WO2017005759A1

WO2017005759A1 - A process to make azaindole derivatives

Info

Publication number: WO2017005759A1
Application number: PCT/EP2016/065894
Authority: WO
Inventors: Christophe Pierre Alain Chassaing; Tanja Schweisel
Original assignee: Intervet International B.V.; Intervet Inc.
Priority date: 2015-07-07
Filing date: 2016-07-06
Publication date: 2017-01-12

Abstract

The subject application is directed to an improved process for producing azaindole derivative compounds of Formula (lb), or a solvate or salt thereof

Description

A PROCESS TO MAKE AZAINDOLE DERIVATIVES BACKGROUND

WO2010/099039, published September 2, 2010, discloses indole derivatives as CRTH2 receptor antagonists and process for making the same. WO2010/031183, published March 25, 2010, also discloses indole derivatives as CRTH2 receptor antagonists and process for making the same.

Molinaro et al, The Journal of Organic Chemistry, 2012, 77, 2299-2309 discloses the CRTH2 Antagonist MK-7246 as well as process for making the same.

U.S. Patent 8,546,422, issued October 1 , 2013 discloses azaindole derivatives as CRTH2 receptor antagonists.

WO2014/060596, published April 24, 2014, discloses process for preparing indole derivatives.

When applied to the synthesis of a 7-azaindole core, the conventional synthetic strategies for the preparation of an indole core (Fischer, Madelung or Reissert reactions) which start from functionalized benzenes and involve the formation of a pyrrole ring suffer from poor yields or do not work at all due to the electron deficient nature of the pyridine ring. See Tetrahedron 2007, 63, 1031-1064 and Tetrahedron 2013, 69, 4767-4834,

With the development of novel transition-metal catalyzed synthetic methods, the formation of azaindoles can be achieved more efficiently and with broader substrate scope. Among these methods, palladium-catalyzed heteroannulations and more especially processes involving intramolecular Heck reactions of an intermediate enamine constitute an attractive approach (J. Org. Chem. 2010, 75, 5316-5319, Angew. Chem. (Int. Ed.) 2004, 43, 4526 -4528, Synthesis 2005, 15, 2571-2577). However, even using these modern protocols, 7-azaindoles are obtained in good yields (>60%) only when easily enolisable ketones such as acetophenones or when 1 ,2- dicarbonyl compounds are used as substrates. The yields usually remain modest when other types of ketones are engaged in the reactions. SUMMARY OF THE INVENTION

An embodiment of the subject invention is a process for preparing a compound of Formula (lb)

lvate or salt thereof,

DETAILED DESCRIPTION

The subject application is directed to an improved process for producing azaindole derivative compounds of Formula (lb).

These compounds are antagonists of the PGD2 receptor CRTH2 and are useful in the treatment and prevention of CRTH2 mediated diseases.

Scheme 1 demonstratesa synthetic access to the azaindole compounds of the subject application.

Scheme 1 Scheme 2 demonstrates another synthetic access to the azaindole compounds of the subject application.

Scheme 2

An embodiment of the invention is a process for transforming the compound of Formula (V) to the compound of Formula (VI) using palladium diacetate, tri-o-tolyl phosphine, trialkyl amine and acetonitrile as solvent. This embodiment provides for the formation of the desired product (VI) in excellent yield. In an embodiment, the trialkyl amine is triethylamine. In another embodiment, the trialkyl amine is tributylamine.

or a solvate or salt thereof, comprising a) reacting a compound of Formula (II)

with an alkyl alcohol to give a compound of Formula (III)

reacting a compound of Formula (III) with a compound of Formula (IV)

to give a compound of Formula (V)

c) reacting a compound of Formula (V) with a palladium catalyst to give a compound of Formula (VI)

d) reacting a compound of Formula (VI) with a compound of Formula (VII) γϋ^³

to give a compound of Formula (VIII)

e) reacting a compound of Formula (VIII) in the presence of a base, preferably Mg(OEt)₂ to give a compound of Formula (ΓΧ)

f) reacting a compound of Formula (ΓΧ) with an acid, preferably, H₂SO₄ or HC1 to form the compound of Formula (X)

g) reacting the compound of Formula (X) with a catalyst to give the compound of Formula (XIa)

h) reacting the compound of Formula (XIa) with an acid and an alkyl alcohol to give a compound of Formula (XI)

wherein R⁷ is alkyl; i) reacting a compound of Formula (XI) with methanesulfonyl or p-toluenesulfonyl chloride to yield a compound of Formula (XII)

wherein R⁹ is either methyl or p-tolyl; j) reacting a compound of Formula (XII) with NaN₃ to produce a compound of Formula (XIII)

k) reducing a compound of Formula (XIII) to yield a compound of Formula (XlVa)

