Title of Invention

"METHOD OF PREPARING POLY(ADP-RIBOSE) POLYMERASES INHIBITORS"

Abstract A method of preparing a compound of formula I wherein R1 is: H; cyano; an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or --C(o)-- R5, where R5 is: H; an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or OR6 or NR6R7, where R6 andR7 are each independently H or an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; R2 is H or alkyl; R3 is H or alkyl; R4 is H, halogen or alkyl, the method comprising: a) Sonogashira coupling of a compound of formula II, wherein X is halogen or CF3SO2-O- with a compound of formula III in the presence of a catalyst to form a compound of formula IV;
Full Text METHOD OF PREPARING POLYfADP-RIBOSEl POLYMERASES INHIBITORS
This application claims the benefit of U. S. Provisional Application No. 60/612,457 filed on
September 22, 2204, the contents of which is hereby incorporated by reference in its entirety.
Field of the Invention
This invention generally relates to methods of preparing compounds that inhibit poly(ADP-ribose)
polymerases, thereby retarding the repair of damage to DNA strands. The inventive method is particularly
useful in preparing compounds that are useful for potentiation of anti-cancer therapies.
Background of the Invention
The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyI}-1 ,3,4,5-tetrahydro-6H-azepinot5,4,3-
cd]indol-6-one represented by formula
is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP). 8-Fluoro-2-{4-
[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one and salts thereof, is
disclosed in U.S. Patent No. 6,495,541 and PCT Application No. PCT/IB2004/000915, International
Publication No. WO 2004/087713, the disclosures of which are incorporated herein by reference in their
entireties. U.S. Provisional Patent Applications No. 60/612,459 and 60/679,296, entitled 'Polymorphic
Forms of the Phosphate Salt of 8-Fluoro-2-[4-[(methylamino)me%l]phenyrh1,3,4,5-tetrahydro-6Hazepino[
5,4,3-cd]indol-6-one," the disclosures of which are incorporated herein by reference in their
entireties, describe novel polymorphic forms of the phosphate salt of 8-fluoro-2-{4-
[(methylaminoJmethylJphenylM.SAS-tetrahydro-eH-azepinolSAS-cdlindol-e-one, and methods for their
preparation. U.S. Provisional Patent Applications No. 60/612,458; and 60/683,006, entitled 'Therapeutic
Combinations Comprising Poly(ADP-Ribose) Polymerases Inhibitor," the disclosures of which are
incorporated herein by reference in its entirety, describe pharmaceutical combinations of 8-fluoro-2-{4-
[(methylamino) methyllphenyl}-! .SAS-tetrahydro-eH-azepinolSAS-cdjindoI-e-one.
To date, eighteen enzymes have been identified by ONA sequence homology in the PARP family
and the biochemical and enzymatic properties of seven have been investigated: PARP-1, and PARP-2
are stimulated by DNA strand breaks, PARP-3 interacts with PARP-1 and the centrosome, PARP-4 also
known as vault PARP (VPARP) is the largest PARP and is associated with cytoplasmic vaults, tankyrase
1 and 2 (PARP-5a and 5b) are associated with telomeric proteins and the function of PARP-7 (TiPARP) is
not clear at present but It may be involved in T-cell function and it can poly(ADP-ribosy!ate) histones (Ame
JC, Splenlehauer C and de Murcia G. The PARP Superfamily. Bioessays 26 882-893 (2004)).
Pharmacology studies have shown that the compound of formula 1 is an inhibitor of PARP-1 (K, = 1.4 nM)
and PARP-2 (K1 = 0.17 nM). Based on structural similarities in the amino acid sequences among the
PARP enzymes, the compound of formula 1 likely binds with high affinity to the other members of the
family as well.
Enzyme-mediated repair of single- or double-strand breaks in DNA is a potential mechanism of
resistance to radiotherapy or cytotoxic drugs whose mechanism depends on DNA damage. Inhibition of
DNA repair enzymes is thus a strategy for the potentiation of these agents. PARP-1, the bestcharacterized
member of the PARP family, is a nuclear enzyme that upon activation by DNA damage
mediates the transfer of ADP-ribose fragments from NAD* to a number of acceptor proteins. Depending
on the extent of DNA damage incurred, PARP-1 activation and subsequent poly(ADP-ribosyl)ation
mediate the repair of the damaged DNA or induce cell death. When DNA damage is moderate, PARP-plays a significant role in the DNA repair process. Conversely, in the event of massive DNA damage,
excessive activation of PARP-1 depletes ATP pools (in an effort to replenish NAD+), which ultimately
leads to cell mortality by necrosis (Tentori L, Portarena I, Graziani G. Potential applications of poly(ADPribose)
polymerase (PARP) inhibitors. Pharmacol Res 2002;45:73-85).
As the result of the dual role of PARP-1, inhibitors of this enzyme, such as 8-fluoro-2-{4-
[(methylaminoJmethyllphenylJ-I.S^.S-tetrahydro-eH-azepinop^.a-cdlindol-S-one, may have a role as
chemosensitizing agents (by preventing DNA repair, for example, after anticancer therapy), or as
treatments for a variety of disease and toxic states that involve oxidative or nitric oxide induced stress and
subsequent PARP hyperactivation. Such conditions include neurologic and neurodegenerative disorders
(eg, Parkinson's disease, Alzheimer's disease) (Love S, Barber R, Witeock GK. Increased poly(ADPribosyl)
atton of nuclear proteins in Alzheimer's disease. Brain 1999;122:247-53; Mandir AS, Przedborski
S, Jackson-Lewis V, et al. Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci USA 1999;96:5774-9),
cardiovascular disorders (eg, myocardial infarction, ischemia-reperfusion injury) (Pieper AA, Walles T,
Wei G, et al. Myocardial postischemic injury is reduced by poly(ADP-ribose) polymerase-1 gene
disruption. J Mol Med 2000;6:271-82; Szabo G, BShrie S, Stumpf N, et al. Poly(ADP-ribose) polymerase
inhibition reduces reperfusion injury after heart transplantation. Circ Res 2002;90:100-6; U.S. Patent
6,423,705), inflammatory diseases, (Szab6 C, Dawson V. Role of poly(ADP-ribose) synthetase in
inflammation and ischaemia-reperfusion. TIPS 1998;19:287-9B), diabetic vascular dysfunction (Soriano
FG, Virag L, Szabo C. Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species
production and poly(ADP-ribose) polymerase activation. J Mol Med 2001;79:437-48), arthritis (Szabo C,
Virag L, Cuzzocrea S, et al. Protection against peroxynitrite-induced fibroblast injury and arthritis
development by inhibition of poly(ADP-ribose) synthase. Proc Natl Acad Sci USA 1998;95:3867-72), and
cisplatin-induced nephrotoxicity (Racz I, Tory K, Gallyas F, et al. BGP-15 - a novel poly(ADP-ribose)
polymerase inhibitor - protects against nephrotoxicity of cisplatin without compromising its antitumor
activity. Biochem Pharmacol 2002;63:1099-111). Furthermore, it was shown that BRCA2 deficient tumor
cells are acutely sensitive to PARP-1 inhibitors (Bryant et al. "Specific killing of BRCA2 deficient tumors
