl)-p-tolyl-methanone 50 (20)
Me Me 55 O OH MnO2
rn 60 N 21 rn Na2 HN / 2O HN 65 19 US 7,652,137 B2 45 46 To a stirred and cooled (-78°C.) solution of bromide 4 -continued (600 mg, 1.91 mmol) in EtO (10.8 mL) was added 1.5 M Me t-BuLi in pentane (2.68 mL, 4.02 mmol) dropwise, followed after 40 min by dropwise addition of TMSC1 (0.36 mL, 3.83 O mmol). The mixture was allowed to warm slowly to r.t. After 18 h the mixture was quenched by the addition of water and then extracted with AcOEt. The organic extract was washed rn with saturated brine, dried (MgSO), filtered and concen N 21 10 trated to afford the crude disilylated azaindoline (508 mg). This was diluted with MeOH (15.6 mL) and 10% HCl (7.8 HN / mL) and stirred vigorously for 20 min. The mixture was basified with saturated NaHCO solution and extracted with AcOEt (2x). The combined organic extracts were dried 15 (MgSO), and concentrated to afford the desired 21 (367 mg, To a stirred solution of the alcohol 20 (15 mg, 0.06 mmol) quantitative over 2 steps). H NMR (400 MHz: CDC1) & 0.22 in CHCl (1.2 mL) was added activated MnO (5.4 mg., 0.06 (s, 9H), 3.04 (m, 2H), 3.60 (t, J=8.3 Hz, 2H), 4.58 (brs, NH), mmol) in one portion. After 0.5 h the mixture was filtered 7.34 (m. 1H), 7.88 (m, 1H). through a pad of silica and the filtrate evaporated. The residue was purified by PTLC with CHCl:MeOH=95:5 as eluent to 5-Trimethylsilanyl-1H-pyrrolo2,3-bipyridine (22) afford ketone 20 (12.5 mg, 88%) as a white solid. "H NMR (400 MHz: CDC1) & 2.47 (s, 3H), 6.63 (d. J=3.3 Hz, 1H), 7.32 (d. J=8.1 Hz, 2H), 7.44 (d, J-3.0 Hz, 1H), 7.75 (d. J=8.1 Hz, 2H), 8.43 (d. J=1.8 Hz, 1H), 8.83 (d. J=1.8 Hz, 1H) and 25 10.14 (brs, NH). TMS TMS Reaction with Halosilanes. Synthesis of TMS Derivative 22. n N 30 MnO, Br TMS Na2 Na2
N 1. t-BuLi N HN HN / 2. TMSC MnO2 21 22 Na2 3. HCMeOH NN2 35
N HN / TBS To a stirred solution of the azaindoline 21 (20 mg 0.10 4 21 mmol) in CHCl (2 mL) was added oven activated MnO, (9 TMS 40 mg, 0.10 mmol) in one portion. After 18 h the mixture was filtered through a silica pad. The pad was washed with AcOEt and the combined organic Solutions evaporated to afford the rs azaindole 22 (17 mg, 86%). H NMR (400 MHz: CDC1) & N n2 45 0.35 (s.9H), 6.50 (d. J–3.5 Hz, 1H), 7.35 (d. J–3.5 Hz, 1H), 8.10 (d. J=1.5 Hz, 1H), 8.40 (d. J=1.5 Hz, 1H), 10.62 (brs, - / NH). 22 Participation of 5-bromoindolines in Suzuki type reac tions. Synthesis of 4-(dimethylamino)phenyl derivatives 23 50 and 24. 5-Trimethylsilanyl-2,3-dihydro-1H-pyrrolo2,3-b pyridine (21) NMe2 NMe2 55 Br TMS Br N 1. t-BuLi N 2. TMSC N 60 B(OH)2 N MnO2 Na2 3. Hol/MeoH N-2 Na2 --
N HN N 2 HN TBS HN 4 21 65 US 7,652,137 B2 47 48 Dimethyl-4-(1H-pyrrolo2,3-bipyridin-5-yl)-phe -continued nyl-amine (24) and methyl-4-(1H-pyrrolo2,3-b pyridin-5-yl)-phenyl-amine (25) NMe2 NHMe 5