1) reacting a compound of Formula (XlVa) with 2,4-dinitrobenzene-l-sulfonyl chloride or 4-nitrobenzene-l-sulfonyl chloride or 2-nitrobenzene-l-sulfonyl chloride to yield a compound of Formula (XV)

m) reacting a compound of Formula (XV) with an alkylating agent to give a compound of Formula (XVI)

wherein R⁴ is alkyl;

n) reacting a compound of Formula (XVI) with a primary alkylamine, preferably n-propyl amine or n-butyl amine to yield a compound of Formula (XVII)

o) reacting a compound of Formula (XVII) with a compound of Formula (XVIII) in the presence of an activating agent

p) reacting a compound of Formula (ΧΓΧ) with an alkali metal hydroxide to yield a compound of Formula (lb); wherein

X² is hydrogen or halogen; R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are independently Ci-C₆ alkyl; R⁹ is methyl or p-tolyl;

R¹⁰ and R¹¹ are independently hydrogen or N0₂ wherein at least one of R¹⁰ or Rⁿ is N0₂

Y¹ is halogen; preferably bromine, iodine, chlorine or triflate; and

Y² is a leaving group, preferably, Br, I, CI, or mesylate. In another embodiment, the reaction of step c is conducted in the presence of an alkylamine preferably triethylamine or «-butylamine.

In another embodiment, the reaction of step c is conducted in the presence of a palladium catalyst and a ligand preferably palladium diacetate and tri-o-tolyl-phosphine.

In another embodiment, the reaction of step d is conducted in the presence of a base. In another embodiment, the reaction of step i is conducted in the presence of a base.

In another embodiment, the reaction of step 1 is conducted in the presence of a base.

In another embodiment, the reaction of step m is conducted in the presence of a base.

In another embodiment, the alkylating agent of step m is an alkyl halide, an alkyl triflate or a dialkyl sulfate In another embodiment, the subject invention is a process for preparing a compound of Formula (lb)

or a solvate or salt thereof, comprising

a) reacting a compound of Formula (V)

with palladium diacetate, tri-o-tolyl phosphine, triethyl amine and acetonitrile to give a compound of Formula (VI)

wherein

Y¹ is halogen; preferably bromine, iodine, chlorine or triflate;

X² is hydrogen or halogen; and

R¹' R², R⁴ and R⁸ are independently Ci-C₆ alkyl. In yet another embodiment, the process further comprising reacting a compound of Formula (VI) with a compound of Formula (VII)

to give a compound of Formula (VIII)

In another embodiment, the above reaction is conducted in the presence of a

Another embodiment is a process for preparing a compound of Formula (lb)

comprising a) reducing a compound of Formula (XIII)

b) reacting a compound of Formula (XlVa) with 2,4-dinitrobenzene-l-sulfonyl chloride or 4-nitrobenzene-l-sulfonyl chloride or 2-nitrobenzene-l-sulfonyl chloride to yield a compound of Formula (XV)

c) reacting a compound of Formula (XV) with an alkylating agent to give a compound of Formula (XVI)

wherein R⁴ is alkyl

wherein

X² is hydrogen or halogen;

4 7 8

R R' and R° are independently Ci-C₆ alkyl; and

R and R^1J are independently hydrogen or N0₂ wherein at least one of R or R¹¹ is N0₂. In another embodiment, the reaction of step b) is conducted in the presence of a base.

In another embodiment, the reaction of step c) is conducted in the presence of a base.

In another embodiment, the alkylating agent is an alkyl halide, an alkyl triflate or a dialkyl sulphate.

In yet another embodiment, the process further comprises: a) reacting a compound of Formula (XVI) with a primary alkylamine, preferably n-propyl amine or n-butyl amine to yield a compound of Formula (XVII)

b) reacting a compound of Formula (XVII) with a compound of Formula (XVIII) in the presence of an activating agent

to yield a compound of Formula (ΧΓΧ)

c) reacting a compound of Formula (ΧΓΧ) with an alkali metal hydroxide to yield a compound of Formula (lb) wherein X² is hydrogen or halogen;

R⁴, R⁷ and R⁸ are independently Ci-C₆ alkyl.

Another embodiment is a process for preparing a compound of Formula (lb)

comprising a) reducing a compound of Formula (XIII)

to yield a compound of Formula (XVII)

to yield a compound of Formula (ΧΓΧ)

c) reacting a compound of Formula (ΧΓΧ) with an alkali metal hydroxide to yield a compound of Formula (lb) X² is hydrogen or halogen;

4 7 8

R , R' and R° are independently Ci-C₆ alkyl.

In another embodiment, the reaction of step a) is conducted in the presence of a trialkylphoshine, prefereably trimethylphosphine, paraformaldehyde and of an hydride reagent. In another embodiment, the reaction of step a) is conducted in the presence of a trialkylphoshine, paraformaldehyde and of an hydride reagent, preferably sodium borohydride.

In an additional embodiment, Formula (lb) is

wherein R⁴ and R⁸ are methyl and X² is F. additional embodiment, Formula (lb) is a hydrate.

An another embodiment of the subject invention is a compound of Formula (V) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (VI) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (VIII) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (XII) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (XIII) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (XIV) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (XV) wherein the compound is

An another embodiment of the subject invention is a compound of Formula (XVI) wherein the compound is

The following definitions are provided to more clearly describe the invention.

"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. In one embodiment alkyl groups contain about 1 to about 12 carbon atoms in the chain. In another embodiment alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, or decyl.