with inhibitors of poly(ADP-ribose)poIymerase," submitted to publication). PARP inhibitors are also
involved in enhancing the induction of the expression of Reg gene in p cells and HGF gene and,
accordingly, promote the proliferation of pancreatic p-cells of Langerhans' islets and suppress apoptosis
of the cells (U.S. Patent Application Publication 2004/0091453; PCT Publication No. WO 02/00665). In
addition, PARP inhibitors are also used in cosmetic preparations, especially in after-sun lotions (PCT
Publication No. WO 01/82877). There are no marketed PARP inhibitors presently.
One method of synthesizing 8-fluoro-2-{4-[(methy)amino)methyl]phenyl}-1,3,4,5-tetrahydro-6Hazepino[
5,4,3-cd]indol-6-one is disclosed in the above-referenced U.S. Patent No. 6,495,541. This
method is a linear 10-step synthesis, which involves a key Leimgruber-Baicho indole formation step and a
Suzuki coupling reaction. Although the current route is an effective synthetic route employed in the
synthesis of toxicology and clinical batches of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-
tetrahydro-6H-azepino[5,4,3-cd]indoi-6-one, it would be desirable to have an alternative convergent route
for eventual commercial manufacturing. The present invention provides a new and convergent route to 8-
fluoro^^KmethylaminoJmethylJphenylJ-I.S^.S-tetrahydro-eH-azepinop^.S-cdJindol-e-one, which route
is developed via a key Sonogashira coupling reaction and a Cul- promoted indole formation.
Summary of the Invention
In one embodiment, the present invention provides a method of preparing a compound of formula I
wherein R1 is:
an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,
or heteroaryl group; or
-C(O)" R5, where R5 is: H; an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or OR6 or NR6R7, where R6 and R7 are each
independently H or an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl,
heterocydoalky!, aryl, or heteroaryl group;
the method comprising:
a) Sonogashira coupling of a compound of formula II, wherein X is halogen or CF3SO2-O•
with a compound of formula III
to form a compound of formula IV;
b) reducing the compound of formula IV to generate a compound of formula V;
c) converting the compound of formula V into a compound of formula VI; and
VI
d) converting the compound of formula VI into the compound of formula I.
In another embodiment, the invention provides a method of preparing 8-fluoro-2-{4-
[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indot-6-one, the method comprising
Sonogashira coupling of a compound of formula VII, wherein X is halogen or CF3SO2-O-,
with (4-ethynyl-ben2y|)-methyl-carbamic acid methyl ester to form 5-fluoro-2-{4-[(rnethoxycarbonyl-methylamino)-
methyl]-phenylethynyl}-3-nitro-benzoic acid methyl ester.
In another embodiment, the invention provides a method of preparing 8-fluoro-2-{4-
[(methylamino)methyl]phenyl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, the method comprising
Sonogashira coupling of a compound of formula VII, wherein X is halogen or GFsSOa-O-,
with (4-ethynyl-benzyl)-methyl-carbamic acid methyl ester to form 5-fluoro-2-{4-[(methoxycarbonyl-methylamino)-
methylj-phenylethynyl}-3-nitro-benzoic acid methyl ester; reducing 5-fluoro-2-{4-
[(methoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-3-nitro-benzoic acid methyl ester into 3-amino-
5-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenylethyny)}-benzoic acid methyl ester;
converting 3-amino-5-fluoro-2-{4-[(methoxycarbonyl-methyl-amlno)-methylJ-phenylethynyl}-benzoicacid
methyl ester into 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-indole-4-carboxylic
acid methyl ester a Cut- promoted indole formation;
treating 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-1 W-indole-4-carboxylic acid
methyl ester with N,N-dimethyl-2-nitroethylenamine to generate 6-fluoro-2-{4-[{methoxycarbonyl-methylamino)-
methyl]-phenyl}-3-((E)-2-nKro-vinyl)-1H-indole-4-carboxylic acid methyl ester;
redudng6-fluoro-2-{4-[(methoxycarbonyl-rnethyl-arnino)-rnethyl]-phenyl}-3-((E)-2-nitro-vinyl)-1H-indole-
carboxylic acid methyl ester into 6-fluoro-2-{4-[(mettioxycarbonyl-methyl-amhTo)-methyl]-phenyl}-3-(2-
nitro-ethyl)-1H-indole-4-carboxylic acid methyl ester;
hydrogenating6-fluoro-2-{4-l 4-carboxylic acid methyl ester to produce [4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5l4,3-cc()indol-
2-yl)-benzyl]-methyl-carbamic acid methyl ester; and
deprotecting^^S-fluorc-e-oxo-S^.S.e-tetrahydro-IH-azepinoIS^.S-cdlindol^-ylVbenzyO-methyl-carbamlc
acid methyl ester to produce 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6Hazepino[
5,4,3-cd]indol-6-one.
-6-
Definitions and Abbreviations
As used herein, the term "alkyl" means a branched- or straight-chained (linear) paraffinic
hydrocarbon group (saturated aliphatic group) having from 1 to 10 carbon atoms in its chain, which may
be generally represented by the formula CkH2k+i, where k is an integer of from 1 to 10. Examples of
groups include methyl, ethyl, n-propy], isopropyl, n-butyl, isobutyl, t-butyl, pentyl, n-pentyl, isopentyl,
neopentyl, and hexyl, and the simple aliphatic isomers thereof. A "lower alkyl" is intended to mean an
alkyl group having from 1 to 4 carbon atoms in its chain.
The term "alkenyl" means a branched- or straight-chained olefinic hydrocarbon group
(unsaturated aliphatic group having one or more double bonds) containing 2 to 10 carbons in its chain.
Exemplary alkenyls include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, and the
various isomeric pentenyls and hexenyls (including both cis and trans isomers).
The term "alkynyl" means a branched or straight-chained hydrocarbon group having one or more
carbon-carbon triple bonds, and having from 2 to 10 carbon atoms in its chain. Exemplary alkynyls include
ethynyl, propynyl, 1-butynyl, 2-butynyl, and 1-methyl-2-butynyl.
The term "carbocycle" refers to a saturated, partially saturated, unsaturated, or aromatic,
monocyclic or fused or non-fused polycyclic, ring structure having only carbon ring atoms (no
heteroatoms, i.e., non-carbon ring atoms). Exemplary carbocycles include cycloalkyl, aryl, and cycloalkylaryl
groups.
The term "heterocycle" refers to a saturated, partially saturated, unsaturated, or aromatic,
monocyclic or fused or non-fused polycyclic, ring structure having one or more heteroatoms selected from
N, O, and S. Exemplary heterocycles include heterocycloalkyl, heteroaryl, and heterocycloalkyl-heteroaryl
groups.
A "cycloalky) group" is intended to mean a non-aromatic monovalent, monocyclic or fused
polycyclic, ring structure having a total of from 3 to 18 carbon ring atoms (but no heteroatoms). Exemplary
cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, adamantyl,
phenanthrenyl, and like groups.
A "heterocycloalkyl group" is intended to mean a non-aromatic monovalent, monocyclic or fused
polycyclic, ring structure having a total of from 3 to 18 ring atoms, including 1 to 5 heteroatoms selected