-- rN in NMe2 NMe2 NHMe Na2 Na2 4 1 MnO2 --- -- 24 25 rs rN in Na2 Nn 2 Na2 4-(2,3-Dihydro-1H-pyrrolo2,3-bipyridin-5-yl)- phenyl-dimethyl-amine (23) 23 24 25 25
30 NMe2 NMe2 To a solution of 23 (11.5g, 48.5 mmol) in CHCl (1L) was added portionwise over 2 h solid MnO, (-75 g, activated by heating at 130°C.) until the TLC showed no starting material Br remaining. The reaction mixture was filtered and the filtrate 35 concentrated. The residual dark brown solid was purified by N SGC using AcOEt:hexane (1:1, dry loading) as eluent to B(OH)2 N Na2 --- afford 24 (9.50g, 83%) as a light orange solid; H NMR (400 MHz, CDC13) & 3.04 (s, 6H), 6.56 (dd, J-3.4, 1.6 Hz, 1H), N 21 40 HN 6.89 (d. J=8.8 Hz, 2H), 7.41 (dd, J=3.4, 2.3 Hz, 1H), 7.57 (d. J=8.8 Hz, 2H), 8.12 (d. J=2.1 Hz, 1H), 8.58 (d. J=2.1 Hz, 1H), HN 10.40-10.60 (bs, NH). The H NMR also showed a small 5 23 amount of 25 (about 8% mol), which could not be separated 45 from 24. Participation of 5-bromoindoles in Suzuki type reactions. Synthesis of 5-substituted 7-azaindoles 24, 28, and 29. A mixture of 5 (29.0 g, 0.146 mol), 4-(dimethylamino) phenylboronic acid (36.05 g, 0.218 mol), LiCl (18.5g, 0.441 mol), (PPh3)PdCl2 (8.60 g, 12.3 mmol) and 10% aqueous 50 NaCO, (364 mL) in EtOH (870 mL):toluene (870 mL) was refluxed for 1 h 30 min. The reaction mixture was cooled to rt., and poured into AcOEt:brine. The organic layer was Br Br separated and the aqueous layer was extracted with CH2Cl2 55 (10x500 mL). Combined organic solutions were dried rs rs (MgSO), concentrated and redissolved in CHC1 (1.5 L). Na2 Na2 The solution was mixed with silicagel (250 mL. Kieselgel 60, 230-400 mesh). Solvent was evaporated and the residual solid N HN 60 loaded on a silicagel column for separation. Purification by TBS means of SGC with CHCl:MeOH as eluent afforded 17.25 g (49%) of desired 23 as tan powder. "H NMR (400 MHz, 4 5 CDC1) & 2.98 (s, 6H), 3.11 (tt, J=8.3, 1.0 Hz, 2H), 3.65 (t, J=8.3 Hz, 2H), 4.44 (bs, 1H), 6.79 (d. J=8.8 Hz, 2H), 7.38 (d. 65 po |Mio J=8.8 Hz, 2H), 7.46 (dt, J=2.0, 1.2 Hz, 1H), 8.02 (dt, J=2.0, 0.9 Hz, 1H). US 7,652,137 B2 49 50 (90 mL) and 0.2 M phosphate buffer pH 7 solution (910 uL) -continued until full consumption of the starting material (TLC). Then, saturated aqueous NaHCO solution (22 mL) was added, and CF3 CF the reaction mixture stirred for 0.5 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3x20 mL). The combined organic solutions were dried (MgSO), concentrated and purified by SGC with hexane: Br Br 21 21 CH2Cl as eluent (in gradient up to 20% CHCl) to give 26 10 (505 mg.97%) as a clear oil; H NMR (400 MHz, CDC1) & n HCI/MeOH, N B(OH)2 n 0.62 (s, 6H), 0.93 (s, 9H), 6.47 (d. J–3.5 Hz, 1H), 7.24 (d. Na Ne He- Nina J=3.5 Hz, 1H), 7.97 (d. J=2.2 Hz, 1H), 8.28 (d. J=2.2 Hz, 1H). N / HN M / TBs HN 5-Bromo-1H-pyrrolo2,3-bipyridine (27) 15 26 27 28 Method 1 from 26
NMe2 NMe2
Br Br
B(OH)2 B(OH)2 n rN 25 Nina HeHCI/MeoH, N-2