"Alkoxy" means an -O-alkyl group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen. "Triflate" means trifluoromethane sulfonate.

With reference to the number of moieties (e.g., substituents, groups or rings) in a compound, unless otherwise defined, the phrases "one or more" and "at least one" mean that there can be as many moieties as chemically permitted, and the determination of the maximum number of such moieties is well within the knowledge of those skilled in the art. When used herein, the term "independently", in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H₂0.

The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.

Mesyl chloride or MesCl or MSC means methane sulfonyl chloride or methanesulfonic acid chloride.

Tosyl chloride means p-toluene sulfonyl chloride.

Reducing agent - Non-limiting examples of reducing agents are lithium borohydride, sodium borohydride, disiamylborane, hydrogen with platinum(IV) oxide, hydrogen with

palladium/carbon, zinc borohydride and the like.

Alkylating agent - an electrophile with an alkyl group. Non-limiting examples of alkylating agents are an alkyl halide, an alkyl triflate or a dialkyl sulfate.

Activating agent - used for the formation of amides from an amine and an acid include; reagents generating acid halides (such as oxalyl chloride, thionyl chloride, Deoxo-Fluor®, DAST, TFFH,

BTFFH); reagents generating carbonic anhydrides (such as EEDQ); carbodiimide reagents(such as DCC, DIC or EDC) or uronium/aminium-phosphonium-immonium salts of benzotriazole or of azabenzotriazole (such as HATU and HBTU; BOP and PyBOP; BOMI and BDMP respectively).

These acronyms, are defined in the following references which are incorporated herein by reference; Valeur, E.; Bradley, M.; Chemical Society Reviews 2009, Vol. 38, p 606-631 ;

Taylor, J. E.; Bull, S. D.; Comprehensive Organic Synthesis 2014 (2nd Edition) Vol. 6, p 427-

478.

Deoxo-Fluor® is bis(2-methoxyethyl)aminosulfur trifiuoride. DAST is diethylaminosulfur trifiuoride. TFFH is N,N^'^-tetramethylfluoroformamidiniurn hexafluorophosphate.

BTFFH is N,N,N' N'-bis(tetramethylene)fluoroformamidinium hexafluorophosphate. EEDQ is N-ethoxycarbonyl-2-ethoxy-l ,2-dihydroquinoline. DCC is ν,,ν'-dicyc!o cxylcarbodiimidc. DIC is .V. V'-d i isopropy lcarbodi i m idc .

EDC is N-ethyl-N'-(3-dimetliylaminopropyl)carbodiiiTiide hydrochloride. HATU is 1 -[bis(dimethy!amino)methylene]- 1 //- 1 ,2,3-tnazoIo[4,5-b]pyridinium 3-oxid hexafluo rophosphate .

HBTU is 2-(l H-benzotriazol-l -yl)-l , 1 ,3,3-tetramethyluronium hexafl.no rophosphate.

BOP is (benzotriazol-l -yloxy)tris(dimethylamino)phosphonium hexafluoropho sphate .

PyBOP is benzotriazol-l -yl-oxytripyrrolidinophosphonium hexafluorophosphate. BOMI is (lH-benzotriazol-l -yloxy)-N,N-dimethylmethaniminium hexachloroantimonate.

BDMP is 5-(lH-benzotriazol-l -yloxy)-3,4-dihydro-l -methyl 2H-pyrrolium

hexachloroantimonate.

EXAMPLES

Example 1 - Synthesis of diethyl 4,4-diethoxyheptanedioate

Diethyl 4-oxoheptanedioate (39 mL; 178 mmol) is dissolved in ethanol (180 mL) in round bottom flask flushed with nitrogen. Triethyl orthoformate (54.5 mL; 321 mmol) and sulfuric acid (0.098 mL; 1.781 mmol) are added under stirring and the mixture is heated to reflux. After 30 min reaction time, monitoring of the reaction by gas chromatography shows 83% conversion into the desired product. Heating is stopped and the reaction mixture is cooled to room temperature with an ice bath. Ethanol is evaporated under reduced pressure, the obtained residue is taken up in toluene (175 mL). The organic phase is sequentially washed with 2% aqueous sodium hydrogen carbonate (175 mL) and with water (70 mL), is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The remaining traces of triethyl orthoformate are removed under high vacuum overnight. The crude product (53.24 g; 154 mmol) is engaged in the next step without further purification.

Standard GC method. Retention tine: 8.58 min.

Example 2 - Synthesis of diethyl 4-[(3-bromo-2-pyridyl)imino]heptanedioate

3-Bromopyridin-2-amine (13.15 g; 76 mmol) is dissolved in xylene (45 mL) under inert atmosphere and a solution of diethyl 4,4-diethoxyheptanedioate (46.3 g; 152 mmol) in xylene (45 mL) is added. The resulting mixture is stirred at 140 °C for 4 h while the generated ethanol is distilled off from the reaction mixture. The reaction mixture is cooled to room temperature and is concentrated under reduced pressure. The obtained crude residue (29.3 g; 76 mmol) is engaged in the next step without further purification.