from nitrogen, oxygen, and sulfur. Illustrative examples of heterocycloalkyl groups include pyrrolidinyl,
tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, and like groups.
The term "aryl" means an aromatic monocyclic or fused polycyclic ring structure having a total of
from 4 to 18, preferably 6 to 18, ring carbon atoms (no heteroatoms). Exemplary aryl groups include
phenyl, naphthyl, anthracenyl, and the like.
A "heteroaryl group" is intended to mean an aromatic monovalent, monocyclic or fused polycyclic,
ring structure having from 4 to 18, preferably 5 to 18, ring atoms, including from 1 to 5 heteroatoms
selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups Include pyrrolyl,
thienyl, oxazolyl, pyrazolyl, thiazolyl, furyl, pyridinyl, pyrazinyl, triazolyl, tetrazolyl, indolyl, quinolinyl,
quinoxalinyl, and the like.
The term "optionally substituted" is intended to indicate that the specified group is unsubstituted
or substituted by one or more suitable substituents, unless the optional substituents are expressly.
specified, in which case the term indicates that the group is unsubstituted or substituted with the specified
substituents. Unless indicated otherwise (e.g., by indicating that a specified group is unsubstituted}, various groups defined above may be generally unsubstituted or substituted {i.e., they are optionally
substituted) with one or more suitable substituents.
The term "substituent" or "suitable substituenf is intended to mean any substituent for a group
that may be recognized or readily selected by the artisan, such as through routine testing, as being
pharmaceutically suitable. Illustrative examples of suitable substituents include hydroxy, halogen (F, Cl, 1,
or Br), oxo, alkyl, acyl, sulfonyl, mercapto, nilro, alkylthio, alkoxy, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, carboxy, amino (primary, secondary, or tertiary), carbamoyl, aryloxy, heteroaryloxy, arylthio,
heteroarylthio, and the like (e.g., as illustrated by the exemplary compounds described herein). Suitable
substituents are seen from the exemplary compounds that follow.
Preferred optional substituents for alkyl and aryl groups in the compounds of the invention include
halogens and aryl groups. Especially preferred for substituted alkyl groups are perfluoro-substltuted
alkyls. Especially preferred optional substituents for aryl moieties include halogen, lower alkyl, -OH, -
NOj, -CN, -C02H, O-lower alkyl, aryl, -0-aryl, aryMower alkyl, ~CO2CH3, -CONH2. -OCH2CONH2, -
NH2, -SO2NH2, -OCHF2, -CF3| -OCF3, and the Jike. Aryl moieties may also be optionally substituted by
two substituents forming a bridge, for example -O-(CH2)z -0-, where 2 is an integer of 1,2, or 3.
As used in the present application, "Et" means ethyl, "Ac" means acetyl, "Me" means methyl, "Ms"
means methanesulfonyl (CH3S02), "IPr" means isopropyl, "HATU" means 2-(7-Aza-1H-benzotriazole-1-
yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, "Ph" means phenyl, *Boc* means tertbutoxycarbonyl,
"EtOAc" means ethyl acetate, "HOAc" means acetic acid, "NEt3" or "Et3N" means
triethylamine, "Tr means trifluoromethansulfonyl, "THF" means tetrahydrofuran, "DIG" means
diisopropylcarbodiimide, "HOBt" means hydroxy benzotriazole, "MeOH" means methanol, "i-PrOAc"
means isopropyl acetate, "KOAc" means potassium acetate, "DMSO" means dimethylsulfoxide, "AcCI"
means acety! chloride, "CDCI3" means deuterated chloroform, "MTBE" means methyl t-butyl ether, "DMF"
means dimethyl formamide, "AcaO" means acetic anhydride, "Me3SOI' means trimethylsulfoxortum
iodide, "DMAP" means 4-dimethylaminopyridine, "dppf means diphenylphosphino ferrocene, "DME"
means ethylene glycol dimethyl ether (1,2-dimethoxyethane), HOBT means 1-hydroxybenzotriazole, EDC
means 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide.
Detailed Description of the Invention
The present invention provides a new and convergent route to the tricyclic inhibitors of poly(ADPribose)
polymerase (PARP), which inhibitors are disclosed in the above-mentioned U.S. Patent No.
6,495,541. For illustrative purposes only, the method of the present invention is demonstrated by the
example of the method of preparing B-fluoro-Z^-KmethylaminoJmethyrjphenylM.S^.S-tetrahydro-eHazepino[
5,4,3-cd]indol-6-one. The reagents and conditions of the reactions described herein, are merely
illustrative of the wide variety of starting materials, their amounts and conditions.which may be suitably
employed in the present invention as would be appreciated by those skilled in the art, and are not
intended to be limiting in any way.
The method of the present invention comprises preparation of 8-fluoro-2-{4-
KmethylaminoJmethyllphenyll-I.S^.S-tetrahydro-eH-azepinoIB^.a-cdJindol-e-one (compound 15) via a
key Sonogashira coupling reaction and a Cul- promoted indole formation according to Scheme 1.
1. Preparation of alkvne B and triflate precursor 8 for Sonogashira coupling
The synthesis of alkyne 5 is shown in Scheme 2. Aldehyde 2, though available from Aldrich, is
expensive, therefore it can be more economical to prepare It from relatively inexpensive 4-
bromobenzaldehyde 1 following a literature procedure as described in Thorand, S. and Krause, N. J. Org.
Chem. 1998, 63, 8551. Next, reductive amination of aldehyde 2 with methylamine can afford amine 3,
which can be subsequently protected to give methyl carbamate 4. Removal of the trimethylsilyl group
(TMS) under basic conditions can yield 5 in 90% yield.
-60% yield overtwo steps from 3 6 Me
The triflate precursor 8 can be prepared via nitration of 5-fluorosalicylic add 6 using
tetramethylamonium nitrate and triflluoroacetic acid anhydride employing standard conditions (Scheme 3).
The desired product 8 can be obtained regiospecifically as a yellow solid after crystallization from
CH3CN/H20 in 63% yield.
II. Synthesis of indole Intermediate 11
As indicated in Scheme 4, although the triflate 16 could be isolated, it is more advantageous to
prepare it in situ.
Me
The formation of triflate 16 and its coupling with the alkyne 5 can be carried out in a one-pot fashion to
afford intermediate 9. The preferred conditions for this coupling are as folows: a CH3CN-solution
containing alkyne 5 and the pre-formed triflate 16 is added to a solution containing 2% PdCI2(PPh3)2 In
CHsCN at 60 °C. Under these conditions, the dimer 17 is determined to be the major by-product Further,
the addition of co-catalyst Cul is found to be detrimental since it promoted more dimer formation. After
work-up, crude product 9 can be reduced with iron powder. Addition of a few drops of concentrated HCI is
very helpful in activating iron powder. Subsequent cyclization of crude compound 10 to indole 11 can
effected with a catalytic amount of Cul in DMF. Indole 11 can be obtained in 51% yield over 3 steps after
trituration with methylene chloride/hexanes in order to remove by-product 17.