NMe2 NMe2 TBS 26 27 30
To a stirred solution of the TBS derivative 26 (1.01 g, 3.3 mmol) in MeOH (10 mL) was added a 10% solution of HCl in N MnO2 N 35 MeOH (7 mL). After 8 min the solvents were evaporated and - || the residue was partitioned between AcOEt and saturated N 2 N 2 aqueous NaHCO. The aqueous layer was extracted with - / - / AcOEt (3x). The combined organic solutions were dried / 40 (MgSO), concentrated and purified by PTLC with CHCl2: TBS MeOH=95:5 as eluent to afford the bromo derivative 27 (0.60 29 24 g, 94%). "H NMR (400 MHz: CDC1) & 6.47 (dd, J=2.0, 3.5 HZ, 1H), 7.37 (dd, J=2.5, 3.5 Hz, 1H), 8.08 (d. J=2.0 Hz, 1H), 8.36 (d. J–2.0 Hz, 1H), 10.24 (brs, H). 45 Method 2 from 5 5-Bromo-1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo 2,3-bipyridine (26) Br Br 50 N N MnO2 Na2 Na2
Br Br 55 HN HN / N N 5 27 DDQ Na2 Na2 To a stirred solution of azaindoline 5 (7.00 g, 35.2 mmol) in 60 CHCl (664 mL) was added activated MnO, (3.06 g., 35.2 N N / mmol), and progress of the reaction was monitored by 'H TBS TBS NMR of reaction aliquots. After 3 days the mixture was 4 26 filtered through a pad of silica, and the pad was washed with 65 EtOAc. The filtrates were concentrated to afford the azain DDQ (about 380 mg, 1.68 mmol) was added in portions to dole 27 (6.98 g. 100%) as a brown solid. "H NMR data as in a solution of 4 (525 mg, 1.68 mmol) in a mixture of CH2Cl Method 1. US 7,652,137 B2 51 52 Dimethyl-4-(1H-pyrrolo2,3-bipyridin-5-yl)-phe afford styrene 28 (51 mg, 46%) as a pale yellow solid. "H nyl-amine (24) NMR (400 MHz. CDC1) & 6.55 (dd, J=2.0, 3.5 Hz, 1H), 7.15 (d. J=16.3 Hz, 1H), 7.31 (d. J=16.3 Hz, 1H), 7.35 (m, 1H), 7.62 (s, 4H), 8.13 (d. J=1.8 Hz, 1H), 8.50 (m. 1H), 9.17 (brs, 5 NH). NMe2 NMe2 {4-1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3- blpyridin-5-yl-phenyl-dimethyl-amine (29)
Br 10
N B(OH)2 N NMe2 NMe2
N n2 Na2 15 / / Br N 27 24 B(OH)2 N Na2 A mixture of bromide 27 (6.00 g, 30.4 mmol), lithium N n2 chloride (3.84g, 90.8 mmol), 4-(N,N-dimethylaminophenyl) / / boronic acid (7.53 g, 45.7 mmol), toluene (171 mL), EtOH TBS N (171 mL), 1 M aqueous NaCO solution (76.2 mL, 76.2 TBS mmol) and (PPh), PdCl (60 mg, 0.080 mmol) was refluxed 25 (bath temp. 105°C.) in the dark under nitrogen for 22 h. The 26 29 mixture was then concentrated to dryness and the residue partitioned between CHCl-water. The layers were sepa A mixture of bromide 26 (500 mg, 1.61 mmol), lithium rated and the aqueous layer was extracted with CHC1. The chloride (204 mg, 4.82 mmol), 4-(N,N-dimethylaminophe combined organic solutions were dried (MgSO), concen 30 nyl)boronic acid (398 mg, 1.61 mmol), toluene (9.6 mL), trated and purified by SGC using AcOEt as eluent to afford EtOH (9.6 mL), 1 Maqueous NaCO, solution (4.0 mL, 4.0 the product 24 (6.32g, 88%) as a pale yellow solid. "H NMR mmol) and (PPh3)2PdCl2 (95 mg, 0.135 mmol) was