Protocol A - Retention time: 1.04 and 1.11 min (m/z 385 and 387).

Example 3 - Synthesis of ethyl 3-[3-(2-ethoxy-2-oxo-ethyl)-lH-pyrrolo[2,3-b]pyridin-2- yljpropanoate

Crude diethyl 4-[(3-bromopyridin-2-yl)imino]heptanedioate (33.1 g; 86 mmol) is dissolved in acetonitrile (215 mL), triethylamine (17.98 ml; 129 mmol) and tri-o-tolylphosphine (8.38 g; 27.5 mmol) are added and argon is bubbled through the reaction mixture for 10 min. Palladium acetate (1.545 g; 6.88 mmol) is added and the reaction mixture is heated to reflux and stirred at this temperature for 4.5 h. The reaction mixture is cooled to room temperature and is concentrated under reduced pressure. The obtained residue is taken up in ethyl acetate (300 mL) and the organic layer is extracted with water (3 x 100 mL). The combined aqueous layers are back extracted with ethyl acetate (100 mL) and the combined organic layers are washed with brine (50 ml), are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The obtained solid is dissolved in a minimal volume of dichloromethane and is purified by elution with dichloromethane (1500 mL) and ethyl acetate (2000 mL) over a fritted funnel loaded with silica gel (330 g). The fractions of interest are pooled and are concentrated under reduced pressure to afford the desired product (21.1 g; 69.4 mmol). Protocol A - Retention time: 0.96 min (m/z 305).

Example 4 - Synthesis of ethyl 3-[l,3-bis(2-ethoxy-2-oxo-ethyl)pyrrolo[2,3-b]pyridin-2- yl]propanoate

Ethyl 3-[3-(2-ethoxy-2-oxoethyl)-lH-pyrrolo[2,3-b]pyridin-2-yl]propanoate (12.2 g; 40.1 mmol) is dissolved in dimethylformamide (65 mL). Under ice bath cooling, ethyl 2-bromoacetate (6.92 mL; 60.1 mmol) is added and followed by cesium carbonate (26.1 g; 80 mmol). The resulting mixture is stirred for 20 min, the ice bath is removed and the reaction is stirred ovemight at room temperature. After dilution with ethyl acetate (250 mL), the organic phase is washed with water (2 x 100 mL) and with brine (50 mL), is dried over magnesium sulphate, filtered and is concentrated under reduced pressure. In case a significant amount of dimethylformamide remains, the residue is taken up in ethyl acetate (100 mL), extracted with half saturated aqueous sodium chloride (100 mL), dried over magnesium sulphate, filtered and is concentrated under reduced pressure. The crude product is purified by elution with dichloromethane (600 mL) and then with a 4 to 1 mixture of dichloromethane and ethyl acetate (600 mL) through a fritted funnel loaded with silica gel (100 g). The fractions of interest are combined and evaporated under reduced pressure to afford the desired product (15.72 g; 39.9 mmol). Έ-NMR (CDCI₃) δ ppm: 1.26 (3H, t, J=7.0 Hz), 1.27 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.1 Hz), 2.67 (2H, t, J=7.8 Hz), 3.12 (2H, t, J=7.8 Hz), 3.75 (2H, s), 4.15 (2H, q, J=7.1 Hz), 4.16 (2H, q, J=7.2 Hz), 4.24 (2H, q, J=7.1 Hz), 5.15 (2H, s), 7.10 (1H, dd, J=4.9, 7.8 Hz), 7.92 (1H, d, J=7.8 Hz), 8.27 (1H, dd, J=1.4, 4.9 Hz).

Protocol C - Retention time: 1.74 min (m/z 391). Example 5 - Synthesis of ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro-6H-pyrido[3,2- b] indolizine-9-carboxylate

Ethyl 3-[l ,3-bis(2-ethoxy-2-oxo-ethyl)pyrrolo[2,3-b]pyridin-2-yl]propanoate (16.09 g; 41.2 mmol) is dissolved in dimethylformamide (70 mL) and magnesium ethoxide (9.43 g; 82 mmol) is added. The resulting mixture is stirred overnight at 45 °C. After 16 h reaction time, the mixture is cooled to room temperature and is diluted with ethyl acetate (125 mL). Aqueous IN hydrochloric acid is added to the reaction mixture until acidic pH is reached. The aqueous phase is separated and the organic phase is extracted with IN hydrochloric acid (100 mL), is dried over magnesium sulphate, is filtered and is concentrated under reduced pressure. The obtained crude residue (12.9 g; 29.5 mmol) is engaged in the next step without further purification. Protocol C - Retention time: 1.34, 1.58 and 1.80 min (m/z 345).