III. Conversion of indole intermediate 11 into target compound 15
Treatment of indole 11 with N,N-dimethyl-2-nitroethylenamine (Wlahboobi, S.; Elbler, E.; Roller,
M.; Kumar, S.; Popp, A. J.Org.Chem. 1999, 64; 4697) in TFA/CH2CI2 furnishes nitroalkene 12 (Scheme
4). Nitroalkene 12 can be then reduced with sodium borohydride in 9:1 EtOH/MeOH mixture to
nitroalkane 13 in 84% yield. Due to the poor solubility of 12 and 13 in EtOH, a high volume of solvent is
necessary to ensure complete conversion. Hydrogenation of 13 to lactam 14 using Pd/C or Pt/C under
neutral condition affords N-hydroxy lactam 18 as a major side product However, when hydrogenation is
carried out under acidic conditions with Pd/C or Pt/C, the formation of 18 is suppressed, but it induces
cleavage of C-N bond in 13 to afford 19 as another major side product. Since Raney-Ni does not promote
cleavage of C-N bonds, hydrogenation reactions under Raney-Ni mediated conditions should be
screened. Surprisingly, it was found that hydrogenation of 13 employing Raney-Ni works well under either
neutral or acidic conditions. Thus, nitroalkane 13, on reduction with Raney-Ni in acetic acid, affords the
corresponding amine acetate which upon treatment with base cyclized to 14 in 96% yield on 20 g scale
without any side products.
Finally. the carbamate group in 14 is readily deprotected by HBr/acetic acid at ambient
temperature to provide 15. Initial attempts to remove carbamate group with alkaline hydrolysis, for
example, 8 N KOH in EtOH at 80 °C lead to an undesired cleavage of the lactam ring in 15. Although
methyl carbamates can also be cleaved by trimethylsilyl iodide, the formation of methyl iodide byproduct
raises a safety concern and makes this method less attractive. On the other hand, the toxic methyl
bromide generated during cleavage with HBr/acetic acid can be efficiently trapped with an ethandamine
scrubber system as described in Hettenbach, K.; Am Ende, D. J.; Leeman, K.; Dias, E.; Kasthurikrishnan,
N.; Brenek, S. J.; Ahlijanian, P. Organic Process Research & Development, 2002, 6,407. In this manner,
a 20 g lot of target compound 15 is prepared which is identical to an authentic sample synthesized by a
previous route.
The disclosures of all cited references are incorporated herein by reference in their entirety.
Examples
The examples and preparations provided below further illustrate and exemplify the methods of the
present invention. It is to be understood that the scope of the present invention is not limited in any way by
the scope of the following examples.
Example 1. Synthesis of 4-trimethvlsilanvlethvnvl-benzaldehvde (2)
4-Bromobenzaldehyde (1) (165 g, 1.0 mole) was dissolved in THF (1 L) followed by addition of
copper(l) iodide (7.6 g, 0.04 mol), dicholobis(triphenylphospine) palladium (II) (14.02 g, 0.02 mol) and
triethylamine (151.5 g, 1.5 mol). Ethynyltrimemylsilane (109.1 g, 1.11 mol) was added from addition
funnel as a solution in THF (0.2 L). The reaction was stirred at 30 °C for 30 min and then at 25 *C for 20
hours. Analysis by HPLC indicated the completion of the reaction. THF was removed and the residue
was treated with hexane (1.8 L). The solid was removed by filtration and the filter cake washed with
hexane (0.3 L). The combined hexane solution was washed with water (2 x 0.5 L). Hexane was removed
in a rotovap. The residue was dissolved in EtOH (0.5 L) at 50 "C. The solution was then slowly cooled to
16 °C and was stirred for 30 minutes. Product started to crystallize. The mixture was further cooled to 5
°C. 1:1 of EtOH/H2O (0.24 L) was added slowly. The mixture was stirred at 5 °C for 30 minutes. Solid was
collected by filtration, washed with 4:1 of EtOWH2O (0.2 L) and dried to provide 137.0 g of product. The
mother liquor was concentrated to dryness. The residue was partitioned between hexane (0.5 L) and
brine (0.25 L). Hexane layer was separated and "concentrated to dryness. The residue was crystallized
from hexane (40 ml) and further recrystallized from 4:1 of EtOH/H2O aldehyde 2 (27.0 g). The combined yield for aldehyde 2 was 81%. 1H NMR (300 MHz, CDCI3) 6 0.081 (s,
9H), 7.41 (d, 2H, J= 8.1 Hz), 7.63(d. 2H, J= 8.4 Hz), 9.81 (s, 1H).
Example 2. Synthesis of methvl-M-trirnethvlsilanvtethynvl-benzvlY-arnine (3)
Methyl amine (8 M in MeOH, 135 ml) and methyl a mine hydrochloride (44.0 g, 0.65 mol) were
dissolved in methanol (900 ml). Aldehyde 2 (44.0 g, 0.22 mol) was added and stirred at room temperature
for 30 min. Sodium cynoborohydride (17.42 g, 0.28 mol) was then added. After addition was complete,
hydrochloride methanolic solution was added to adjust the pH to 5 while the temperature was held at -°C. The reaction was stirred for 2 hours. The pH of the reaction mixture was maintained between 4 and 6
by addition of hydrochloride solution in MeOH. The reaction solvent was removed. The residue was
taken up with water (400 ml) and brine (50 ml). The mixture was extracted with methylene chloride (2 x
300 ml). T,
-85% yield), which was used directly in the next step without further purification. 1H NMR (300 MHz,
CDCI3) 6 0.254(s, 9H), 2.434(s, 3H), 3.736(s, 2H), 7.25(d, 2H. J= 9 Hz), 7.43(d, 2H, J= 9 Hz). Exact mass
calculated for C13H2oNSi: 218.1365. Found: 218.1357.
Example 3. Synthesis of methvl-(4-trimethvlsilanvlethvnvl-benzvn-carbamic acid methyl ester Ml
Amine 3 (90.0 g, -0.41 mol) was dissolved in methylene chloride (810 ml). Triethylamine (66.6 g,
0.66 mol) was added and the solution was cooled to 5 °C. Methyl chloroformate (47.0 g, 0.50 mol) in
methylene chloride (100 ml) was then added slowly and the reaction temperature was maintained
between 10 °C and 14 °C. After addition was complete, the reaction solution was stirred at room
temperature for 12 hours. Water (540 ml) was added. Aqueous phase was separated. Organic phase
was concentrated to dryness to afford crude compound 4. The crude product was used in the next step
without further purification. 'H NMR (300 MHz, CDCI3) 6 0.279(s, 9H), 2.86(d, br, 3H), 3.774(s, 3H),
4.484(s, br, 2H), 7.190(s, br, 2H), 7.46(d, 2H, J= 8.10 Hz).
Example 4. Synthesis of (4-ethvnvl-benzvl)-methvl-carbamlc acid methyl ester fSl
ml)- Potassium carbonate (10.5 g, 0.08
mol) was added. The reaction mixture was stirred at room temperature for 1 hour. TLC analysis indicated
the completion of the reaction. White solid was filtered off. Methanol was removed by distillation under
reduced pressure to afford yellow oil. The oil was further purified by column chromatography (silica gel,
hexane/EtOAc) to yield 50.2 g of compound 5 (-60% yield over two steps from amine 3). 1H NMR (300
MHz, CDCfe) 6 2.85(d, br, 3H). 3.068(s, 1H), 3.744(s, 3H), 4.468(s. br, 2H), 7.195(s, br, 2H), 7.46(d, 2H,
J= 8.1 Hz). Exact mass calculated for C12Hi«N02:204.1025. Found: 204.1022. .
5. Synthesis of 5-fluorosalicvlic acid methyl ester (7)
5-Huorosalicylic acid (272.6 g, 1.74 mol) was dissolved in methanol (1.3 L) to form a clear