stirred in (400 MHz: CDC1) & 2.98 (s, 6H), 3.11 (tt, J=8.3, 1.0 Hz, 2H), the dark under nitrogen at r.t. overnight and at 105°C. for 1 h. 3.65 (t, J=8.3 Hz, 2H), 4.44 (bs, 1H), 6.79 (d. J=8.8 Hz, 2H), The mixture was then partitioned between AcOEt (20 mL) 7.38 (d. J=8.8 Hz, 2H), 7.46 (dt, J=2.0, 1.2 Hz, 1H), 8.02 (dt, 35 and brine (20 mL). The layers were separated and the aqueous J=2.0, 0.9 Hz, 1H). layer was extracted with AcOEt (3x20 mL). The combined organic Solutions were dried (MgSO4), concentrated and 5-2-(4-Trifluoromethyl-phenyl)-vinyl 1H-pyrrolo2. purified by SGC using hexane:CHCl as eluent (up to 30% 3-bipyridine (28) CHCl) to give 29 as a white solid (423 mg, 75%); H NMR 40 (400 MHz, CDC13) & 0.56 (s, 6H), 0.87 (s, 9H), 2.89 (s, 6H), 6.45 (d. J=3.5 Hz, 1H), 6.74 (d. J=8.8 Hz, 2H), 7.15 (d, J-34 HZ, 1H), 7.44 (d. J=8.8 Hz, 2H), 7.90 (d. J=2.3 Hz, 1H), 8.42 CF CF (d. J–2.2 Hz, 1H).
45 Participation of 5-bromoindoles in the Stille Reaction. Syn thesis of Thiophene Derivative 30. 5-Thiophen-2-yl-1H-pyrrolo2,3-bipyridine (30) Br 21 21 50
B(OH)2 N
Br Na2 Na2 N S I-4 i? 4 55 N SnBus 27 28 Na2 To a solution of bromide 27 (76 mg, 0.39 mmol), lithium / chloride (49 mg, 1.16 mmol), trans-24-(trifluoromethyl)- 60 TBS phenyl vinylboronic acid (125 mg, 0.58 mmol) in a mixture 26 30 of toluene (3 mL), EtOH (3 mL) and 1 Maqueous NaCO solution (0.96 mL, 0.96 mmol) was added (PPh), PdCl (27 mg, 0.04 mmol) in one portion. The mixture was heated in the A solution of bromide 26 (150 mg, 0.48 mmol), 2-(tribu dark to 105°C. under a nitrogen atmosphere for 20h, filtered 65 tylstannyl)thiophene (270 mg. 0.72 mmol), tri-o-tolylphos through a pad of cotton wool and concentrated. The residue phine (29 mg, 0.10 mmol) and PdCl2(MeCN) (12.5 mg, 0.05 was purified by PTLC with CHCl:MeOH=98:2 as eluent to mmol) in toluene (3 mL) was stirred at 85°C. for 18 hunder US 7,652,137 B2 53 54 N. The mixture was partially purified by PTLC using hexa 5-(2-Phenoxy-pyridin-3-yl)-1H-pyrrolo2,3-bipyri ne: AcOEt=200:1 to afford a mixture of the desired product30 dine (33) and tin-containing impurities (205 mg). This mixture was dissolved in CHCl and extracted with 10% aqueous HCl (4x). The combined aqueous Solutions were washed with 5 CHC1 (3x) and basified to pH 12 with 50% NaOH. The aqueous layer was extracted with CHCl (3x) and the com bined organic extracts dried (MgSO), filtered and evaporated r O to afford the azaindole30 (22.7 mg, 23%) as a white solid. "H 10 ) ( - N1so O O I NMR (400 MHz. CDC1) 6.55 (dd, J=3.5, 1.8 Hz, 1H), 7.13 NY 32 (dd, J=5.2, 3.5 Hz, 1H), 7.30-7.33 (m, 2H), 7.41 (dd, J=3.5, 2.4 Hz, 1H), 8.16 (d. J=2.0 Hz, 1H), 8.64 (brs, 1H), 10.45 (br N s, NH). Palladium-catalysed installation of boronic acid/ester 15 Na2 functionality at C(5) of the 7-azaindole system. Synthesis of 5-(hetero)aryl derivatives 33, 35 and 37 via Suzuki reaction.