Example 6 - Synthesis of 2-(8-oxo-7,9-dihydro-6H-pyrido[3 -b]indolizin-5-yl)acetic acid

Ethyl 5-(2-ethoxy-2-oxo-ethyl)-8-oxo-7,9-dihydro-6H-pyrido[3,2-b]indolizine-9-carboxylate (4.1 g; 9.41 mmol) is slurred in concentrated sulfuric acid (31.4 mL; 94 mmol), the mixture is degassed with argon and is heated at 81 °C inside temperature under an argon flow for 1 h. After cooling to room temperature, aqueous 4N sodium hydroxide is added under ice bath cooling until pH 4 is reached (about 50 mL). The precipitate formed is filtered and the filtrate is extracted with tetrahydroiuran (3 x 100 mL). The combined organic layers are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford a solid which is combined with the precipitate. After drying under high vacuum the desired product is obtained (1.48 g; 6.08 mmol). ¹ H-NMR (DMSO- d₆) δ ppm: 2.70 (2H, bt, J=6.7 Hz), 3.23 (2H, bt, J=6.7 Hz), 3.70 (2H, s), 4.79 (2H, s), 7.11 (1H, dd, J=4.7, 7.8 Hz), 7.91 (1H, dd, J=1.5, 7.8 Hz), 8.19 (1H, dd, J=l .5, 4.7 Hz). Protocol D - Retention time: 1.21 min (m/z 245).

Example 7 - Synthesis of ethyl 2-[(85)-8-hydroxy-6,7,8,9-tetrahydropyrido[3,2-b]indoliziii- 5-yl] acetate

Triethylamine (1.4 mL) is slowly added to formic acid (3.5 mL) and (4-methyl-N-((15',25 -2-((2- ((4-methylbenzyl)oxy)ethyl)amino)-l ,2-diphenylethyl)phenylsulfonamido)ruthenium(II) chloride (0.026 g; 0.04 mmol) in a dried round bottom flask under argon atmosphere. Under ice bath cooling, a slurry of 2-(8-oxo-7,9-dihydro-6H-pyrido[3,2-b]indolizin-5-yl)acetic acid (1.97 g; 8.07 mmol) in dimethylformamide (7.00 mL) is added and the mixture stirred at 60 °C for 80 min to ensure complete conversion of the starting material (Protocol D - Retention time: 1.17 min (m/z 247). The reaction mixture is cooled to room temperature, is diluted with ethanol (28.3 mL; 484 mmol) and concentrated sulfuric acid (1.179 mL; 22.1 1 mmol) is added carefully under stirring. The resulting mixture is heated to 80 °C and is reacted at this temperature for 1 h. The volatiles are then removed under reduced pressure, the obtained residue is taken up with ethyl acetate (100 mL) and is extracted with saturated aqueous sodium hydrogen carbonate (50 mL). The aqueous phase is extracted with ethyl acetate (2 x 50 mL) and the combined organic layers are dried over magnesium sulphate. After filtration and evaporation under reduced pressure, the residue is dried under high vacuum to afford the crude desired product (1.64 g; 5.92 mmol) which is engaged into the next step without further purification. The desired product is obtained in 95.4 % e.e. as determined by chiral HPLC using a Chiralpak AD-H column.

Protocol E - Retention time: 1.03 min (m/z 275). Example 8 - Synthesis of ethyl 2-[(8S)-8-methylsulfonyloxy-6,7,8^-tetrahydropyrido[3,2- b]indolizin-5-yl]acetate

Ethyl 2-[(85 -8-hydroxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (2.755 g; 10.04 mmol) is dissolved in dichloromethane (50.2 mL) and triethylamine (1.680 mL; 12.05 mmol) is added. The resulting solution is cooled to - 60 °C and methanesulfonyl chloride (0.861 mL; 1 1.05 mmol) is added drop wise under stirring. After 1 h reaction time at -60 to -50 °C, saturated aqueous sodium hydrogen carbonate is added until pH 8 is reached. The phases are separated and the aqueous phase is washed twice with dichloromethane (10 mL). The combined organic layers are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product as a crude (4.1 g, 10.24 mmol).

Protocol C - Retention time: 1.40 min (m/z 353).

Example 9 - Synthesis of ethyl 2-[(8R)-8-azido-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5- yl] acetate

Ethyl 2-[(85 -8-methylsulfonyloxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (4.10 g; 10.24 mmol) is dissolved in dimethylformamide (51.2 mL) and sodium azide (3.33 g, 51.2 mmol) is added. The resulting mixture stirred overnight at 60 °C. After cooling to room temperature, the reaction is diluted with ethyl acetate (100 mL) and is extracted with water (50 mL). The aqueous phase is extracted with ethyl acetate (2 x 25 mL). The combined organic layers are extracted with half saturated aqueous sodium chloride (2 x 50 mL) are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product as a crude. The residue is purified by elution with dichloromethane (500 mL) and then a 4 to 1 mixture of dichloromethane and ethyl acetate (400 mL) through a fritted funnel loaded with silica gel (40 g). The fractions of interest are combined and evaporated under reduced pressure to afford the desired product (2.29 g; 7.42 mmol).

Protocol C - Retention time: 1.54 min (m/z 300).