solution. Concentrated sulfuric acid (50 ml) was slowly added to the methanol solution with vigorous
stirring. The solution was heated to reflux for 4 hours. Trimethy! orthoformate (200 ml) was added slowly
to the reaction solution. 300 ml of solvents (methyl formate and methanol) was distilled off. The
remaining reaction solution was heated at 66 °C (refluxing temperature) for 16 hours. HPLC analysis
indicated that the reaction was complete. Reaction solution was cooled to ambient temperature. Solvent
was removed under reduced pressure. The residue was partitioned between water (140 ml) and
methylene chloride (220 ml). Organic layer was separated. Aqueous layer was extracted with methylene
chloride (3 x 220 ml). The combined organic layer was washed with water (270 ml), brine (270 ml) and
dried with MgSO4. The organic solution was concentrated to dryness to afford crude product (293.8 g).
This crude material was used in the next step without further purification. 1H NMR (300 MHz, CDCI3) C
3.96(s, 3H), 6.94(dd, 1H, J= 4.5 Hz and J= 9.0 Hz), 7.19(m, 1H), 7.50(dd, 1H, J= 3.3 Hz and J= 8.7 Hz),
10.508(8,1H).
Example 6. Synthesis of 5-fiuoro-2-hvdroxv-3-nltro-benzoic acid methyl ester (8)
Tetramethylammonium nitrate (98.4 g, 0.72 mol) was suspended In methylene chloride (800 ml).
Triflouroacetic anhydride (180.3 g, 0.857 mol) was added to the mixture with stirring. The mixture was
cooled to 8 °C. The solution of ester 7 (106 g, 0.624 mol) in CH2CI2 (150 ml) was then added slowly to the
reaction flask over 25 minutes while the temperature was maintained between 5 °C and 10 °C. Reaction
mixture was stirred at 8 °C for additional 40 minutes after addition was complete. Saturated aqueous
sodium bicarbonate (500 ml) was added slowly to quench the reaction. Organic layer was separated,
washed with water (2 x 500 ml) and concentrated to dryness to afford crude solid. The solid was dissolved
in acetonitrile (300 ml) at 55 *C. Water (100 ml) was added slowly to the acetonitrile solution with stirring
and solid precipitated out. The suspension was cooled to 18 °C and stirred at this temperature for 30
minutes. It was then cooled to 3 °C and stirred at this temperature for 30 minutes. The solid was collected
by filtration. The filter cake was washed with cold solvent CH3CN/H2O (2/1, 100 ml) and dried to afford
78.49 g of light yellow product (57% yield over two steps). 1H NMR (300 MHz, CDCI3) 6 4.035(s, 3H),
J= 9.0 Hz), 7.94(dd, 1H, J= 3.3 Hz and J= 7.5 Hz), 11.71(s, 1H). Exact mass
calculated for CeHsFNOs: 214.0152. Found: 214.0141.
Example 7. Synthesis of 5-Fluoro-2-{4-f(methoxvcarbonvl-methvl-amino)-methyll-phenvlethvn¥]V-3-oitrobenzoic
acid methyl ester (91
MeO2C
The nitro compound 8 (47.87 g, 0.223 mol) was dissolved in acetonitrile (240 ml) and cooled to -8
°C. Triethylamine (33.8 g, 0.334 mol) was added. A clear dark solution was formed. Triflic anhydride
(69.17 g, 0.245 mol) was added slowly and the reaction temperature was maintained at -10 °C. 10
minutes after addition was complete, TLC analysis indicate the completion of triflate formation. Cooling
bath was removed. Alkyne 5 (47.46 g, 0.234 mol) was added. The solution was degassed 3 times by
evacuating the flask and backfilling it with nitrogen. The solution was then transferred into an addition
funnel. Into a separate reaction flask was added acetonitrile (240 ml) and triethylamine (22.5 g, 0.223
mol). The solution was degassed 3 times by exposing the reaction flask to vacuum and nitrogen
alternatively. Dichlorobis(triphenylphosphine) palladium (II) (3.13 g, 0.0045 mol) was added to the solution
and the solution was degassed again 3 times. This solution was heated to 65 °C under protection of
nitrogen. Once the temperature reached 65 °C, one quarter of the solution of alkyne 5 and triflate in
addition funnel was quickly added to the reaction flask. The remaining solution in addition funnel was
added over 30 minutes at 65 °C. After the addition was complete, the reaction solution was stirred at 65
°C for 2 hours. HPLC analysis indicated the reaction was complete. Reaction mixture was cooled to room
temperature. Solvent was removed under reduced pressure. The residue was dissolved In ethyl acetate
(500 ml) and washed with water (300 ml). The aqueous phase was separated and back extracted with
ethyl acetate (200 ml). The combined organic solution was washed with water (200 ml). It was then
concentrated to dryness to provide a dark oil residue (140 g). This crude product was used in the next
step without further purification. 1H NMR (300 MHz, CDC13) 6 2.87(d, br, 3H), 3.755(s, 3H), 4.011(s, 3H),
4.50(s, br, 2H), 7.21(s, br, 2H), 7.55(d, 2H, J= 9 Hz), 7.80(dd, 1H, J= 2.7 Hz and J= 7.2 Hz), 7.86(dd, 1H,
J= 2.7 Hz and J= 8.1 Hz).
Example 8. Synthesis of 3-amino-S-fluoro-2^4-[(methoxvcarbonvl-methvl-amlno)-methvl]-
DhenvlethvnvlVbenzoic acid methyl ester (101
The crude compound 9 (140 g) was dissolved in methanol (1.05 L). Iron powder (325 mesh, 76.2
g, 1,36 mol) was added followed by addition of saturated aqueous ammonium chloride (210 ml). The
solution was heated to 65 °C. Aqueous hydrochloric acid (16 wt %, 32 ml) was added. The reaction was
heated at 65°C for 2 hours. HPLC analysis indicated the completion of the reaction. The reaction mixture
was cooled to room temperature. Soiid was removed by filtration. The filter cake was washed with
methanol (2 L). The combined methanol solution was concentrated to dryness. The residue was
partitioned between ethyl acetate (800 ml) and diluted aqueous hydrochloric solution (0.5 M, 300 ml).
Organic layer was separated. Aqueous layer was extracted with ethyl acetate (3 x 200 ml). The combined
organic solution was washed with brine (200 ml). The solution was then concentrated to dryness to afford
122.8 g of crude product as dark oil. This crude product was used in the next step without further
purification. 'H NMR (300 MHz, CDCI3) 6 2.87(d, br, 3H), 3.491 6.60(dd, 1H, J= 2.7 Hz and J= 9.9 Hz), 7.04(dd, 1H, J= 2.4 Hz and J= 9.0 Hz), 7.237(s, br, 2H), 7.52(d.
2H, J= 8.1 Hz). ,
Example 9. Synthesis of 6-fluoro-2-f4-f(methoxvcarbonvl-methvl-amino)-methvll-Phenvl}-1H-indole-4-
carboxvlic acid methvl ester (11)
Crude compound 10 (114.37 g, -0.309 mol) was dissolved in DMF (1.5 L). Copper (I) iodide
(99.9999% purity, 5.8 g, 0.0309 mol) was added. The reaction mixture was degassed 4 times by
exposing the reaction flask to vacuum and nitrogen alternatively. The reaction mixture was then heated at
100 °C for 44 hours under protection of nitrogen. HPLC analysis indicated the disappearance of starting
material. Reaction mixture was cooled to ambient temperature. Solvent was removed under reduced
pressure (9 mbar) at 35 °C. The black residue was dissolved in CH2CI2 (0.15 L). The mixture was passed
through a Celite pad. The organic solution was then passed through a silica gel pad (300 g of silica gel).