31 5-(4,4,5,5-Tetramethyl-1,3,2dioxaborolan-2-yl)- 1H-pyrrolo2,3-bipyridine (31)
25 Br OY-y O rn OM O N 2 PdCl2(dppf) 30 33 H /
27 A mixture of pinacol ester 31 (200 mg. 0.88 mmol), iodide 35 32 (390 mg, 1.32 mmol), LiCl (112 mg, 2.63 mmol), PdCl (PPh), (62 mg, 0.088 mmol), 1.0 M aq. NaCO, (2.2 mL, 2.19 mmol) in EtOH (4.0 mL) and toluene (4.0 mL) were refluxed for 5 h. After cooling the reaction mixture was par 40 titioned between EtOAc/brine. The aqueous layer was O O extracted with more EtOAc (2x) and the combined organic NY extracts were dried (MgSO) and concentrated. The residue was purified by silicagel chromatography using EtOAc:hex ane (1:1) (gradient elution) to give 33 (106 mg, 42%); H rs 45 NMR (400 MHz, CDC1) & 6.26 (bs, 4H), 6.55 (s, 1H), 7.38 Na2 (bs, 3H), 7.82 (s, 1H), 8.18 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H), - / 10.73 (bs, NH). H Pyrimidin-2-yl-[2-(1H-pyrrolo2,3-bipyridin-5-yl)- 31 50 phenyl-amine (35)
N21 A mixture of 27 (500 mg, 2.54 mmol), 1,1'-bis(diphe 55 nylphosphino) ferrocenedichloropalladium. HC1 complex O PdCl2(dppf) (24.0 mg, 0.0298 mmol), bis(pinacolato)dibo N N ron (966 mg, 3.81 mmol) and potassium acetate (747 mg, 7.61 Br mmol) in DMF (15 mL) were heated at 80° C. overnight. 34 More palladium catalyst (24 mg) was added and the stirring 60 (PPh3)2PdCl2 continued overnight. The reaction mixture was cooled, poured onto water, extracted with ethyl acetate. The com bined organic extracts were dried (MgSO4) and concentrated. The residual solid was extracted with diethyl ether. The solu 65 tion was concentrated to give 31 as a tan Solid (650 mg. 112%).