Example 10 - Synthesis of ethyl 2-[(8R)-8-amino-6,7,8^-tetrahydropyrido[3,2-b]indoliziii-5- yl] acetate

Ethyl 2-[(8i?)-8-azido-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (1.016 g; 3.39 mmol) is dissolved in ethanol (34 mL) under nitrogen atmosphere. Palladium on carbon (0.022 g, 0.204 mmol) is added, nitrogen is bubbled through the solution before a hydrogen atmosphere is applied and the mixture is stirred overnight. The reaction mixture is filtered over a short pad of Celite which is thoroughly washed with ethanol. The filtrate is finally concentrated under reduced pressure to afford the desired product as crude (0.947 g; 3.46 mmol). 'H-NMR (DMSO- d₆) 5 ppm: 1.17 (3H, t, J=7.1 Hz), 1.60 - 1.63 (IH, m), 1.75 - 1.92 (IH, m), 1.98 - 2.04 (IH, m), 2.74 - 2.85 (IH, m), 3.07 (IH, td, J=5.2, 17.1 Hz), 3.56 (IH, dd, J=12.1, 8.3 Hz), 3.68 (2H, s), 4.05 (2H, q, J=7.1 Hz), 4.35 (IH, dd, J=4.3, 12.1 Hz), 7.04 (IH, dd, J=4.7, 7.8 Hz), 7.81 (IH, dd, J=l .5, 7.8 Hz), 8.14 (IH, dd, J=1.5, 4.7 Hz). The desired product is obtained in 93.5 % e.e. as determined by chiral HPLC using a Chiralpak AD-H column.

Protocol A - Retention time: 0.86 min (m/z 274). Example 11 - Synthesis of ethyl 2-[(8R)-8-(methylamino)-6,7,8,9-tetrahydropyrido[3,2- b]indolizin-5-yl]acetate

Step 1 : Ethyl 2-[(8i?)-8-amino-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (647 mg; 2.367 mmol) is dissolved in a mixture of isopropyl acetate (7.0 mL) and water (3.0 mL), sodium carbonate (376 mg; 3.55 mmol) is added and the mixture is stirred until a clear solution is obtained. A solution of 2,4-dinitrobenzene-l-sulfonyl chloride (631 mg; 2.367 mmol) in isopropyl acetate (2.0 mL) is added drop wise under stirring and the reaction mixture is stirred further at room temperature for 1 h until complete conversion is observed. The aqueous phase is separated and the organic phase is washed with water (2 x 2.5 mL), is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product as crude.

Protocol C - Retention time: 1.74 min (m/z 504).

Step 2: Ethyl 2-[(8i?)-8-[(2,4-dinitrophenyl)sulfonylamino]-6,7,8,9-tetrahydropyrido[3,2- b]indolizin-5-yl] acetate (1.14 g; 2.264 mmol) is dissolved in dimethylformamide (5.5 mL) and potassium carbonate (0.532 g; 3.85 mmol) and iodomethane (0.241 mL; 3.85 mmol) are added. The mixture is stirred at room temperature for 2 h is then diluted with ethyl acetate (20 mL) and is extracted with water (2 x 15 mL). The aqueous phase is backwashed with ethyl acetate (10 mL) and the combined organic layers are washed with half saturated aqueous sodium chloride (10 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product as crude.

Protocol C - Retention time: 1.85 min (m/z 518).

Step 3: Ethyl 2-[(8i?)-8-[(2,4-dinitrophenyl)sulfonyl-methyl-amino]-6,7,8,9- tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (1.09 g; 2.106 mmol) is dissolved in dichloromethane (8 mL), propylamine (1.732 mL; 21.06 mmol) is added drop wise and the resulting mixture is stirred at room temperature for 30 min. until complete conversion is observed. The mixture is diluted with dichloromethane (125 mL) and is extracted with IN aqueous hydrochloric acid (3 x 50 mL). It is ensured that no remaining desired product is present in the organic phase. The combined aqueous layers are backwashed with dichloromethane (25 mL) and are brought to neutral pH by the addition of solid sodium hydrogen carbonate and are extracted with dichloromethane (3 x 100 mL). The presence of desired product in the aqueous phase is controlled and in case remaining traces of desired product are detected, the aqueous phase is saturated with solid sodium chloride and is extracted with dichloromethane (2 x 100 mL). The combined organic layers are dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product as crude (365 mg; 1.26 mmol). The desired product is obtained in 92.1 % e.e. as determined by chiral HPLC using a Chiralpak AD-H column.

Protocol A - Retention time: 0.96 min (m/z 288). Example 12 - Synthesis of ethyl 2-[(8R)-8-(methylamino)-6,7,8,9-tetrahydropyrido[3,2- b]indolizin-5-yl]acetate