CH2CI2 (2.3 L) was used to elute compound from silica gel pad. Organic solution was concentrated to
dryness. The residue was dissolved CH2Cl2 (0.15 L). Hexane (1 L) was added slowly to the solution with
stirring. The precipitated product was collected by filtration, washed with EtOAc (0.2 L) and dried to afford
31.34 g of product The EtOAc wash was combined with mother liquor. The solution was concentrated to
dryness. The residue was dissolved in CH2CI2 (0.15 L). The solution was then passed through a pad of
silica gel (300 g). The silica gel pad was washed with CH2CI2 to elute out the compound. The organic
solution was concentrated to dryness. The residue was dissolved CH2CI2 (0.07 L). Heptane (0.22 L) was
added to precipitate out product. Solid was collected, washed with 1:3 of CH2CI2/heptane (0.06 L) and
dried to provide additional 27.51 g of product. The combined product weighed 58.85 g, which translated
to 51% yield over 3 steps from compound 8.1H NMR (300 MHz, CDCI3) 6 2.896(s, 3H), 3.779(s, 3H),
4.006(s, 3H), 4.516(s, 2H). 7.31(dd, 2H, J= 1.5 Hz and J= 8.7 Hz), 7.429 (s, 1H), 7.65{m, 3H), 9.17(d, br,
1H). Exact mass calculated for CzoHaoFNzO^ 371.1407. Found: 371.1418.
Example 10. Synthesis of 6-FluorD-2-M-Hmethoxvcarbonvl-methvl-aminol-methy|l-phenvl)-3-((EV2-
nitro-vinvn-1H-indole-4-carboxvlic acid methyl ester M21
Trifluoroacetic acid (0.14 L) was cooled to 5 °C. 1-N,N-dimethylamino-2-nitro ethylene (15.0 g,
0.129 mol) was added to TFA in portions at 5-8 °C. A clear solution was formed. Indole 11 was added several portions. CH2CI2 (0.02 L) was then added. The reaction solution was stirred at ambient
temperature for 44 hours. TLC analysis indicated that the reaction was complete. Solvent was removed
under reduced pressure at 23 °C (47 mbar). The residue was poured slowly into a flask containing CH2CI2
(0.4 L) and saturated aqueous NaHC03 (0.5 L). The final pH for the aqueous phase was 5.0. Organic
phase was separated. Aqueous phase was extracted with CH2CIZ (2 x 100 ml). The organic solution was
combined and concentrated in a rotovap until solid crashed out. Heptane (0.2 L) was added to the CH2CI2
suspension and the mixture was stirred for 30 minutes. Solid was collected, washed with 1:4 of
CH2CI2/heptane (100 ml) and dried in air to afford 49.18 g of product (95% yield). 1H NMR (300 MHz,
DMSO-de) 6 2.88(s, 3H), 3.661(s, 3H), 3.920(s, 3H), 4.554(s, 2H), 6.86(d, 1H, J= 13.5 Hz), 7.46(d, 2H, J=
7.5 Hz), 7.52(d, 2H, J= 9.3 Hz), 7.65(d, 2H, J= 8.1 Hz), 8.69(d, 1H, J= 13.5 Hz), 12.895(s, br, 1H). Exact
mass calculated for C22H2iFN3O6: 442.1414. Found: 442.1420.
Example 1 1 , Synthesis of 6-fluoro-2-M-r(methoxvcarbonvl-methvl-amino)-methvn-DhenylV3-(2-nitroethvn-
1H-indole-4-carboxvlic acid methvl ester EtOH (900 ml) and MeOH (90 mi) were added to a 2L flask. Powdered sodium borohydride (20.5
g, 0.55 mol) was then added. The suspension was cooled to 15 °C. Nitroalkene 12 (49.0 g, 0.11 mol) was
added in portions over 45 minutes while the temperature was maintained at ~16 °C. After addition was
complete, additional EtOH (800 ml) was added. The reaction mixture was stirred for 15 minutes. TLC
analysis indicated the completion of the reaction. A mixture of acetic acid (40 ml) and water (40 ml) was
added slowly to quench the excess of sodium borohydride. A reddish suspension was obtained. Solvent
was removed In a rotovap. The residue was partitioned between EtOAc (600 ml) and water (300 ml).
Aqueous phase was separated. The solid in organic layer was collected by filtration and dried to afford
21.94 g of product 13 (45% yield). The organic filtrate was concentrated to dryness. The residue was
then reslurried with EtOAC (70 ml) Vheptane (200 ml). The solid was collected by filtration and dried to
afford second crop of product (21.74 g, 44% yield). The combined yield for this step is 89%. 'H NMR (300
MHZ, DMSO-d6) 6 2.B7(s, 3H), 3.584(t, 2H, J= 7.8 Hz), 3.661 (s, 3H), 3.903{s, 3H), 4.519(8, 2H), 4.607(t,
2H, J- 7.8 Hz), 7.41(m, 4H), 7.58(d, 2H. J= 8.10 Hz), 12.0(s, br, 1H). Exact mass calculated for
6: 444.1571. Found: 444.1559.
Example 12. Synthesis of [4-(8-Fluoro-6-oxo-3.4.5.6-tetrahvdrQ-1^-a2epinoi5.4.3-cdlindol-2-vn-benzvl]-
methvl-carbamic acid methyl ester (14)
Raney nickel (30 ml, A-5000 from Active Metals) was washed with water (2 x 50 ml), MeOH (2 x
50 ml) and HOAc (50 ml). It was then mixed with HOAc (400 ml) and transferred to a 2L hydrogenator.
Nitro compound 13 (19.33 g, 0.044 mol) was added. The suspension was hydrogenated at 150 psi at
ambient temperature for 20 hours. HPLC analysis indicated the starting material 13 disappeared. Catalyst
was filtered off and the filter cake was washed with EtOH (200 ml). (Caution: Raney nickel may ignite in
air. Never let the filter cake run dry). EtOH wash was combined with the filtrate. The solution was
concentrated to dryness in a rotovap to give a green residue. The green residue was dissolved in MeOH
(200 ml). Ammonium hydroxide (40 ml) was added to adjust the pH of the solution to -10. The solution
was then heated at 45 °C for 8 hours to cyclize the amine intermediate to lactam 14. White solid
precipitated out over the course of cyclization. HPLC analysis indicated the completion of the reaction.
The suspension was cooled to room temperature. The white solid was collected by filtration, washed with
MeOH (20 ml) and dried in air to afford 8.9 g of product (98% yield). 1H NMR (300 MHz, DMSO-d6) 6
2.85(8. 3H), 3.05(m, 2H), 3.39(m, 2H), 3.66(s, 3H), 4.486(8, 2H), 7.39(m, 4H), 7.76(d, 2H, J* 8.10 Hz),
8.24(t, 1H, J= 5.7 Hz), 11.66(s, 1H). Exact mass calculated for CziHjiFNsOa: 382.1567. Found: 382.1552.
Example 13. Synthesis of 8-Fluoro-2-(4-methvlamlnomethyl-DhenvlV1.3.4.5-tetrahvdro-azepino[5.4.3jcdlindol-
6-one (151 i
Lactam 14 (14.42 g, 0.038 mol) was dissolved in hydrobromic acid in acetic acid (30%-32%, 140
ml). The reaction solution was stirred for 46 hours at room temperature in a 500ml flask that was
connected to an ethanolamine scrubber system. HPLC analysis indicated the completion of the reaction.
Ice (30 g) was added to the reaction solution followed by addition of aqueous NaOH (327 ml, 10 M, mol) while the temperature was maintained between 25 °C and 35 °C. When addition of NaOH was
complete, the pH was 10. The resulting solid was collected by filtration, washed with water (2 x 50 ml).
The filter cake was then suspended In water (125 ml) and stirred for 2 hours. The solid was collected by
filtration, washed with water (2 x 25 ml) and dried to afford 10.76 g of product (88% yield). 1H NMR (300
MHz, DMSO-d6) 6 2.577(s, 3H), 3.053(m, 2H), 3.406(m, 2H), 4.159(s, 2H), 7.36{dd, 1H, J= 2.4 Hz and J=
9.3 Hz), 7.44(dd, 1H, J= 2.4 Hz and J= 11.1 Hz), 7.63(d, 2H, J=8.1 Hz), 7.70(d, 2H, J= 8.1 Hz), 8.265(t,
1H, J= 5.7 Hz), 11.77(s, 1H). Exact mass calculated for C19H19FN30: 324.1512. Found: 324.1497.