US 7,652,137 B2 57 58 Synthesis of Boronic Derivative 38 trated. The residue was partially purified by preparative TLC (4x1 mm, 60% ethyl acetate in hexane eluent) to give 40 (120 mg, 124%). Br B(OR)2 5-2-(Pyrimidin-2-yloxy)-phenyl)-1H-pyrrolo2,3-b N N pyridine (41) 1. n-BuLi Na2 Hs2. B(OMe), Nae - / / 10 TBS TBS 26 38 O lsON R = H, Me 15 HCI N To n-BuLi (0.54 mL, 1.35 mmol, 2.5M in hexane) in THF (4.0 mL), cooled to -78°C., was added dropwise a solution of Na2 26 (200 mg, 0.624 mmol) in THF (1.0 mL) and the solution stirred at -78° C. for 10 min. Trimethylborate (87 uL, 0.77 / mmol) was added in one portion and the reaction mixture TBS stirred at -78°C. for 1 h then at room temperature for 2 h. The 40 reaction mixture was poured onto a mixture of Saturated aq. NaHCO/ethyl acetate. The organic layer was separated and the aqueous aqueous phase extracted with ethyl acetate (2x). 25 The combined organic solutions were washed with water, Ols ON dried (MgSO) and concentrated to give product 38 as an oil (200 mg). LCMS of 38 showed a mixture of boronic acid and its methyl ester. 30 1-(tert-Butyl-dimethyl-silanyl)-5-[2-(pyrimidin-2- yloxy)-phenyl)-1H-pyrrolo2,3-bipyridine (40)
35 A mixture of 40 prepared above (120 mg, approx. 0.24 B(OR)2 O mmol), MeOH (1.1 mL) and 10% aq. HCl (2.4 mL) were N 1s, stirred at room temperature for 1 h then poured onto saturated 40 aq. NaHCO/ethyl acetate. The aqueous phase was extracted Na2 I 39 with more ethyl acetate and the combined organic extracts / dried (MgSO4) and concentrated to give pure product 41 TBs/ (40.8 mg. 44% over 3 steps from 26); H NMR (400 MHz, 45 CDC1) & 6.40 (dd, J=3.4, 1.6 Hz, 1H), 6.76 (t, J–4.8 Hz, 1H), 38 7.21 (m, 2H), 7.32 (dt, J=7.8 Hz, 1.8 Hz, 1H), 7.39 (dt, J=7.8, R = H, Me 1.8 Hz, 1H), 7.46 (dd, J=7.5, 1.8 Hz, 1H), 8.04 (d. J–2.0 Hz, 1H), 8.30 (d. J–4.8 Hz, 2H), 8.37 (d. J=2.0 Hz, 1H), 10.26 (bs, NH). O N 50 Installation of stannane at C(5) of the 7-azaindole system via 5-lithio derivative. rs Synthesis of 5-(hetero)aryl Derivative 43 Using Stille Reac Na2 tion. - / 55 Br SnBus TBS 40 N N 60 1. n-BuLi F A mixture of 38 (100 mg, 0.36 mmol), iodide 39 (72 mg, Na2 He2. Busni Ne 0.24 mmol), LiCl (31 mg, 0.72 mmol), PdCl(PPh3) (31 mg, --- 0.024), 1 Maq. NaCO, (603 uL, 0.60 mmol) intoluene (1.66 / N / PdCl2(MeCN)2 mL) and EtOH (1.66 mL) was refluxed for 5 h. The reaction mixture was cooled, poured onto ethyl acetate/brine and the 65 TBs^ TBs/ aqueous phase extracted with more ethyl acetate (2x). The 26 42 combined organic solutions were dried (MgSO4) and concen US 7,652,137 B2 59 60 A mixture of stannane 42 (200 mg 0.384 mmol), 1-fluoro -continued 3-iodobenzene (170 mg. 0.767 mmol), PdCl2(MeCN), and P(o-tolyl) in toluene (3.3 mL) were heated at 85°C. over night. The reaction mixture was diluted with ethyl acetate, extracted with 10% aq. HCl (4x1 mL) and the HCl extracts basified with saturated aq. NaHCO, then extracted with ethyl acetate (3x). The combined organic extracts were dried (MgSO) and concentrated. Purification by preparative TLC 10 (1 mm plate, 60% ethyl acetate in hexane eluent) afforded 43 (8.0 mg, 10%); H NMR (400 MHz, CDC1,) & 6.57 (dd. J=3.5, 1.7 Hz, 1H), 7.06 (m. 1H), 8.13 (d. J=2.1 Hz, 1H), 7.34 (m. 1H), 7.42 (m,3H), 8.56 (d. J=2.1 Hz, 1H), 10.66 (bs, NH).