A solution of trimethylphosphine in toluene (340 mL, 340 mmol) is added at 10 °C to a solution of ethyl 2-[(8i?)-8-azido-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (107 g, 357 mmol) in dichloromethane (800 mL). After the slight exotherm has ceased, the mixture is allowed to reach room temperature to react for 90 min. The temperature is then lowered to 0 °C and paraformaldehyde (1 1.2 g, 357 mmol) is added. After 10 min reaction time, sodium borohydride (27 g, 715 mmo) in ethanol (1 L) is added and the resulting mixture is stirred for 100 min. The reaction mixture is then added under stirring to an aqueous saturated solution of sodium hydrogencarbonate (2 L). Water (1.5 L) is added to dissolved the precipitated salts in order to obtain a clear separation of the aqueous and organic phases. The aqueous phase is collected and is extracted with ethyl acetate (1 L). The combined organic layers are washed with brine (1 L), dried over sodium sulphate, filtered and are concentrated under reduced pressure to afford a yelllow oil. The crude product is dissolved in tetrahydrofuran (190 mL) and triethylamine (11.7 mL, 83 mmol) followed by ethyl 2,2,2 -trifiuoroacetate (15 mL, 125 mmol) are added. After almost complete conversion of the primary amine is ensured, the reaction is concentrated under reduced pressure. The obtained residue is taken up in ethyl acetate (500 mL) and is extracted with 0.5 M hydrochloric acid (750 mL). The aqueous phase is collected, the pH is adjusted to 10 by the addition of 2 M sodium hydroxide and the aqueous phase is extracted with ethyl acetate (2 x 500 mL). The combined organic layers are washed with brine (500 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the desired product as a yellow oil (73.1 g, 255 mmol).

Protocol A - Retention time: 0.96 min (m/z 288).

Example 13 - Synthesis of ethyl 2-[(8R)-8-[[(2R)-2-(4-fluorophenyl)propanoyl]-methyl- amino]-6,7,8,9-tetrahydropyrido[3,2-b]indoliziii-5-yl]acetate

(2i?)-2-(4-Fluorophenyl)propanoic acid (33.1 g; 187 mmol) and l-[bis(dimethylamino) methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafiuorophosphate (78 g; 206 mmol) are suspended in a mixture of tetrahydrofuran (148 mL) and dimethylformamide (52 mL) under inert atmosphere. The suspension is cooled to 5 °C and 2,6-lutidine (27.8 mL; 239 mmol) is slowly added in order to maintain the temperature below 10 °C. After completion of the addition, the mixture is allowed to reach room temperature and is stirred for 15 min. A solution of ethyl 2- [(8i?)-8-(methylamino)-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (31.97 g; 117 mmol) in a mixture of tetrahydrofuran (37 mL) and dimethylformamide (13 mL) is added drop wise and the resulting mixture is stirred at 38 °C for 16 h. The solvents are removed under reduced pressure and the obtained residue is taken up in ethyl acetate (200 mL). The organic layer is extracted with half saturated aqueous sodium chloride (2 x 200 mL), saturated aqueous sodium hydrogen carbonate (200 mL), 0.5 M aqueous hydrochloric acid (200 mL) and with brine (100 mL). The organic layer is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford brown oil. Purification by column chromatography on silica gel using the following eluents (methyl-tert-butylether/petroleum ether 4: 1; methyl-tert-butylether and methyl-tert-butylether/ethyl acetate 4: 1) affords the desired product as a pale yellow solid (44.3 g; 103 mmol). Protocol A - Retention time: 1.06 min (m/z 424).

Example 14 - Synthesis of 2-[(8R)-8-[[(2R)-2-(4-fluorophenyl)propanoyl]-methyl-amino]- 6,7,8,9-tetrahydropyrido[3,2-b]indoliziii-5-yl]acetic acid

A solution of ethyl 2-[(8i?)-8-[[(2i?)-2-(4-fiuorophenyl)propanoyl]-methyl-amino]-6, 7,8,9- tetrahydropyrido[3,2-b]indolizin-5-yl]acetate (44.3 g; 103 mmol) in acetonitrile (200 mL) is degassed for 10 min and a degassed 2 N aqueous solution of lithium hydroxide (77 mL; 154 mmol) is added. The resulting mixture is stirred at room temperature until complete conversion of the starting material is observed (about 3 h). The reaction mixture is concentrated to a volume of about 60 mL under reduced pressure and is diluted to 100 mL with water. The pH is carefully adjusted to 5 by the addition of aqueous 1 M hydrochloric acid and the white precipitate formed is filtered off. The precipitate is washed with water (2 x 20 mL) and with petroleum ether (2 x 20 mL) and is then dried under vacuum to afford the desired product as a white solid (39 g; 95 mmol). Protocol B - Retention time: 0.97 min (m/z 410).

The compounds were named using the software Accelrys Draw 4.1 SP1 (Accelrys, Inc.).

ANALYTICS

Standard GC Method In some instance, the compound analysis was performed using a GC Agilent 7890A system (Agilent, Santa Clara, CA, USA), equiped with a capillary column Agilent 19091 J-413 (30 m length x 320 μιη diameter x 0.25 μιη film), a TCD and a FID detector (both run at 280 °C). The oven was run at a linear temperature gradient from 60 to 300 °C in 14 min.