We claim:
1. A method of preparing a compound of formula I
(Formula Removed)
wherein R1 is:
H;
cyano;
an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or
--C(O)--R5, where R5 is: H; an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or OR6 or NR6R7, where R6 and R7 are each independently H or an optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;
R2 is H or alkyl;
R3 is H or alkyl;
R4 is H, halogen or alkyl,
the method comprising:
a) Sonogashira coupling of a compound of formula II, wherein X is halogen or CF3SO2-O-
(Formula Removed)
with a compound of formula III
in the presence of a catalyst to form a compound of formula IV;
(Formula Removed)
b) reducing the compound of formula IV to generate a compound of formula V;
(Formula Removed)
c) converting the compound of formula V in the presence of a catalyst into a compound
of formula VI;
(Formula Removed)
d) introducing a nitrovinyl substitutent at the 3-position of the compound of formula VI
to form a compound of formula VII;
(Formula Removed)
e) reducing the compound of formula VII to form a compound of formula VIII; and
(Formula Removed)
f) reducing the compound of formula VIII under hydrogenation conditions and cyclizing
the reduced compound in the presence of a base to provide the compound of formula I.
2. The method as claimed in claim 1, wherein the step c) comprises a Cul-promoted indole formation.
3. The method as claimed in claim 1 for preparing 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-l,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one, the method comprising:
a) Sonogashira coupling of a compound of formula IX, wherein X is CF3SO2-O- or
halogen;
(Formula Removed)
with (4-ethynyl-benzyl)-methyl-carbamic acid methyl ester to form 5-fluoro-2-{4[(methoxycarbonyl-methylamino)-methyl]-phenylethynyl}-3-nitro-benzoic acid methyl ester;
b) reducing 5-fluoro-2- {4-[(methoxycarbonyl-methyl-amino)-methyl] -phenylethynyl} -3-
nitro-benzoic acid methyl ester to provide 3-amino-5-fluoro-2-{4-[(methoxycarbonyl-methyl-
amino)-methyl-phenylethynyl} -benzoic acid methyl ester;
c) converting 3-amino-5-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-benzoic acid methyl ester into 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-lH-indole-4-carboxylic acid methyl ester;
d) treating 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-lH-indole-4-carboxylic acid methyl ester with N,N-dimethyl-2-nitroethylenamine to generate 6-fluoro-2- {4- [(methoxycarbony 1-methy l-amino)-methy 1] -phenyl} -3 -((E)-2-nitro-vinyl)-1H-indole-4-carboxylic acid methyl ester;
e) reducing 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl }-3-((E)-
2-nitro-vinyl)-lH-indole-4-carboxylic acid methyl ester into 6-fluoro-2-{4-[(methoxycarbonyl-
methyl-amino)-methyl]-phenyl}-3-(2-nitro-ethyl)-lH-indole-4-carboxylic acid methyl ester;
f) converting 6-fluoro-2-{4-[(methoxycarbonyl-methyl-amino)-methyl]-phenyl}-3-(2-
nitro-ethyl)-lH-indole-4-carboxylic acid methyl ester into [4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-
lH-azepino[5,4,3-cd]indol 2-yl)-benzyl]-methyl-carbamic acid methyl ester; and
g) deprotecting [4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-lH-azepino[5,4,3-cd]indol-2-yl)-
benzyl]-methyl-carbamic acid methyl ester to produce 8-fluoro-2-{4-
[(methylamino)methyl]phenyl)-l,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.
4. The method as claimed in claim 3, wherein X is CF3SO2-O-.
5. The method as claimed in claim 3, wherein X is bromine.
6. The method as claimed in claim 3, wherein the step b) comprises a Cul-promoted indole formation.
7. The method as claimed in claim 3, wherein the step e) comprises hydrogenation.