43 15 Synthesis of Ketone 45
1-(tert-Butyl-dimethyl-silanyl)-5-tributylstannanyl 1H-pyrrolo2,3-bipyridine (42)
ONY O Br Br SnBus B /N 25 O O N N 1. n-BuLi rn Na2 --2. Busni Na2 Na2 - is 30 - / / / / / H TBS TBS 27 26 42
35 To 2.5 Mn-BuLi in hexane (0.67 mL, 1.69 mmol) in THF OMe (5 mL), cooled to -78°C., was added a solution of 26 (0.25 g, 0.80 mmol) in THF (1.0 mL) dropwise. The solution was Sl OMe stirred at -78°C. for 10 min then a solution of BuSnI (446 O O mg, 0.96 mmol) in THF (0.5 mL) was added in one portion. NY O The reaction mixture was stirred at -78° C. for 1 h then at 40 room temperature for 2 h, then poured onto a mixture of ethyl acetate/saturated aq. NaHCO. The aqueous phase was N C extracted with more ethyl acetate (2x). The combined organic Solutions were dried (MgSO4) and concentrated to give stan N 2 nane 42 as a light orange oil (483 mg, 1.15%); H NMR (400 45 MHz, CDC1) & 0.71 (s, 6H), 0.98 (t, J–74 Hz, 9H), 1.02 (s, H- / 9H), 1.15-1.70 (m. 18H), 6.56 (d. J=3.5 Hz, 1H), 7.26 (d. 44 J–3.5 Hz, 1H), 8.01 (d. J=1.4 Hz, 1H), 8.33 (d.J=1.4 Hz, 1H). 5-(3-Fluoro-phenyl)-1H-pyrrolo2,3-bipyridine (15) 50 OMe
OMe
55 O SnBus F
N F I N 60 rs Na2 PdCl2(MeCN), 2 N 21 / / - / N / H T B S H 45 43 65 US 7,652,137 B2 61 62 5-(4,4,5,5-Tetramethyl-1,3,2dioxaborolan-2-yl)- 1H-pyrrolo2,3-bipyridine (44) -continued
OMe
OMe
O
10 OS B-O Sl N Na2 Br OS B -O o1 B Yo H / rs N 45 Na2- - is N 21 / / H H To the crude pinacol ester 44 (310 mg, 1.27 mmol) in dry 27 44 toluene (25 mL) was sequentially added cesium carbonate (2.07 g. 6.35 mmol), tetrakis(triphenylphosphine)palladium 25 (0) (73 mg, 0.06 mmol) and 3,4-dimethoxybenzoyl chloride (510 mg, 2.54 mmol). The mixture was heated at 100° C. in The 5-bromo-7-azaindole 27 (0.5g, 2.54 mmol), bis(pina the dark. After 28 h a further portion of tetrakis(triph colato)diboron (0.968 g, 3.81 mmol), potassium acetate enylphosphine)palladium(0) (90 mg 0.08 mmol) was added. (0.748 g, 7.61 mmol), 1,1'-bis(diphenylphosphino)fer 30 Following another 22 h the mixture was allowed to cool to rocenedichloropalladium(II) complex with CHCl (1:1) (49 ambient temperature and diluted with EtOAc and water and mg, 0.06 mmol) and DMF (11 mL) were heated in a sealed partitioned. The organic layer was washed with saturated tube at 80°C. After 44 h, the reaction mixture was allowed to Sodium hydrogen carbonate, Saturated brine, dried (MgSO4), cool to room temperature, diluted with EtOAc and saturated brine, and partitioned. The aqueous layer was extracted with 35 filtered and concentrated. The crude residue was purified by EtOAc (3x). The combined organic extracts were washed preparative LCMS (column LUNA 10u C18(2) 00G-4253 with brine (1x), dried (MgSO), filtered and concentrated in