HPLC-MS Methods System 1

In some instance, the compound analysis was performed using a UHPLC/MS 1290 series (Agilent, Santa Clara, CA, USA) having a binary pump (G 4220A) including a degasser, a well plate sampler (G4226A), a column oven (G1316C), a diode array detector (G4212A), a mass detector (6130 Quadrupole LCMS) with ESLAPCI-source. Protocol A

The column used was this protocol was a XB ridge BEH CI 8 (Waters, Milford, MA,

USA),having a 2.1 mm diameter and 50 mm length and 2.5μ packing. The column was operated at 40 °C. The injection volume was 0.5 the flow rate was 0.8 mL/min and the run time was 2 min (equilibration included). Two eluents were used with the following gradients:

The samples were diluted in a 1 : 1 mixture of solvents A and B before analysis. The detection methods were UV at 210 and 254 nm; ESI/APCI/MS (70-1000 m z), positive ions.

Protocol B

The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 40 °C. The injection volume was 0.5 μί, the flow rate was 1.2 mL/min and the run time was 3.2 min (equilibration included). Two eluents were used with the following gradients:

System 2

In some instance, the compound analysis was performed using HPLC/MSD 1100 series (Agilent, Santa Clara, CA, USA) having a binary pump (G 1312A) with a degasser (G1379A), a well plate sampler (G1367A), a column oven (G1316A), a diode array detector (G1315B), a mass detector (G1946D SL) with ESI source and a NQ AD 500.

Protocol C

The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 35 °C. The injection volume was 1.2 μί, the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:

Time Solvent A (%) Solvent B (%) (min) water/formic acid: 99.9/0.1 (v/v) acetonitrile/formic acid: 99.9/0.1 (v/v)

0.0 90 10

2.0 0 100

2.7 0 100

3.0 90 10

The samples were diluted in a 1 : 1 mixture of solvents A and B before analysis. The detection methods were UV at 210, 254 and 280 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.

Protocol D

The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 30 °C. The injection volume was 1.0 μί, the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:

The samples were diluted in a 1 : 1 mixture of solvents A and B before analysis. The detection methods were UV at 210 and 254 nm; ESI/MS (70-1000 m/z), positive ions and NQAD.

Protocol E The column used was this protocol was a Chromolith FastGradient RP-18 e 50-2mm (Merck, Darmstadt, DE), having a 2.0 mm diameter and 50 mm length. The column was operated at 35 °C. The injection volume was 1.0 μί, the flow rate was 1.2 mL/min and the run time was 3.5 min (equilibration included). Two eluents were used with the following gradients:

Claims

1. A process for preparing a compound of Formula (lb)

or a solvate or salt thereof,

comprising

a) reacting a compound of Formula (II)

with an alkyl alcohol to give a compound of Formula (III)

b) reacting a compound of Formula (III) with a compound of Formula (IV)

to give a compound of Formula (V)

reacting a compound of Formula (VI) with a compound of Formula (VII)

to give a compound of Formula (VIII)

e) reacting a compound of Formula (VIII) in the presence of a base, preferably Mg(OEt)2 to give a compound of Formula (ΓΧ)

f) reacting the compound of Formula (ΓΧ) with an acid, preferably, H₂SO₄ or HC1 to form the compound of Formula (X)

i) reacting a compound of Formula (XI) with methanesulfonyl or 4-toluenesulfonyl chloride to yield a compound of Formula (XII)

reacting a compound of Formula (XII) with NaN₃ to produce a compound of Formula

k) reducing a compound of Formula (XIII) to yield a compound of Formula (XVII)

1) reacting a compound of Formula (XVII) with a compound of Formula (XVIII) in the presence of an activating agent

m) reacting a compound of Formula (ΧΓΧ) with an alkali metal hydroxide to yield a compound of Formula (lb); wherein

X² is hydrogen or halogen;

R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are independently Ci-C₆ alkyl; R⁹ is methyl or p-tolyl; R¹⁰ and Rⁿ are independently hydrogen or N0₂ wherein at least one of R¹⁰ or Rⁿ is N0₂; Y¹ is halogen; preferably bromine, iodine, chlorine or triflate; and Y is a leaving group, preferably, Br, I, CI, or mesylate.

2. A process for preparing a compound of Formula (lb)

or a solvate or salt thereof, comprising

a) reacting a compound of Formula (V)

wherein

Y¹ is halogen; preferably bromine, iodine, chlorine or triflate;

X² is hydrogen or halogen; and

R¹' R², R⁴ and R⁸ are independently Ci-C₆ alkyl.

3. The process of claim 2, further comprising reacting a compound of Formula (VI) with a compound of Formula (VII)

to give a compound of Formula (VIII)

4.

The process of claim 1 further comprising a) reducing a compound of Formula (XIII)

to yield a compound of Formula (XlVa)

d) reacting a compound of Formula (XVI) with a primary alkylamine, preferably n-propyl amine or n-butyl amine to yield a compound of Formula (XVII)

wherein

X² is hydrogen or halogen;

R⁴, R⁷ and R⁸ are independently Ci-C₆ alkyl.

R¹⁰ and Rⁿ are independently hydrogen or N0₂ wherein at least one of R¹⁰ or Rⁿ is N0₂;

5.

The process of claiml , wherein the compound of Formula (XIII) is reduced in the presence of a trialkylphoshine, prefereably trimethylphosphine, of paraformaldehyde and of an hydride reagent, preferably sodium borohydride.

The process of any one of claims 1-5 wherein Formula (lb)