Documents:

1465-DELNP-2007-Abstract-(10-03-2011).pdf

1465-delnp-2007-abstract.pdf

1465-DELNP-2007-Assignment-(02-07-2010).pdf

1465-DELNP-2007-Claims-(10-03-2011).pdf

1465-delnp-2007-claims.pdf

1465-DELNP-2007-Correspondence Others-(31-05-2011).pdf

1465-DELNP-2007-Correspondence-Others-(02-07-2010).pdf

1465-DELNP-2007-Correspondence-Others-(10-03-2011).pdf

1465-delnp-2007-correspondence-others-1.pdf

1465-delnp-2007-correspondence-others.pdf

1465-delnp-2007-description (complete).pdf

1465-delnp-2007-form-1.pdf

1465-delnp-2007-form-18.pdf

1465-delnp-2007-form-2.pdf

1465-delnp-2007-form-3.pdf

1465-delnp-2007-form-5.pdf

1465-DELNP-2007-GPA-(02-07-2010).pdf

1465-DELNP-2007-GPA-(10-03-2011).pdf

1465-delnp-2007-pct-210.pdf

1465-delnp-2007-pct-220.pdf

1465-delnp-2007-pct-237.pdf

1465-delnp-2007-pct-304.pdf

1465-delnp-2007-pct-311.pdf

1465-delnp-2007-pct-402.pdf

1465-delnp-2007-pct-409.pdf

1465-delnp-2007-pct-416.pdf

1465-DELNP-2007-Petition 137-(02-07-2010).pdf

1465-DELNP-2007-Petition 137-(10-03-2011).pdf


Patent Number 247864
Indian Patent Application Number 1465/DELNP/2007
PG Journal Number 22/2011
Publication Date 03-Jun-2011
Grant Date 27-May-2011
Date of Filing 23-Feb-2007
Name of Patentee PFIZER INC.,
Applicant Address 235 EAST 42ND STREET, NEW YORK, NEW YORK 10017, USA
Inventors:
# Inventor's Name Inventor's Address
1 CHUNRONG MA C/O AGOURON PHARMACEUTICALS,INC., A PFIZER COMPANY,10777 SCIENCE CENTER DRIVE,SAN DIEGO,CA 92121,USA
2 NARESH NAYYAR C/O AGOURON PHARMACEUTICALS,INC., A PFIZER COMPANY,10777 SCIENCE CENTER DRIVE,SAN DIEGO,CA 92121,USA
3 NEBOJSA SLOBODAN STANKOVIC C/O AGOURON PHARMACEUTICALS,INC., A PFIZER COMPANY,10777 SCIENCE CENTER DRIVE,SAN DIEGO,CA 92121,USA
PCT International Classification Number C07D 487/06
PCT International Application Number PCT/IB2005/002881
PCT International Filing date 2005-09-12
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/612,457 2004-09-22 U.S.A.