VO 250x50 mm) using water acetonitrile (0.1% AcOH) as vacuo. The crude pinacol ester 44 was used directly for the eluent (in gradient; flow 80 mL/min) to afford ketone 4512.6 next step without any further purification. H NMR (400 mg, 3.6% (2 steps) as a white solid. "H NMR (400 MHz: MHz: CDC1) & 1.38 (s, 12H), 6.51 (d. J=3.5 Hz, 1H), 7.32 (d. 40 CDC1) & 3.99 (s.3H), 4.00 (s.3H), 6.54 (dd, J-2.0 and 3.5 J–3.5 Hz, 1H), 8.42 (d. J=1.2 Hz, 1H), 8.63 (d. J=1.2 Hz, 1H) HZ, 1H), 6.98 (d. J=8.5 Hz, 1H), 7.38 (dd, J=2.5 and 3.5 Hz, and 10.59 (brs, NH). 1H), 7.71 (d, J-2.0 Hz, 1H), 7.81 (dd, J=0.7 and 2.5 Hz, 1H), 7.93 (dd, J=2.0 and 8.5 Hz, 1H), 8.22 (d. J=2.5 Hz, 1H) and (3,4-Dimethoxy-phenyl)-(1H-pyrrolo2,3-bipyridin 45 5-yl)-methanone (45) 8.90 (brs, NH).
The invention claimed is: 50 1. A compound of formula (I)
OMe
55 O O NY O (I)
N C 60 Na2
H- / 44 65 US 7,652,137 B2 63 64 wherein X is R'S(O), (R')Si, RC(O), ROCH, 6. A method for synthesizing a compound of formula (I) as RNSO, ROC(O) R' (RO)CH R'CHCH , claimed in claim 2, comprising brominating a compound of formula (II; RCH , PhC(O)CH-CH=CH-, CICHCH , Br PhC , Ph.(4-pyridyl)C , MeN , HO CH , ROCH (R')SiOCH (RO)CH-, t-BuOC(O) CH , MeNCH- and tetrahydropyranylamine; rs rs wherein R' is C, alkyl, C. cycloalkyl, Chaloalkyl, Nn 2 Nn 2 or C. carbocyclyl: optionally substituted with one or N N more of C alkyl, Si(R), OR, NO, CO, COR, M M halogen, haloalkyl, SR, CN, NRCOR, X X COR CONRR, (II) (I) wherein R is hydrogen or C, alkyl, wherein X is (R')Si or ROCH, and R' is C alkyl or with the proviso that when X is R'OC(O)—, R is not Cs-12aryl. 7. A method as claimed in claim 6 wherein the bromination PhCH. is carried out using Br, dioxane dibromide, pyridinium per 2. The compound of claim 1, wherein X is (R') Si or bromide or NBS. R'OCH2, and R' is C, alkyl or C-2 aryl. 8. A method as claimed in claim 6 wherein X is (R') Si and 3. The compound of claim 1, wherein X is (R'),Si and R' 20 R is methyl, ethyl, propyl, butyl or phenyl. is methyl, ethyl, propyl, butyl or phenyl. 9. A method as claimed in claim 7 wherein X is (R') Si and 4. The compound of claim 1, wherein X is TBS. R" is methyl, ethyl, propyl, butyl or phenyl. 5. The compound of claim 1, wherein X is PhSO. k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION
PATENT NO. : 7.652,137 B2 Page 1 of 1 APPLICATION NO. : 10/54862 DATED : January 26, 2009 INVENTOR(S) : Graczyk et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:
On the title page, * Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 USC 154(b) by 450 days. Delete the phrase by 450 days and insert -- by 851 days --
Signed and Sealed this Sixth Day of July, 2010
David J. Kappos Director of the United States Patent and Trademark Office